A Phase IIa, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of BI 706321 Orally Administered for 12 Weeks in Patients With Crohn's Disease (CD) Receiving Ustekinumab Induction Treatment
Phase: PHASE2
Conditions: Crohn Disease
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c33919902-05
EudraCT No.
EU Trial No.
2020-004527-16
BI Trial No.
1425-0003
BI Investigational 
Medicinal Product(s)
BI 706321
Title
A Phase IIa, randomised, double-blind, placebo-controlled trial 
to evaluate the safety, efficacy, pharmacokinetics and 
pharmacodynamics of BI 706321 orally administered for 12 
weeks in patients with Crohn`s Disease (CD) receiving 
ustekinumab induction treatment
Lay Title
A study to test whether BI 706321 combined with ustekinumab 
helps people with Crohn’s Disease
Clinical Phase
IIa 
Clinical Trial Leader
Phone: +
Fax: +
Email:
Coordinating 
Investigator
Phone: 
Email: 
Status
Final Protocol
Version and Date:
Version: 5.0
Date: 04 Aug 2023
Page 1 of 119
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2023 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.
Boehringer 
~1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim Pharma GmbH & Co. KG
Protocol date
26 Apr 2021
Revision date
27 Jul 2023
BI trial number
1425-0003
Title of trial
A Phase IIa, randomised, double-blind, placebo-controlled trial to 
evaluate the safety, efficacy, pharmacokinetics and
pharmacodynamics of BI 706321 orally administered for 12 weeks 
in patients with Crohn’s Disease (CD) receiving ustekinumab 
induction treatment
Coordinating 
Investigator
Phone: 
Email:
Trial site(s)
Multi-center trial
Clinical phase
IIa
Trial rationale
Crohn’s disease (CD) is characterized by transmural inflammation 
with ulcerative lesions affecting any site within the gastrointestinal 
tract, with most frequent involvement of the terminal ileum, often 
combined with inflammation in the colon. CD incidence and 
prevalence have been rising in all ethnic groups, the unmet medical 
need in patients with moderate to severe CD is the highest. The 
modest efficacy of the current drugs which address different 
components of the dysregulated inflammatory response in patients 
with CD suggests that multiple pathologic pathways need to be 
targeted in tandem to make major progress in treatment of this often 
severe and disabling disease. Combination treatments of established 
anti-inflammatory drugs with new medicines with a novel and 
differentiated mode of action might offer greater efficacy, in 
particular if such a combination partner would be orally available, 
safe and tolerable. BI 706321 may be such a candidate drug.
Trial objective(s)
The main objectives of this trial are to investigate a first signal of 
efficacy, safety and tolerability of BI 706321 in combination with 
ustekinumab treatment compared to placebo with ustekinumab 
treatment in patients with moderately to severely active CD at 12 
weeks. 
The primary objective is to estimate the difference in change from 
baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) 
after 12 weeks. The primary treatment comparison will be between 
treatment groups while on treatment during the 12 week induction 
period.

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Trial endpoints
Primary endpoint
Absolute change from baseline in Simple Endoscopic Score for 
Crohn’s disease (SES-CD) at week 12.
Secondary endpoints

Percent change in SES-CD from baseline at Week 12

Endoscopic response (defined as >50% SES-CD reduction 
from baseline, or for an induction baseline SES-CD of 4, at 
least a 2 point reduction from induction baseline)) at Week 
12

Endoscopic response (defined as >50% SES-CD reduction 
from baseline, or for an induction baseline SES-CD of 4, at 
least a 2 point reduction from induction baseline)) at Week 
48

Endoscopic remission (defined as SES-CD score of ≤2) at 
week 12

Endoscopic remission (defined as SES-CD score of ≤2) at 
week 48.

Biological remission, defined as C-reactive protein (CRP) < 
5 mg/L and faecal calprotectin (FCP) < 250 ug/g at week 
12

Biological remission, defined as CRP < 5 mg/L and FCP < 
250 ug/g at week 48

Clinical remission at week 12, defined as a Crohn’s Disease 
Activity Index (CDAI) score of <150

Clinical remission at week 48, defined as a CDAI score of 
<150

Clinical response at week 12, defined by a CDAI reduction 
from baseline of at least 100 points, or a CDAI score of 
<150

Number of patients with treatment-emergent adverse event 
(TEAE) through end of treatment (EoT) and the residual 
effect period (REP) (i.e. through Visit 9)
Trial design
Multicentre, randomised, parallel, double-blind (patient, 
investigator), placebo-controlled trial with a 12 week BI 706321 
treatment period in combination with a backbone ustekinumab 
induction regime
Total number of 
patients randomised 
50 (up to 76 – if applicable, ref to Section 7.2.7)
Number of patients on 
each treatment
25 (up to 38 – if applicable, ref to Section 7.2.7)
Diagnosis
Crohn`s disease
Main in- and exclusion 
criteria
Key inclusion criteria:

Male or female patients.

≥ 18 – ≤ 75 years, at date of signing informed consent.

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
Diagnosis of CD for at least 3 months prior to Visit 1, as 
confirmed at any time in the past by endoscopy and/OR 
radiology, and supported by histology.

Elevated CRP (≥ 5 mg/L) OR elevated fecal calprotectin (≥ 
250 µg/g)

Symptomatic CD defined as CDAI ≥150

Presence of mucosal ulcers in at least one segment of the 
ileum or colon and a SES-CD score ≥ 7 (for patients with 
isolated ileitis ≥4).

Patients who are experienced to at least 1 tumor necrosis 
factor (TNF) antagonist at a dose approved for CD. Patients 
may have stopped TNF antagonist treatment due to primary 
or secondary non-responsiveness, intolerance, or for other 
reasons.

May be receiving a therapeutic dose of the following:
o
Oral 5-aminosalicylic acid (5-ASA) compounds 
must have been at a stable dose for at least 4 weeks 
prior to randomisation and must continue on this 
dose until week 12 and/or
o
Oral corticosteroids if indicated for treatment of CD 
must be at a prednisone equivalent dose of ≤ 20 
mg/day, or ≤ 9 mg/day of budesonide, and have 
been at a stable dose for at least 2 weeks 
immediately prior to randomisation and must 
continue on this dose until week 12. and/or
o
Azathioprine (AZA), mercaptopurine (MP), 
6-thioguanine (6-TG), or methotrexate (MTX), 
provided that dose has been stable for the 8 weeks 
immediately prior to randomisation and must 
continue on this dose until week 12.
Key exclusion criteria:

Have any current or prior abscesses, unless they have been 
drained and treated at least 6 weeks prior to randomisation 
and are not anticipated to require surgery. Patients with 
active fistulas may be included if there is no anticipation of 
a need for surgery and there are currently no abscesses 
present based on investigator`s judgement.

Have complications of CD such as strictures, stenosis, short 
bowel syndrome, or any other manifestation that might 
require surgery, or could preclude the use of SES-
CD/CDAI to assess response to therapy, or would possibly 
confound the evaluation of benefit from treatment with BI 
706321 (based on investigator’s judgement).

Patient with an inflammatory bowel disease (IBD) 
diagnosis other than CD.

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
Have had any kind of bowel resection or diversion within 4 
months or any other intra-abdominal surgery within 3 
months prior to Visit 1. Patients with current ileostomy, 
colostomy, or ileorectal anastomosis are excluded.

Treatment with:
o
any non-biologic medication for IBD (e.g.
tacrolimus or mycophenolate mofetil, systemic 
corticosteroids), other than those allowed per 
inclusion criteria, within 30 days prior to 
randomisation
o
any biologic treatment with a TNF-alpha antagonist 
(adalimumab, infliximab, golimumab, certolizumab
pegol) or vedolizumab (or a biosimilar of these 
drugs) within 4 weeks prior to randomisation. (If 
drug level testing for previously used biologic 
treatment confirms no detectable drug level before 
randomisation, patient can be enrolled despite not 
having completed 4 weeks from last treatment.)
o
any previous treatment with ustekinumab (or a 
biosimilar of this drug)
o
any previous treatment with an investigational (or 
subsequently approved) non-biologic/biologic drug 
for CD (including but not limited to JAK inhibitors
[e.g. upadacitinib], S1P modulators, interleukin 
(IL)-23 inhibitors [e.g. risankizumab], 
anti-integrins).
o
any investigational drug for an indication other than 
CD during the course of the actual study and within 
30 days or 5 half-lives (whichever is longer) prior to 
randomisation.
o
any prior exposure to rituximab within 1 year prior 
to randomisation. 

Increased risk of infectious complications (e.g. recent 
pyogenic infection, any congenital or acquired 
immunodeficiency (e.g. human immunodeficiency virus 
[HIV]), past organ or stem cell transplantation (with 
exception of a corneal transplant > 12 weeks prior to 
screening) or have ever received stem cell therapy (e.g., 
Prochymal). Prior treatment with a somatic cell therapy 
product (e.g. Alofisel) is not excluded, provided it was 
administered > 8 weeks prior to randomisation.

Live or attenuated vaccination within 4 weeks prior to 
randomisation.

Presence of clinically significant acute or chronic infections
not otherwise listed, including viral hepatitis, COVID-19, 
or others based on investigator’s judgement. 

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
Pathological safety lab parameters (one retesting is 
allowed):
o
Haemoglobin < 8.5 g/dL
o
White blood cell (WBCs) < 3,500 cells/mm3
o
Neutrophils < 1,500 cells/mm3
o
Platelets < 100,000 /mm3
o
Estimated glomerular filtration rate (eGFR) ≤ 60 
ml/(min*1,73 m²)
o
Aspartate aminotransferase (AST) OR Alanine 
aminotransferase (ALT) > 2 times the Upper Level 
of Normal (ULN). Total bilirubin > 2 x ULN with 
ratio of direct/indirect >1 (patients with Gilbert’s 
syndrome are not excluded), 
o
Troponin: > ULN

A marked baseline prolongation of QT/QTc interval (such 
as QTcF intervals that are greater than 450 ms for men, 470 
ms for female) or any other relevant electrocardiogram 
(ECG) finding at screening. Both have to be confirmed by 
repeated ECG recording.
Test product(s)
BI 706321
dose
8 mg daily
mode of 
administration
oral
Comparator product(s)
Placebo matching BI 706321
dose
Not applicable
mode of 
administration
oral
Duration of treatment
12 weeks
Criteria for 
Pharmacokinetics:
Population pharmacokinetics from plasma concentrations of BI 
706321 sampled during the treatment period
Statistical methods
Primary endpoint analysis: Restricted maximum likelihood 
estimation based ANCOVA model will be used to obtain adjusted
means for the treatment effect. This model will include treatment
and baseline corticosteroid use as discrete fixed effects along with
baseline SES-CD score as a continuous covariate. The primary 
treatment comparisons will be the contrast between the two
treatments at 12 weeks.

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FLOW CHART
Trial Periods
ScreeningH 
Induction Treatment H
Follow-up period H
Visit
1G,U
2*
3P
4
5
6
7
8 EOT
End of Treatment/Early 
EoTR
8A
8
B
8C
9R
10
11
12
13 
EOS
End of 
study/e
arly 
EoS
Days
-28 to -1
1E
4
8
15
29
57
85
86
89
91
113
16
9
22
4
281
336
Weeks 
0
0
1
2
4
8
12
12
16
24
32
40
48
Time window for visits (days)
±0 
+1
±2
±2
±2 
±
5
±5
+1
±1
±1
±5
±7
±7
±7
±7
Fasted (f) / not fasted (nf)T
nf
f
nf
nf
nf
f
f
f
nf
nf
nf
f
nf
nf
nf
nf
Informed consentA
X
Demographics, medical history, baseline 
conditions
X
Review of in-/-exclusion criteria
X
X
Physical examination (full) 
X
X
X
X
X
X
X
X
Physical examination (symptomatic-
driven) 
X
X
X
X
X
X
X
X
Vital signsD, S (incl. height at Visit 1 only)
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests (blood/urine/stool)C
X
X
X
X
X
X
X
X
X
X
X
X
X
Infection testingF
X
Infection testing for SARS-CoV-2 in case 
of symptoms and if locally required 
before trial procedures (locally done) 
XZ
Test previously used biologic treatment (if 
applicable)Y
X
Pregnancy TestM
X
X
X
X
X
X
DNA Sampling (Blood, pre-specified),I
X
II 
-
-
-
I 
I 
C 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 

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Trial Periods
ScreeningH 
Induction Treatment H
Follow-up period H
Visit
1G,U
2*
3P
4
5
6
7
8 EOT
End of Treatment/Early 
EoTR
8A
8
B
8C
9R
10
11
12
13 
EOS
End of 
study/e
arly 
EoS
Days
-28 to -1
1E
4
8
15
29
57
85
86
89
91
113
16
9
22
4
281
336
Weeks 
0
0
1
2
4
8
12
12
16
24
32
40
48
Time window for visits (days)
±0 
+1
±2
±2
±2 
±
5
±5
+1
±1
±1
±5
±7
±7
±7
±7
Fasted (f) / not fasted (nf)T
nf
f
nf
nf
nf
f
f
f
nf
nf
nf
f
nf
nf
nf
nf
12-lead ECG (central reading)D
X
XV
X
X
XV
X
XV
X
Ileocolonoscopy for SES-CD (and 
CDEIS) assessment (centrally read), incl. 
biopsies (Ribonucleic acid (RNA) in 
colonic and/ileal tissues, IHC, histology)R
XG
X (at V8 or V8A plus one day, 
i.e. at the latest 2 days after
last IMP intake)
X
Crohn’s Disease Activity Index (CDAI, 
Diary)Q
X
X
X
X
X
X
X
X
X
X
X
X
Body weight (for CDAI) 
X
X
X
X
X
X
X
X
X
X
X
X
IBDQ
X
X
X
X
X
X
X
X
Dispense Patient DiaryK
X
Collect & Review Patient Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
11 
rl 
-
-
11 
-
I 
I 
-
I 
I 
I 

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Trial Periods
ScreeningH 
Induction Treatment H
Follow-up period H
Visit
1G,U
2*
3P
4
5
6
7
8 EOT
End of Treatment/Early 
EoTR
8A
8
B
8C
9R
10
11
12
13 
EOS
End of 
study/e
arly 
EoS
Days
-28 to -1
1E
4
8
15
29
57
85
86
89
91
113
16
9
22
4
281
336
Weeks 
0
0
1
2
4
8
12
12
16
24
32
40
48
Time window for visits (days)
±0 
+1
±2
±2
±2 
±
5
±5
+1
±1
±1
±5
±7
±7
±7
±7
Fasted (f) / not fasted (nf)T
nf
f
nf
nf
nf
f
f
f
nf
nf
nf
f
nf
nf
nf
nf
Intake of trial drug at the site
XO
X
X
X
X
X
Dispense trial drugs for intake at home
X
X
X
X
X
Drug accountability check
X
X
X
X
X
X
Administer ustekinumab i.v.B
XO
Administer ustekinumab s.c. B
X
X
X
X
X
W
Ustekinumab serum levelN
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event (AE)X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Completion of patient participation 
X
SES-CD: Simple Endoscopic Score for Crohn’s Disease; CDEIS: Crohn’s Disease Endoscopic Index of Severity
*
Day of Randomisation / Day of first intake of randomised medication
A
Subject must be informed and written informed consent obtained prior to starting any screening procedures. For the biobanking samples a separate informed consent (optional) will be 
taken.
B
Treatment with ustekinumab in the trial will follow current version of SmPC/US PI and cost will be covered by Sponsor. For more information refer to Section 3.1.
The ustekinumab intravenous (i.v.) administration has to be done at the site under the supervision of a trained site personal.
The ustekinumab s.c. administration should be done during the visit at the site. 
C
Laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis as well as CRP, fecal calprotectin and fecal entric pathogens, and will be performed centrally. 
Patients who have a laboratory test value that makes their participation uncertain may have the test repeated once to determine eligibility; however, the result must be available prior to 
Visit 2. See Section 5.2.3 for a complete list and timepoints of testing required.
D
Assessment of vital signs (ref. Section 5.2.2) and ECG measurements should always precede blood sampling and drug administration. All ECGs will be evaluated by the investigator or a 
designee.
,J 
--
-
-
I 
I 
,--
I 
-
I 
I 
I 
' 

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E
During the observation period patients are receiving ustekinumab treatment alone and in an open-label fashion.
F
Infection testing includes TB screening, hepatitis B, hepatitis C, and HIV assessments, as well as SARS-CoV-2
G
Screening procedures have to be performed within 28 days before randomisation and can be done at different days. The here described order should be followed: first all non-ileo-
colonoscopy / non-CDAI assessments have to be performed. Only if these assessments show that patients are eligible, the CDAI eligibility has to be checked (i.e. investigator is defining 
the 7 days for calculation of the CDAI score). Only patients who also meet the CDAI eligibility criterion have to undergo ileo-colonoscpy in a last step. 
Screening period could be extenended for additional 21 days, if this is required due to logistical reasons (e.g. delay in lab assessment) and approved by sponsor.
H
In the follow-up period, if the decision is made for a patient to permanently discontinue ustekinumab treatment early but between V8 and V9, V9 should be performed as the last trial visit 
at least 16 days after the last BI 706321/placebo dose. In the follow-up period, if a patient permanently discontinues ustekinumab treatment early but after V9, early EoS visit should be 
performed within 14 days after decision has been made to discontinue ustekinumab treatment. Over-night stays within the site-unit due to logistical reasons are allowed and not considered 
as SAE (applicable for the whole trial).
I
Pre-specified PGx sample is mandatory.
J
PK sampling timepoints at each visit are given in Table 10.1: 1. The 6-hours sample of Visit 2 can also be taken as late as appr. 24 h after first dosing at the next day to allow flexibility. 
K
The patient has to document the date and time of the Investigational Medicinal Product (IMP) intake at home in the patient medication diary. 
L
Fecal studies: Stool samples will be aliquotted for miRNA and microbiome analysis, exploratory protein biomarkers analysis and for biobanking. This exploratory protein biomarker
analysis will only be performed at Visit 2, Visit 6, Visit 8 and Visit 13. Stool samples for Fecal calprotectin and Fecal lactoferrin analysis will be collected at V1, V2, V6, V7, V8, V9, 
V10, V11, V12 and V13. Ref. to Section 5.2.3. Stool sampling can be done any time during a visit or at home, i.e. collecting the first stool of the day as close as possible to the planned 
visit; date and time need to be noted on the collection container.
M
Pregnancy test: Serum pregnancy test (performed at screening). Urine pregnancy tests will be performed at all other visits indicated. Urine pregnancy testing should be done prior to study 
drug administration. Study drug should only be administered in case of a negative test result. In case of a positive urine pregnancy test, a serum pregnancy test will be done.
N
Done as part of clinical monitoring with a provided test kit. At Visit 2 pre-dose to assess for pre-existing anti-drug antibody.
O
Trial drug (BI 706321 or Placebo) and ustekinumab are recommended to be given simultaneously.
P
Visit at the site or done at patient`s home (by site personnel at patient´s home), as appropriate.
Q
The patient will have to complete the CDAI symptom score in a Diary every day (i.e. compliance reason) after dispensing the Diary to the patient at V1. The 7 days preceding a visit 
(scheduled and unscheduled) will be taken for the CDAI calculation. The score will be displayed to the investigator to judge treatment efficacy. For details see Section 5.1.2 and Appendix 
10.5.
At screening: After all non-ileo-colonoscopy assessments have shown that a patient is eligible, the investigator is defining 7 days for the CDAI assessment. After the CDAI eligibility is 
confirmed the patient will undergo the ileo-colonoscopy. 
Visit 8/Visit 13: the day before the ileo-colonoscopy assessment will not be used for the CDAI calculation. 
R
Patients who discontinue BI 706321/placebo trial treatment and/or ustekinumab treatment before completing 10 weeks of treatment in the induction treatment period should undergo the 
procedures of the early end of treatment (EoT) visit within 14 days after the last BI 706321/placebo dose and Visit 9 (4 weeks after early EoT visit). If Visit 9 is performed as the last visit 
in the trial, ustekinumab should not be administered at this Visit 9 as the part of the trial. Further CD treatment has to be defined by the investigator. If a patient discontinues BI 
706321/placebo trial treatment after completing 10 weeks of treatment in the induction treatment period (early EoT visit has to be performed) and if it is medically appropriate to continue 
treatment with ustekinumab, the patient may remain in the trial and follow the visit schedule and perform end of study (EoS) visit as planned. Ref. to Section 6.2.2 for more information 
about ileo-colonoscopy assessment in case patients discontinue early. After the early EoT visit patients should undergo only Visit 9 for early completion of the trial (not EoS visit). 
S
Body temperature will only be assessed until Visit 9 (i.e. V 1 – V 9). 

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T
“Fasted” is defined as patients are not allowed to take any food for at least 6 hours prior to the visit procedures and until the blood samples are taken. At visits where fasting is not 
specifically required, it is acceptable for patients to be administered trial medication either fasted or non-fasted (as preferred by the patient). Fasting is not required for post-dose PK 
sampling.
U
If a rescreening will be performed the ileocolonoscopy has only to be repeated if the time between the original screening ileocolonoscopy and randomisation is >6 weeks (time intervals 
slightly longer than 6 weeks have to be discussed with the Sponsor and can be approved if medically appropriate). If the reason for the screen failure was an enteric infection (including 
SARS-CoV-2 infections, only if GI symptoms were present due to the SARS-CoV-2 infection) the ileo-colonoscopy must be repeated. Depending on the reason, rescreening is allowed up 
to two times.
If at screening, PCR test for SARS-CoV-2 is positive and patient is asymptomatic, re-test SARS-COV-2 PCR test is allowed (up to 4 times) to confirm patient's eligibility before 
ileocolonoscopy and/or visit 2. If re-test SARS-COV-2 PCR test is negative, patient must meet all other eligibility criteria according to the CTP before patient is randomized at Visit 2. 
Already performed screening assessment do not need to be repeated. 
V
An additional ECG assessment has to be performed:
- for Visit 2: before the 3-hours PK blood sample is taken (i.e. two assessments – pre-dose and before the 3-hours PK sample).
- for Visit 6 and Visit 8: before the 6-hours PK blood sample is taken (i.e. two assessments – pre-dose and before the 6-hours PK sample).
W
Further CD treatment has to be defined by the investigator. End of treatment with ustekinumab in the trial is V12.
X
After the (early) EoS visit (=individual patient’s end of the trial) the investigator should report only any cancers of new histology and exacerbations of existing cancer, trial drug related 
SAEs and trial drug related AESIs of which the investigator may become aware of and only via the BI`s SAE form, please see Section.5.2.6.2.1.
Y
Patients are not allowed to get any biologic treatment with a TNF-alpha antagonist (adalimumab, infliximab, golimumab, certolizumab) or vedolizumab (or a biosimilar of these drugs) 
within 4 weeks prior to randomisation. If drug level testing for previously used biologic treatment confirms no detectable drug level before randomisation, patient can be enrolled despite 
not having completed 4 week from last treatment.
Z
Patients tested positive for SARS-CoV-2 during the trial and who are asymptomatic can continue with the clinical trial as described in the CTP, based on Investigator’s judgment. If 
subject develops any symptoms of SARS-CoV-2 infection, the discontinuation rules apply according to Section 3.3.4.1.

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TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................20
1.1
MEDICAL BACKGROUND.............................................................................20
1.2
DRUG PROFILE................................................................................................21
1.2.1
BI 706321 .............................................................................................................21
1.2.2
Ustekinumab (Stelara)........................................................................................27
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................27
1.4
BENEFIT - RISK ASSESSMENT.....................................................................28
1.4.1
Benefits.................................................................................................................28
1.4.2
Risks .....................................................................................................................29
1.4.2.1
Trial medication-related risks ...............................................................................29
1.4.2.2
Risks related to ustekinumab administration ........................................................32
1.4.2.3
Procedure-related risks..........................................................................................33
1.4.2.4
COVID-19.............................................................................................................34
1.4.3
Discussion.............................................................................................................34
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................36
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........36
2.1.1
Main objectives....................................................................................................36
2.1.2
Primary endpoint................................................................................................36
2.1.3
Secondary endpoints...........................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................39
3.1
OVERALL TRIAL DESIGN.............................................................................39
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................40
3.3
SELECTION OF TRIAL POPULATION .......................................................41
3.3.1
Main diagnosis for trial entry ............................................................................42
3.3.2
Inclusion criteria .................................................................................................42
3.3.3
Exclusion criteria ................................................................................................43
3.3.3.1
Gastrointestinal Exclusion Criteria.......................................................................43
3.3.3.2
Infectious Disease Exclusion Criteria...................................................................44
3.3.3.3
General Exclusion Criteria....................................................................................45
3.3.4
Withdrawal of patients from treatment or assessments..................................46

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3.3.4.1
Discontinuation of trial treatment .........................................................................46
3.3.4.2
Withdrawal of consent to trial participation .........................................................47
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................47
4.
TREATMENTS...................................................................................................49
4.1
INVESTIGATIONAL TREATMENTS ...........................................................49
4.1.1
Identity of the Investigational Medicinal Products..........................................49
4.1.2
Selection of doses in the trial and dose modifications......................................49
4.1.3
Method of assigning patients to treatment groups...........................................50
4.1.4
Drug assignment and administration of doses for each patient......................50
4.1.5
Blinding and procedures for unblinding...........................................................51
4.1.5.1
Blinding.................................................................................................................51
4.1.5.2
Unblinding and breaking the code ........................................................................52
4.1.6
Packaging, labelling, and re-supply...................................................................52
4.1.7
Storage conditions...............................................................................................53
4.1.8
Drug accountability.............................................................................................53
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................54
4.2.1
Other treatments and emergency procedures..................................................54
4.2.2
Restrictions ..........................................................................................................55
4.2.2.1
Restrictions regarding concomitant treatment ......................................................55
4.2.2.2
Restrictions on diet and life style..........................................................................59
4.2.2.3
Contraception requirements..................................................................................59
4.3
TREATMENT COMPLIANCE........................................................................60
5.
ASSESSMENTS..................................................................................................61
5.1
ASSESSMENT OF EFFICACY........................................................................61
5.1.1
Ileocolonoscopy-related assessments (SES-CD and CDEIS) ..........................61
5.1.2
Crohn’s Disease Activity Index (CDAI)............................................................62
5.1.3
Inflammatory Bowel Disease Questionnaire (IBDQ) ......................................62
5.2
ASSESSMENT OF SAFETY.............................................................................62
5.2.1
Physical examination ..........................................................................................62
5.2.2
Vital signs.............................................................................................................62
5.2.3
Safety laboratory parameters ............................................................................63
5.2.4
Electrocardiogram ..............................................................................................67
5.2.5
Other safety parameters.....................................................................................68
5.2.5.1
Patient Diary .........................................................................................................68
5.2.6
Assessment of adverse events.............................................................................68
5.2.6.1
Definitions of AEs ................................................................................................68
5.2.6.1.1
Adverse event........................................................................................................68
5.2.6.1.2
Serious adverse event............................................................................................69
5.2.6.1.3
AEs considered “Always Serious”........................................................................69
5.2.6.1.4
Adverse events of special interest.........................................................................69
5.2.6.1.5
Intensity (severity) of AEs....................................................................................70
5.2.6.1.6
Causal relationship of AEs....................................................................................70
5.2.6.2
Adverse event collection and reporting ................................................................71
5.2.6.2.1
AE Collection........................................................................................................71

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5.2.6.2.2
AE reporting to the sponsor and timelines............................................................71
5.2.6.2.3
Pregnancy..............................................................................................................72
5.5
BIOBANKING ....................................................................................................75
5.6
OTHER ASSESSMENTS...................................................................................75
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................75
6.
INVESTIGATIONAL PLAN.............................................................................77
6.1
VISIT SCHEDULE.............................................................................................77
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................78
6.2.1
Screening and run-in period(s)..........................................................................78
6.2.2
Treatment period(s)............................................................................................78
6.2.3
Follow-up period and trial completion..............................................................79
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................80
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................80
7.2
PLANNED ANALYSES.....................................................................................80
7.2.1
General considerations .......................................................................................80
7.2.2
Primary endpoint analyses.................................................................................81
7.2.3
Secondary endpoint analyses .............................................................................81
7.2.5
Safety analyses.....................................................................................................82
7.2.7
Interim Analyses .................................................................................................84
7.3
HANDLING OF MISSING DATA ...................................................................84
7.4
RANDOMISATION ...........................................................................................85
7.5
DETERMINATION OF SAMPLE SIZE .........................................................85
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........87
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................87
8.2
DATA QUALITY ASSURANCE ......................................................................88
8.3
RECORDS...........................................................................................................88
8.3.1
Source documents ...............................................................................................88
8.3.2
Direct access to source data and documents.....................................................89

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8.3.3
Storage period of records ...................................................................................89
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................90
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........90
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................90
8.6
TRIAL MILESTONES.......................................................................................90
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................91
9.
REFERENCES....................................................................................................93
9.1
PUBLISHED REFERENCES............................................................................93
9.2
UNPUBLISHED REFERENCES......................................................................94
10.
APPENDICES.....................................................................................................95
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................95
10.3
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE (SES-CD)....98
10.4
CROHN’S DISEASE ACTIVITY INDEX (CDAI) .........................................99
10.5
EQUIVALENT DOSES OF CORTICOSTEROIDS.....................................100
10.6
CLINICAL CRITERIA FOR DIAGNOSIS OF ANAPHYLAXIS..............100
10.7
DEFINITION OF PRIMARY, SECONDARY NONRESPONSE OR 
INTOLERANCE TO ANTI-TNF THERAPY ...............................................101
10.7.1
Primary non-response (inadequate initial response) to TNF antagonists ...101
10.7.2
Secondary non response (response followed by loss of response) to TNF 
antagonists .........................................................................................................102
10.7.3
Intolerance to TNF antagonists .......................................................................103
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................106
11.1
GLOBAL AMENDMENT 1 ............................................................................106
11.2
GLOBAL AMENDMENT 2 ............................................................................108
11.3
GLOBAL AMENDMENT 3 ............................................................................109
11.4
GLOBAL AMENDMENT 4 ............................................................................115

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ABBREVIATIONS
6-TG
6-thioguanine
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AP
Abdominal Pain
ASA
Aminosalicylic Acid
AST
Aspartate Aminotransferase
AUC
Area under the Curve
AxMP
Auxiliary Medicinal Products
AZA
Azathioprine
BA
Bioavailability
BCG
Bacillus Calmette-Guerin
BI
Boehringer Ingelheim
CD
Crohn`s Disease
CDAI
Crohn’s Disease Activity Index
CDEIS
Crohn’s Disease Endoscopic Index of Severity
COVID-19
Coronavirus of 2019
Cmax
Maximum Plasma Concentration
Cmax,ss
Maximum Plasma Concentration at Steady State
Cmin
Minimum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRP
C-Reactive Protein
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A
Cytochrome P450 3A

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DDI
Drug-Drug Interactions
DILI
Drug Induced Liver Injury
DMETTM
Drug Metabolism Enzymes and Transporters
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
eGFR
Estimated Glomerular Filtration Rate
EoS
End of Study (corresponds with End of Trial)
EoT
End of Treatment
ePRO
Electronic Patient Reported Outcome
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FAS
Full Analysis Set
FCP
Faecal Calprotectin
FDA
Food and Drug Administration
FE
Food Effect
GCP
Good Clinical Practice
GHAs
Global Histologic Disease Activity Score
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
gRT
global Randomisation Team
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IGRA
Interferon Gamma Release Assay
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational Medicinal Product
IRB
Institutional Review Board

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IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
intention-to-treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
i.v.
Intravenous
JAK
Janos Kinase
LPLT
Last patient last treatment
LOCF
Last observation carried forward
MAPK
Mitogen-Activated Protein Kinase
MDP
Muramyl Dipeptide
MedDRA
Medical Dictionary for Drug Regulatory Activities
MP
Mercaptopurine
MRD
Multiple Rising Dose
MTX
Methotrexate
NCF
Non-completers considered failure
nf
Not fasted
NIMP
Non-Investigational Medicinal Product
NOAEL
No-Observed-Adverse-Effect Level
NOD
Nucleotide Oligomerization Domain
NRI
Non Response Imputation
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamics
P-gP
P-glycoprotein
PK
Pharmacokinetics
p.o.
per os (oral)
PPD
Purified Protein Derivative
PROs
Patient Reported Outcomes
PRR
Pattern Recognition Receptors
q.d.
quaque die (once a day)
QT/QTc
Measurement representing the total time from ventricular depolarization
to complete repolarization (uncorrected and corrected)
REP
Residual effect period

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REML
Restricted maximum likelihood
RHI
Robarts histopathology index
RIPK2
Receptor-Interacting Protein Kinase-2
RNA
Ribonucleic Acid
RS
Randomised set
S1P
Sphingosine-1-phosphate receptor modulator
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus Type 2
s.c.
Subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s disease
SF
Stool Frequency
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half life time
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
tmax
Timepoint of maximum plasma concentration
TMF
Trial Master File
TNFi
Tumor Necrosis Factor Inhibitor
TRUC
T-bet−/−RAG2−/−ulcerative colitis
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TST
Tuberculin Skin Test
ULN
Upper limit of normal
US PI
US Package Insert
WBC
White blood cell count
WHO
World Health Organisation
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Crohn’s disease (CD) is characterized by transmural inflammation with ulcerative lesions 
affecting any site within the gastrointestinal tract, with most frequent involvement of the 
terminal ileum, often combined with inflammation in the colon. CD incidence and prevalence 
have been rising in all ethnic groups; the recent incidence and prevalence have been reported 
to range from 7.9 to 20.2 and from 161 to 319 per 100,000, respectively [R13-2231]. CD 
typically follows a relapsing and remitting course, and causes substantial acute and long-term 
morbidity and increased mortality. Patients often develop local complications (for example 
(e.g.) fistulas, abscesses, strictures, or perforations), extra-intestinal manifestations (e.g. 
uveitis, arthritis, primary sclerosing cholangitis), or side effects of treatment, and may require 
major surgery. A recent review highlights the substantial direct and indirect costs associated 
with CD to patients and wider society [R18-2865]. Roughly a third of patients fall into each 
of the categories of mild, moderate, and severe disease.
Unmet need in CD is highest in patients with moderate to severe disease. Patients not
responding to conventional therapy of glucocorticoids and immunomodulator agents 
(azathioprine (AZA) or mercaptopurine (MP) or methotrexate (MTX)), are treated with 
biologic tumor necrosis factor (TNF) α inhibitors (TNFi). However, treatment with a TNFi 
results in clinical remission in less than half of patients. Another 30-40% of patients receiving 
TNFi have only a limited response, or lose their response over time. Increasingly it has also 
been recognized that clinical response and more objective markers of inflammation are not 
always well-correlated in CD, and thus improvement in inflammation as documented by 
endoscopy is an emerging treatment goal. Real world evidence suggests that only about 25% 
of patients treated with TNFi have long term endoscopic remission. Additionally, there 
remain concerns over infection, lymphoma risks and melanoma with these agents. Additional 
biologic options (vedolizumab [an integrin antagonist] and ustekinumab [IL-12/23p19 
inhibitor]) offer alternative treatment options for patients, but response rates to these agents 
do not exceed those associated with TNFi treatment. Furthermore, most trials suggest a lower 
efficacy of any compound in patients who previously failed TNFi treatment compared to 
patients who are TNFi naïve, probably reflecting that patients in this sub-population are more 
refractory. Medical treatment options for fistulizing and fibrotic disease remain limited. Thus, 
a substantial unmet need remains for agents with greater efficacy than current therapies, 
either as a stand-alone therapy or when added to existing therapies.
In CD, mucosal inflammation is driven by a disruption of the intestinal barrier in the context 
of a dysbiosis of the microbial flora, which leads to bacterial translocation into the bowel wall
mucosa and submucosa followed by aberrant stimulation of immune and non-immune cells in 
the gut. Microbial stimulation of somatic cells is partially mediated by Nucleotide 
Oligomerization Domain (NOD) pattern recognition receptors through Receptor-Interacting 
Protein Kinase-2 (RIPK2) at the earliest stage in the development of the immuno-
inflammatory cascade. RIPK2 inhibition is postulated to blunt the dominant NOD1/2-driven 
inflammatory response to the microbiome in the gut, while sparing other microbial sensing 
pathways to prevent broad immunosuppression.

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NOD sensing and RIPK2 signaling amplifies pattern recognition receptors (PRR) induced 
NFkB/MAPK signalling and the NOD/RIPK2 pathway becomes the dominant PRR during 
chronic bacterial challenge.
NFκB, nuclear factor κB; NOD, nucleotide-binding oligomerisation domain-containing protein; RIPK2, receptor interacting 
serine/threonine-protein kinase 2; PRR, pattern recognition receptor; TLR toll-like receptor
Figure 1.1: 1 Therapeutic concept of BI 706321
RIPK2 inhibition will result in reduced levels of inflammatory cells and inflammatory 
mediators in intestinal tissue, in particular of the innate immune system, and improved 
epithelial barrier function, which is expected to lead to clinical and endoscopic response in 
CD. Oral medicines with a novel mode of action that include regulation of the complex 
interaction between microbiome and intestinal tissue, and have additional effects on epithelial 
barrier function would be particularly attractive for the current unmet need in CD, especially 
if they can be combined with current standard of care. Therefore, Boehringer Ingelheim (BI) 
is developing a RIPK2 inhibitor candidate, BI 706321.
1.2
DRUG PROFILE
1.2.1
BI 706321
Mode of action
BI 706321 is a potent and specific inhibitor of the human RIPK2 kinase.
Data from non-clinical studies
Relevant non-clinical pharmacology, Pharmacokinetics (PK), and toxicology study results are 
summarized below.
In vitro and ex vivo studies with BI 706321 have shown that it is effective at normalizing the 
induction of inflammation or inflammatory processes in several different types of disease 
relevant human primary cells and complex intestinal cellular systems. In vivo, RIPK2 
Epithelial Barrier 
Damage 
[ Loss of function] 
Loss of integrity 
Aberrant Tissue 
Remodeling 
Sustained 
inflammation 

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inhibition was also demonstrated to significantly improve signs and symptoms of intestinal 
inflammation in the spontaneous T-bet/Rag2 knockout (TRUC) mouse model of 
Inflammatory Bowel Disease (IBD).
The toxicity profile of BI 706321 has been assessed in safety pharmacology, genetic
toxicity, embryo-fetal development, and repeat dose toxicity studies of up to 13-
weeks in rat and monkey, respectively. RIPK2 is highly conserved across rat and cynomolgus 
monkey where sequences within the kinase domains are 95% and 97% identical to human, 
respectively. 
The no-observed-adverse-effect level (NOAEL) in the 13-week monkey study was 8 
mg/kg/day, corresponding to a steady state mean exposure of 988 nM maximum plasma 
concentration (Cmax) and 6,060 nM•h AUC0-24h (combined genders). These exposures are 28X 
(Cmax) or 12X (AUC0-24h) the exposure at the 8 mg daily dose in this trial.
The NOAEL in the 13-week rat study was 4 mg/kg/day in males and 1 mg/kg/day in females. 
The 4 mg/kg/day dose to male rats corresponded to a steady state mean exposure of 289 nM 
Cmax and 2,250 nM•h AUC0-24h, providing exposures 8X (Cmax) or 4X (AUC0-24h) the 
exposure at the 8 mg daily dose. The 1 mg/kg/day NOAEL in female rats corresponded to a 
steady state mean exposure of 47.5 nM Cmax and 505 nM•h AUC0-24h, providing 1.4X (Cmax) 
or 1X (AUC0-24h) the exposure at the 8 mg daily dose. 
The NOAEL in the most sensitive species, rat, was defined by reversible ovarian finding of 
degeneration of the corpora lutea. Therefore, at clinically relevant BI 706321 exposures in 
women of child bearing potential, there is potential for effects to the ovary that may affect 
fertility. However, this finding is not clinically relevant in females who are not seeking to 
become pregnant. Considering that women of childbearing potential are required to use a 
highly effective method of contraception (see below) in BI 706321 clinical trials, the male 
NOAEL applies to both males and females using highly effective contraception. A human 
dose of 8 mg daily is 8X and 4X below current male rat NOAEL exposures for Cmax and Area 
under the Curve (AUC), respectively.
There is risk for adverse effects to embryo-fetal development (embryolethality and 
fetotoxicity) at human exposures exceeding exposures at the NOAEL in rats, the most 
sensitive species (5 mg/kg/day to rats, corresponding to Cmax of 184 nM and AUC0-24h of 
2,060 nM•h), which provide 5X and 4X human steady state exposure Cmax and AUC for an 
8 mg dose once daily. Therefore, pregnant women should be excluded from clinical trials and 
a highly effective method of birth control should be utilized for women of childbearing 
potential.
BI 706321 is considered non-genotoxic. BI 706321 is not likely to be phototoxic at clinically 
relevant doses. 
In summary, non-clinical BI 706321 safety data demonstrated an acceptable profile to 
support clinical trials in males and non-pregnant females of child bearing potential who are 
using highly effective methods of birth control.

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For full details on the nonclinical pharmacology, pharmacokinetics in animals and specific 
toxicology results refer to the current IB [c26475781], and Section 1.4.2.
Data from clinical studies
As of April 2021, two clinical trials, a first in human Single Rising Dose (SRD) study 
1425-0001 and an Multiple Rising Dose (MRD) study 1425-0002, are clinically complete. 
The SRD study consisted of two parts: an SRD part (part I), and a relative bioavailability 
(BA) and food effect (FE) (part II) that compared tablet and capsule formulations, and 
assessed the effect of food on the tablet formulation. The SRD part consisted of 8 dose 
groups of 8 healthy male subjects each (6 active, 2 placebo) with dose levels of 0.3 mg, 
0.6 mg, 1.2 mg BI 706321 administered as oral solution, and 2 mg, 4 mg, 8 mg, 15 mg and 
25 mg of BI 706321 administered as a capsule. The relative bioavailability (BA) had a three-
way crossover design with 12 healthy male subjects receiving the capsule fasted and a tablet 
given fasted and after a standardized high-fat meal.
In the MRD study, healthy male and female subjects of non-child bearing potential were 
given a single dose of BI 706321; then, following a five-day washout, these subjects were 
administered BI 706321 daily for 14 days. There were four dose levels of BI 706321 
capsules: 2 mg q.d., 5 mg q.d., 8 mg q.d., and 10 mg q.d. There were 10 subjects (8 active, 
2 placebo) in each dose group.

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Clinical Safety
The first in human studies 1425-0001 (SRD) and 1425-0002 (MRD) are clinically complete. 
In the SRD part I, single doses of 0.3-25 mg of BI 706321 were well tolerated by healthy 
male subjects (n = 46). Based on preliminary analysis, the frequency of subjects with at least 
one treatment-emergent Adverse Event (AE) ranged from 0/6 (0%) to 3/5 (60%) of subjects 
in active treatment dose groups as compared to 6/15 (40%) of subjects on placebo. AEs 
reported in >1 subject on active treatment were coded as diarrhea (n=2, loose stool (8 mg) 
and watery stool (25 mg)) and nasopharyngitis (n=2, 0.6 and 15 mg). No such events were 
reported for subjects on placebo. Five drug related AEs were observed: dry lips (0.3 mg), 
dizziness (15 mg), generalized sensation of cold (25 mg), loose stool (8 mg) and watery stool 
(25 mg). 
In the SRD part II (BA and FE), 4 mg tablets and capsules were administered to an additional 
12 healthy male subjects under both fed and fasted conditions and were well-tolerated. Based 
on preliminary analysis, the total number of subjects with at least one treatment-emergent AE 
was 4/12 (33.3%) of subjects while on active treatment. Three subjects experienced drug 
related AEs: headache, loose stools, and decreased snoring. 
In the MRD, multiple doses of 2-10 mg BI 706321 (n = 32) were well tolerated by healthy 
subjects for up to 14 days of dosing. Based on preliminary analysis, the frequency of subjects 
with at least one treatment-emergent AE ranged from 3/8 (37.5%) to 6/8 (75%) subjects on 
BI 706321 dose groups as compared to 1/7 subjects (14.3%) on placebo. AEs reported in >1 

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subject on active treatment were coded as influenza like illness (reported as ”flu like 
symptoms” n=5; 5 mg [1], 8 mg [2], 10 mg [2]), abdominal discomfort (n= 4; 5 mg [3] and 
10 mg [1]), diarrhea (n=4; 5 mg [1], 8 mg [1], 10 mg [2]), headache (n=4; 5 mg [2], 8 mg [1], 
10 mg [1]), constipation (n=2, 2 mg and 5 mg), and contusion (n=2; 5 mg and 10 mg). No 
such events were reported for subjects on placebo. One subject (2.6%) had on-treatment AEs 
which were considered drug related by the investigator (dry mouth and somnolence, 2 mg).
”Flu like symptoms” were considered mild-moderate in severity and were characterized by 
intermittent low-grade temperature elevations (maximum temperature 38.1oC), over a 
duration of 1-3 days. Concomitant headache and dysuria were experienced by one subject 
each. Minor, transient, elevations of C-reactive protein (CRP) were noted with these 
symptoms. All symptoms resolved spontaneously while on continuous BI 706321 treatment. 
Based on the brief and self-limited nature of the symptoms, they were considered to be of 
minor clinical significance.
Events coded as diarrhea were all mild in intensity and of short duration (< 1-3 days). Events 
coded as constipation and abdominal discomfort were all mild in intensity.
In both the SRD and MRD trials there were no AEs that led to discontinuation of the study 
drug; neither serious adverse event (SAE) nor severe AE were observed. Vital sign evaluation 
and safety laboratory testing did not reveal clinically relevant findings. No clinically relevant 
changes in any cardiac intervals as measured by centralized electrocardiogram (ECG) were 
observed in any subject exposed to BI 706321.
Overall, single dose administration of BI 706321 at doses of up to 25 mg and multiple-dose 
administration of BI 706321 at doses of up to 10 mg for up to 14 days, was generally well 
tolerated by healthy volunteers.
For a more detailed description of the BI 706321 profile, please refer to the current 
Investigator’s Brochure (IB) [c26475781].
1.2.2
Ustekinumab (Stelara)
Ustekinumab is a fully human monoclonal IgG1 antibody directed against the p40 subunit of 
interleukin (IL)-12 and IL-23, approved since 2016 for the treatment of moderate or severe 
CD.
For a more detailed description of ustekinumab, please refer to the current version of
Summary of Product Characteristics (SmPC) or US Package Insert (US PI) for ustekinumab.
1.3
RATIONALE FOR PERFORMING THE TRIAL
As outlined in Section 1.1, despite therapeutic progress and three licensed biologic drug 
classes with different mechanisms of action, modest primary effect sizes and the phenomenon 
of secondary loss of response to these current available therapies sustain a significant unmet 
medical need in CD. The modest efficacy of the current drugs which address different 
components of the dysregulated inflammatory response in patients with CD suggests that 

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multiple pathologic pathways need to be targeted in tandem, to make major progress in 
treatment of this often severe and disabling disease. Combination treatments of established 
anti-inflammatory drugs with new medicines with a novel and differentiated mode of action 
might offer greater efficacy, in particular if such a combination partner would be orally 
available, safe and tolerable. BI 706321 may be such a candidate drug.
Pre-clinical evidence suggests that BI 706321 will not only inhibit the dysregulated innate 
immune response, but also normalize the expression of genes related to inflammation and 
intestinal barrier function (ref. to current version of the IB [c26475781]). Thus, its MoA 
targets two major aspects of CD pathogenesis, which are well differentiated from the MoA of 
ustekinumab (Stelara®), which via IL-12/23 inhibition primarily targets the dysregulated 
adaptive T cell response. Through these complementary effects of combination therapy, a 
substantial improvement in clinical and endoscopic outcomes may be achievable. At the same
time, ustekinumab offers a well characterized and favorable safety profile and thus represents 
a well-suited combination partner for BI 706321. Combination therapy at the time of 
induction is proposed as this will provide the best opportunity to observe potential additive 
efficacy in participating patients. Additionally, the long-term effects of combination 
induction on endoscopic and clinical remission endpoints can be assessed. BI 706321 
efficacy and safety data obtained by this trial will support its further development in the 
indication of CD.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (see Section 5.4). If the patient agrees, banked samples may 
be used for future biomarker research and drug development projects, e.g. to identify patients 
that are more likely to benefit from a treatment or experience an adverse event (AE), or to 
gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
All patients enrolled in this study will have experienced and failed or developed intolerance 
to one or two TNFi previously, and thus are candidates to receive ustekinumab treatment as 
standard of care. Ustekinumab has been approved for treatment of various indications since 
2009, and was specifically approved for the indication of Crohn’s disease since 2016; the 
safety profile has been well-characterized and is considered mild. Within this trial, all 
patients will receive the approved dose of ustekinumab treatment for 48 weeks (ref. to 
Section 3.1). In addition, patients will receive during the induction period a 12-week 
randomised combination treatment with BI 706321 or placebo. BI 706321 has not yet been 
administered to any patients and its efficacy cannot be assumed. Therefore, participation in 
this clinical trial may not provide an additional individual benefit for patients with CD, as 
compared to them receiving standard ustekinumab treatment outside this clinical study.
However, based on the pre-clinical data summarized in Section 1.2, BI 706321 is 
hypothesized to have therapeutic efficacy in patients with moderate to severely active CD by 
blunting the chronic immune cell stimulation by the microbiome via reduced signal 

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transduction from the NOD1/2 pattern recognition receptors and normalizing genes related to 
intestinal barrier function. Furthermore, exploratory target engagement assessed pre- and 
post-treatment in the SRD trial of healthy volunteers suggests that BI 706321 will have 
biological activity at the doses given to patients in this trial.
Participation in this study may generate future benefit for the CD patient population as a 
whole if BI 706321 proves to show additional efficacy.
1.4.2
Risks
Subjects are exposed to risks related to the exposure to BI 706321 and ustekinumab, as well 
as the risks of study procedures.
1.4.2.1
Trial medication-related risks
Trial medication related safety risks may be assumed from the current knowledge (or the lack 
thereof) regarding the following:
Specific RIPK2 inhibition is a novel mechanism of action for which there is no precedent 
clinical data for multiple dose administration in patients. No other RIPK2 inhibitors are 
currently approved that could provide information on identified risks in molecules of this 
class. BI 706321 in single doses of 0.3 – 25 mg and multiple doses of 2 – 10 mg for 14 days
were generally well tolerated by healthy subjects in the SRD and MRD trials. Below are the 
theoretical risk considerations based on literature, pre-clinical studies, and preliminary 
clinical studies, as well as general safety considerations of immunomodulatory drugs.
Impaired host defense
Based on the role of RIPK2 in the innate arm of the immune system, impaired host defense is 
a theoretical target-related pharmacologic effect of selective RIPK2 inhibition (see IB Section 
7.6.1 [c26475781]). However, the translatability between preclinical models of infection or 
genetic loss of function mutations and usually incomplete pharmacologic inhibition of RIPK2 
kinase activity in humans is unknown. It is important to note that RIPK2 inhibition will 
selectively block the NOD-RIPK2 pathway, but leave the remaining innate pattern 
recognition receptor signaling pathways (e.g. Toll-like receptor signaling) intact.
There is no clear signal of infectious risk identified in the nonclinical general toxicity studies 
with BI 706321. The AE of “nasopharyngitis” was experienced by two subjects in the 
1425-0001 trial on active treatment as compared with none on placebo. Five subjects in the 
1425-0002 MRD trial on active treatment with BI 706321 experienced “flu like symptoms” 
as compared with none on placebo. ”Flu like symptoms” were considered mild-moderate in 
severity and were characterized by intermittent low-grade temperature elevations (maximum 
temperature 38.1oC), over a duration of 1-3 days. Concomitant headache and dysuria were 
experienced in one subject each. Minor, transient, elevations of CRP were noted with these 
symptoms. All symptoms spontaneously resolved without change in BI 706321 treatment. 
Based on the brief and self-limited nature of the symptoms, they were considered to be of 
minor clinical significance. 

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In the SRD trial 1425-0001, one subject in the 25 mg dose group reported a brief generalized 
sensation of cold approximately 10 hours after dosing with associated mild transient increase 
in temperature (37.4°C) and CRP (35.4 mg/L). In the MRD trial 1425-0002, minor transient 
elevations in CRP, up to a maximum value of 19.7 mg/L, were observed in a subset of 
subjects beginning after approximately 3-6 days of multiple dosing. CRP levels subsequently 
normalized within 48-96 hours while dosing was ongoing. Some of these subjects 
experienced symptoms reported as “flu like symptoms” described above, while other subjects 
had no such symptoms associated with these changes in CRP values. No clinically significant 
changes from baseline in ferritin, haptoglobin, or fibrinogen were observed. Given the minor 
and transient nature of these observed changes in CRP, in the absence of clinical symptoms, 
they were not considered clinically relevant.
Similar to other treatments that modulate the immune system, there is a lack of data with 
respect to vaccine safety and effectiveness in populations on such therapies. Live vaccines are 
not permitted 4 weeks prior to screening and throughout the study. It is not known whether 
non-live vaccinations (including, but not limited to currently available COVID-19 vaccines) 
received while in this trial will elicit an immune response sufficient to prevent disease. It is, 
however, unlikely that there will be any specific risks due to interactions between these non-
live vaccines and BI 706321.
Risk mitigation: Patients with clinically relevant infections are excluded (ref. to 
Section 3.3.3.2) “Infectious Disease Exclusion Criteria”). All patients will closely be 
monitored by the investigators and trial team for the emergence of clinical Adverse Events 
(AE) related to infection and systemic inflammation. Severe and/or serious infections are also 
reflected in the individual patient treatment stopping rules. CRP levels in patients in this trial 
will be measured at every study visit, (including at Visit 3) after start of treatment. 
Body temperature in this trial will be measured at every study visit, (including at Visit 3) 
after start of treatment and until Visit 9. Serum amyloid A, haptoglobin, ferritin and 
fibrinogen as markers of the acute phase response will also be monitored. For advice on 
COVID-19 vaccination, please refer to Section 4.2.2.1.
Cardiovascular system
In rats, repeat dosing up to 13 weeks resulted in increased incidence/severity of mononuclear 
infiltrates. Infiltrates were associated with an increased incidence of myocardial degeneration 
at higher exposure levels (97X/66X the estimated human steady state for Cmax and AUC0-24
respectively for the 8 mg once daily dose). The finding in rats may be a species specific 
exacerbation of a common spontaneous background finding in rats. There were no 
histopathologic changes to the heart of monkeys at the highest dose levels in the 4- and 13-
week studies that achieved 78X and 11X human exposure with a 8 mg dose once daily, 
respectively.
There is low risk for relevant cardiovascular effects at the exposures expected in this trial. 
Studies in monkeys showed potential for prolongation of QT/QTc intervals. In the MRD trial, 
an exploratory analysis of central ECG data was conducted to characterise the effects of 
BI 706321 on QT/QTc. Based on preliminary analysis using random coefficient modelling, 

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the predicted mean differences between BI 706321 and placebo in QTcF change from 
baseline at gMean of Cmax,ss were below 10 msec at all dose levels; however, they slightly 
exceeded 5 msec in the 8 and 10 mg dose groups. No clinically relevant individual QTcF 
changes have been observed in any subject exposed to BI 706321; no relevant blood pressure 
and heart rate changes were noted.
Risk mitigation: A marked baseline prolongation of QT/QTc interval (such as QTcF intervals 
that are greater than 450 ms for men, 470 ms for female) or any other relevant ECG finding at 
screening or clinically relevant abnormal findings on physical examination of the 
cardiovascular system in the judgement of the investigator are excluded. ECG monitoring 
will be done, and concomitant medications with a known risk of increasing exposures of BI 
706321 or known risk of QTc prolongation are to be used with caution. Troponin levels will 
be regularly monitored with safety labs.
Gastrointestinal system 
A single dose resulted in an increased rate of gastric emptying and intestinal transit, and 
liquid accumulation to intestinal contents in rats. Repeat dosing resulted in soft, loose, wet, or 
liquid stool in rats and monkeys. Clinical events coded as diarrhea in the Phase I program 
were all mild in intensity and of short duration (< 1-3 days).
Risk mitigation: AEs consistent with alterations in stool consistency will be monitored.
Hepatobiliary system 
In rats, there were increases in the incidence/severity of mononuclear cell infiltrates to the 
liver (occasionally associated with hepatocellular necrosis) at all dose levels, and increases in 
serum AST and ALT that did not consistently correlate with the liver infiltrates. In monkeys, 
there was hypertrophy of sinusoidal (Kupffer) cells that also was not associated with 
increases to AST or ALT. Because of the nature of the findings, these tissue changes are not 
considered a relevant risk in humans. No clinically significant changes in liver transaminases 
have been observed in completed or ongoing clinical studies with BI 706321.
Additionally, although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure subjects safety.
Risk mitigation: Liver function tests will be monitored.
Genotoxicity, reproductive and developmental toxicity
In vitro and in vivo genetic toxicology studies indicated that BI 706321 is free of any 
genotoxic potential.
Reproductive findings were only seen in the rat studies. In female rats, reversible adverse 
effects to the ovaries (corpora lutea degeneration) were observed in females at 11X/7X the 
estimated human steady state for Cmax and AUC0-24 respectively for a dose of 8 mg once 
daily. In male rats, there were reversible decreases in testes weights/size and seminiferous 
tubular degeneration/atrophy with epididymal oligospermia at very high exposures (97X/66X 

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the estimated human steady state for Cmax and AUC0-24 respectively for a dose of 8 mg once 
daily).
Potential effects on embryo-fetal development were evaluated in pregnant rats and rabbits. In 
rats, there was embryolethality (increased post-implantation loss) and evidence of fetotoxicity 
(adverse effects on fetal growth) at 10 mg/kg/day, and no effects to embryo fetal 
development at ≤5 mg/kg/day. In rabbits, there were no effects to embryo-fetal development 
at ≤7 mg/kg/day. Therefore, there is potential risk for adverse effects to development at human 
exposures exceeding the embryo-fetal NOAEL in the rat (Cmax of 184 nM and AUC0-24h of 2,060 
nM•h), which provided 5X and 4X estimated human steady state exposure Cmax and AUC for a 
dose of 8 mg once daily.
As BI 706321 is not genotoxic nor suspected of human teratogenicity or fetotoxicity at 
subtherapeutic systemic exposure levels, the potential risk to embryo-fetal development as a 
result of vaginal or placental transfer from a male clinical trial participant to a female partner 
is considered negligible.
There is low risk for relevant reproductive effects at the exposures expected in this trial in 
males, and females who are not considering pregnancy. For safety margins between 
maximum exposures and GLP reproductive findings in rats, refer to Section 1.2.1.
Risk mitigation: Women of childbearing potential (WOCBP) who participate in the trial have 
to use highly effective methods of birth control as described in the eligibility criteria. Periodic 
pregnancy tests will be performed in WOCBP. Monitoring of male sex hormones as a 
measure of testicular function in males will be done every four weeks for the duration of 
BI 706321 therapy.
Hematopoietic toxicity
Reversible hematopoietic effects were seen in both rats and cynomolgus monkeys, as detailed 
in the current version of the IB. In trials 1425-0001 and 1425-0002, no clinically significant 
changes in blood counts were observed in healthy volunteers. 
Risk mitigation: Subjects with significantly abnormal baseline peripheral blood counts will be 
excluded from participation (see Section 3.3.3). Complete blood counts with differential will 
be monitored.
Drug-drug interactions (DDI)
Based on in vitro studies, clinically relevant DDIs with BI 706321 are possible. For pre-
clinical and clinical DDI potential and concomitant medications restrictions, see 
Section 4.2.2.1.
1.4.2.2
Risks related to ustekinumab administration
Ustekinumab is proven to be safe and tolerable in CD patients and thus represents a well-
suited combination partner for BI 706321. Patients in this study will be exposed to the 

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standard risks associated with ustekinumab administration (ref. to current version of 
SmPC/US PI). Some of them are:

Infections: Serious infections have occurred. Do not start ustekinumab during any 
clinically important active infection. If a serious infection or clinically significant 
infection develops, consider discontinuing ustekinumab until the infection resolves.

Theoretical Risk for Particular Infections: Serious infections from mycobacteria, 
salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in 
patients genetically deficient in IL12/IL-23. Diagnostic tests for these infections 
should be considered as dictated by clinical circumstances.

Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with 
ustekinumab. 

Malignancies: ustekinumab may increase risk of malignancy. The safety of 
ustekinumab in patients with a history of or a known malignancy has not been 
evaluated.

Hypersensitivity Reactions: Anaphylaxis or other clinically significant 
hypersensitivity reactions may occur.
1.4.2.3
Procedure-related risks
Risks of participating in this study include risks related to the trial specific procedures blood 
sampling, endoscopy with biopsy:
Blood sampling / Total blood volume
As with all blood sampling, there is a risk of mild pain, local irritation, or bruising (a black or 
blue mark) at the puncture site. Furthermore, there is a small risk of light-headedness and/or 
fainting. In rare cases, the puncture site can also become infected or nerves may be damaged, 
inducing long-lasting abnormal sensations (paresthesia), impaired sensation of touch and 
persistent pain.
The total volume of blood withdrawn during the entire study per patient will not exceed the 
volume of a normal blood donation (approximately 500 mL). No health-related risk is 
expected from this blood withdrawal.
Ileo-colonoscopy with biopsy
Ileo-colonoscopy with biopsy, although generally well tolerated, can be associated with 
diarrhoea, abdominal pain, perforation, bleeding, effects from anaesthetic medications, and 
infection. Patients scheduled for ileo-colonoscopy need to undergo bowel cleansing.
Patients who are unable and unwilling to undergo the procedure are excluded from the trial.
The potential risks which are described above will be minimized by close monitoring and 
selection of experienced trial sites. These risks are considered manageable and outweighed by 
the potential benefits at this stage of clinical development. For further details see current 
version of the IB [c26475781].

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1.4.2.4
COVID-19
BI 706321 
The available pharmacological, non-clinical and clinical data do not indicate an increased risk 
of contracting SARS-CoV-2 or severe clinical courses due to the treatment with BI 706321. 
However, similar to standard practice with other immune-modulating treatments, given the 
theoretical increased risk of infections, risk mitigation measures such as exclusion of subjects 
with underlying immunological disorders, monitoring for infectious adverse events, 
laboratory monitoring, and adherence to appropriate exposure safety margins have been 
implemented as outlined in the clinical trial protocols and patient informed consent forms.
Risk mitigation: Even though the risks associated with BI 706321 treatment are considered 
low, patients with active or recent SARS CoV-2 infection will not be included in the trial 
(see Section 3.3.3). A suspected SARS CoV-2 infection while in the trial will result in an 
immediate test. If positive, trial treatment will be discontinued or interrupted (see 
Section 3.3.4.1). Investigator and sponsor will closely align on the appropriate measures for 
monitoring, treatment and quarantine. Trial treatment may be resumed following recovery if 
clinical benefit is expected
Trial procedures
Trial conduct and protocol-defined procedures do not specifically impose more 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.
Other risks
Travelling to the site or being at the site for trial visits may potentially increase the risk of 
contracting a SARS CoV-2 infection. 
Risk mitigation: The number of site visits is limited to the minimum required for the 
successful conduct of the trial. Measures are in place to ensure continued patient treatment, 
monitoring, and safety even if site visits are not possible (see Sections 4.1 and 6.2).
1.4.3
Discussion
BI 706321 is entering Phase II development, and clinical efficacy has not yet been proven.
Crohn’s disease patients participating in this clinical trial cannot be assumed to have an 
individual (therapeutic) benefit, however this early phase trial will use a BI 706321 dose that 
is anticipated to be in the therapeutically effective dose range and may contribute to 
alleviation of the signs and symptoms of CD when administered with ustekinumab; CD 
patient participation in studies is of major importance for the overall development of 
BI 706321, which represents a novel approach for the treatment of patients with CD.
Participation in this study may generate future benefit for other CD patients if BI 706321 is 
proven to show additional efficacy. The current clinical safety data in healthy volunteers as 
well as the results from toxicity and safety pharmacology studies demonstrate an acceptable 

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profile for this trial. The potential risks which are described in Section 1.4.2 will be 
minimized by careful patient and site selection as well as close monitoring. 
In conclusion, in the context of the unmet medical need in CD, safety profile of BI 706321 
and the study design, the benefit-risk evaluation of BI 706321 in this study is considered 
favourable for this stage of clinical development.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
This is a Phase IIa trial evaluating proof of clinical principle based on the efficacy, 
tolerability, and safety of one dose regimen of BI 706321 compared to placebo in patients 
with moderate to severely active CD receiving ustekinumab induction treatment.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of this trial are to investigate a first signal of efficacy, safety and 
tolerability of BI 706321 in combination with ustekinumab treatment compared to placebo 
with ustekinumab treatment in patients with moderately to severely active CD at 12 weeks. 
The primary objective is to estimate the difference in change from baseline in Simple 
Endoscopic Score for Crohn’s disease (SES-CD) after 12 weeks. The primary treatment 
comparison will be between treatment groups while on treatment during the 12 week 
induction period.
In addition, the long-term effects of combination induction compared to monotherapy 
ustekinumab induction on endoscopic and clinical endpoints during maintenance therapy will 
be assessed.
2.1.2
Primary endpoint
Absolute change from baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) at 
week 12.
2.1.3
Secondary endpoints

Percent change in SES-CD from baseline at Week 12

Endoscopic response (defined as >50% SES-CD reduction from baseline, or for 
aninduction baseline SES-CD of 4, at least a 2 point reduction from induction 
baseline) at Week 12

Endoscopic response (defined as >50% SES-CD reduction from baseline, or for an
induction baseline SES-CD of 4, at least a 2 point reduction from induction baseline) 
at Week 48

Endoscopic remission (defined as SES-CD score of ≤2) at week 12

Endoscopic remission (defined as SES-CD score of ≤2) at week 48.

Biological remission, defined as CRP < 5 mg/L and faecal calprotectin (FCP) < 250 
ug/g at week 12

Biological remission, defined as CRP < 5 mg/L and faecal calprotectin (FCP) < 250 
ug/g at week 48

Clinical remission at week 12, defined as a Crohn’s Disease Activity Index (CDAI)
score of <150

Clinical remission at week 48, defined as a CDAI score of <150

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
Clinical response at week 12, defined by a CDAI reduction from baseline of at least 
100 points, or a CDAI score of <150

Number of patients with treatment-emergent adverse event (TEAE) through end of 
treatment (EoT) and the REP period (i.e. through Visit 9)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a Phase IIa, randomised, double-blind, placebo-controlled evaluation of 
approximately 50 male and female patients with CD, using BI 706321 therapy in combination 
with a backbone ustekinumab induction regimen.
Patients will be randomised (1:1) to one of two arms as following:
Group 1: BI 706321 8 mg p.o. QD for 12 weeks in conjunction with standard induction 
dosing of ustekinumab*, followed by ustekinumab maintenance dosing for an additional 36 
weeks.
Group 2: Placebo p.o. QD for 12 weeks in conjunction with standard induction dosing of 
ustekinumab*, followed by ustekinumab maintenance dosing for an additional 36 weeks. 
Figure 3.1: 1 Overview of study design and dosing
* Single IV infusion of 260 mg ustekinumab (body weight ≤55 kg), 390 mg ustekinumab (body weight 55-85 kg), or 520 mg 
ustekinumab (body weight >85 kg), followed by s.c. injection of 90 mg ustekinumab every 8 weeks
After the 12-week induction treatment period, patients will be treated with an additional 36 
weeks of follow-on ustekinumab open label maintenance monotherapy. Ustekinumab therapy 
in both induction and maintenance will be administered in an open-label fashion. Both safety 
and efficacy data will be collected during the follow-up period. 
The primary analysis will be performed soon after the last patient completes Week 12 visit 
procedures, including ileo-colonoscopy. However, treatment assignments during the initial 
12-week induction phase will remain blinded to sites/investigators for the duration of the 
maintenance phase, in order to mitigate bias in the later assessments.
baseline
Ileo-colonoscopy
12
*Primary 
Endpoint: ileo-
colonoscopy
BI 706321 + ustekinumab 
ustekinumab
48
End of study
Ileo-
colonoscopy
PBO + ustekinumab
ustekinumab
screening 
period
0
N=25
N=25
Weeks
8
16
24
32
40
ustekinumab IV
ustekinumab SC 
I 
I 
I 
I 
I 
I 

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Patients will be permitted to continue during the induction phase the following therapies if 
dose levels have been stable for the designated time frames before randomisation (see 
Section 3.3.2 for details): oral corticosteroids (prednisone <20 mg/day or equivalent; 
budesonide <9 mg), antibiotics, 5-aminosalicylic acid (5-ASA), AZA, MP, 6-thioguanine (6-
TG), or MTX.
However, the use of biological therapies other than ustekinumab (e.g., TNFα-antagonists, 
integrin inhibitors) will be prohibited during the trial.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The treatment duration with BI 706321 of 12 weeks is driven by the maximum treatment 
duration covered by current preclinical toxicology data.
The double-blind concept was chosen to reduce investigator and patient expectation bias with 
regard to the treatment dependent effects as much as possible.
The use of a combination study design in the development of BI 706321 is justified by its 
complementary and differentiated effects as compared to ustekinumab. Ustekinumab is a 
current treatment standard for our study population of patients who have tried and failed or 
lost response to TNFi. However, ustekinumab treatment leads to only 38% and 21% clinical 
response Crohn’s Disease Activity Index (CDAI 100 point) and clinical remission at Week 8 
respectively, in CD patients who had failed or were intolerant to prior treatment with a TNFi
(ref. to current version of SmPC/US PI). Though clinical response and remission rates in a 
subsequent study of ustekinumab therapy are higher (> 50%) by 16 weeks of treatment, rates 
of endoscopic response and remission at that time remain quite low (37.8% and 11.1% 
respectively, in patients who have been exposed to at least one biologic) [R21-1348].
BI 706321 blunts inflammatory signaling from innate microbial sensing by epithelial, 
myeloid, and endothelial cells, and has effects on epithelial barrier function, whereas 
ustekinumab targets the p40 subunit common to IL-12 and IL-23 and primarily exerts its anti-
inflammatory effects by modulation of T lymphocytes and Natural killer cells (NK cells). 
Therefore, all patients in the placebo and active treatment groups will benefit from receiving 
ustekinumab, which represents current standard of care for patients failing one or more TNFa 
inhibitors. This design also reduces the risk to the patient of worsening of disease if treated 
with placebo therapy alone.
It is postulated that combination induction therapy will offer better overall efficacy due to the 
complementary and differentiated immune-modulating effects of the two agents, as well as 
the additional effects of BI 706321 on epithelial barrier function.
The overall trial duration with ustekinumab of 48 weeks followed by a final ileo-colonoscopy 
will allow assessment of the long-term effect of the initial 12 week period of BI 706321 
combination induction treatment on the endoscopic endpoints at the end of monotherapy 
maintenance. This is with the understanding that early effects on endoscopic scores may be 
observed in a subset of patients by 12 weeks, however maximal endoscopic improvement and 

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separation from the ustekinumab+placebo arm may not be reached in the majority of patients 
until 6-12 months after initiation of therapy - particularly in patients who are TNFi-
experienced. Therefore, patients will be followed for up to 36 weeks on maintenance 
monotherapy to monitor further structural improvement using fecal, and blood biomarkers 
(at 16, 24, 32, 40, and 48 weeks), as well as a repeat ileo-colonoscopy with tissue sampling at 
week 48. Treatment assignments during the initial 12-week induction phase will remain 
blinded to sites/investigators for the duration of the maintenance phase, in order to mitigate 
bias in the later assessments.
There may be patients who fail to have an adequate response to therapy or lose response to 
therapy during the follow-on ustekinumab treatment. If ustekinumab dose escalation or 
treatment cessation is deemed necessary by the investigator, these patients will exit the study 
and be managed according to best local medical practice. Clinical and endoscopic data will 
be obtained prior or soon after such early treatment discontinuation. 
The group size (approximately 25 patients per treatment group) is sufficient for assessing first 
therapeutic effects and safety, tolerability, PK and Pharmacodynamics (PD) of BI 706321 in 
combination with ustekinumab. For information can be found in Section 7.5. 
3.3
SELECTION OF TRIAL POPULATION
Approximately 50 male and female adult patients suffering from moderately to severely 
active CD will be included in several countries in approximately 50 sites. The number of sites 
might be increased in case the recruitment is slower than initially expected. Sufficient 
subjects will be screened to ensure that 50 eligible subjects are randomised.
An interim assessment of baseline biomarkers will be performed after approximately 20 
patients are entered (refer to Section 7.2.7). Based on this assessment and if no individual 
stopping rules are met, the Sponsor may recruit additional patients to improve the sensitivity 
of exploring the relationship between RIPK2 pathway-specific biomarkers and endoscopic 
responses among the treatment groups after 12 weeks, however the total number of 
randomised patients will not exceed 76 (i.e. 13 additional patients per treatment arm, so as to 
limit total additional enrolment to no greater than ~50% of the originally proposed sample 
size).
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the Sponsor should be contacted immediately to 
whether the subject may proceed with the study or should be discontinued.

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3.3.1
Main diagnosis for trial entry
Male and female patients with documented history of ileal, colonic, or ileocolonic CD 
diagnosed by local standards and current presence of mucosal ulcers in at least one segment 
of the ileum or colon and a SES-CD score ≥7 (for patients with isolated ileitis ≥4), as 
assessed by ileo-colonoscopy and confirmed by central independent reviewer(s) before start 
of study treatment, and are clinical candidates for treatment with ustekinumab as judged by 
the investigator and according to local reimbursement guidelines (where applicable).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Male or female patients.
2. ≥18 – ≤75 years, at date of signing informed consent.
3. Diagnosis of CD for at least 3 months prior to Visit 1, as confirmed at any time in the 
past by endoscopy and/OR radiology, and supported by histology.1
4. Elevated CRP (≥5 mg/L) OR elevated fecal calprotectin (≥250 µg/g)
5. Symptomatic CD defined as CDAI ≥150.
6. Presence of mucosal ulcers in at least one segment of the ileum or colon and a 
SES-CD score ≥7 (for patients with isolated ileitis ≥4), as assessed by ileo-
colonoscopy and confirmed by central independent reviewer(s) before start of study 
treatment.
7. Patients who are experienced to at least 1 TNF antagonist at a dose approved for CD. 
Patients may have stopped TNF antagonist treatment due to primary or secondary 
non-responsiveness, intolerance (see definitions in Appendix 10.7), or for other 
reasons.
8. May be receiving a therapeutic dose of the following:
o
Oral 5-ASA compounds must have been at a stable dose for at least 4 weeks 
prior to randomisation and must continue on this dose until week 12 and/or
o
Oral corticosteroids if indicated for treatment of CD must be at a prednisone 
equivalent dose of ≤ 20 mg/day, or ≤ 9 mg/day of budesonide, and have been 
at a stable dose for at least 2 weeks immediately prior to randomisation and 
must continue on this dose until week 12. [Allowed steroid treatments: Locally 
administered steroids as e.g. intra-articular, nasal inhalation or intra-ocular 
administration are allowed.] and/or
o
AZA, MP, 6-TG, or MTX, provided that dose has been stable for the 8 weeks 
immediately prior to randomisation and must continue on this dose until week 
12.
1 That means, the imaging part can be confirmed at any time in the past (which is more than 3 months prior Visit 1) by 
endoscopy and/or radiology. Radiology however, is not necessarily required. In addition, the histology result should be 
available also and it should support the diagnosis of CD.

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9. Women of childbearing potential (WOCBP)2 must be ready and able to use highly 
effective methods of birth control per International Councila on Harmonisation (ICH)
M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information or in Section 4.2.2.3.
10. Signed and dated written informed consent in accordance with ICH- Good Clinical 
Practice (GCP) and local legislation prior to admission to the trial.
3.3.3
Exclusion criteria
3.3.3.1
Gastrointestinal Exclusion Criteria
1. Have any current or prior abscesses, unless they have been drained and treated at least 
6 weeks prior to randomisation and are not anticipated to require surgery. Patients 
with active fistulas may be included if there is no anticipation of a need for surgery 
and there are currently no abscesses present based on investigator`s judgement.
2. Have complications of CD such as strictures, stenosis, short bowel syndrome, or any 
other manifestation that might require surgery, or could preclude the use of SES-
CD/CDAI to assess response to therapy, or would possibly confound the evaluation of 
benefit from treatment with BI 706321 (based on investigator’s judgement).
3. Patient with an inflammatory bowel disease (IBD) diagnosis other than CD.
4. Have had any kind of bowel resection or diversion within 4 months or any other intra-
abdominal surgery within 3 months prior to Visit 1. Patients with current ileostomy, 
colostomy, or ileorectal anastomosis are excluded.
5. Treatment with:
o
any non-biologic medication for IBD (e.g. tacrolimus or mycophenolate 
mofetil, systemic corticosteroids), other than those allowed per inclusion 
criteria, within 30 days prior to randomisation
o
any biologic treatment with a TNF-alpha antagonist (adalimumab, infliximab, 
golimumab, certolizumab pegol) or vedolizumab (or a biosimilar of these 
drugs) within 4 weeks prior to randomisation. (If drug level testing for 
previously used biologic treatment confirms no detectable drug level before 
randomisation, patient can be enrolled despite not having completed 4 week 
from last treatment.)
o
any previous treatment with ustekinumab (or a biosimilar of this drug)
o
any previous treatment with an investigational (or subsequently approved) 
non-biologic/biologic drug for CD (including but not limited to JAK inhibitors
[e.g. upadacitinib], S1P modulators, IL-23 inhibitors [e.g. risankizumab], anti-
integrins).
o
any investigational drug for an indication other than CD during the course of 
the actual study and within 30 days or 5 half-lives (whichever is longer) prior 
to randomisation.
o
any prior exposure to rituximab within 1 year prior to randomisation. 
2 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.

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6. Positive stool examination for C difficile (toxin A/B and GDH antigen – test positive) 
or other intestinal pathogens <30 days prior to randomisation. Re screening can be 
undertaken following documented successful treatment, no sooner than 1 week after 
last intake of antimicrobial therapy. If stool examination for C. Diff is indeterminate 
(toxin A/B positive and GDH antigen negative or toxin A/B negative and GDH 
antigen positive), a reflex PCR test must be done to assess eligibility. A positive PCR 
test will lead to exclusion.
7. Evidence of colonic moderate/severe mucosal dysplasia or colonic adenomas, unless 
properly removed.
8. Fecal transplant ≤ 30 days prior to randomisation.
3.3.3.2
Infectious Disease Exclusion Criteria
9. Increased risk of infectious complications (e.g. recent pyogenic infection, any 
congenital or acquired immunodeficiency (e.g. Human immunodeficiency virus 
(HIV)), past organ or stem cell transplantation (with exception of a corneal transplant 
> 12 weeks prior to screening) or have ever received stem cell therapy (e.g., 
Prochymal). Prior treatment with a somatic cell therapy product (e.g., Alofisel) is not 
excluded, provided it was administered >8 weeks prior to randomisation.
10. Live or attenuated vaccination within 4 weeks prior to randomisation.
11. Have received BCG vaccines ≤1 year prior to randomisation.
12. Active or latent TB:
o
Patients with active tuberculosis are excluded.
o
Patients will be screened with Interferon Gamma Release Assay (IGRA) such 
as QuantiFERON or T spot, the patient may also be evaluated for the presence 
of TB with any additional test required by local practice. Patients with positive 
test results are excluded unless patient is known to have had a previous 
diagnosis of active or latent TB and has completed appropriate treatment per 
local practice/guidelines within the last 3 years and at least 6 months before 
first administration of trial medication under this protocol (patients may be 
rescreened once to meet this specific criterion)
o
Patients with indeterminate QuantiFERON or invalid/borderline T spot may 
be re-tested with IGRA (once), and if again inconclusive, should have a 
Purified Protein Derivative (PPD) skin test.
o
If IGRA is not available or result remains indeterminate after repeat testing, 
tuberculin skin test (TST) should be performed: A tuberculin skin test positive 
reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent) is 
considered positive. Patients with a positive TST are excluded unless they 
have completed treatment as above.
13. Presence of clinically significant acute or chronic infections not otherwise listed, 
including viral hepatitis, COVID-19, or others based on investigator’s judgement. A 
patient can be rescreened (up to two times) if the patient was treated and is cured from 
the acute infection. If at screening, PCR test for SARS-CoV-2 is positive and patient 
is asymptomatic, re-test SARS-COV-2 PCR test is allowed (up to 4 times) to confirm 
patient's eligibility before ileo-colonoscopy and/or Visit 2. If re-test SARS-COV-2 
PCR test is negative, patient must meet all other eligibility criteria according to the 

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CTP before patient is randomized at Visit 2. Already performed screening assessment 
do not need to be repeated. 
3.3.3.3
General Exclusion Criteria
14. Have any documented active or suspected malignancy or history of malignancy 
within 5 years prior to screening except appropriately treated basal cell carcinoma or 
squamous cell carcinoma of the skin, or history of in situ carcinoma of uterine cervix
(treated >3 years); patients with a remote history of malignancy (≥ 5 years prior to 
screening) may be considered and have to be discussed with sponsor on a case-by-
case basis.
15. Major surgery (major according to the investigator’s assessment) performed within 16 
weeks prior to randomisation or planned within 4 months after screening, e.g. hip 
replacement.
16. Pathological safety lab parameters (one retesting is allowed):
o
Haemoglobin <8.5 g/dL
o
White blood cell (WBCs) <3,500 cells/mm3
o
Neutrophils <1,500 cells/mm3
o
Platelets <100,000 /mm3
o
Estimated glomerular filtration rate (eGFR) ≤60 ml/(min*1,73 m²)
o
Aspartate aminotransferase (AST) OR Alanine aminotransferase (ALT) >2 
times the Upper Level of Normal (ULN). Total bilirubin >2x ULN with ratio 
of direct/indirect >1 (patients with Gilbert’s syndrome are not excluded), 
o
Troponin: >ULN
17. Currently enrolled in another investigational device or drug study (for investigational 
studies, except any patient who has completed investigational drug treatment 
including residual effect period) or receiving other investigational treatment(s).
18. Women who are pregnant, nursing, or planning pregnancy (both men and women) 
while enrolled in the study.
19. Patients who must or wish to continue the intake of restricted medications (see
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial.
20. Evidence of a current or previously disease, medical condition (including chronic 
alcohol or drug abuse, or chronic liver disease with hepatic impairment) other than 
CD, surgical procedure, medical examination finding (including vital signs and ECG),
or laboratory value at the screening visit outside the reference range that in the 
opinion of the investigator is clinically significant and would make the study 
participant unreliable to adhere to the protocol or complete the trial, compromise the 
safety of the patient, or compromise the quality of the data.
21. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals that are 
greater than 450 ms for men, 470 ms for female) or any other relevant ECG finding at 
screening. Both have to be confirmed by repeated ECG recording.
22. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient an unreliable trial 
participant).
23. History of allergy/hypersensitivity to trial medication excipients.

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24. Have previously undergone allergy immunotherapy for prevention of anaphylactic 
reactions
25. Are unable or unwilling to undergo multiple venepunctures, ileo-colonoscopies (with 
biopsies) or preparation for ileo-colonoscopies.
26. Previous enrolment in this trial, except if meets re-screening criteria.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Section 3.3.4.1 and 
Section 3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial follow up data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and case report form (CRF). If applicable, 
consider the requirements for Adverse Event collection reporting (please see 
Section 5.2.6.2.1 and Section 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment (including ustekinumab open-label 
maintenance treatment after week 12) if:

The patient wants to discontinue trial treatment, without the need to justify the 
decision.

The patient 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.

The patient needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment. Please refer to 
Sections 4.2.1 and 4.2.2

The patient can no longer receive trial treatment and/or ustekinumab treatment for 
medical reasons (such as surgery, adverse events, other diseases, or pregnancy), e.g. 
(but not limited to):
o
Symptomatic SARS-CoV-2 infection, confirmed by lab testing
o
if, in the investigator’s opinion, the patient requires alternative biologic therapy or 
an increased dose of ustekinumab for their CD due to persistently high disease 
activity or worsening based on CDAI score (>450, or an increase by 100 points 
from baseline), the study treatment may be stopped and patients may receive 
medical treatment for active disease as per investigator’s judgement.
o
Diagnosis with a malignant neoplasm, severe infection, serious infection, and 
opportunistic or tuberculosis infection.
o
At week 24 (Visit 10):

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•
Absence of at least CDAI-70 clinical response as defined by a 
reduction from baseline in the CDAI score of ≥70 points, or a CDAI 
score of <150. 
In case of a temporary treatment discontinuation for a medical reason of up to 14 days (i.e. 
once per patient in the trial), trial treatment may be restarted if medically justified by the 
investigator.
If the trial treatment (BI 706321/placebo and/or ustekinumab) is discontinued before 
completing 10 weeks of treatment in the induction treatment period, the patients should
undergo the procedures of the early EoT visit and Visit 9 as the last visit in the trial as 
outlined in the Flow Chart and in Section 6.2.2. If a patient has to stop BI 706321/placebo
trial treatment after completing 10 weeks of treatment in the induction treatment period and if 
it is medically appropriate to continue treatment with ustekinumab, the patient may remain in 
the trial and follow the visit schedule as planned. If in the opinion of the investigator it is not 
medically appropriate to continue treatment with ustekinumab, the patient should perform an 
early EoT visit and Visit 9 as the last visit in the trial. Further CD treatment has to be defined 
by the investigator.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients
or take any other appropriate action to guarantee the safety of the trial patients.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient 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 overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.

Including, but not limited to, the following scenario, further enrolment, randomisation 
into the trial, and treatment of already randomised patients will be interrupted by the 
sponsor if:
o
2 patients on active treatment with serious adverse reactions representing the same 
MedDRA preferred term (and not reflecting exacerbations of the underlying CD) 
and

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o
Which, after evaluation by the Sponsor, are considered to have a reasonable causal 
relationship to BI 706321, and are not typically observed with ustekinumab 
therapy
After the trial has been interrupted, it will only be restarted after an appropriate safety 
evaluation has been conducted and concluded that the benefit-risk of the overall trial is 
still favourable, and appropriate risk-mitigation measures have been implemented if 
needed. If a re-start is appropriate, additional patients may be enrolled to replace the 
patients who were discontinued early due to the trial interruption.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
4. Termination of drug development either overall or in this indication
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The Investigational Medicinal Products BI 706321will be provided by BI.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Description of test product BI 706321
Substance:
BI 706321
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1 mg, 2 mg and 5 mg
Posology:
once per day, 8 mg per day in total (3 tablets per day 
in total)
Method and route of administration:
Oral
Table 4.1.1: 2
Description of test product placebo matching BI 706321
Substance:
Placebo matching BI 706321
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
not applicable
Posology:
once per day (3 tablets per day in total)
Method and route of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
BI 706321 dose selection for this trial is based on data obtained in the first-in-human SRD 
(1425-0001) and MRD (1425-0002) trials. In these trials single dose levels up to 25 mg and 
multiple dose levels up to 10 mg were safe and well tolerated. 

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4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups according to a randomisation plan in a 1:1 ratio with corticosteroid use 
(yes or no) as a stratification factor. Randomisation will be performed at Visit 2 using a 
central randomisation center and Interactive Response Technology (IRT) system to allocate 
patients to treatment groups. Note that the medication number is different from the patient 
number (the latter is generated during screening via the IRT system).
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be dispensed in a double-blinded manner to patients. That means, 
investigators and patients will not know if a patient is assigned to BI 706321 or placebo.
All patients will be dispensed the trial medication consisting in total 17 trial medication kits
(i.e. dispensing will be done during the trial stepwise via the IRT system at Visit 2, Visit 4, 
Visit 5, Visit 6 and Visit 7.

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Further information can be found in the ISF.
The trial medication can be taken with or without food.
At Visit 2, patients will be instructed by a qualified site staff member to take their trial
medication once daily in the morning. This should be done every day approximately at the
same time. Patients will be requested to document the time points of intake in their patient 
diary.
On visit days (i.e. Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8), the trial medication 
has to be taken in the morning at the trial site.
No double doses should be taken, and dose reductions are not permitted.
If a scheduled dose is missed by:

Less than 12 hours after the scheduled dose time, the patient must take the missed 
dose and take all remaining doses at scheduled time. The error must be documented in 
the patient diary and reported to the study doctor at the next study visit.

12 hours or more after the scheduled dose time, the patient must skip the missed dose 
and take the next scheduled dose; subsequent doses must be taken at the scheduled 
time. The error must be documented in the patient diary and reported to the study 
doctor at the next study visit.
The date and time of study drug administration at the trial visits (i.e. at the site, Visit 3, Visit 
4, Visit 5, Visit 6, Visit 7 and Visit 8) will be captured in the eCRF.
In case of a temporary treatment discontinuation for a medical reason of up to 14 days (i.e. 
once per patient in the trial), trial treatment may be restarted if medically justified by the 
investigator, please see Section 3.3.4.1.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6), physical patient visits to the sites may not be feasible or may need to be 
restricted to ensure patient safety. Based on a thorough assessment of the benefits and risks, 
the investigator may still decide to continue trial treatment. Where permitted by local law and 
regulations, the trial site team may arrange a transfer of the trial medication to the patient’s 
home (e.g. site staff delivers the trial medication to the patient after assignment by the IRT 
system). In agreement with the sponsor, a home visit service or telemedicine may assist the 
patient with medication administration.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Table 4.1.5.1: 1 summarizes the masking/blinding level of individual functions involved in 
the trial.

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Table 4.1.5.1: 1
Overview about blinding status of trial role and functions
Role/function
Timing of Unblinding/receiving access to the treatment
information (including rationale)
Patients 
Blinded until data ready for final analysis.
Investigators/site staff
Blinded until data ready for final analysis.
Sponsor (incl. clinical
trial/project team)
Unblinded descriptive analyses will be performed at different 
time points during the trial conduct (see Section 7.2.7). The 
release of treatment codes at the individual time points will be 
documented accordingly.
Independent centralised assessments of endoscopic scores will be performed in a blinded 
fashion as described in Section 3.2.
The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo/comparator patients. Bioanalytics will not disclose the randomisation code or the 
results of their measurements until the trial is officially unblinded
During the time a role/function is blinded, the treatment information are kept restricted by the 
global Randomisation Team (gRT) per Sponsor Standard Operating Procedure (SOP).
Ustekinumab treatment is open-label for the Sponsor, patients and investigator/site staff.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via the IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.

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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 according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC)

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

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,

Availability of the proof of a medical license for the Principal Investigator (if 
applicable),

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
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 patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
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
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. 
At the time of return to the sponsor or appointed CRO, the investigator or designee must 
verify that all unused or partially used drug supplies have been returned by the clinical trial
patient and that no remaining supplies are in the investigator’s possession.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Ustekinumab is classified as an Auxiliary Medicinal Products (AxMP) / Non-Investigational 
Medicinal Product (NIMP) (i.e. used as described in the current version of SmPC/US PI) and 
will be paid for by BI. However if mandated by local requirements ustekinumab can be 
regarded as Investigational Medicinal Product (IMP).
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (see Section 3.3) may 
be permissible. Other concomitant therapies should be limited to those essential for the non-
CD related care of the patient and should be carefully evaluated by the Investigator and the 
Sponsor should be contacted when there are questions regarding concomitant medications.
All concomitant medications and the reason(s) for use will be documented throughout the 
course of the study.
If the patient requires additional CD therapy or dose increase of concomitant CD
medication(s) to treat the underlying CD due to disease worsening (see Section 3.3.4.1 and 
Section 4.2.2), the study drug must be discontinued and patients treatment should be managed 
according to local standard of care. Such patients should complete early EoT and Visit 9 or 
early EoS visit as described in Sections 6.2.2 and 6.2.3.
Management of Adverse Events:
In case of AEs in need of treatment, symptomatic therapy according to investigator 
judgement will be permitted. All concomitant therapies will be recorded on the appropriate 
pages of the eCRF.
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
Any hypersensitivity reactions should be treated according to medical standards. To be able 
to prospectively define and assess any potential cases of anaphylaxis, the clinical criteria for 
diagnosis of anaphylaxis defined in Section 10.6 are to be considered [R11-4890]
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA [R11-4890] suspected to be caused by ustekinumab, the investigator should 
discontinue treatment with ustekinumab and study drug. Follow instructions for preparation 
and handling of ustekinumab as per current version of SmPC/US PI.
Severe infections, serious infections, opportunistic or tuberculosis infections. 

Treatment of infections should be initiated promptly according to local standard of 
care. No further trial medication should be administered until the active infection has 
resolved. Treatment with study drug may be restarted when the patient has recovered 
according to investigator’s assessment.

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Malignancies

In case of new occurrence of malignant neoplasm, the investigator should discontinue 
treatment with study drug. Diagnostics and treatment have to be initiated according to 
local standard of care. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Tables 4.2.2.1:1 and 4.2.2.1:2 must not 
be taken for the time periods as specified.
If patients receive optional concomitant CD treatment, these need to be on stable doses prior 
to randomisation until Visit 8/week 12, as specified in eligibility criteria (see Section 3.3.2
and Section 3.3.3).
Patients are encouraged to receive COVID-19 vaccination according to local public health 
advice and vaccine availability. If possible, vaccination should be completed 4 weeks prior to 
study screening. The patient may receive (non-live) COVID-19 vaccine(s) during the study, 
however there is no specific data available with regard to vaccine efficacy while receiving BI 
706321 treatment.

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Table 4.2.2.1: 1
Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction
Investigational products not otherwise 
described below
Within 30 days or 5 half-lives (whichever is 
longer) prior to randomisation and until the end 
of the trial
Any biologic approved for CD1 (except 
ustekinumab): adalimumab, infliximab, 
certolizumab pegol, vedolizumab, 
natalizumab (or a biosimilar of these 
drugs)
Not allowed from 4 weeks prior to 
randomisation or from time when no detectable 
drug level was confirmed until end of the trial
For use as a CD treatment medication, refer to 
Section 4.2.1
5-ASA compounds
Rectal 5-ASA compounds are not permitted 
during the study and must have been 
discontinued at least 4 weeks prior to Visit 
2.
Oral 5-ASA compounds must have been at 
a stable dose for at least 4 weeks prior to 
Visit 2, and remain stable at this dose until 
week 12.
If oral 5-ASA compounds were recently
discontinued, they must have been 
discontinued at least 4 weeks prior to Visit 
2.
Immunomodulators
Patients receiving chronic treatment with 
AZA, MP, 6-TG, or MTX prior to Visit 2 
must have been on a stable dose for at least 
8 weeks prior to Visit 2 and must continue 
on this same dose during the study.
Patients who have discontinued therapy with 
AZA, MP, 6-TG, or MTX must have 
stopped the medication at least 8 weeks 
prior to Visit 2 to be considered eligible for 
randomisation.
Patients must not have received therapy 
with other known immunomodulators (e.g., 
cyclosporine, tacrolimus, sirolimus, 
pentoxifylline, or mycophenolate mofetil) 
within 8 weeks or 5 half-lives of agent from 
Visit 2, whichever is longer, and until the 
end of the trial.
Footnotes are provided on the next page
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Table 4.2.2.1: 1
Restrictions regarding previous and concomitant treatment (cont`d)
Medication or class of medications
Restriction
Systemic corticosteroids (e.g., 
prednisone, budesonide)
Parenteral (SC, IM, or IV) or rectal 
corticosteroids are not permitted during the 
study and must not have been used within a 
4-week period prior to Visit 2, and until the 
end of the trial.
Oral corticosteroids must be at a prednisone 
equivalent dose of ≤20 mg/day, or ≤9
mg/day of budesonide, and have been at a 
stable dose for at least 2 weeks prior to Visit 
2, and must remain stable until week 12.
If oral corticosteroids were recently 
discontinued, discontinuation must have 
been completed at least 2 weeks prior to 
Visit 2.
CD specific antibiotics
If using a CD-specific antibiotic for 
treatment of CD, patients must have been 
using the antibiotic for at least 4 weeks 
before Visit 2 at a stable dose and should 
continue this at the same dose until week 12. 
If not currently using a CD specific 
antibiotic, the stop date must have been at 
least 4 weeks prior to Visit 2.
Opioids
Patients with regular daily opioid or 
cannabis use for more than 3 months prior to 
Visit 2 are excluded due to the interference 
of such medications with key efficacy 
endpoints (CDAI)
Any investigational (or subsequently 
approved) or non-approved non-
biologic/biologic for CD (including but 
not limited to IL-23 inhibitors [e.g. 
risankizumab], anti-integrins, JAK 
inhibitors [e.g. upadacitinib], S1P 
modulators)
Prior to the study and for the trial duration up to 
EOS visit
For use as a CD treatment medication, refer 
to Section 4.2.1
1
As of the date of the initial clinical trial protocol (i.e. 26 Apr 2021)
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Tapering of corticosteroids
The tapering of systemic corticosteroids is requested for patients achieving clinical remission 
at or after week 12 (Visit 8) of the study. In such patients steroids must be tapered at a 
maximum rate of prednisone 2.5 mg per week (or equivalent – see Appendix 10.5) to a 
dosage of 0. If a patient experiences a loss of clinical response (increase in CDAI of at least 
100 points from baseline on 2 consecutive visits) during steroid tapering, the dosage of 
prednisone may be increased back to the dosage used at study entry.
Drugs with potential to prolong the QT/QTc interval
Caution is advised with concomitant use of drugs that may increase the exposure of BI 
706321 (e.g. strong CYP3A inhibitors) or have high risk of prolonging the QTc interval (e.g. 
Tricyclic anti-depressants, erythromycin) during the period from 1 week prior to 
randomisation until Visit 9/week 16. If such concomitant use is planned, close ECG 
monitoring by the investigator is advised. A list to support the identification of drugs that 
may increase the exposure of BI 706321 (e.g. strong CYP3A inhibitors) or have a high risk 
for prolonging the QT can be found in the ISF. 
Drug-drug interactions (DDI)
Based on in vitro studies, clinically relevant drug-drug interactions (DDI) with BI 706321 are 
possible. Particularly, based on in vitro data, BI 706321 is metabolized via CYP3A and is 
also a substrate of P-glycoprotein (P-gp). A clinical DDI study to evaluate the effect of 
itraconazole (dual inhibitor of CYP3A and Pgp) on the PK of BI 706321 has been completed
[c35839633]. For details, refer to Section 1.2.1 Drug Interactions.
At the 8 mg dose selected for this trial, in vitro data suggests that DDI potential due to the 
inhibition of P-gp by BI 706321 is possible. Clinically relevant DDIs due to inhibition of all 
other investigated transporters are considered unlikely.
Concomitant medications which are moderate and strong CYP3A inducers and P-gp 
substrates for which an increase in exposure could present a potential patient risk should not 
be co-administered together with BI 706321.
DDI potential of other co-administered CD treatments
The metabolism of 5-ASA compounds, AZA, MP, 6-TG, and MTX is primarily based on 
processes that do not involve cytochrome P450 (CYP) enzymes. None of these compounds 
are known to be P-gp substrates (MP is a substrate of ENT2 and MTX is a substrate of BCRP 
and MRP2). Given that there is no clear clinical evidence showing the modulation of CYP3A 
or P-gp by these compounds, clinically relevant DDIs between these compounds and 
BI 706321 are not expected.
The overall DDI risk with co-administration of corticosteroids is acceptable. Prednisone, 
methylprednisolone, and dexamethasone are weak CYP3A inducers, thus the exposure of 
BI 706321 might be slightly reduced when co-administered. In vitro studies report 21-
desacetyl deflazacort, deflazacort, budesonide, methylprednisolone, and prednisone are P-gp 
substrates. As they are also CYP3A4 substrates, most clinical DDI findings regarding these 
corticosteroids resulted from CYP3A induction or inhibition, although inhibition and 

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induction of P-gp may also have contributed. When corticosteroids are co-administered 
together with BI 706321, the exposure of these corticosteroids might be slightly increased 
due to the inhibition of P-gp by BI 706321, however given the dosage limitations specified in 
the trial inclusion criteria (prednisone equivalent dose of ≤ 20 mg/day or ≤ 9 mg/day of 
budesonide, see Section 3.3.2), and the potential degree of increase (approximately <1.5X 
AUC), this range of interaction is considered acceptable.
Table 4.2.2.1: 2
Restricted concomitant medication and foods1 – from 1 week prior to 
randomisation until Visit 9/week 16 (list of medications is in ISF).
Medications or class of medications
Specified restriction time
Drugs or foods that are strong or moderate CYP3A 
inducers (e.g. phenytoin, carbamazepine, 
phenobarbital, rifampin) 
1 week prior to randomisation 
until Visit 9 / week 16
Drugs that are P-gp substrates for which an increase in 
exposure could present a potential patient risk (e.g., 
dabigatran, digoxin, fexofenadine) 
1
Patients should avoid foods that are known strong or moderate inducers of CYP3A e.g., St. John’s Wort
A list to support the identification of drugs that may have potential DDI interactions with BI 
706321 can be found in the ISF. The list does not contain medications which are used for CD 
therapy (see Table 4.2.2.1:1). The list is not comprehensive. For example, drugs that are 
solely indicated for disease that are excluded in this trial, such as cancer drugs, may not be 
listed. For further guidance investigators are referred to the current IB [c26475781] and/or 
may contact the Sponsor. All other concomitant medications will be recorded in the eCRF up 
to the EoS visit.
4.2.2.2
Restrictions on diet and life style
Blood samples for safety should be taken after patient has fasted for at least 6 hours as 
indicated in the Flow Chart (only Visit 2, 6, 7, 8 and 9). Please also see Section 4.1.4.
After randomisation, participants should avoid foods that are known strong or moderate 
inducers of CYP3A such as St. John’s Wort.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.3) must use one medically approved 
method of birth control from screening through Visit 8, and for a period of at least 28 days
(i.e. until Visit 9) after last trial drug intake.
WOCBP (trial participant) must use a highly effective (non-barrier) method of birth control 
per ICH M3 (R2) that results in a failure rate of less than 1% per year when used consistently 
and correctly if their sexual partner is a man able to father a child.

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

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
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Or: Patients must abstain from male-female sex. This is defined as being in line with 
the preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, 
ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the 
duration of exposure to study drug; and withdrawal are not acceptable.
After Visit 9 the current version of SmPC/US PI for ustekinumab has to be followed. 
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of actually taken 100
Number of tablets which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80-120% site staff will explain to the patient the 
importance of treatment compliance.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Efficacy will be assessed both on investigator (or designee) examinations and assessments
and on Patient Reported Outcomes (PROs).
The endoscopy (ileocolonoscopy) examination provides information on the inflammatory
status of the terminal ileum and colon. Endoscopy examinations will be centrally reviewed
and assessed based on the SES-CD. Mucosal biopsies obtained from the terminal ileum and 
colon will be used for histopathologic examination and exploration of disease and RIPK2 
pathway specific biomarkers.
Clinician’s assessment portion of CDAI assesses the CD disease activity.
PROs include the IBDQ, and the diary portion of the CDAI. The Patient reported outcome-2 
(PRO-2) includes only the two CDAI items stool frequency and abdominal pain and will be 
analyzed retrospectively based on those recorded elements of the CDAI score.
5.1.1
Ileocolonoscopy-related assessments (SES-CD and CDEIS)
The endoscopy (ileocolonoscopy) examination provides information on the inflammatory
status of the terminal ileum and colon. The endoscopic CD activity will be assessed using the 
Simple Endoscopic Score for Crohn’s Disease (SES-CD). The SES-CD is a numerical 
grading system generating a total score (0-56) composed of 4 variables (presence of ulcers, 
ulcerated surface, affected surface, and presence of narrowings), all of which are recorded in 
5 segments: terminal ileum, right colon, transverse colon, left colon, and rectum [R16-0177]. 
The SES-CD calculation details are provided in Appendix 10.3.
The Crohn’s Disease Endoscopic Index of Severity (CDEIS) is a scoring system in which 6 
endoscopic variables (presence of ulcers, superficial ulcers, nonulcerated stenosis, ulcerated 
stenosis, proportion of ulcerated surface, proportion of surface affected by disease) are 
assessed in each of the 5 ileocolonic segments: rectum, sigmoid and left colon, transverse 
colon, right colon, and ileum. CDEIS scores range from 0 to 44 with higher scores indicating 
more severe disease [R97-2645].
The SES-CD and CDEIS will be measured at the timepoints noted in the Flow Chart. 
Ileocolonoscopy videos will be done as described in the Endoscopy Video Instruction Manual 
filed in the ISF and digitally transferred for central review within a pre-specified time period 
and the central review is conducted as outlined in the Central Imaging Vendor Manual.
Central review will be assessed based on both the SES-CD and CDEIS.
Further information can be found in the Vendor Manual.

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The patient has to undergo bowel preparation before each ileocolonoscopy, following the 
local standards.
5.1.2
Crohn’s Disease Activity Index (CDAI)
The clinical changes in CD activity during the trial will be assessed using the Crohn’s 
Disease Activity Index (CDAI) [R15-5253]. The patient will have to complete the CDAI 
symptom score data in a Diary daily. The CDAI will be assessed at the timepoints noted in 
the Flow Chart and it is provided in Appendix 10.5.
5.1.3
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ [R97-3472] is a 32-item self-report questionnaire for patients with IBD to evaluate
the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal
pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance,
need to cancel social events), and emotional function (anger, depression, irritability). Scores
range from 32 to 224 with higher scores indicating better outcomes.
The IBDQ will be measured at the timepoints noted in the Flow Chart. 
The IBDQ has a 2-week recall period.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete and symptomatic physical examination will be performed at the time points 
specified in the Flow Chart. 
A complete physical examination (indicated in the Flow Chart as “full”) includes at a 
minimum general appearance, neck, lungs, cardiovascular system, abdomen, extremities and
skin.
A symptomatic physical examination will be performed at the timepoints specified in the
Flow Chart. It includes an examination which is driven by signs and symptoms reported by 
the patients or identified by the investigator.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
Measurement of height and body weight (including determination of the ideal body weight) 
will be performed at the time points specified in the Flow Chart.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.

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This includes body temperature (only at Visit 1 until Visit 9), systolic and diastolic blood 
pressure and pulse rate (electronically or by palpation count for 1 minute) in a seated position 
after 5 minutes of rest. The results must be included in the source documents available at the 
site.
Body weight and height will be evaluated at the time points specified in the Flow Chart, both 
should be done with shoes and clothes and in the same way throughout the trial.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (see Section 5.2.6.1 and the DILI Checklist provided in the ISF). The amount of 
blood taken from the patient concerned will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor, excluding 
Ustekinumab drug levels and anti-drug antibody levels (for all visits) and for the screening 
visit: Enteric pathogens, Previously used biologic treatment, Infection testing .

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Table 5.2.3: 1 
Laboratory tests
Functional lab group
Test name
Only
Screening
V 2, 
V4 –
V 9*
Only 
V3
V10 
-
V13
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count/Thrombocytes (quant)
X
X
X
Reticulocytes (relative and absolute)
X
X
Automatic WBC 
differential
(relative and 
absolute)
Neutrophils, eosinophils, basophils,
monocytes, lymphocytes
X
X
X
Manual differential 
WBC (if
Automatic differential 
WBC is abnormal
and clinically relevant 
in the opinion of the 
investigator), relative 
and absolute
Polymorphonuclear neutrophils (segs),
band neutrophils (stabs), eosinophils,
basophils, monocytes, lymphocytes
X
X
X
Coagulation
Activated Partial Thromboplastin Time 
(aPTT)
Prothrombin time (INR)
Fibrinogen
X
X
Enzymes
AST (GOT), SGOT 
ALT (GPT), SGPT
Alkaline phosphatase (AP)
X
X
X
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Amylase
X
X

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Table 5.2.3: 1
Laboratory tests (cont`d)
Functional lab group
Test name
Only
Screening
V 2, 
V4 –
V 9*
Only 
V3
V10 
-
V13
Substrates
Glucose
BUN (blood urea nitrogen)
Creatinine
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Protein, total
Serum albumin
X
X
X
Uric acid
Haptoglobin
Ferritin
Troponin
X
X
Cholesterol, total
HDL cholesterol
LDL cholesterol
Triglycerides
Only 
V2, 
V6, 
V7, 
V8, 
V9
eGFR (estimated by CKD-EPI formula) 
X
C-Reactive Protein (CRP, high sensitivity)
X
X
X
X
Substrates
Serum Amyloid A (SAA)
X
X
X
Electrolytes
Sodium
Potassium
Calcium
Chloride
Bicarbonate
X
X
X
Hormone panel 
(males only); 
Testicular function panel: FSH (follicle 
stimulating hormone), LH (luteinizing 
hormone), total testosterone, free testosterone 
X
Only 
V6, 
V7, 
V8
Urine Macro and 
Micro Panel
Color & Clarity
Specific Gravity
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Nitrite
Leukocyte Esterase
X
X

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Table 5.2.3: 1
Laboratory tests (cont`d)
Functional lab 
group
Test name
Only 
Screening
V 2, V4 – V 9*
Only 
V3
V10 
-
V13
Urine 
Pregnancy test 
(only for 
WOCBP)
Human Chorionic Gonadotropin in the 
urine
X
X
Serum 
Pregnancy test 
(only for 
WOCBP) at 
screening or if 
urine 
pregnancy test 
is positive
Human Serum Chorionic Gonadotropin
X
X
Fecal studies
Enteric pathogens:
Salmonella
Shigella
Yersinia
Campylobacter
Vibrio
E. coli O157/H7
Clostridia difficile toxin (toxin A/B and 
GDH antigen), if results indeterminate, 
a reflex PCR test will be done; Enteric 
parasites and their ova (including 
Cryptosporidia)
X
As part of the “Faecal sampling for 
Biomarkers”

Fecal calprotectin

Fecal lactoferrin
X
Only V2, V6, V7, 
V8 and V9
X
Ustekinumab 
drug levels and 
anti-drug 
antibody levels 
(only as per 
flowsheet)
Serum ustekinumab concentration
Antibodies to ustekinumab 
Only V2, V6, V7 
and V8
Only 
V10 
and 
V13
Previously 
used biologic 
treatment
adalimumab, infliximab, golimumab, 
certolizumab pegol, vedolizumab
(only if patients previously treated with 
and < 4 weeks since last dose)
X
Hormones
Thyroid stimulating hormone (TSH)
(free T3 and T4, reflex in case of 
abnormal TSH )
X

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Table 5.2.3: 1
Laboratory tests (cont`d)
Functional lab group
Test name
Only 
Screening
V 2, 
V4 –
V 9*
Only 
V3
V10 
-
V13
Infection testing
Hepatitis B Surface antigen (qualitative)
Hepatitis B Core antibody (qualitative)
Hepatitis B-DNA (reflex in case of positive 
HBV Core Antibody and negative HBV 
Surface Antigen)
Hepatitis C antibody (qualitative)
Hepatitis C Virus RNA PCR (reflex in case of 
positive HCV antibody and treated HCV 
infection)
HIV-1 and HIV-2 antibody (qualitative)
QuantiFERON®-TB*
COVID-19 (can be repeated during the trial 
in the case of a suspected SARS-COV2 
infection)
*There is the trial site option to perform a TST 
(PPD skin test). If the first Quantiferon®-TB-
Gold Plus test result is indeterminate, a re-test 
should be performed. If the Quantiferon®-TB-
Gold Plus re-test is indeterminate, a PPD skin 
test should be performed.
X
* Not Visit 8A, 8B, 8C
5.2.4
Electrocardiogram
Twelve-lead resting triplicate ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded
using a computerised electrocardiograph at the time points given in the Flow Chart.
Precise 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). ECGs may be repeated for quality reasons and the repeated recording used
for analysis.
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 patients are at
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in
one position. 
ECG recording will always precede all other study procedures scheduled for the
same time to avoid compromising ECG quality. At Visit 2 an additional assessment after the 
intake of the trial medication should be done before the 3-hours PK blood sample is taken
(i.e. 3 hours PK postdose sample). At Visit 6 and Visit 8 an additional assessment after the 

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intake of the trial medication should be done before the 6-hours PK blood sample is taken 
(i.e. 6 hours PK postdose sample).
If necessary, additional ECGs may be recorded for safety reasons. These unscheduled ECGs 
will also be centrally read and assigned to “UNSCHED/Unscheduled”-time point in the 
Sponsor’s database. UNSCHED locally read ECGs will not be captured in the eCRF, only as 
AE, if any.
The digital ECG recordings will be transmitted to a vendor for central evaluation. The
evaluation will be performed during the study and/or after the study but will not influence the
treatment of the patient. All ECGs will be stored electronically in the system of the vendor. In
case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded.
UNSCHED ECGs (for safety reasons) will be transferred to the central ECG lab but will not
be included into the statistical analysis of interval lengths. Data transfer from the central ECG
lab to the sponsor is described in a document that is filed in the Trial Master File (TMF).
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements
[R07-4722, R16-0366] as well as the Food and Drug Administration (FDA) requirements for
annotated digital ECGs [R09-4830].
In addition, all ECGs will be evaluated by the investigator or a designee. Clinically relevant
abnormal findings (the investigator is instructed to give special attention to the QT values)
will be reported either as baseline condition (if identified at the Visit 1A) or otherwise
as AEs and will be followed up and/or treated as medically appropriate.
5.2.5
Other safety parameters
5.2.5.1
Patient Diary
The diary will be given to the patient at Visit 1. Patients are asked to complete the diary on a 
daily basis which will cover the trial medication intake (time and with/without food, i.e. from 
Visit 2 to Visit 8) and the CDAI score. 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.

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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 exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity, 

is a congenital anomaly / birth defect,

is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement 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.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 

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Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters:: 

An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood sample, or in samples drawn within 30 days of each 
other, or

ALT and / or AST elevations ≥10-fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is / are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, 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 trial 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).

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
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 trial 
drug concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial 
(= the End of Study (EoS) visit): 
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and trial drug related SAEs and trial drug related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form 
(see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the CRO’s unique entry point within 24 hours 
of becoming aware of the event, the country specific process will be specified in the ISF. The 
same timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the Contract Research Organisation (CRO) or Sponsor upfront via 
telephone. This does not replace the requirement to complete 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. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient 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 CRO’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the CRO’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE 
form is to be completed. If there is an SAE and / or AESI associated with the pregnancy an 
SAE form must be completed in addition.

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5.5
BIOBANKING
Blood samples (10 ml) and stool samples (1-5 g) will be collected at timepoints indicated in 
the Flow Chart for the analysis of biomarkers.
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
5.6
OTHER ASSESSMENTS
N/A
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements conducted for primary and secondary endpoints are using standard
methods. 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

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pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used
assessments of drug exposure. The biomarkers and pharmacodynamic parameters and
measurements outlined in Section 5.4 are of exploratory nature.

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6.
INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, Sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, and home healthcare nurse visits. Such alternative measures will be mentioned 
in the patient information.
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart.
Each visit date (with its window) is to be counted from Day 1 (i.e. Visit 2, the randomisation
visit). If any visit has to be rescheduled, subsequent visits should follow the original visit date
schedule. Unscheduled visits may be included as deemed necessary by the investigator.
Patients will get a patient diary for documentation of trial medication intake and 
documentation of parameter for the CDAI scoring. 
If a patient 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.
Depending on the reason, rescreening is allowed up to two times (ref. to Flow Chart and 
Section 3.3 for more information). If a rescreening will be performed the ileo-colonoscopy 
will need to be repeated if the time between the original screening ileocolonoscopy and 
randomisation is > 6 weeks. If the reason for the screen failure was an enteric infection 
(including SARS-CoV-2 infections, only if GI symptoms were present due to the SARS-
CoV-2 infection) the ileo-colonoscopy must be repeated.
If at screening, PCR test for SARS-CoV-2 is positive and patient is asymptomatic, re-test 
SARS-COV-2 PCR test is allowed (up to 4 times) to confirm patient's eligibility before ileo-
colonoscopy and/or Visit 2. If re-test SARS-COV-2 PCR test is negative, patient must meet 
all other eligibility criteria according to the CTP before patient is randomized at Visit 2. 
Already performed screening assessment do not need to be repeated.
On visit days (i.e. Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8), the trial medication 
has to be taken in the morning at the trial site.
In situations where an individual patient is unable to attend a clinic visit (because e.g. of force 
majeure or other disrupting circumstances such as pandemic, war) the investigator must 
assess the risk-benefit for the individual patient and may decide to perform a visit remotely or
home visit if this is in the best interest of the patient and if agreed with the Sponsor. The 
visits when the ileocolonoscopy is performed can only be done at the clinical site.

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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Screening Period
All patients must sign an Informed Consent consistent with ICH GCP guidelines prior to any
study specific procedures; this includes the option that the patient signs the Informed Consent
during an extra contact to the study site prior to the actual screening visit. The patient should
be recorded on the enrolment log as a screened patient when Visit 1 is performed.
Screening period could be extenended for additional 21 days, if this is required due to 
logistical reasons (e.g. delay in lab assessment) and approved by sponsor.
Run-in Period
N/A.
Baseline Conditions
Any pre-existing medical conditions considered as relevant by the investigator, excluding the
indication of the trial, are to be recorded into the eCRF in the appropriate page. Any 
abnormal clinically significant findings observed at Visit 1 need to be documented as
Baseline Conditions.
Medical History:
All relevant medical history according to the investigator judgment will be captured in the
eCRF.
6.2.2
Treatment period(s)
On Visit 2 the first intake of the trial medication will be done under direct supervision of the 
investigator or 
designee. Induction treatment period includes visits until Visit 8, when the 
last intake of BI 706321 or placebo occurs. 
Details on administration of study treatment are described in Section 4.1.4. The treatment 
with ustekinumab will start together with trial medication treatment.
If a patient permanently discontinues BI 706321/placebo and/or ustekinumab treatment 
before completing 10 weeks of treatment in the induction treatment period, an early EoT visit 
is required within 14 days after the last BI 706321/placebo dose. This early EoT visit will 
include the same procedures as a normal EoT visit (i.e. Visit 8), except there will be no 
endoscopic assessment if <6 weeks of trial treatment is received. Assessment of CDAI does
not need to be repeated if early EoT is done within 7 days after a previous visit. For early 
completion of the trial after the early EoT visit, patients should undergo only Visit 9 (and not 
EoS visit).
If a patient discontinues BI 706321/placebo trial treatment after completing 10 weeks of 
treatment of the induction treatment period (early EoT visit has to be performed) and if it is 
medically appropriate to continue treatment with ustekinumab, the patient may remain in the 
trial and follow the visit schedule and perform EoS visit as planned. If patients discontinue 

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after completing 10 weeks of treatment, the endoscopic assessment should be performed at 12 
weeks after randomisation.
Assessments have to be performed as per the Flow Chart.
6.2.3
Follow-up period and trial completion

In this trial the follow-up period starts with Visit 8A. Throughout the follow-up period 
the patient will receive ustekinumab. The last administration of ustekinumab in the 
trial is V12.

If the decision is made for a patient to permanently discontinue ustekinumab 
treatment early but between Visit 8 and Visit 9, Visit 9 should be performed as the 
last trial visit at least 16 days after the last BI 706321/placebo dose.

If a patient permanently discontinues ustekinumab treatment early during the follow-
up period but after Visit 9, an early EoS visit is required within 14 days after the 
decision had been made to discontinue ustekinumab treatment. If early 
discontinuation occurs after week 24 or beyond, the ileo-colonoscopy assessment of 
the EoS visit should be performed.

For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be 
recorded in the eCRF. These data will be included in the trial database and reported. 

At visit EoS the investigator will decide on the further treatment of CD, which is not 
in the scope of this clinical trial.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
This is a Phase IIa, randomised, double-blind, placebo-controlled study to investigate a first 
signal of efficacy, safety and tolerability of BI 706321 in combination with ustekinumab 
treatment in patients with moderately to severely active CD. This is an exploratory trial. No 
confirmatory testing is performed and hence no null and alternative hypotheses are defined. A 
justification of the sample size is provided in Section 7.5.
7.2
PLANNED ANALYSES
The primary analyses will be conducted after the last patient completes the (e)EOT visit and
will be based on the intent-to-treat (ITT) principle, comprising all participants who were 
randomised and received at least one dose of assigned therapy during the trial.
Safety analyses will be based on actual treatment received.
7.2.1
General considerations
Patient analysis sets:

Randomised set (RS): all randomised patients, treated or not.

Treated set (TS): all patients who received at least one dose of trial medication.
Treatment assignment will be as treated.

Full analysis set (FAS): all patients in the RS who received at least 1 dose of trial 
medication and have analysable post-baseline data (observed or imputed) in at least 
one efficacy parameter. Treatment assignment will be as randomised.
The FAS will be used for all efficacy endpoints. The TS will be used in all safety evaluations. 
The efficacy analyses will follow the ITT principle in assigning patients to treatment groups, 
therefore, efficacy analyses will be analysed as randomised using the FAS. Safety analysis 
will be performed on randomised patients who received at least one dose of trial medication 
and will be based on the actual treatment received. The FAS and other patient analysis sets 
will be fully specified in the TSAP. Additional patient analyses sets not listed above may be 
defined with details also included in the TSAP.
Handling of Intercurrent Events
The intercurrent events that defined in this trial are discontinuation of BI 706321 during the 
first 12 weeks.
Strategies for handling of intercurrent events may include:

Treatment Policy: Intercurrent events are not considered relevant. This strategy is in 
line with an ITT approach.

Composite: Individuals who experience an intercurrent event will be considered as 
treatment failure.

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All intercurrent events involving early treatment discontinuation as well as other additional
unexpected events will be reviewed during the conduct of the trial. Handling of these as well 
as other potential strategies will be documented in the TSAP.
7.2.2
Primary endpoint analyses
The FAS will be used for the analysis of the primary endpoint. The primary analysis is a 
restricted maximum likelihood (REML) based analysis of covariance (ANCOVA) comparing 
the absolute change from baseline in SES-CD scores at Week 12. Baseline will be the based 
on screening endoscopic assessment (See Flow Chart). For the ANCOVA model, absolute 
change in SES-CD score will be the dependent variable, treatment group and baseline 
corticosteroid use (yes/no) will be fixed effects and baseline SES-CD score will be
continuous covariate. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom and adjust standard errors. Adjusted means for each group 
and mean difference between treatment groups will be presented along with confidence 
intervals (95%).
In line with the treatment policy approach all patients with post-baseline endoscopic 
assessments will be included in the analysis regardless of the occurrence of intercurrent 
events. Since there is only one planned post baseline endoscopic assessment at Week 12, 
patients without a post baseline assessment will be excluded from the primary analysis.
To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of baseline corticosteroid use, the same ANCOVA model will be fitted, but also including the 
treatment by baseline corticosteroid use interaction. A descriptive p-value of treatment effect 
homogeneity will be calculated. No overall treatment effect will be estimated from this model 
as it is not interpretable.
Sensitivity analyses
Depending on the timing of intercurrent events and consequences they may have on the 
timing of the post-baseline endoscopic assessment, specific rules for handling of missing data 
or data collected prior to Week 12 may be implemented for additional analysis of changes in 
SES-CD.
Descriptive tabulations and figures for SES-CD scores and changes at each visit (baseline, 
Week 12, Week 48) with the change from baseline will be produced.
Additional details of these analyses will be included in the TSAP. 
7.2.3
Secondary endpoint analyses
Percent change from baseline to Week 12 in SES-CD score will be analysed in the same 
manner as the primary endpoint.
Unadjusted absolute rate difference between treatment groups will be calculated simply as the 
difference in the observed proportion of patients who achieve binary response and remission 

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endpoints. The influence of stratification factors (baseline corticosteroid use or other potential 
prognostic factors) and/or baseline SES-CD will also be explored. These analyses will be 
specified in the TSAP.
Consistent with a composite strategy for handling of interrcurrent events and potential 
missing data, Non Response Imputation (NRI) will be applied to clinical and endoscopic
response and remission endpoints, that is imputing as failure to achieve a response.
Further details will be given in the TSAP.
7.2.5
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. All AEs with an onset between 
start of BI 706321/placebo + ustekinumab and end of the REP, a period of 16 days after the 
last dose of trial medication (BI 706321/placebo), will be assigned to the Induction period for 
evaluation. Additionally, AEs with an onset between start of BI 706321/placebo + 
ustekinumab and (e)EOS will be assigned to the Induction + Follow-up period. AEs with 
onset before the first intake of any trial medication will be assigned to the Screening period. 
All treated patients (i.e. the TS) will be included in the safety analysis. In general, safety 
analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring only during the Induction period or the 
Induction+Follow-up period as defined above will be considered ‘treatment-emergent’ during 
the respective period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA
at database lock. Summaries will be presented by treatment for all AEs and the defined 
AESIs.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 

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reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examination findings, or other safety-relevant data observed at 
screening, baseline, during the course of the trial and at the end-of-trial evaluation will be 
assessed with regard to possible changes compared to findings before start of treatment.
Summaries of EEG data will be specified in the TSAP.

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7.2.7
Interim Analyses

An interim analysis is planned after approximately 20 patients have been randomised 
into the study to assess baseline biomarkers associated with the RIPK2 pathway. This 
assessment of the RIPK2 pathway-specific biomarkers may lead to an increase in the 
final sample size to improve the sensitivity of exploring the relationship between 
RIPK2 pathway-specific biomarkers and endoscopic responses among the treatment 
groups following 12 weeks of treatment. This potential sample size increase may be 
up to 26 additional patients.

Additional unblinded assessments (i.e. unblinded descriptive analyses) of secondary 
and further endpoints as data are collected may also be performed in order to assess
the RIPK2 efficacy and enable the review of safety data. Further details and time 
points for analysis will be specified in a separate operational plan. 
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will
still occur and approaches to handle this are proposed below for the induction period.
With respect to safety evaluations, it is not planned to impute missing values.
Details on deriving the CDAI total score and its components in case of missing data will be 
included in the TSAP
Depending on the nature and timing of intercurrent events and the collection of the post-
baseline endoscopic assessment during the first 12 weeks, rules for handling of these SES-CD 

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assessments as they relate to the change from baseline at week 12 may be considered for 
sensitivity analyses. Additional details will be documented in the TSAP.
Generally, with regards to handling of missing data on the binary secondary endpoints the
NRI will be applied, that is imputing as a failure to achieve a response after 12 Weeks.
For binary endpoints that are collected at multiple visits, if there are data at visits both before 
and after the visit with a missing outcome, then impute as success only if both neighbouring 
visits also represent a success, otherwise impute as failure.
Other imputation approaches may be considered for the primary and secondary endpoints.
These approaches along with rules for handling of missing data for further endpoints will be 
specified in the TSAP.
The handling of missing data for the population PK analysis will be described in a separate 
Population PK Analysis Plan.
7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
An IRT system will be used for the assignment of patients to treatment groups. Patients will 
be randomised (1:1) to the either BI 706320 + ustekinumab or Placebo + ustekinumab for 12 
weeks.
Randomisation will be stratified based on baseline corticosteroid use (yes/no). 
7.5
DETERMINATION OF SAMPLE SIZE
This is an exploratory trial and is planned to include 50 patients to investigate efficacy and 
tolerability and safety of BI 706321 in combination with ustekinumab treatment in patients 
with moderately to severely active CD. The sample size is chosen with the objective to 
primarily have low error probabilities to:

observe a positive outcome given that ustekinumab + BI 706321 is not more effective 
compared to ustekinumab + placebo

observe a negative outcome given that ustekinumab + BI 706321 is more effective 
than ustekinumab + placebo
Table 7.5:1 below show the criteria considered for treatment effects and observed outcomes 
that would be considered positive and negative.

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Probabilities were calculated from simulations under the assumptions that changes in SES-
CD scores are normally distributed with a common standard deviation of 7.0 for each group.
Under these assumptions and conditions, the probability of observing an improvement of ≥ 2 
points in SES-CD given ustekinumab+BI 706321 is not more effective compared to 
ustekinumab+placebo is 16.0% and the probability of observing an insufficient level of 
improvement in SES-CD of <0.5 given that ustekinumab+BI 706321 is more effective in 
SES-CD by 2.5 points than ustekinumab+placebo is 15.3%.
Table 7.5: 1 Criteria considered for treatment effect, positive/negative outcome and error 
probabilities for N=25 per group
Assumed true treatment effect
Observed outcome
Error probability*
Combination treatment is 
insufficiently effective (no 
difference between groups)
Positive: Observe an 
improvement of ≥ 2 points in 
SES-CD score between groups 
under the assumption that the 
combination treatment effect is 
insufficient.
Observe a positive outcome with 
an ineffective treatment(i.e. false 
positive)
16.0%
Combination treatment is 
sufficiently effective
(combination therapy is better 
with an improvement of 2.5 
points in SES-CD score)
Negative: Observe insufficient
improvement (Δ<0.5) in SES-
CD between groups under the 
assumption that the 
combination treatment effect is 
sufficient
Observe a negative outcome 
with an effective treatment (i.e. 
false negative)
15.3%
*Calculated from 10,000 simulations for two groups with N=25/group and assuming a normal distribution for change in 
SES-CD score and standard deviation of 7.0 in each group. SAS version 9.4 was used for simulations.
Using the same assumptions of true insufficient and sufficient effect, the probability for 
observing a negative outcome (difference < 0.5) if combination treatment is ineffective is 
59.7% and the probability of observing positive outcome (difference of ≥ 2) if combination 
treatment is effective is 60.3%. This leaves about 24% uncertainty where the observed 
outcome is neither positive nor negative (i.e. between 0.5 and 2.0) under each assumed true 
effect. In this case, the evaluation of expression in RIPK2 pathway genes will be needed to
assess whether the combination treatment may be effective or not.
Assessing the proportion of patients with elevated expression in RIPK2 pathway genes at the 
interim analysis will inform on the potential need to increase the sample size up to a 
maximum of 76.

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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 directive 
2001/20/EC / EU regulation - 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to
protect the trial patients 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. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT 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 according to national and international regulations. The same 
applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative [applies to all countries except 
Germany]) 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 patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient
information must be given to each patient or the patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient 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 

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(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. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan 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 patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source files (ECG, endoscopy) will be provided to vendor (central reading, 
imaging). Before sending or uploading those copies, the investigator must ensure that all 
patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.

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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient
was informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if 
available))

Serious adverse events (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)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient 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 patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.
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 CRA, 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.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6), site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely, based on a documented risk 
assessment and in alignment with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).

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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 PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation (WHO) GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’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
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).

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The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial medication treatment (as 
scheduled per protocol or prematurely). Individual investigators will be notified of SUSARs 
occurring with the trial medication until 30 days after LPLT at their site. Early termination 
of the trial is defined as the premature termination of the trial due to any reason before the 
end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data 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).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to a CRO`s web portal to access documents provided by 
the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required 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 Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by a CRO with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.

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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.
A central laboratory service, a central images service, an electronic Patient Reported 
Outcome (ePRO) service and an IRT vendor will be used in this trial. Details will be 
provided in the respective Manual, available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P21-04028
Novak G, Parker CE, Pai RK, et al. Histologic scoring indices for 
evaluation of disease activity in Crohn’s disease. Cochrane Database of 
Systematic Reviews 2017;7:1-55.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) 2005.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide. 2005.
R11-4890
Sampson HA, et al. Second symposium on the definition and management 
of anaphylaxis: summary report - second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol. 2006;117(2):391-397.
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R15-5253
Khanna R, Zou G, D'Haens G, et.al. A retrospective analysis: the 
development of patient reported outcome measures for the assessment of 
Crohn's disease activity. Aliment Pharmacol Ther. 2015;41:77-86.
R16-0177
Khanna R, Bouguen G, Feagan BG, et.al. A systematic review of 
measurement of endoscopic disease activity and mucosal healing in Crohn's 
disease: recommendations for clinical trial design. Inflamm Bowel Dis. 
2014;20(10):1850-1861.
R16-0366
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
R16-4652
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a 
histological index for UC. Gut 2015;66:50-58.
R18-2865
Gater A, Kitchen H, Heron L, et al. Development of a conceptual model 
evaluating the humanistic and economic burden of Crohn's disease: 
implications for patient-reported outcomes measurement and economic 
evaluation. Expert Rev. Pharmacoeconomics Outcomes Res. 
2015;15(4):643-656.
R97-2645
Mary JY, Modigliani R. Development and validation of an endoscopic 
index of the severity for Crohn's disease: a prospective multicentre study. 
Gut 1989;30:983-989.
R97-3472
Irvine EJ, Feagan B, Rochon J, et al et.al. Quality of life: A valid and 
reliable measure of therapeutic efficacy in the treatment of inflammatory 
bowel disease. Gastroenterology 1996;106:287-296.
R21-1348
Danese S, Vermeire S, D'Haens G, et al. Clinical and endoscopic response 
to ustekinumab in Crohn's disease: week 16 interim analysis of the 
STARDUST trial. J Crohns Colitis 2020;14:49-52.

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9.2
UNPUBLISHED REFERENCES
c26475781
BI 706321 Investigator’s Brochure. Current version.
c34844753
TMCP List of Analyses for BI 706321
c35839633
BI 706321 Clinical Trial Report 1425-0010

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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Table 10.1: 1
Time schedule for PK blood sampling
Visit
Week 
Day
Timepoint
Planned 
Time*
PK 
Sample
Sampling
Window
2
0
1
Predose
-1:00
X
60 to 5 minutes 
before start of
dosing
1 hour 
postdose
1:00
X
0:30 h – 1:30 h 
postdose
3 hours 
postdose***
3:00
X
2:30 h – 3:30 h 
postdose
6 hours 
postdose**
6:00
X
5:00 h – 7:00 h 
postdose or at next 
day in the morning
3
1
4
Predose
71:00
X
60 to 5 minutes 
before start of
dosing
4
1
8
Predose
167:00
X
60 to 5 minutes 
before start of
dosing
5
2
15
Predose
335:00
X
60 to 5 minutes 
before start of
dosing
6
4
29
Predose
671:00
X
60 to 5 minutes 
before start of
dosing
1 hour 
postdose
673:00
X
0:30 h – 1:30 h 
postdose
3 hours 
postdose
675:00
X
2:30 h – 3:30 h 
postdose
6 hours 
postdose***
678:00
X
5:00 h – 7:00 h 
postdose
7
8
57
Predose
1343:00
X
60 to 5 minutes 
before start of
dosing

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Table 10.1: 1
Time schedule for PK blood sampling (cont`d)
Visit
Week 
Day
Timepoint
Planned 
Time*
PK 
Sample
Sampling
Window
8 (EOT†)
12
85
Predose
2015:00
X
60 to 5 minutes 
before start of
dosing
1 hour 
postdose
2017:00
X
0:30 h – 1:30 h 
postdose
3 hours 
postdose
2019:00
X
2:30 h – 3:30 h 
postdose
6 hours 
postdose***
2022:00
X
5:00 h – 7:00 h 
postdose
8A
12
86
24 hours 
postdose
2040:00
X
24:00 h – 48:00 h 
postdose
8B
12
89
96 hours 
postdose
2112:00
X
96:00 – 120:00 h 
postdose
8C
12
91
144 hours 
postdose
2160:00
X
144:00 h – 156:00 h 
postdose
*The PK analysis for this study will use a population PK approach. Therefore, samples do not have to be taken precisely at 
the Planned Time. Instead they must be taken at any time during the Sampling Window that corresponds to the Planned 
Time in this table. However, it is essential that the exact sample date and time, as well as the date and time of the 
dose before the PK sample is taken are recorded.
**This sample can also be taken as late as approximately 24 h after first dosing at the next day to allow flexibility. Such a 
visit has to be captured as UNSCHED visit.
***an ECG assessment has to be performed before blood sample is taken.
† If a patient terminates the study before Visit 8, the early EoT visit needs to be scheduled within 14 days after the last dose. 
If the early EoT visit is scheduled within 3 days after the last dose, 4 PK samples will be collected at timepoints 
relative to the regular dosing time during the early EoT visit. If the early EoT visit is scheduled more than 3 days after 
the last dose, 1 PK sample will be collected at regular dosing time during the early EoT visit. It is essential that the 
exact sample date and time, as well as the date and time of the last IMP intake are recorded.

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10.3
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE (SES-CD)
Table 10.3: 1
SES-CD Score
Variable
SES CD score
0
1
2
3
Size of ulcers
None
Aphthous ulcers
Large ulcers
Very large 
ulcers
(W0.1-≤0.5 cm)
(W>0.5- ≤2 
cm)
(>W2 cm)
Extent of ulcerated 
surface
None
<10%
10-30%
>30%
Extent of affected 
surface
Unaffected 
segment
<50%
50-75%
>75%
Presence and type of 
narrowings
None
Single, can be 
passed
Multiple, can 
be passed
Cannot be 
passed
Score 0 - 3
Ileum
Right 
colon
Transverse 
colon
Left 
colon
Rectum
SUM
Size of ulcers
+
Extent of ulcerated 
surface
+
Extent of affected 
surface
+
Presence and type of 
narrowings
=
Sum of all 
variables Total

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10.4
CROHN’S DISEASE ACTIVITY INDEX (CDAI)
The Crohn’s Disease Activity Index (CDAI) is comprised of eight variables which are 
summed after adjustment with a weighting factor.
Table 10.4: 1
Activity score for Crohn’s Disease
Variable
Weighting Factor
Sum of daily number of liquid or very soft stools in the last 7 days
x 2
Abdominal pain: Sum of daily rating in the last 7 days
(0=none, 1=mild, 2=moderate, 3=severe)
x 5
General well-being: Sum of daily rating in the last 7 days
(0=generally well, 1=slightly under par, 2=poor, 3=very poor,
4=terrible)
x 7
Extra-intestinal manifestations, Current
- Arthritis/arthralgia
- Iritis/uveitis
- Erythema nodosum, pyoderma gangrenosum, aphthous stomatitis
- Anal fissure, fistula, or abscess
- Other bowel-related fistulae
- Fever over 37.8°C (100°F) during past 7 days
x 20
Taking medication for diarrhea in the last 7 days
x 30
Abdominal mass 
(0=no, 2=Questionable, 5=Definite)
x 10
Local Hematocrit (difference standard - current, in % rounded to 
whole)
47% if male
42% if female
x 6
Body weight: Deviation from ideal body weight in %
x 1

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10.5
EQUIVALENT DOSES OF CORTICOSTEROIDS
Table 10.5: 1
Equivalent doses of Corticosteroids
Drug
Equivalent dose (mg)
Conversion factor
Prednisone
5.00
X 1.00
Prednisolone
5.00
X 1.00
Triamcinolone
4.00
X 1.25
6-Methylprednisolone
4.00
X 1.25
Dexamethasone
1.00
X 5.00
Betamethasone
0.75
X 6.70
16-Methylprednisolone
6.00
X 0.80
Fluocortalon
5.00
X 1.00
Cloprednol
3.75 – 5.00
X 1.00 – 1.50
Deflazacort
6.00
X 0.80
Cortisol (hydrocortisone)
20.0
X 0.25
Cortisone
25.0
X 0.20
10.6
CLINICAL CRITERIA FOR DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]:
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongueuvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced
PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)

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2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lipstongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 
+[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.
10.7
DEFINITION OF PRIMARY, SECONDARY NONRESPONSE OR 
INTOLERANCE TO ANTI-TNF THERAPY
The criteria for primary non-response (inadequate initial response), secondary non response
(response followed by loss of response), or intolerance to TNF antagonists are described 
below.
10.7.1
Primary non-response (inadequate initial response) to TNF antagonists
Eligible patients must satisfy criteria A, B, and C.
A. Have received induction doses of:

Infliximab (2 or 3 doses of ≥ 5 mg/kg) or

Adalimumab (at a dose of 160 mg followed by a dose ≥ 80 mg or at a dose of 80 mg 
followed by a dose ≥ 40 mg or

Certolizumab pegol (2 or 3 doses of ≥ 400 mg)
AND
B. Did not initially respond to these induction doses of infliximab, adalimumab, or 
certolizumab pegol as evidenced by the presence of at least 1 of the following signs or 
symptoms related to persistence of Crohn’s Disease, as assessed by a treating physician:

Lack of improvement or worsening in stool frequency.

Lack of improvement or worsening in daily abdominal pain.

Occurrence, lack of improvement, or worsening of fever thought to be related to 
Crohn’s Disease.

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
Recurring drainage from a previously nondraining fistula or development of a new 
draining fistula.

Lack of improvement or worsening in rectal bleeding.

Initiation or increase in antidiarrheal medication.
These signs and symptoms of Crohn’s Disease must have occurred ≥ 2 weeks after receiving
the last induction dose of infliximab, adalimumab or certolizumab pegol and are offered only 
as a benchmark of the minimally acceptable criteria required to designate a patient as having 
had an inadequate initial response to infliximab, adalimumab or certolizumab pegol therapy. 
This benchmark acknowledges that the CDAI is not routinely recorded in clinical practice.
AND
C. Have documentation available to the investigator that meets the following 2
requirements:

Provide the dates and doses of the failed infliximab, adalimumab or certolizumab 
pegol induction therapy. 

Documents that the patient had persistence of disease activity following infliximab, 
adalimumab, or certolizumab pegol therapy.

Examples of acceptable documents include: medical records, letter provided by a 
referring physician, or other “reason for referral” documents (e.g., insurance 
authorization form).
10.7.2
Secondary non response (response followed by loss of response) to TNF 
antagonists
Eligible patients must satisfy criteria A, B, C, and D.
A. Initially responded to induction therapy
AND
B. Have received at least 2 maintenance doses of:

Infliximab (at a dose of ≥ 5 mg/kg) or

Adalimumab (at a dose of ≥ 40 mg) or

Certolizumab pegol (at a dose of ≥ 400 mg)
AND
C. Have or had at least 1 of the following signs or symptoms related to recurrence of Crohn’s 
Disease, as assessed by a treating physician:

Worsening in stool frequency.

Worsening in daily abdominal pain.

Occurrence or worsening in fever thought to be related to Crohn’s Disease.

Recurring drainage from a previously nondraining fistula or development of a new 
draining fistula.

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
Worsening in rectal bleeding.

Initiation or increase in antidiarrheal medication.
These signs and symptoms of Crohn’s Disease must have occurred ≥ 2 weeks after receiving
the last maintenance dose of infliximab, adalimumab, or certolizumab pegol and are offered
only as a benchmark of the minimally acceptable criteria required to designate a patient as 
having lost response to infliximab, adalimumab, or certolizumab pegol therapy. This
benchmark acknowledges that the CDAI is not routinely recorded in clinical practice.
AND
D. Have documentation available to the investigator that meets the following 2
requirements:

Provide the dates and doses of the failed infliximab, adalimumab, or certolizumab 
pegol maintenance therapy.

Documents that the patient had recurrence of disease activity despite infliximab, 
adalimumab, or certolizumab pegol therapy.
Examples of acceptable documents include: medical records, letter provided by a referring
physician, or other “reason for referral” documents (e.g., insurance authorization form).
10.7.3
Intolerance to TNF antagonists
Eligible patients must satisfy criteria A and B.
A. Have had an adverse reaction that meets 1 of the following 3 criteria:
1. Significant acute infusion/administration reaction;
2. Significant delayed infusion/administration reaction (for example, delayed 
hypersensitivity or serum-sickness like reaction);
3. Significant injection site reaction.
Definitions of these 3 criteria are provided below. Adverse reactions also must have
followed ≥ 1 dose of infliximab, adalimumab, or certolizumab pegol and, in the treating
physician’s opinion, precluded continued use of the therapy.

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A significant acute infusion/administration reaction is defined as an adverse
reaction that was:

Manifested through ≥ 1 of the following symptoms.
i. Fever greater than 100°F (37.8°C).
ii. Chills or rigors.
iii. Itching.
iv. Rash.
v. Flushing.
vi. Urticaria or angioedema.
vii. Breathing difficulties (dyspnea, chest paint or tightness, shortness of 
breath, wheezing, stridor).
viii. Clinical hypotension (pallor, diaphoresis, faintness, syncope), blood 
pressure less than 90 mm Hg systolic and 60 mm Hg diastolic, or a systemic or
orthostatic drop in systolic blood pressure of greater than 20 mm Hg.
AND

Was considered related to the infusion/administration of infliximab, adalimumab, or 
certolizumab pegol.
A significant delayed infusion/administration reaction is defined as an adverse reaction 
that:

Was manifested through 1 or more of the following symptoms:
i. Myalgias
ii. Arthralgias
iii. Fever greater than 100°F (37.8°C).
iv. Malaise
v. Rash.
AND

Occurred > 24 hours and < 15 days after infusion/administration of infliximab, 
adalimumab, or certolizumab pegol
AND

Was considered related to the infusion/administration of infliximab, adalimumab, or 
certolizumab pegol.
A significant injection site reaction is defined as an adverse reaction that:

Was manifested through 1 or more of the following symptoms:
i. Significant bruising.
ii. Erythema.
iii. Hemorrhage.
iv. Irritation.
v. Pain.
vi. Pruritus.
vii. “Injection site reaction.

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AND

Occurred within 24 hours of an SC injection of adalimumab or certolizumab pegol.
AND

Was considered related to the injection.
B. Have documentation available to the investigator that meets the following 2 requirements:

Provides the date of discontinuation of infliximab, adalimumab, or certolizumab 
pegol.

Documents that the patient had intolerance to infliximab, adalimumab, certolizumab 
pegol therapy.
Examples of acceptable documents include: medical records, letter provided by a referring
physician, or other “reason for referral” documents (e.g., insurance authorization form).

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
01 Jul 2021
EudraCT number
EU number
2020-004527-16
BI Trial number
1425-0003
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
A Phase IIa, randomised, double-blind, placebo-
controlled trial to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of BI 
706321 orally administered for 12 weeks in 
patients with Crohn`s Disease (CD) receiving 
ustekinumab induction treatment
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
The title was corrected from:
“A Phase IIa, randomised, double-blind, placebo-
controlled trial to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of BI 
706321 orally administered for 12 weeks in 
patients with Crohn’s Disease (CD)”
To:
“A Phase IIa, randomised, double-blind, placebo-
controlled trial to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of BI 
706321 orally administered for 12 weeks in 
patients with Crohn’s Disease (CD) receiving 
ustekinumab induction treatment”
Rationale for change
Correction of reflect the full and correct title in 
the synopsis (no content-wise change)
Section to be changed
Flowchart
Description of change

Dispense Patient Diary: “X” at Visit 2, 
Visit 4, Visit 5, Visit 6 and Visit 7 were 
deleted as the patient will get a diary at 
Visit 1 for the entire section.

Collect & Review Patient Diary: “X” were 
added to Visit 3, Visit 8A, Visit 8B, Visit 
I 
I 
-

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8C, Visit 9, Visit 10, Visit 11, Visit 12, 
Visit 13

Footnote “X”: “CRO`s SAE form” was 
changed to “BI`s SAE form”.
Rationale for change
Corrections to reflect the content of the respective 
sections, no content-wise change.
Section to be changed
1.2.1 (Data from non-clinical studies)
Description of change
The sentence were corrected from:
“In vivo, RIPK2 inhibition was also demonstrated 
to significantly improve signs and symptoms of 
intestinal inflammation in the spontaneous T-
bet/Rag2 knockout (TRUC) mouse model of 
Inflammatory Bowl Disease (IBD).”
To:
“In vivo, RIPK2 inhibition was also demonstrated 
to significantly improve signs and symptoms of 
intestinal inflammation in the spontaneous T-
bet/Rag2 knockout (TRUC) mouse model of 
Inflammatory Bowel Disease (IBD).”
Rationale for change
Correction of the typo (bowel), no content-wise 
change.
Section to be changed
3.3.2
Description of change
Inclusion criteria 9 and 10 were merged (i.e. no 
content change). The inclusion criterion # 11 of 
version 1.0 of the CTP is now inclusion criterion 
# 10. 
Rationale for change
Correction, inclusion criterion was splitted 
incorrectly during the formatting process. No 
content-wise change.
Section to be changed
3.3.41
Description of change
“An individual patient will discontinue trial 
treatment and/or ustekinumab treatment after 
week 12 if:…” 
were changed to 
“An individual patient will discontinue trial 
treatment (including ustekinumab open-label 
maintenance treatment after week 12) if:”
Rationale for change
FDA request during initial submission
Section to be changed
3.3.4.1
Description of change
The sublisting of the last bullet point were 
corrected and for the very last sublisting bullet 

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point the wording “o At week 24 (visit 10):” 
were visualised.
Rationale for change
Correction of listing formatting and formatting 
mistake (i.e. hidden text).
Section to be changed
3.3.4.3
Description of change
The second discontinuation criterion was 
amended with 
“

Including, but not limited to, the following 
scenario, further enrolment, r
randomisation into the trial, and treatment 
of already randomised patients will be 
interrupted by the sponsor if:
o
2 patients on active treatment with 
serious adverse reactions 
representing the same MedDRA 
preferred term (and not reflecting 
exacerbations of the underlying 
CD) and
o
Which, after evaluation by the 
Sponsor, are considered to have a 
reasonable causal relationship to 
BI 706321, and are not typically 
observed with ustekinumab 
therapy
After the trial has been interrupted, it will only be 
restarted after an appropriate safety 
evaluation has been conducted and concluded that 
the benefit risk of the overall trial is still 
favourable, and appropriate risk-mitigation 
measures have been implemented if needed. If a 
re-start is appropriate, additional patients may be 
enrolled to replace the patients who were 
discontinued early due to the trial interruption.”
Rationale for change
FDA request during initial submission
11.2
GLOBAL AMENDMENT 2
Global Amendment 2 was created to fulfil the requirements of the French Ethics committee 
and Health Authority. Due to non-participation of France, Global Amendment 2 was never 
effective and never implemented.

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11.3
GLOBAL AMENDMENT 3
Date of amendment
16 May 2022
EudraCT number
EU number
2020-004527-16
BI Trial number
1425-0003
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
A Phase IIa, randomised, double-blind, placebo-
controlled trial to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of BI 
706321 orally administered for 12 weeks in 
patients with Crohn`s Disease (CD) receiving 
ustekinumab induction treatment
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated ≥50% SES-CD to >50% SES-CD
Rationale for change
Alignment with more recent consensus 
definitions.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Re-wording of inclusion criterion No. 3
Rationale for change
Clarification of inclusion criterion.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Update of inclusion criterion No. 5
Rationale for change
Based on sponsor internal assessment and 
investigators’ feedback.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Update of inclusion criterion No. 7
Rationale for change
Based on sponsor internal assessment and 
investigators’ feedback.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Update of exclusion criterion No. 7 (Pathological 
safety lab parameters)
Rationale for change
Correction of typo.
Section to be changed
Flowchart
Description of change
Update of days at week 16 to 113

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Rationale for change
Correction of typo.
Section to be changed
Flowchart
Description of change
Addition of screening period extension.
Rationale for change
Due to logistical reasons screening period could 
be extended, if approved by sponsor.
Section to be changed
Flowchart
Description of change
Update of test kits for Ustekinumb serum level.
Rationale for change
Updated according central laboratory procedure.
Section to be changed
Flowchart
Description of change
Footnote U updated to allow re-test for SARS-
CoV-2 infected patients who are asymptomatic.
Rationale for change
Updated to reflect changing knowledge regarding 
COVID-19 pandemic.
Section to be changed
Flowchart
Description of change
Footnote Z added to give guidance in case a 
patient tests positive during the trial.
Rationale for change
Updated to reflect changing knowledge regarding 
COVID-19 pandemic.
Section to be changed
1.2.1
Description of change
Based on in vitro studies, clinically relevant drug-
drug interactions (DDI) with BI 706321 are 
possible. Based on in vitro data, BI 706321 is 
mainly metabolized via CYP3A and is also a 
substrate of P-glycoprotein (P-gp). A clinical DDI 
study (study 1425-0010) to evaluate the effect of 
itraconazole (dual strong inhibitor of CYP3A and 
P-gp) on the PK of BI 706321 is ongoing has 
been completed. A 2 week administration of 
itraconazole resulted in only ~2.2 fold increase 
in AUC of BI 706321.
Physiologically-based pharmacokinetic 
(PBPK) modelling of BI 706321 was conducted 
using data from 1425-0001, 1425-0002, and 
1425-0010 in order to assess CYP3A DDI 
liabilities. Simulations based on the PBPK 
model were congruent with the results seen in 
1425-0010 and additionally showed that no 
relevant DDI is expected following 
administration of weak CYP3A perpetrators, 
and at most a minor increase in exposure is 

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expected following moderate CYP3A 
inhibitors [c34844753]. Furthermore, based on 
the only ~2.2-fold increase in AUC of BI 
706321 following 2-week administration with 
itraconazole, as seen in study 1425-0010, even 
in the presence of strong CYP3A inhibitors, 
exposures are not expected to exceed any 
safety thresholds.
Based on the high permeability of BI 706321, 
inhibition of P-gp is not expected to have a 
clinically relevant effect; this is supported by 
PBPK modelling, whereby the complete 
removal of P-gp transport (equivalent to 100% 
inhibition of P-gp) resulted in no noticeable 
change in exposure.
Concomitant medications which are moderate and 
strong CYP3A inducers or inhibitors and P-gp 
inhibitors or P-gp substrates are discussed in 
Section 4.2.2.1
Rationale for change
Drug interactions information updated with data 
from completed clinical study and modelling.
Section to be changed
1.4.2
Description of change
Addition of caution for attention to QTc to be 
taken in the event of use of concomitant 
medications with a known risk of increasing 
exposures of BI 706321.
Rationale for change
Removal of some drug-drug interaction 
restrictions due to new clinical and modelling 
data, which may result in circumstances where 
limited increases in BI 706321 exposures may 
occur.
Section to be changed
2.1.3
Description of change
Updated ≥50% SES-CD to >50% SES-CD
Rationale for change
Alignment with more recent consensus 
definitions.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Re-wording of inclusion criterion No. 3
Rationale for change
Clarification of inclusion criterion.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Update of inclusion criterion No. 5

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Rationale for change
Based on sponsor internal assessment and 
investigators’ feedback.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Update of inclusion criterion No. 7
Rationale for change
Based on sponsor internal assessment and 
investigators’ feedback.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Update of exclusion criterion No. 6
Confirmatory PCR test added if C difficile toxin 
A/B and antigen test is indeterminate.
Rationale for change
Clarification of C diff testing instructions in case 
of indeterminate first result.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Addition of text to exclusion criterion No. 13:
If at screening, PCR test for SARS-CoV-2 is 
positive and patient is asymptomatic, re-test 
SARS-COV-2 PCR test is allowed (up to 4 
times) to confirm patient's eligibility before 
ileo-colonoscopy and/or visit 2. If re-test 
SARS-COV-2 PCR test is negative, patient 
must meet all other eligibility criteria 
according to the CTP before patient is 
randomized at visit 2. Already performed 
screening assessment do not need to be 
repeated.
Rationale for change
Updated to reflect changing knowledge regarding 
COVID-19 pandemic
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Update of exclusion criterion No. 16:
Aspartate aminotransferase (AST) and OR
Alanine aminotransferase (ALT) > 2 times the 
Upper Level of Normal (ULN). Total bilirubin > 
2 x ULN with ratio of direct/indirect >1 (patients 
with Gilbert’s syndrome are not excluded), 
Rationale for change
Correction of typo.
Section to be changed
3.3.4.1
Description of change
Absence of at least CDAI-70 clinical response as 
defined by a reduction from baseline in the 
CDAI score of ≥ 70 points, or a CDAI score of 
<150.
Rationale for change
Wording added for clarification.

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Section to be changed
4.2.2
Description of change
Removal of restrictions to concomitant use of 
moderate and strong CYP3A inhibitors. Removal 
of restrictions to concomitant use of Pgp-
inhibitors.
Addition of caution for attention to QTc to be 
taken in the event of use of concomitant 
medications with a known risk of limited 
increases in exposures of BI 706321 (e.g. strong 
CYP3A inhibitors)
Rationale for change
Data from clinical DDI study 1425-0010 and 
modelling now available which shows no clinical 
effect on exposures of BI 706321 due to Pg-p 
inhibition, minor increase in exposures of BI 
706321 due to moderate CYP3A inhibitors, and 
limited effects on increase in exposures of BI 
706321 in the presence of strong CYP3A 
inhibitors which are not expected to exceed safety 
thresholds. 
Section to be changed
5.2.3
Description of change
Data transfer from Central Laboratory to BI 
deleted.
Rationale for change
Specific data analyzed by the central laboratory 
will not be transferred to BI, according to 
specification with central laboratory.
Section to be changed
5.3.2.1
Description of change
Blood volume deleted.
Rationale for change
Blood volume is stated in central laboratory 
specifications.
Section to be changed
5.4.1
Description of change
Stool samples will be collected to assess changes 
in the levels of inflammatory markers such as but 
not limited to fecal calprotectin, lactoferin, 
haptoglobin, hemoglobin, MMP12, MPO, 
proteinase 3, resistin, serpin A4, PGRPS, 
properdin, chitinase 3L like 1, lipocalin 2, 
HMGB1 and neopterin pre- and (at various time 
points) post-treatment in both treatment groups.
Rationale for change
Adaption based on current development 
approach.

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Section to be changed
6.1
Description of change
Addition of text:
If at screening, PCR test for SARS-CoV-2 is 
positive and patient is asymptomatic, re-test 
SARS-COV-2 PCR test is allowed (up to 4 
times) to confirm patient's eligibility before 
ileo-colonoscopy and/or visit 2. If re-test 
SARS-COV-2 PCR test is negative, patient 
must meet all other eligibility criteria 
according to the CTP before patient is 
randomized at visit 2. Already performed 
screening assessment do not need to be 
repeated.
Rationale for change
Updated to reflect changing knowledge regarding 
COVID-19 pandemic
Section to be changed
6.2.1
Description of change
The patient should be recorded on the enrolment 
log as a screened patient when Visit 1A is 
performed.
Rationale for change
Correction of typo.
Section to be changed
6.2.1
Description of change
Addition of screening period extension.
Rationale for change
Due to logistical reasons screening period could 
be extended, if approved by sponsor.
Section to be changed
7.2.1
Description of change
Full analysis set (FAS): all patients in the RS who 
received at least 1 dose of trial medication and 
have analysable data (observed or imputed) in 
at least one efficacy parameter.
Rationale for change
Added for clarification
Section to be changed
7.2.2
Description of change
The FAS will be used for the analysis of the 
primary endpoint. The primary analysis is a 
restricted maximum likelihood (REML) based 
analysis of covariance (ANCOVA) analysis of 
covariance comparing the absolute change from 
baseline in SES-CD scores at Week 12.
Rationale for change
Correction of typo.
Section to be changed
7.2.6
Description of change
Note that not all analyses of biomarker data will 
be reported in the main CTR and some (e.g. 

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transcriptomic analyses) will may be reported 
separately
Rationale for change
Correction of typo.
Section to be changed
10.2: 1
Description of change
Update of days at week 16 to 113
Rationale for change
Correction of typo.
Section to be changed
10.3
Description of change
Specification of scores and wording Updated.
Rationale for change
To be consistent with central reading center.
Section to be changed
10.4.1
Description of change
Average changed to sum.
Rationale for change
Correction of typo.
11.4
GLOBAL AMENDMENT 4
Date of amendment
04 Aug 2023
EudraCT number
EU number
2020-004527-16
BI Trial number
1425-0003
BI Investigational Medicinal 
Product(s)
BI 706321
Title of protocol
A Phase IIa, randomised, double-blind, placebo-
controlled trial to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of BI 
706321 orally administered for 12 weeks in 
patients with Crohn`s Disease (CD) receiving 
ustekinumab induction treatment
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title page
Description of change
Update of Clinical Trial Leader name and contact 
data
Rationale for change
New Clinical Trial Leader assigned

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Section to be changed
Clinical Trial Protocol Synopsis, Flow Chart 
Footnote Y, and Section 3.3.3.1
Description of change
Exclusion criterion No. 5: “Treatment with: (…)
o
any biologic treatment with a TNF-alpha 
antagonist (adalimumab, infliximab, 
golimumab, certolizumab pegol) or 
vedolizumab (or a biosimilar of these 
drugs) within 4 weeks prior to 
randomisation (…)”
Rationale for change
Biosimilars added for clarity
Section to be changed
Clinical Trial Protocol Synopsis and Section 
3.3.3.1
Description of change
Exclusion criterion No. 5: “Treatment with: (…)
o
any previous treatment with ustekinumab 
(or a biosimilar of this drug) (…)”
Rationale for change
Biosimilars added for clarity
Section to be changed
Clinical Trial Protocol Synopsis and Section 
3.3.3.1
Description of change
Exclusion criterion No. 5: “Treatment with: (…)
o
any previous treatment with an 
investigational (or subsequently 
approved) non-biologic/ or biologic drug 
for CD (including but not limited to JAK 
inhibitors [e.g. upadacitinib], S1P 
modulators, IL-23 inhibitors [e.g. 
risankizumab], anti-integrins) (…)”
Rationale for change
Exclusion criteria clarified to reflect the change 
of marketing status of risankizumab and 
upadacitinib for CD from investigational to 
approved 
Section to be changed
Clinical Trial Protocol Synopsis, Sections 3.1, 
3.3.2, and 4.2.2.1 (Table 4.2.2.1: 1)
Description of change
6-TG added as an allowed concomitant 
medication and removed from the list of restricted 
medications
Rationale for change
To accommodate 6-TG usage in the trial as a 
standard of care for CD in some countries
Section to be changed
Flow Chart
Description of change
CDEIS scoring system added for the evaluation 
of ileocolonoscopy results
Rationale for change
For consistency with Sections 2.2.2 and 5.1.1

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Section to be changed
Flow Chart Footnote O
Description of change
“Trial drug (BI 706321 or Placebo) and 
ustekinumab will are recommended to be given 
simultaneously.”
Rationale for change
To add more flexibility for investigators
Section to be changed
Flow Chart Footnote T
Description of change
It was specified that fasting is not required for 
post-dose PK sampling.
Rationale for change
For clarity
Section to be changed
Flow Chart Footnote U
Description of change
“If a rescreening will be performed the ileo-
colonoscopy has only to be repeated if the 
rescreening is done later than 6 weeks after the 
initial screening if the time between the original 
screening ileocolonoscopy and randomisation 
is >6 weeks (time intervals slightly longer than 
6 weeks have to be discussed with the Sponsor 
and can be approved if medically appropriate)
(…)”
Rationale for change
For consistency with Section 6.1
Section to be changed
Flow Chart Footnote W
Description of change
Added: “End of treatment with ustekinumab in 
the trial is V12.”
Rationale for change
Added for clarity
Section to be changed
Flow Chart, Sections 3.3.4.1, 4.2.1, 6.2.2, and 
6.2.3
Description of change
Procedures for early termination of trial drug 
clarified 
Rationale for change
Additional details provided to cover all possible 
scenarios for patients who early terminate trial 
treatment
Section to be changed
Flow Chart and Section 6.2.1
Description of change
Screening period extended to 21 days
Rationale for change
Due to logistical reasons screening period could 
be extended if approved by the sponsor
Section to be changed
Abbreviations
Description of change
List of abbrevations updated
Rationale for change
To reflect changes in the document

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Section to be changed
1.4.2.2
Description of change
“Tuberculosis (TB): Evaluate patients for TB 
prior to initiating treatment with ustekinumab. 
Initiate treatment of latent TB before 
administering ustekinumab.”
Rationale for change
Sentence deteted for consistency with Section 
3.3.3.2, Excl. 12
Section to be changed
4.2.1, 4.2.2.1 (Table 4.2.2.1: 1)
Description of change
‘Rescue therapies/medication’ language updated
Rationale for change
No rescue therapy defined for the trial
Section to be changed
4.2.2.1
Description of change
Table 4.2.2.1: 1 (restrictions regarding previous 
and concomitant treatment): Any biologics 
approved for CD class of medication clarified by 
adding a footnote and biosimilars
Rationale for change
For clarity
Section to be changed
4.2.2.1
Description of change
Table 4.2.2.1: 1 (restrictions regarding previous 
and concomitant treatment) updated to add 
restrictions on the use of JAK inhibitors 
(including upadacitinib), S1P modulators, and 
IL-23 inhibitors (including risankizumab)
approved for CD
Rationale for change
Updated to reflect the change of marketing status 
of risankizumab and upadacitinib for CD from 
investigational to approved 
Section to be changed
4.2.2.1
Description of change
Table 4.2.2.1: 1 “(…) Patients with regular daily 
opioid or cannabis use over the past for more 
than 3 months prior to Visit 2 are excluded due 
to the interference of such medications with key 
efficacy endpoints (CDAI) (…)”
Rationale for change
Reworded for clarity
Section to be changed
5.1.1
Description of change
Description of CDEIS assessment added
Rationale for change
To provide details on the CDEIS assessment 

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Section to be changed
5.4.3
Description of change
Minor change in the description of biopsy sample 
collection
Rationale for change
For consistency with the lab manual
Section to be changed
6.2.3
Description of change
“(…) Throughout the follow-up period the patient 
will receive ustekinumab. The last 
administration of ustekinumab in the trial is 
V12. , until the EoS visit is reached (Visit 13). 
(…)”
Rationale for change
For consistency with the Flow Chart
Section to be changed
8.1
Description of change
Exception on legal representatives added for 
Germany
Rationale for change
To meet local regulatory requirements
Section to be changed
9.1
Description of change
List of references updated
Rationale for change
To reflect changes in the document
Section to be changed
10.1
Description of change
A footnote added to Table 10.1: 1 to describe PK 
sampling in case of early termination of trial 
treatment before Visit 8
Rationale for change
To clarify the process of PK samling in case a 
patient terminates the study before Visit 8
Section to be changed
10.4
Description of change
Minor rewordings
Rationale for change
For consistency with the eCRF
Section to be changed
Throughout the Clinical Trial Protocol
Description of change
Minor changes made throughout the document
Rationale for change
Correction of minor grammatical or typographical 
errors

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33919902
5.0
clinical-trial-protocol-version-05
A Phase IIa, randomised, double-blind, placebo-controlled trial to evaluate the safety,
efficacy, pharmacokinetics and pharmacodynamics of BI 706321 orally administered
for 12 weeks in patients with Crohn`s Disease (CD) receiving ustekinumab induction
treatment
Approval-Clinical Program 
07 Aug 2023 15:15 CEST
Author-Trial Statistician
07 Aug 2023 16:38 CEST
Approval-Clinical Trial Leader
08 Aug 2023 08:05 CEST
Verification-Paper Signature
Completion
08 Aug 2023 08:11 CEST
f?.l\ll
l Boehri~ger 
~1llhv Ingelbe1m 

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33919902
5.0

Boehringer Ingelheim 
04 Aug 2023 
BI Trial No.: 1425-0003 
c33919902-05 
Trial Protocol 
Page 1 of 1 
Proprietary confidential information © 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 001-MCS-40-106_RD-30 (1.0) / Saved on: 24 Mar 2021 
CO-ORDINATING INVESTIGATOR SIGNATURE 
 
 
 
 
Trial Title: 
 
A Phase IIa, randomised, double-blind, placebo-controlled trial to 
  
 
evaluate the safety, efficacy, pharmacokinetics and 
 
  
 
pharmacodynamics of BI 706321 orally administered for 12 weeks 
  
 
in patients with Crohn`s Disease (CD) receiving ustekinumab  
  
 
induction treatment 
 
Trial Number:  
1425-0003 
 
Protocol Version: 
5.0 
 
 
 
I herewith certify that I agree to adhere to the trial protocol and to all documents 
referenced in the trial protocol. 
 
 
Date: 
_______________________ 
 
 
Name: 
 Signature: ____
____________ 
 
 
 
Affiliation: 
 
 
 
 
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