Loss of RESponse to Ustekinumab Treated by Dose Escalation
Phase: PHASE3
Conditions: Crohn Disease
Sponsor: Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW

confidential 
Page 1 of 45 
Protocol Full Title: 
Loss of RESponse to Ustekinumab treated by dose Escalation 
The REScUE study
REScUE -BIRD2018001 
EudraCT number: 2018-004269-14 
Protocol Version 1.7; Feb 09, 2022 
Sponsor :
Belgian IBD research and development group (BIRD) 
Leuvensesteenweg 643 
1930 Nossegem 
BE 0465 587 924, RPR Brussel 
Tel: +32 (0)499 31 70 05 
Email: ingrid.arijs@birdgroup.be  
Principal Investigator : 
Dr. Peter Bossuyt 
Imelda Ziekenhuis Bonheiden 
Imeldalaan 9 
2820 Bonheiden 
Tel +32 15 50 51 65 
Peter.bossuyt@imelda.be  
Advisory group 
Prof. Séverine Vermeire 
University Hospitals Leuven 
Herestraat 49 
3000 Leuven 
Tel +32 16 34 42 25 
Severine.Vermeire@uzleuven.be 
Prof. Jean-François Rahier  
Service d'Hépato-gastroentérologie 
CHU UCL Namur, site Godinne 
5530 Yvoir 
Tel: +32 81 42 32 51  
jfrahier@gmail.com  
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 2 of 45 
 
Signature page 
SPONSOR: BIRD (Belgian IBD research and development) 
President: Dr. Filip Baert  
Signature    
                                          
 
 
 Date    
 
 
 
PRINCIPAL INVESTIGATOR: Dr Peter Bossuyt 
Signature                                          
Date    
 
 
 
SITE INVESTIGATOR:  
I will conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) and with 
the protocol agreed to by the sponsor and given approval / favourable opinion by the IRB/IEC and 
competent authority. I agree to comply with procedure for data recording/reporting, especially to 
report all SAE to the sponsor within 24H of awareness, to permit monitoring, auditing and inspection 
and to retain the trial related essential document until the sponsor informs me / my institution that 
these documents are no longer needed. 
I will conduct the trial within the time designated. 
I understand that all information concerning the study supplied to me by BIRD in connection with this 
trial and not previously published is considered confidential information. 
I agree that documents and other data pertinent of this trial are property of BIRD. 
I understand that any changes in the protocol must be approved in writing by BIRD and the IRB / IEC 
before implementation. 
By my signature below, I hereby attest that I have read, understood and agree to abide by all condition, 
instructions and restriction contained in the protocol. 
Name  _________________________ 
 
 
Signature  _________________________  
 
 
Date___________________ 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2
2/9/2022
2/9/2022

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 3 of 45 
 
1 Table of Contents 
2 
Study Synopsis ................................................................................................................................. 6 
3 
Background and rationale ............................................................................................................... 9 
4 
Study Design and objectives .......................................................................................................... 11 
4.1 
Study objectives .................................................................................................................... 11 
4.1.1 
Primary objective........................................................................................................... 11 
4.1.2 
Secondary objectives ..................................................................................................... 11 
4.2 
Study Design .......................................................................................................................... 12 
4.2.1 
Definitions ..................................................................................................................... 12 
4.2.2 
Description of design ..................................................................................................... 12 
4.2.3 
Participating centers ...................................................................................................... 12 
4.3 
Study diagram........................................................................................................................ 13 
4.4 
Timelines ............................................................................................................................... 13 
4.5 
Study Flowchart ..................................................................................................................... 14 
5 
Selection and withdrawal of subjects ........................................................................................... 15 
5.1 
Patient selection .................................................................................................................... 15 
5.2 
Inclusion criteria .................................................................................................................... 15 
* the criterium used to proof loss of response does not have to be identical to the one used to 
proof primary response: e.g. one can use an increase in biomarkers to proof primary respons and a 
relapse on endoscopy to proof loss of response .............................................................................. 17 
5.3 
Exclusion criteria ................................................................................................................... 17 
5.4 
Criteria for Discontinuation or Withdrawal of a Subject ....................................................... 17 
5.5 
Expected duration of study ................................................................................................... 18 
5.6 
Closure of a study site ........................................................................................................... 18 
6 
Randomization .............................................................................................................................. 18 
7 
Study medication ........................................................................................................................... 19 
7.1 
Randomization ...................................................................................................................... 19 
7.2 
Dosing .................................................................................................................................... 19 
7.3 
Investigational product supply .............................................................................................. 19 
7.4 
Treatment compliance .......................................................................................................... 20 
7.5 
Concomitant medication during the study ........................................................................... 20 
8 
Endpoints ....................................................................................................................................... 20 
8.1 
Primary endpoint ................................................................................................................... 20 
8.2 
Secondary endpoints (unranked) .......................................................................................... 20 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 4 of 45 
 
8.3 
Exploratory endpoints ........................................................................................................... 21 
9 
Study Procedures .......................................................................................................................... 21 
9.1 
Assessments at inclusion ....................................................................................................... 21 
9.1.1 
Informed Consent Procedure ........................................................................................ 21 
9.1.2 
Demographics, Medical History, and Medication History Procedure ........................... 22 
9.1.3 
Disease Activity Measurements .................................................................................... 22 
9.1.4 
Physical exam ................................................................................................................ 22 
9.1.5 
Documentation of Concomitant Medications ............................................................... 23 
9.1.6 
Procedures for Clinical Laboratory Samples .................................................................. 23 
9.1.7 
Spared blood sample for biomarker research ............................................................... 23 
9.1.8 
Endoscopy ..................................................................................................................... 23 
9.2 
Assessments during prospective follow up ........................................................................... 25 
9.2.1 
Scheduled visits week 4/8/12/20/28/36 (allowed window: +/- 5 days) ....................... 25 
9.2.2 
Visit W44 (allowed window: +/- 5 days) ........................................................................ 26 
9.2.3 
Unscheduled visit .......................................................................................................... 27 
9.2.4 
End of study visit (allowed window: +/- 5 days) and early termination visit ................ 27 
10 Informed consent procedure ........................................................................................................ 27 
11 Assessment of Safety ..................................................................................................................... 28 
11.1 
Adverse Events ...................................................................................................................... 28 
11.2 
Serious Adverse Events ......................................................................................................... 29 
11.3 
SUSAR reporting .................................................................................................................... 30 
11.4 
Definitions of Adverse Event Severity ................................................................................... 30 
11.5 
Relationship to Study Drug .................................................................................................... 30 
11.6 
Notification ............................................................................................................................ 31 
11.7 
Pregnancy .............................................................................................................................. 31 
11.8 
Biological and other abnormalities ....................................................................................... 32 
11.9 
Safety committee .................................................................................................................. 32 
12 Statistics ........................................................................................................................................ 33 
12.1 
Assumption ............................................................................................................................ 33 
12.2 
Planned analysis .................................................................................................................... 33 
12.3 
Power calculation .................................................................................................................. 33 
13 Quality Assurance .......................................................................................................................... 33 
14 Direct access to source data and documents ................................................................................ 34 
15 Ethics and regulatory approvals .................................................................................................... 34 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 5 of 45 
 
16 Data Management ......................................................................................................................... 35 
17 Data ownership ............................................................................................................................. 35 
18 Publication Policy .......................................................................................................................... 35 
19 Insurance/Indemnity ..................................................................................................................... 36 
20 Financial Aspects ........................................................................................................................... 36 
21 Abbreviations ................................................................................................................................ 36 
22 Bibliography ................................................................................................................................... 39 
23 Appendices .................................................................................................................................... 39 
23.1 
Appendix 1: PRO-2 ................................................................................................................. 39 
23.2 
Appendix 2: SES-CD ............................................................................................................... 40 
23.3 
Appendix  3: SF-36 ................................................................................................................. 40 
23.4 
Appendix 4:WPAI -CD ............................................................................................................ 44 
 
 
 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 6 of 45 
 
2 Study Synopsis 
 
Title of clinical study 
 
 
REScUE: loss of RESponse to Ustekinumab treated by dose 
Escalation 
Protocol Short Title/Acronym 
 
 
REScUE -BIRD2018001 
Sponsor name 
 
 
BIRD (Belgian IBD research and development group) 
EudraCT number 
 
2018-004269-14 
Principal Investigator 
 
 
Dr. Peter Bossuyt 
Medical 
condition 
or 
disease 
under 
investigation 
 
Crohn’s disease 
Aim of clinical study 
 
 
To investigate the effect of re-induction with ustekinumab 
≈6mg/kg IV  followed by two different maintenance dosing 
regimens 90 mg SC Q8W vs 90 mg SC Q4W on clinical, 
biological and pharmacological outcomes in patients with 
Crohn’s disease who show a secondary loss of response 
over time 
Primary endpoint 
 
Proportion of patients with steroid free clinical remission 
(PRO-2 remission: abdominal pain ≤ 1 AND stool 
frequency ≤ 3) and FCP <250µg/g at week 48.  [SF: 
average number of liquid stools for 1 week AP: average 
scoring for abdominal pain for 1 week (0=none; 1=mild, 
2=moderate; 3= severe)] 
Secondary endpoints 
 
 
Proportion of patients with complete endoscopic 
remission (SES-CD <3) at week 48 
Proportion of patients with endoscopic remission (SES-CD 
<5) at week 48 
Proportion of patients with endoscopic response (≥50% 
decrease in SES-CD) at week 48 
Proportion of patients with clinical remission (PRO-2 
remission: AP ≤ 1 AND SF ≤ 3) at week 48 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 7 of 45 
 
Proportion of patients with biomarker remission (CRP <5 
mg/L and FCP <250 µg/g) at week 48 
Proportion of patients with at all time points after 
baseline UST TC > 1.4 μg/mL  
Proportion of patients with SAE at week 48 
Exploratory endpoints 
Pharmacodynamic and pharmacokinetic evaluation. 
Time till clinical relapse (based on physicians discretion) 
after week 8. 
Time to clinical remission (PRO-2 remission: AP ≤ 1 AND 
SF ≤ 3) 
IBD related hospitalization. 
Need for IBD related intestinal resection. 
Improvements in quality of life based on SF-36. 
Pharmacoeconomic evaluation (drug cost, 
hospitalization, work absenteeism, surgery). 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Serious adverse events (SAE). 
Extra intestinal manifestation (joint). 
Study Design 
 
 
Prospective double blind multicenter interventional study  
Sample Size 
 
108 patients 
Number of participating sites 
 
17 sites in Belgium 
Summary of major eligibility criteria 
 
  
1. ≥18 years  
2. Diagnosis of Crohn’s disease by endoscopic and/or 
radiologic examination. 
3. Patient currently treated with UST, independent of 
previous biological exposure. 
4. Patients treated with maintenance dose of UST SC 90 
mg q8w 
5. Documented primary response at any time point 
during induction (up to week 20) defined as a clinical 
response (physician discretion)  
AND confirmed by either any of the following: 
1. A documented decrease in biomarkers based on 
a value during induction period compared to a 
value prior to UST induction (max. 3 months prior 
to start of UST induction)  
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 8 of 45 
 
a. A decrease in CRP 
OR 
b. A decrease in FCP  
2. A documented endoscopic 
improvement (evaluation during the 
induction period compared to an evaluation prior 
to UST induction (max. 6 months  prior to start of 
UST induction) 
6. Documented loss of response after induction (at any 
timepoint after week 16) assessed by the physician as 
moderate to severe active Crohn’s disease.  
The increase in symptoms reported by the patient is 
defined as: PRO-2 (AP > 1 AND SF > 3) 
AND confirmed by either any of the following: 
1. Documentation of endoscopic lesions in at least 
one segment of the ileum or colon as assessed by 
ileocolonoscopy AND a documented increase 
in biomarkers based on an increased 
value  compared to the lowest value obtained 
during induction or after  week 16 UST induction.  
a. An increase in CRP and >5 mg/L  
         OR 
b.   An increase in FCP and > 250 µg/mg 
2.    A documented relapse on endoscopy: Presence 
of mucosal ulcers in at least one segment of the ileum 
or colon and a SES-CD ≥6 (for patients with isolated 
ileitis ≥4), as assessed by ileocolonoscopy  
 
7. Adequate contraception in female of reproductive 
age. 
8. Have the capacity to understand and sign an 
informed consent form. 
9. Be able to adhere to the study visit schedule and 
other protocol requirements. 
10. All Crohn’s Disease treatments stable for at least 2 
weeks prior to baseline. 
 
Period of evaluation of a subject in the study 
 
48 weeks 
Version and date of final protocol 
 
Version 1.4, 06 Jan 2020 
Version and date of protocol amendments 
 
Version 1.7, 09 Feb2022 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 9 of 45 
 
3 Background and rationale 
Crohn’s disease (CD) is an immune disorder that can involve the complete gastrointestinal tract but 
predominantly presents in the terminal ileum and the colon. Although the exact cause is unknown, it 
is assumed that it results from an inappropriate inflammatory reaction to the gut microbiome in 
genetically predisposed patients. Treatment goals include the achievement of sustained clinical 
remission, endoscopic remission and improved quality of life 1 .   
The advent of anti-tumour necrosis factor (anti-TNF) agents such as infliximab and adalimumab 
brought a significant revolution in the therapeutic management of inflammatory bowel disease (IBD). 
Where conventional therapy mainly targeted symptom control, anti-TNF agents started to alter the 
natural history of CD. The mechanisms by which they could do this is through means of  induction of 
mucosal healing, which in turn leads to a reduction in hospitalization and surgery rates 2. As a 
consequence, anti-TNF therapy has for many years become the mainstay of therapy in CD patients 
refractory to corticosteroids and/or immunomodulatory agents. The therapeutic options have 
expanded over the last year with the introduction of anti-adhesion molecules, such as vedolizumab, 
targeting the addressin-integrin interaction by blocking α4β7. Furthermore, compounds targeting the 
IL12/23 pathway such as ustekinumab (UST) (anti body against p40  subunit of IL12/23) have entered 
the market. These compounds are of high importance since a significant subset of patients shows no 
or incomplete response to anti-TNF or loose response over time. Patients loosing response to a first 
anti-TNF agent, may benefit from switching to another anti-TNF agent, but the efficacy of this second 
anti-TNF agent has been shown to be lower than in anti-TNF naïve patients. Moreover, some patients 
need to stop anti-TNF therapy due to intolerance or significant side effects. Considering the life-long 
nature of the disease, new therapies targeting other immune pathways were needed.   
Ustekinumab induces and maintains clinical response and remission in patients with moderate-to-
severe Crohn’s disease as demonstrated by the phase III randomized controlled UNITI program 3. The 
clinical response after induction at week 6 was 34% in anti-TNF experienced and 55% in anti TNF naïve 
patients using ≈6mg/kg IV regime 3. For patients responding to the induction phase and continuing 
maintenance treatment with UST 90mg subcutaneous every 8 or 12 weeks, clinical remission was 
achieved at week 44 in 53% and 49% of patients, respectively. The totality of the efficacy outcomes 
and certainly also the exposure–response data favour administration of UST every 8 weeks.  
Ustekinumab has been approved for the treatment of patients with moderate to severe Crohn’s 
disease (CD), following successful completion of the UNITI and IM-UNITI phase 3 programs.  As 
described in the Stelara® SmPC, the recommended dose regimen of Stelara® is ≈6mg/kg administered 
by intravenous infusion at week zero.  The first subcutaneous administration of 90 mg Stelara®  should 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 10 of 45 
 
take place at week 8 after the intravenous dose. After this, dosing every 12 weeks is recommended. 
Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may 
receive a second subcutaneous dose at this time. Patients may subsequently be dosed every 8 weeks 
or every 12 weeks according to clinical judgment. Based on the dose response correlation and data on 
drug exposure in real world setting, a Q8W is preferred.  
Some patients who have experienced a decrease in their response may benefit from an re-induction 
with ≈6mg/kg  and/or an increase in dosing frequency to Stelara® 90 mg every four weeks (Q4W). Data 
on this dose intensification of Stelara® in patients who lose response are scarce and mainly 
observational or retrospective. In a Canadian cohort study in patients with CD achieving steroid-free 
response with UST induction, 64% of patients maintained endoscopic or radiographic response, but 
the cumulative probability of loss of response was 28.2% after 1 year. In this cohort dose escalation 
was required in 17 patients (16.3%) leading to recapturing of response in 9/17 (52.9%). The most 
common escalated maintenance dosing was UST 90 mg given subcutaneously every 4 or 6 weeks. 
Combined re-induction and escalation was effective in 4/7 (57.1%) patients 4. The GETAID experience 
with UST came to similar conclusions: the UST failure-free persistence rates were 78% at 12 months, 
66% at 24 months and 55% at 36 months 5. Loss of response was also here observed in a proportion of 
patients and different dose intensification regimens (dose increase, interval shortening and 
combination) were used and resulted in overall response rates of  56%. While these real-world data 
used SC induction regimens, similar conclusions were reached in a Belgian cohort of refractory CD 
patients who received IV induction followed by 8 weekly UST 90 mg SC. In this cohort, 43% of patients 
reported primary non response and only very limited mucosal healing (3%) was observed 6. When 
looking at UST drug levels, an association was seen between UST exposure and clinical and biological 
remission, suggesting that higher dosing could lead to better outcomes. A recent PK-PD analysis of the 
UNITI and IM-UNITI programs came to the same conclusion. UST serum levels correlate with clinical 
and endoscopic response and remission rates, and inversely correlate with CRP levels 7. 
Similar to other biologic agents used in IBD, there also seems to be inter-individual variation in drug 
exposure and this will depend on the inflammatory burden, BMI, and possibly other factors. 
Insufficient exposure leads to lower response rates, but also to secondary loss of response over time. 
Optimizing drug exposure by either increasing the dose or shortening the interval between 
administrations, has demonstrated to be a successful strategy to regain response in anti-TNF treated 
patients. Although re-induction or dose intensification seem both effective in retrospective studies 
with UST the safety profile of dose intensification remains unknown 8.  It is furthermore unknown what 
the most optimal way is to restore response. Although a single UST IV re-induction seems to restore 
response in a considerable proportion of patients, we hypothesize that this is insufficient to maintain 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 11 of 45 
 
clinical response and remission in the long term, since the PK change is probably limited over time and 
has no beneficial long term PD effect. In contrary, if the observed PD effect is longer than the expected 
short term PK effect of a single re-induction, it may then support the use of single re-induction followed 
to continuation of UST 8weekly maintenance to recover response with UST. These re-induction 
schemes need to be explored in both bio-naive or bio-experienced CD patients who had an objective 
clinical and biological response. No data exist that suggest that the mechanism of secondary loss of 
response to UST is different between these two groups. We suggest that the main driver of secondary 
loss of response is a high inflammatory burden in association with low UST exposure. 
4 Study Design and objectives 
4.1 Study objectives 
4.1.1 Primary objective  
• 
to assess the clinical effect of ustekinumab re-induction ≈6mg/kg IV  followed by either 90 mg 
SC Q8W or 90 mg SC Q4W in patients with CD who show a secondary loss of response over 
time 
4.1.2 Secondary objectives  
• 
to assess the endoscopic effect of ustekinumab re-induction ≈6mg/kg IV followed by either 90 
mg SC Q8W or Q4W in patients with CD who show a secondary loss of response over time. 
• 
to assess the biochemical effect of ustekinumab re-induction ≈6mg/kg IV followed by either 
90 mg SC Q8W or Q4W in patients with CD who show a secondary loss of response over time. 
• 
to assess the pharmacodynamic and pharmacokinetic aspects of ustekinumab re-induction 
≈6mg/kg IV followed by either 90 mg SC Q8W or Q4W in patients with CD who show a 
secondary loss of response over time 
• 
to assess the quality of life of patient treated with ustekinumab re-induction ≈6mg/kg IV 
followed by either 90 mg SC Q8W or Q4W in patients with CD after experiencing a secondary 
loss of response over time. 
• 
to assess the safety of ustekinumab re-induction ≈6mg/kg IV followed by either 90 mg SC Q8W 
or Q4W in patients with CD who show a secondary loss of response over time 
• 
to assess socio-economic impact of ustekinumab re-induction ≈6mg/kg IV followed by either 
90 mg SC Q8W or Q4W in patients with CD who show a secondary loss of response over time. 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 12 of 45 
 
4.2 Study Design 
4.2.1 Definitions  
Clinical remission: PRO-2 remission: AP ≤ 1 AND SF ≤ 3 [SF: average number of liquid stools for 1 week 
AP: average scoring for abdominal pain for 1 week (0=none; 1=mild, 2=moderate; 3= severe)] 
Complete endoscopic remission: SES-CD <3 
Endoscopic remission: SES-CD <5 
Endoscopic response: ≥50% decrease in SES-CD from baseline 
Biomarker remission: CRP <5 mg/L and FCP <250 µg/g 
4.2.2 Description of design  
The study is a prospective double blind interventional study in patients with CD treated with 
ustekinumab that show an objective secondary loss of response to ustekinumab after induction 
treatment (>W16). Patients can be screened during a four week period. The screening includes a 
clinical, biochemical and endoscopic assessment. A prior endoscopy (ileocolonoscopy) can be used as 
the screening endoscopy if this endoscopy has been performed within 10 weeks prior to the baseline 
visit under the following conditions: the endoscopy must have been recorded (all 5 segments must 
have been visualized – ensure no sensitive data are on the video) and a local SES-CD scoring must 
have been performed. Patients will be randomized 8 weeks after the last SC injection with 
ustekinumab. All patient will receive an IV re-induction with ustekinumab ≈6mg/kg at baseline (8 
weeks after last SC administration). For the IV re-induction a window of maximum 3 days is 
authorized.  After the IV re-induction, the patients receive either ustekinumab 90 mg SC Q4W or 
Q8W (altered with q4w placebo) till week 48. Clinical and biochemical evaluation will be planned 
every 8 weeks until week36 with a final evaluation at week 48. Primary endpoint will be assessed at 
week 48. Final assessment at week 48 will include clinical, biochemical and endoscopic evaluation. 
For all visits, a window of maximum 5 days is authorized. 
 
4.2.3 Participating centers 
The study is a multicenter trial conducted in Belgium.  17 centers will participate in the study. The 
recruitment is competitive between the different centers.  As q4w weekly administration of 
ustekinumab is not in the label in Belgium, the only way to start extra q4w dosing of ustekinumab in 
patients with CD will be by inclusion in this blinded clinical trial.  
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 13 of 45 
 
 
4.3 Study diagram 
  
 
 
 
4.4 Timelines  
Q1 2020: First Patient In 
Q4 2023: Last Patient In  
Q1 2021: Fist Patient Out 
Q4 2024: Last Patient Out 
Q1 2025: final analysis  
Q2 2025: submission abstract congress 
Q3 2025: publication data 
 
 
 
 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 14 of 45 
 
4.5 Study Flowchart 
 
 
Screening visit*** 
Baseline** 
W 
4* 
W 
8* 
W 
12* 
W 
20* 
W 
28* 
W 
36* 
W 
44* 
W 
48* 
unscheduled 
Early termination 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
x 
 
 
 
 
 
 
 
 
 
 
 
Disease 
characteristics  
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
Current 
and 
past 
treatments for 
CD 
x 
x 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
Endoscopy 
xa 
 
 
 
 
 
 
 
 
x 
 
x 
Laboratory 
evaluationb, 
x 
x c 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
pK samplingd 
 
x 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
Disease activity 
assessmente 
x 
x c 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
Physical 
examination 
x 
x 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
Vital signsf 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
IV re-induction 
 
x 
 
 
 
 
 
 
 
 
 
 
SC injection on 
site Q4Wg 
 
 
X 
x 
x 
x 
x 
x 
x 
x 
 
 
SC injection on 
site Q8Wh 
 
 
X 
x 
x 
x 
x 
x 
x 
x 
 
 
Drug 
accountability 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 15 of 45 
 
Questionnaire 
work 
and 
quality of lifei 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
Collection 
of 
extra samplesj 
 
x 
X 
x 
x 
x 
x 
x 
 
x 
x 
x 
Check 
occurrence of 
(S)AE since last 
visit 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
a 
A prior endoscopy (ileocolonoscopy) can be used as the screening endoscopy if this endoscopy has been performed 
within 10 weeks prior to the baseline visit under the following conditions: the endoscopy must have been recorded 
(video should not contain any sensitive data): all 5 segments (ileum, ascending colon, transverse colon, 
descending/sigmoid colon and rectum) must have been visualized and a local SES-CD scoring must have been 
performed. 
b  
serum albumin, fecal calprotectin, C-reactive protein, thrombocytosis, hemoglobin. In case of doubt, a pregnancy 
test can be performed   
c 
In case the laboratory evaluation was done max. 2 weeks before the baseline, this evaluation does not need to be 
repeated at baseline. In case the PRO-2 evaluation was done max. 2 weeks before the baseline, this evaluation does 
not need to be repeated at baseline 
d 
serum to be collected pre dosing 
e  
PRO-2: do not include the day of or day before the endoscopy (in case the bowel preparation was performed the day 
before the endoscopy) 
f 
blood pressure and pulse (bpm) 
g 
for Q4w: patients will be administrated blinded UST study labelled vials on site at week 4 and week 12 and thereafter 
every 8 weeks on site. The administration on the study visit of week 8 and week 48 will be done with commercial 
drug that the patient will bring from home. All other administrations with commercial drug will be done by the 
patient itself at home at weeks 16, 24, 32 and 40  
h 
for Q8w patients:  patients will be administrated blinded placebo study labelled vials on site at week 4 and week 12 
and thereafter every 8 weeks on site. The administration on the study visit of week 8 and week 48 will be done with 
commercial drug that the patient will bring from home. All other administrations with commercial drug will be done 
by the patient itself at home at weeks 16, 24, 32 and 40  
i 
 36-Item Short Form Survey Instrument (SF-36) questionnaire and Work Productivity and Activity Impairment (WPAI) 
questionnaire  
i 
collection of serum and whole blood to be stored locally and centralized later on – only in those patients that signed 
the additional ICF for the substudy  
*** 
Screening period of max. 4 weeks 
** 
allowed window: +/- 3 days 
* 
allowed window: +/- 5 days 
 
5 Selection and withdrawal of subjects 
5.1 Patient selection 
Patients will be selected in 17 centers in Belgium.  
5.2 Inclusion criteria  
1. ≥18 years  
2. Diagnosis of Crohn’s disease for at least 3 months prior to visit 1 by endoscopic and/or 
radiologic examination. 
3. Patient currently treated with UST, independent of previous biological exposure. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 16 of 45 
 
4. Patients treated with maintenance UST SC 90 mg Q8W (meaning after a minimum of 2 SC 
injections)  
5. Documented primary response at any time point during induction (up to week 20) defined as 
a clinical response (physician discretion)                                                
AND confirmed by either any of the following: 
1. A documented decrease in biomarkers based on a value during induction period 
compared to a value prior to UST induction (max. 3 months prior to start of UST 
induction)  
a. A decrease in CRP 
OR 
b. A decrease in FCP  
2. A documented endoscopic improvement (evaluation during the induction period 
compared to an evaluation prior to UST induction (max. 6 months  prior to start of 
UST induction) 
 
6. Documented loss of response after induction (at any timepoint after week 16) assessed by 
the physician as moderate to severe active Crohn’s disease. The increase in symptoms 
reported by the patient is defined as: PRO-2 (AP > 1 AND SF > 3)  
AND confirmed by either any of the following*:  
1. Documentation of endoscopic lesions in at least one segment of the ileum or colon 
as assessed by ileocolonoscopy AND a documented increase in biomarkers based on 
an increased value compared to the lowest value obtained during induction or after 
week 16 UST induction.   
a. An increase in CRP and >5 mg/L  
OR  
b. An increase in FCP and > 250µg/mg  
2.  A documented relapse on endoscopy: Presence of mucosal ulcers in at least one 
segment of the ileum or colon and a SES-CD ≥ 6 (for patients with isolated ileitis ≥4), 
as assessed by ileocolonoscopy.                                                                                                                             
7. Adequate contraception in female of reproductive age (oral contraception, intra uterine 
device, sterilisation or barrier method). 
8. Have the capacity to understand and sign an informed consent form. 
9. Be able to adhere to the study visit schedule and other protocol requirements. 
10. All Crohn’s Disease treatments stable for at least 2 weeks prior to baseline. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 17 of 45 
 
* the criterium used to proof loss of response does not have to be identical to the one used to 
proof primary response: e.g. one can use an increase in biomarkers to proof primary respons 
and a relapse on endoscopy to proof loss of response 
5.3 Exclusion criteria  
1. Ongoing treatment with   
a. other concomitant biological (vedolizumab, anti-TNF) 
b. Steroids >20 mg prednisolone or equivalent at baseline (budesonide >6 mg); >5 mg 
beclomethasone dipropionate at baseline 
c. Q4w ustekinumab 
2. Women that are pregnant, nursing, or planning pregnancy 
3. Have screening laboratory test results within the following parameters: 
a. Haemoglobin < 8.5 g/dL 
b. Platelets < 100,000 /mm3 
c. Serum creatinine ≥ 1.7 mg/dL 
d. AST and ALT > 3 times the ULN range 
e. Direct (conjugated) bilirubin ≥ 3.0 mg/dL. 
4. Have current signs or symptoms of infection confirmed by positive stool or blood testing 
(including gastrointestinal pathogens, TB, HIV, Hep B, Hep C). 
5. Patients with a positive stool sample for gastrointestinal pathogen including Clostridium 
difficile. 
6. Evidence of current or previous clinically significant disease, medical condition other than CD, 
finding of the medical examination, or laboratory value at the screening visit outside the 
reference range that is of clinical relevance, that in the opinion of the Investigator, would 
compromise the safety of the patient or the quality of the data.  
7. Patients with an ileostomy  
8. Patients that received an IV re-induction with UST within the 6 months prior to baseline. 
9. Patients with an impassable stenosis even after attempt of endoscopic balloon dilation.  
10. Patients with an abscess. 
5.4 Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study should be recorded 
in the case report form using the following categories.  
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 18 of 45 
 
1. Significant protocol deviation. The discovery post inclusion that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health. 
2. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.  
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded, but patient does not 
need to justify its withdrawal. 
4. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
5. Significant adverse or serious adverse event, as judged by the investigator after reporting of 
the (S)AE. 
6. Incompliance of the subject to the protocol instruction and medication administration as 
assessed by the investigator 
5.5 Expected duration of study  
The recruitment period is 45 months starting from the first patient included into the study. A total of 
108 patients will be recruited. The screening period has a maximum of four weeks. The patients will 
be followed prospectively in the trial for 48 weeks after the baseline.  
5.6 Closure of a study site 
Frequent monitoring will be performed during the study period of all study sites.  If during these 
monitoring visits important violations of the protocol or insufficient data collection are encountered 
than the PI and steering committee of the study can decide to exclude the site from further 
recruitment of patients in the study or to close the study site. 
6 Randomization 
A centralized online randomization system, stratified by previous exposure to anti-TNF and steroids at 
baseline will be implemented. The draw will be made in blocks of permutation whose size will not be 
disclosed to investigators.  Patients will be randomized 1:1 in 2 treatment groups as described in the 
section below. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 19 of 45 
 
7 Study medication 
7.1 Randomization 
Randomization (allocation to treatment group 1 or 2) will be done at day 0 after the relevant 
information has been entered into the database. Randomization to 1 of the 2 treatment group will be 
stratified according to previous exposure to anti-TNF and steroids at baseline. Patients and 
investigators and study related personnel remain blinded to the treatment group allocation.  
7.2 Dosing 
All eligible subjects will receive a re-induction at baseline, with intravenous ustekinumab, in line with 
the EU SmPC, on a weight-tiered basis at a dose of approximately 6 mg/kg IV. Subjects with body 
weight ≤55 kg at Week 0 will receive 260 mg IV ustekinumab. Those subjects with body weight >55 kg 
and ≤85 kg will receive 390 mg IV ustekinumab. Subjects with body weight >85 kg at Week 0 will receive 
520 mg IV ustekinumab.  For IV administration, the study drug will be administered to each subject 
over a period of not less than 1 hour. The infusion should be completed within 5 hours of preparation. 
Patient has to stay 1 hour after finalizing the IV administration for safety surveillance.  At week 4, the 
subjects in the Q4W arm will receive a 90 mg SC injection of ustekinumab.  Subjects in the Q8W arm 
receive placebo at week 4.  Subsequently, subjects in the Q4W arm will continue to receive 90 mg 
ustekinumab SC at designated 4-weekly injection times (see supply in section 7.3). The subjects in the 
Q8W arm will receive a 90 mg SC injection of ustekinumab every 8 weeks and placebo every 4 weeks 
in between (see supply in section 7.3).   Subjects who have been trained how to self-inject may self-
administer (in compliance with the EU SmPC) SC study drug at the times instructed by the investigator. 
Study-site personnel will remind subjects on how to store ustekinumab for at-home use as indicated 
by the SmpC, which is known practice to the subjects as they were already under ustekinumab 
treatment. Investigational product is stable for max. 6 hours at room temperature.  For each 
administration of study drug, the date and hour of injection will be recorded in the CRF, whether study 
drug was self-administered, and if so, whether SC administration was complete  
7.3 Investigational product supply  
This is an investigator initiated study from the Belgian IBD research and development group.  It is the 
only option in Belgium to treat patients with ustekinumab dose intensification after documented loss 
of response.  Dose intensification from q8w to q4w weeks is currently not reimbursed in Belgium.  For 
this the study has two arms.  Both arms will receive an IV reinduction with approximately 6 mg/kg 
commercial ustekinumab. Janssens will deliver vials for the re-induction. The “q4w arm” will receive 
commercial available q8w ustekinumab (90 mg SC syringe) alternated with q8w double blind active 
ustekinumab in study labelled vials provided by Janssen.  The “q8w arm” will receive commercial 
available q8w ustekinumab alternated with q8w double blind active placebo (NaCl 0.9%) prepared in 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 20 of 45 
 
the pharmacy of each participating site in study.  After central randomization organized by BIRD, the 
pharmacist will be informed on the type of syringes to prepare (ustekinumab or placebo). These 
blinded syringes will be delivered to the study department with subject specific labelling.  Janssen will 
provide the 90 mg vials to the pharmacy through a third party CSM® (Clinical Supplies Management)  
as well as cold packs and storage devices for cooled transport of the study drugs by the patient as 
foreseen in the initial reimbursement request at the start of Stelara®. 
7.4 Treatment compliance 
Study drug will be administered as a single IV infusion (baseline) by qualified staff followed by SC 
injections (Week 4 investigational product or placebo and onwards every 4 weeks). Details of each 
administration will be recorded in the CRF, including date, time of injection, and start and stop times 
and volume infused (for the IV infusion). Subjects may self-administer (in compliance with the EU 
SmPC) SC injections of study drug under the supervision of the investigator.  
7.5 Concomitant medication during the study 
5-aminosalicylate: any dosing, need to be stable during the study 
Steroids: prednisolone equivalent ≤ 20 mg at baseline, from week 16 tapering with 5 mg per week 
prednisolone equivalent is obligatory (for beclomethasone diproprionate, taper via EOD or magistral 
preparation).  If tapering is applied, restart or increasing of the dose is allowed during the study.  
Initiation of steroids during the study is allowed as of week 24 . 
Azathioprine/6-mercaptopurine/methotrexate: stable dosing during study, except stop for side-
effects, initiation not allowed during study, switch from azathioprine to 6-mercaptopurine (and vice 
versa) allowed at equivalent dose.  
Biologics: not allowed 
Jak inhibitors: not allowed 
Non registered investigational product: not allowed 
Antibiotics: allowed if not started for luminal CD 
8 Endpoints 
8.1 Primary endpoint 
• 
Proportion of patients with steroid free clinical remission (PRO-2 remission: AP ≤ 1 AND SF ≤ 
3) and FCP <250µg/g at week 48. 
8.2 Secondary endpoints (unranked) 
• 
Proportion of patients with complete endoscopic remission (SES-CD <3) at week 48 
• 
Proportion of patients with endoscopic remission (SES-CD <5) at week 48 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 21 of 45 
 
• 
Proportion of patients with endoscopic response (≥50% decrease in SES-CD) at week 48. 
• 
Proportion of patients with clinical remission (PRO-2 remission: AP ≤ 1 AND SF ≤ 3) at week 
48. 
• 
Proportion of patients with clinical remission (PRO-2 remission: AP ≤ 1 AND SF ≤ 3) at week 8 
after IV re-induction. 
• 
Proportion of patients with biomarker remission (CRP <5 mg/L and FCP <250 µg/g) at week 
48. 
• 
Proportion of patients with UST TC > 1.4 μg/mL at all time points (w4-8-16-24-32-40-48) after 
baseline in the different treatment arms. 
• 
Proportion of patients with SAE in the different treatment arms. 
8.3 Exploratory endpoints 
• 
Pharmacodynamic and pharmacokinetic evaluation. 
• 
Time to clinical response 
• 
Time till clinical relapse (based on physicians discretion) after week 8. 
• 
IBD related hospitalization. 
• 
Need for surgery. 
• 
Improvements in quality of life. 
• 
Pharmacoeconomic evaluation (drug cost, hospitalization, work absenteeism, surgery). 
• 
SUSAR  
• 
SAE. 
• 
Extra intestinal manifestation (joint). 
9 Study Procedures 
9.1 Assessments at inclusion 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects will be assessed by the investigator. The Schedule of Study Procedures is in section 4.5.  
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in section 10. 
Informed consent must be obtained prior to the subject entering the study, and before any protocol-
directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the time 
of screening (see section 16); this subject number will be used throughout the study. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 22 of 45 
 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include year of birth or age, sex, ethnic origin as 
described by the subject, smoking status, date of diagnosis of CD, and CD Montreal classification of the 
subject at screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study (including extra intestinal manifestations) 
that stopped at or prior to signing of informed consent. IBD surgeries need to be specified by number 
of resections, length of resections of small intestine, location of colonic resection, perianal surgical 
interventions. Ongoing conditions are considered concurrent medical conditions.  
Medication history information to be obtained includes any medication relevant to eligibility criteria 
stopped at or within 3 months prior to signing of informed consent. Next to that, all IBD treatments in 
the past need to be recorded. 
9.1.3 Disease Activity Measurements 
Disease activity will be measured based on the patient reported outcome (PRO-2).  Objective markers 
of disease activity will be collected locally.  These markers are C-reactive protein and faecal 
calprotectin.  
9.1.4 Physical exam 
9.1.4.1 Physical Examination Procedure 
A baseline physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) 
other. All subsequent physical examinations should assess clinically significant changes from the 
assessment prior baseline physical examination. 
9.1.4.2 Weight, Height  
A subject should have weight and height measured while wearing indoor clothing and without shoes. 
The standard for collecting height is centimetres without decimal places and for weight it is kilograms 
(kg) with 1 decimal place.  
9.1.4.3 Vital Sign Procedure 
Vital signs will include blood pressure and pulse (bpm). 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 23 of 45 
 
9.1.5 Documentation of Concomitant Medications 
Concomitant medication is any drug given during the study. These may be prescribed by a physician or 
obtained by the subject over the counter. All medication used to treat IBD including vitamin 
supplements, over-the-counter medications, and oral herbal preparations, must also be recorded in 
the CRF.  
9.1.6 Procedures for Clinical Laboratory Samples 
All laboratory tests will be done at the local hospital labs according to standard care. The lab tests are: 
serum albumin, faecal calprotectin, C-reactive protein, thrombocytosis and haemoglobin. A list of 
normal values will be centrally collected.  Furthermore, a serum sample will be collected pre-dosing, 
stored locally and collected for central PK analysis at the Laboratory For Therapeutic And Diagnostic 
Antibodies of KU Leuven. 
9.1.7 Spared blood sample for biomarker research  
On top of routine laboratory tests, extra serum and blood samples will be taken for biomarker research 
(including proteomics and genomics). At the end of the study, these tubes will be transferred and the 
Biobanking will be centralized at the “UZ Leuven Biobank”, Herestraat 49, 3000 Leuven 
(wbb@uzleuven.be)  
Biological samples will be kept at -80°C for 10 years. Afterwards the samples will be destroyed. 
A laboratory manual will be available to define SOPs for collection, storage and the shipment 
procedures of the biologicals samples (in according to the procedures of the central lab). 
Additional Patient Inform Consent is required and must be documented, by asking the patient to sign 
a specific Informed Consent Form for biological samples collection. If a patient disagree to have his 
samples kept for the biological collection, the physician will inform the project team so that no sample 
is kept after the mandatory protocol analysis. This will not affect patient follow up in anyway. 
9.1.8 Endoscopy 
The following aspects are required for the endoscopy and recording of the endoscopy in the study. 
9.1.8.1 Preparation and recording 
Bowel cleansing should be done with PEG or picosulphate solutions. Last stool before endoscopy 
should be water clear without faecal parts. Each ileocolonoscopy should be done with the best locally 
available endoscope, preferentially a high definitions endoscope. Only white light endoscopy must be 
performed during recording. All evaluable segments need to be recorded during withdrawal 
endoscopy. Five segments are recorded:  
1. Ileum 
2. Ascending colon 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 24 of 45 
 
3. Transverse colon 
4. Descending/sigmoid colon 
5. Rectum  
The complete recording time is preferentially 6 min (always <10:00 min) with a minimum of 30 and a 
maximum of 90 seconds per segment depending on the quality of the preparation and the presence 
of lesions. Images should be anonymized completely and identification of each segment must be 
clearly marked on the screen (ileum, ascending colon, transverse colon, descending/sigmoid colon and 
rectum). The transition of each segment needs to be highlighted (or by switch of the endoscopy light 
or by stopping the recording for 2 seconds). Each endoscopic recording is divided in 5 segments. In 
case of incomplete resection of a segment (ex. segmental sigmoidectomy, minor ileocecal resection) 
the partial segment in situ must be counted and marked on the screen. Perianal region must be 
documented adequately if possible by retroflexion in the rectum. Bowel wall must be cleaned 
sufficiently before recording. If biopsies are taken in a segment, then the segment must be filmed first 
and biopsies should be taken afterwards. Endoscopic pictures must be taken during endoscopy without 
stopping the recording. In case lesions are detected, then the lesions must be approached for more 
precise evaluation. A stenosis needs to be marked on the screen. A stenosis may be dilated during 
endoscopy after previous adequate documentation of the stenosis. The proximal (not injured by 
balloon dilation) segment may be recorded afterwards. If polyps are seen during endoscopy, then 
these can be resected according the ECCO guidelines. Polypectomy should be recorded even if 
performed during introduction of the scope. Chromoendoscopy is not allowed during recording but 
can be done afterwards.  
9.1.8.2 Storing of endoscopic recording 
The recording of the endoscopy will be stored locally on coded USB stick. The central storing of the 
images will be done on a secured web-based platform of BIRD. The image storing will be done with an 
adequate quality level (dpi, format). Transfer from the local data can be done by a secured data 
transfer system. The recording will by identified by a unique code as described in section 16. Exp: XX - 
XXX. 
9.1.8.3 Central reading 
All endoscopic videos will be scored locally with the SES-CD.  After the study all endoscopic videos 
will be re-read by a blinded central reader.  In case of discrepancy based on a sliding scale: 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 25 of 45 
 
 
In case of disagreement between the local and central reader a second central reader will perform an 
adjudication reading.  In case of agreement the average score of the agreeing scores will be used as 
final score.  If no 2 scores were in agreement (within respective predefined confines), the average of 
CR 1 and CR 2 will be used. 
 
9.2 Assessments during prospective follow up 
9.2.1 Scheduled visits week 4/8/12/20/28/36 (allowed window: +/- 5 days) 
9.2.1.1 Physical Examination Procedure 
A baseline physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) 
other. All subsequent physical examinations should assess clinically significant changes from the 
assessment prior baseline physical examination. 
9.2.1.2 Weight 
A subject should have weight measured while wearing indoor clothing and without shoes. The 
standard for collecting weight is kilograms (kg) with 1 decimal place.  
9.2.1.3 Vital Sign Procedure 
Vital signs will include blood pressure and pulse (bpm). 
9.2.1.4 Disease Activity Measurements 
Disease activity will be measured based on the PRO-2 based on the 7 days before the visit excluding 
the day of colon prep and day of colonoscopy if applicable. Objective markers of disease activity will 
be collected locally.  These markers are C-reactive protein and faecal calprotectin.  
9.2.1.5 Documentation of Concomitant Medications 
Concomitant medication is any drug given during the study. These may be prescribed by a physician or 
obtained by the subject over the counter.  All medication including vitamin supplements, over-the-
counter medications, and oral herbal preparations, must be recorded in the eCRF. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 26 of 45 
 
9.2.1.6 Procedures for Clinical Laboratory Samples 
All laboratory tests will be done at the local hospital labs according to standard care. The lab tests are: 
serum albumin, faecal calprotectin, C-reactive protein, thrombocytosis and haemoglobin. A list of 
normal values will be centrally collected.  Furthermore, a serum sample will be collected pre-dosing, 
stored locally and collected for central PK analysis at the Laboratory For Therapeutic And Diagnostic 
Antibodies of KU Leuven.  
 
 
9.2.1.7 Spared blood sample for biomarker research  
On top of routine laboratory tests, extra serum and blood samples will be taken for biomarker research 
(including proteomics and genomics). These tubes will be transferred and the Biobanking will be 
centralized at the “UZ Leuven Biobank”, Herestraat 49, 3000 Leuven (wbb@uzleuven.be)  
Biological samples will be kept at -80°C for 10 years.  
A laboratory manual will be available to define SOPs for collection, storage and the shipment 
procedures of the biologicals samples (in according to the procedures of the central lab).  
Additional Patient Inform Consent is required and must be documented, by asking the patient to sign 
a specific Informed Consent Form for biological samples collection. If a patient disagree to have his 
samples kept for the biological collection, the physician will inform the project team so that no sample 
is kept after the mandatory protocol analysis. This will not affect patient follow up in anyway. 
 
9.2.1.8 Assessment of adverse events 
Any adverse or serious adverse events that occurred between two visits should be recorded and the 
severity as well as the correlation to the investigational product should be clarified.   
9.2.1.9 Drug accountability 
For each administration of study drug, the date of injection will be recorded in the CRF, whether 
study drug was self-administered, and if so, whether SC administration was complete. 
Sites will be informed on procedures to follow to ensure product stability. Each site will receive a 
procedure from the sponsor to keep track of shipment, receipt, disposition, return and destruction of 
the IMP. 
 
9.2.2 Visit W44 (allowed window: +/- 5 days) 
Patients will be seen by the study coordinator or physician to administer the study drug (ustekinimab 
or placebo). 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 27 of 45 
 
9.2.3 Unscheduled visit 
Patients will be seen unscheduled in case of a disease flare or a CD related event. During the 
unscheduled visit, all assessments as for the scheduled visit (see section 9.2.1) needs to be done. 
9.2.4 End of study visit (allowed window: +/- 5 days) and early termination visit 
At the end of the study (week 48) next to the complete evaluation as described in section 9.2.1 an 
endoscopic evaluation will be performed according to the methodology described in section 9.1.7.    
10 Informed consent procedure 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all applicable 
laws and regulations. The informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting the 
study. The informed consent form and the subject information sheet (if applicable) further explain the 
nature of the study, its objectives, and potential risks and benefits, as well as the date informed 
consent is given. The informed consent form will detail the requirements of the participant and the 
fact that he or she is free to withdraw at any time without giving a reason and without prejudice to his 
or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved by 
both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information sheet 
(if applicable) must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the subject, 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 28 of 45 
 
or the subject’s legally acceptable representative, determines he or she will participate in the study, 
then the informed consent form and subject authorization form (if applicable) must be signed and 
dated by the subject, or the subject’s legally acceptable representative, at the time of consent and 
prior to the subject entering into the study. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The investigator must also sign and date the informed consent form and subject 
authorization (if applicable) at the time of consent and prior to subject entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and subject 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies of 
the signed informed consent form, the signed subject authorization form (if applicable), and subject 
information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the relevant 
subject’s legally acceptable representative in the same manner as the original informed consent. The 
date the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised informed consent form. 
11 Assessment of Safety 
11.1 Adverse Events    
Definition: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated 
with the use of a drug, whether or not the event is considered causally related to the use of the drug.  
Worsening of a pre-existing condition or illness is considered an adverse event. An elective 
surgery/procedure scheduled to occur during a study will not be considered an adverse event if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/ procedure has 
been pre planned prior to study entry. However, if the pre-existing condition deteriorates 
unexpectedly during the study (e.g., surgery performed earlier than planned), then the deterioration 
of the condition for which the elective surgery/procedure is being done will be considered an adverse 
event. Laboratory abnormalities judged as clinically significant should be regarded as adverse event.   
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 29 of 45 
 
The investigator will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study. The investigator will assess and record any adverse event in detail 
including the date of onset, description, severity, time course, duration and outcome, relationship of 
the adverse event to study drug, if known, and any action(s) taken by reporting this information in the 
CRF. 
11.2 Serious Adverse Events  
 If an adverse event meets any of the following criteria, it is regarded as serious adverse event (SAE) 
and should be reported within 24 hours of the site being made aware of the serious adverse event to 
BIRD. 
• 
Death of Subject An event that results in the death of a subject.  
• 
Life-Threatening An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not include an event 
that would have been fatal if it had occurred in a more severe form.  
• 
Hospitalization An event that results in an admission to the hospital for any length of time. 
This does not include an emergency room visit or admission to an outpatient facility.  
• 
Prolongation of Hospitalization An event that occurs while the study subject is hospitalized 
and prolongs the subject's hospital stay.  
• 
Congenital Anomaly An anomaly detected at or after birth, or any anomaly that results in fetal 
loss. 
• 
Persistent or Significant Disability/Incapacity An event that results in a condition that 
substantially interferes with the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). 
• 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome An important medical event that may not be immediately life-threatening or result 
in death or hospitalization, but based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any of the outcomes listed above (i.e., 
death of subject, life-threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 30 of 45 
 
• 
Spontaneous Abortion Miscarriage experienced by study subject.  
• 
Elective Abortion Elective abortion performed on study subject.   
11.3 SUSAR reporting  
A suspected unexpected serious adverse reaction (SUSAR) on the study drug(s), which is lethal or life-
threatening, must be reported to the Competent Authority, the central Ethics Committee and the 
investigators within 7 days from the time-point when the responsible investigator is aware of the 
event. A complement of the report is sent to the authorities within a maximum of 15 days.  
A suspected unexpected serious adverse reaction (SUSAR) on the study drug(s), which is not lethal or 
life-threatening, must be reported the Competent Authority, the central Ethics Committee and the 
investigators within 15 days from the time-point when the responsible investigator is aware of the 
event. A complement of the report is sent to the authorities as soon as possible.   
11.4 Definitions of Adverse Event Severity  
 The investigator will use the following definitions to rate the severity of each adverse event:  
• 
Mild The adverse event is transient and easily tolerated by the subject.   
• 
Moderate The adverse event causes the subject discomfort and interrupts the subject's usual 
activities.   
• 
Severe The adverse event causes considerable interference with the subject's usual activities 
and may be incapacitating or life-threatening.  
11.5 Relationship to Study Drug  
 The investigator will use the following definitions to assess the relationship of the adverse event to 
the use of study drug:  
• 
Probably Related An adverse event has a strong temporal relationship to study drug or recurs 
on re-challenge and other cause of event is unlikely or significantly less likely.   
• 
Possibly Related An adverse event has a strong temporal relationship to the study drug and 
another cause of event is equally or less likely compared to the potential relationship to study 
drug.   
• 
Unlikely: An adverse event for which an alternative explanation is more likely, e.g., 
concomitant drug(s), concomitant disease(s), or the relationship in time suggests that a causal 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 31 of 45 
 
relationship is unlikely. The patients will be specifically assessed for infection and malignancies 
and the incidence rates of these events will be presented as descriptive summary statistics and 
the number and percentage of patients who experience adverse events will be tabulated.    
11.6 Notification  
All adverse events as well as ustekinumab drug product quality complaints will be recorded by the 
investigator in the CRF.  
All life-threatening adverse events and all deaths must be notified within 24 hours to the Sponsor with 
standard forms. A serious adverse event regarded by the investigator as related to the patient 
participating in the study, even if it occurred before or after study treatment administration, must be 
reported. Serious Adverse Event up to 60 days after the last study treatment will be reported. All 
Serious Adverse Events will be followed until resolution or until it is confirmed by the PI and/or the 
Study Responsible Physician that it is no longer necessary to do so. In case the investigator knows 
about a serious adverse event after the patient withdrawal from the study, he must inform the sponsor 
as far as he considers the serious adverse event as related to the study treatment.  
For all serious adverse events, the Serious Adverse Event Report Form must be filled and sent to BIRD 
within 24 hours. Rules and regulations: By agreeing with this study procedures, the investigator 
commits himself to take these responsibilities.  
SERIOUS ADVERSE EVENTS MUST BE REPORTED TO BIRD Central Office by using sae@birdgroup.be  
Alternatively, notifications can also be done by phone (+32 499 31 70 05). Using the postal address 
(Leuvensesteenweg 643, 1930 Nossegem) is only an option for notification of additional information 
as the initial 24h window of reporting cannot be guaranteed. 
Rules and regulations: By agreeing with this protocol, the investigator commits himself to take these 
responsibilities.  
BIRD commits to fulfil the annual DSUR reporting to the CA and central EC. In the event of SUSAR 
occurrence, BIRD will comply to necessary reporting to CA and central EC as well as informing the 
investigators.  
11.7 Pregnancy  
 Female subjects who become pregnant while participating in this study will be the subject of a 
notification to the coordinators within two weeks after notification of the pregnancy with the help of 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 32 of 45 
 
the « Pregnancy Initial Statement ». The pregnancy will result in the patient’s withdrawal from the 
study but a follow-up will continue until the pregnancy is carried to full term.  
Male subjects whose partner becomes pregnant while participating in this study will be the subject of 
a notification to the coordinators within two weeks after notification of the pregnancy with the help 
of the « Pregnancy Initial Statement ». The pregnancy will not result in the male subject’s withdrawal 
from the study but a follow-up will continue until the pregnancy is carried to full term on the condition 
that the partner has signed an ICF given permission to collect information regarding pregnancy follow-
up and outcome. The pregnancy follow-up will be recorded on a « Pregnancy Follow-Up » form, which 
will be sent to the investigator within 6 to 8 weeks following the presumed date of term. Pregnancy is 
not considered as an adverse event but any complication such as spontaneous miscarriage or 
therapeutic interruption of the pregnancy will have to be considered as an adverse event.  
11.8 Biological and other abnormalities  
 Biological abnormalities (biochemistry, haematology, urinalysis) or abnormal results of exams (ECG, 
X-Ray…) considered as clinically significant by the investigator, must, if corresponding to the definition 
of an adverse event (serious or not), be recorded. Biological abnormalities or abnormal exams 
regarded as clinically significant by the investigator are considered adverse event if they are detected 
after administration of the study drug or are present upon inclusion and worsen during study.  
On the contrary, biological abnormalities or abnormal results of exams regarded as clinically significant 
by the investigator are not considered as adverse or serious adverse even if they are related to the 
disease under therapy (except if they are more severe than expected according to the patient's 
condition) or are present before inclusion (or discovered at inclusion) and did not worsen during the 
study.  
11.9 Safety committee 
A Safety Committee composed of two international IBD experts (W. Reinish and D. Laharie) not 
involved in the study will be constituted to consider life-threatening adverse events and fatalities 
occurring during the study. According to recommendations of this committee, the Principal 
Investigators can decide to interrupt the study as appropriate. 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 33 of 45 
 
12 Statistics 
12.1 Assumption  
The proportion of patients in steroid-free clinical and biological (FCP) remission is assumed to be higher 
in the IV re-induction followed by Q4W maintenance arm compared to the UST IV re-induction 
followed by Q8W maintenance.  The study will be powered to have at least 80% power detect a 30% 
difference between the 2 treatment groups regardless of the rate in the reference group (Q8W 
maintenance group). 
12.2 Planned analysis  
Baseline characteristics will be tabulated and differences between the two treatment groups will be 
examined by means of descriptive statistics. 
The primary analysis set will be based on all patients randomized following the intention to treat  
principle. In addition, also secondary analyses in a per protocol analysis set will be performed.  
Primary and secondary outcomes will be compared between treatment arms. The primary endpoint 
will be analysed using a stratified (on both factors on which randomisation was performed) risk 
difference with a 95% two-sided confidence interval. Multiple imputation will be performed to deal 
with missing data.  
A full statistical analysis plan will be written before data base lock. 
 
12.3 Power calculation 
To achieve 80% power to detect an expected 30% difference in proportions of treatment response 
between the two study arms using a chi-square test with a two-sided alpha of 5%, between 64 to 86 
patients in total are necessary depending on the rate in the reference group ranging from 10% to 60%. 
The maximum sample size of 86 patients corresponds with about a 35% vs 65% response rate and has 
90% power for a reference rate of 10% or 60%. To account further for an expected attrition rate of 
20%, the study therefore requires 108 patients (54 patients in each treatment arm) to achieve at least 
80% power regardless of the response rate in the reference group.  
 
13 Quality Assurance 
A Monitoring Plan will be set up by the BIRD and regular monitoring will be performed centrally or at 
site to ensure quality of the data. Protocol deviations will be discussed with the Investigator and 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 34 of 45 
 
retraining will be provided as appropriate. The investigator and co-investigators agree to welcome the 
BIRD’s monitors or designee as needed for monitoring purposes. After each site visit, monitors will 
complete a Monitoring Visit Report (MVR) and send a follow up letter to the Investigator to address 
issues requiring follow up. The MVR will be kept at BIRD and is available for review by regulatory 
authorities as needed.  
Investigator will contact BIRD immediately if they are informed of an upcoming inspection by 
regulatory authority for the study at their site. 
14 Direct access to source data and documents 
The investigator and the institution will permit study-related monitoring, audits, EC review, and 
regulatory inspections (where appropriate) by providing direct access to source data and other 
documents (i.e. patients’ case sheets). Investigators agree to make themselves available for discussion 
on findings and corrective actions as needed.  
15 Ethics and regulatory approvals 
The study will be conducted in compliance with the principles of the Declaration of Helsinki (2008), the 
principles of GCP and in accordance with all applicable regulatory requirements. This protocol and 
related documents will be submitted for approval to Ethics Committee and for notification to 
Competent Authority according to the latest Belgian regulation.   
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, or 
their legal representatives, to participate in the Study. The Participating Site shall obtain a signed 
informed consent form (ICF) for all patients prior to their enrollment and participation in the Study in 
compliance with all applicable laws, regulations and the approval of the (local) Ethics Committee, if 
required. The Participating Site shall retain such ICFs in accordance with the requirements of all 
applicable regulatory agencies and laws. 
The Investigator and the Participating Site shall treat all information and data relating to the Study 
disclosed to Participating Site and/or Investigator in this Study as confidential and shall not disclose 
such information to any third parties or use such information for any purpose other than the 
performance of the Study. The collection, processing and disclosure of personal data, such as patient 
health and medical information is subject to compliance with applicable local law and personal data 
protection and the processing of personal data (Belgian law of December 8, 1992 on the Protection of 
the Privacy in relation to the Processing of Personal Data). 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 35 of 45 
 
According to the European General Data Protection Regulation 2016/679, the subjects will be informed 
through the ICF that the sponsor will hold responsibility for the processing of their data relating to the 
study. This ICF will contain the contact details for the local data protection officer at the site where 
they have been enrolled in this study as well as contact details for the Belgian authority agency for 
data protection. 
16 Data Management 
Demographics, disease characteristics, medical history and current and past treatments for CD will be 
recorded on a study worksheet if not available in the patient’s medical file to be used as source 
document and collected afterwards in an electronic CRF (eCRF) provided by BIRD. Endoscopy video 
images will be recorded electronically and will be stored in a secured electronic video database. The 
data in the eCRF and the video database will be coded with a unique code to assure anonymization 
of the subject included in the study. The code is a 5-digit code based consecutively number, based 
on the 2 digits site number and the 3 digits inclusion number. Exp:  XX - XXX. 
17 Data ownership 
All data that will be acquired in the trial will be the property of the Belgian IBD research and 
development group.  No use and no transmission to a third party will be made possible without its 
prior consent 
18 Publication Policy 
It is anticipated that the results of the overall Study shall be published in a multi-centre publication, 
involving the data of all clinical sites participating in the Study. 
Participating Site is not allowed to publish any data or results from the Study prior to the multicentre 
publication, provided however that Participating Site can publish the results generated at the 
Participating Site if the multicentre publication has not occurred after 12 months from Study database 
lock. 
Any publication by Participating Site will be submitted to the Sponsor for review at least fourteen (14) 
days prior to submission or disclosure. Sponsor shall have the right to delay the projected publication 
for a period of up to three (3) months from the date of first submission to the Sponsor to enable the 
Sponsor to take steps to protect its intellectual property rights and know-how.  
Publications will be coordinated by the BIRD. Authorship to publications will be determined in 
accordance with the requirements published by the International Committee of Medical Journal 
Editors and in accordance with the requirements of the respective medical journal.  PB will be first 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 36 of 45 
 
author and SV will be last author on the principal paper. JFR and *** will have a significant place 
(second or second last) in the author list on the principal paper based on significant scientific 
contribution.  All investigators will be mentioned as co-author on the principal paper depending on 
their input (number of included patients > input in data evaluation > input in the manuscript writing). 
19 Insurance/Indemnity 
According to Belgian Law of May 7, 2004, BIRD contracted an insurance policy with the  
 MS AMLIN Insurance SE group covering civil liability for potential damages that could happen to any 
subject involved in this research in Belgium under agreement No  LXX080984.  The sponsor shall 
secure and maintain at their own expense in full force and effect through the performance of the 
Study (and following termination of the Study to cover any claims arising from the Study) insurance 
coverage in amounts appropriate to the conduct of the Study and in conformance with applicable 
legal and regulatory requirements as well as comprehensive and professional liability insurance of 
reasonable policy limits for their own country. 
 In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
National Coordinator Institution shall assume, even without fault, the responsibility of any damages 
incurred by a Study Patient and linked directly or indirectly to the participation to the Study, and shall 
provide compensation therefore through its insurance.” 
BIRD reserves the right to terminate the study at any time for medical or administrative reasons 
without any compensation other than for work already performed. The investigator will be notified in 
this case. 
20 Financial Aspects 
The funding of the trial is based on an investigator initiation research funding by Janssen-Cilag NV.  
21 Abbreviations  
 
AP 
 
abdominal pain 
AST 
 
aspartate aminotransferase 
ALT 
 
alanine aminotransferase 
BIRD 
 
Belgian IBD research and development group 
BMI 
 
body mass index 
CD 
 
Crohn’s disease 
CRF 
 
clinical research file 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 37 of 45 
 
CRP 
 
C-reactive protein 
ECG 
 
electrocardiogram 
EU 
 
European Union 
FCP 
 
fecal calprotectin 
GCP 
 
good clinical practice 
GETAID  
Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif 
Hep 
 
hepatitis 
HIV 
 
Human immunodeficiency virus 
IBD 
 
inflammatory bowel disease  
ICF 
 
informed consent form  
IEC 
 
institutional ethical committee  
IHC 
 
international health council 
IL 
 
interleukin 
IRB 
 
institutional review board 
IV 
 
intravenous 
MVR 
 
Monitoring Visit Report 
PD 
 
pharmacodynamics 
PK 
 
pharmacokinetic 
PRO 
 
patient reported outcome 
SAE 
 
Serious adverse event 
SC 
 
subcutaneous 
SES-CD  
simple endoscopic score for Crohn’s disease 
SF 
 
stool frequency 
SF-36  
36-Item Short Form Survey Instrument   
SmPC  
Summary of the Product Characteristics 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TB 
 
Tuberculosis 
TC 
 
trough concentration 
TNF  
 
tumour necrosis factor  
ULN 
 
upper limit of normal  
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 38 of 45 
 
UST 
 
ustekinumab 
WPAI   
Work Productivity and Activity Impairment 
 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 39 of 45 
 
22 Bibliography 
1. 
Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet 2017;389:1741-
55. 
2. 
Pouillon L, Bossuyt P, Peyrin-Biroulet L. Considerations, challenges and future of anti-tnf 
therapy in treating inflammatory bowel disease. Expert Opin Biol Ther 2016;16:1277-90. 
3. 
Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance 
therapy for crohn's disease. N Engl J Med 2016;375:1946-60. 
4. 
Ma C, Fedorak RN, Kaplan GG, et al. Long-term maintenance of clinical, endoscopic, and 
radiographic response to ustekinumab in moderate-to-severe crohn's disease: Real-world 
experience from a multicenter cohort study. Inflamm Bowel Dis 2017;23:833-9. 
5. 
Wils P, Bouhnik Y, Michetti P, et al. Long-term efficacy and safety of ustekinumab in 122 
refractory crohn's disease patients: A multicentre experience. Aliment Pharmacol Ther 
2018;47:588-95. 
6. 
Verstockt, al Be. Ustekinumab induces limited mucosal healing after 6 months in a real-life, 
prospective cohort of patients with refractory crohn’s disease.  . ECCO 2018, 2018: poster 
704. 
7. 
Adedokun OJ, Xu Z, Gasink C, et al. Pharmacokinetics and exposure response relationships of 
ustekinumab in patients with crohn's disease. Gastroenterology 2018;154:1660-71. 
8. 
Heron, al Ve. Reinduction with ustekinumab in crohn’s disease patients with a loss of 
response to treatment. ECCO 2018 poster 438. 
 
23 Appendices 
23.1 Appendix 1: PRO-2 
Variable 
Day 
7 day average 
 
1 
2 
3 
4 
5 
6 
7 
 
Number of 
liquid or very 
soft stools per 
day 
 
 
 
 
 
 
 
 
Abdominal 
pain: none=0, 
mild=1, 
moderate=2, 
severe=3 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 40 of 45 
 
23.2 Appendix 2: SES-CD 
 
 
23.3 Appendix  3: SF-36 
INSTRUCTIONS: Please answer every question. Some questions may look like others, but each one is 
different. Please take the time to read and answer each question carefully by circling the number 
that best represents your response. 
 
1. In general, would you say your health is? 
Excellent 
(1) 
Very Good 
(2) 
Good 
(3) 
Fair 
(4) 
Poor 
(5) 
 
2. Compared to one year ago, how would you rate your health in general now? 
Much better 
now than one 
year ago 
Somewhat 
better now than 
one year ago 
About the same 
as one year ago 
Somewhat worse 
now than one 
year ago 
Much worse now 
than one year 
ago 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 41 of 45 
 
(1) 
(2) 
 
(3) 
(4) 
(5) 
 
3. The following questions are about activities you might do during a typical day. Does your health 
now limit you in these activities? If so, how much: (circle one number on each line) 
 
Yes, 
Limited A 
Lot 
Yes, 
Limited A 
Little 
No, Not 
Limited 
At All 
A. Vigorous activities, such as running, lifting heavy 
objects participating in strenuous sports 
1 
2 
3 
B. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
1 
2 
3 
C. Lifting or carrying groceries  
1 
2 
3 
D. Climbing several flights of stairs 
1 
2 
3 
E. Climbing one flight of stairs 
1 
2 
3 
F. Bending, kneeling, or stooping 
1 
2 
3 
G. Walking more than a mile 
1 
2 
3 
H. Walking several hundred yards 
1 
2 
3 
I. Walking one hundred yards 
1 
2 
3 
J. Bathing or dressing yourself 
1 
2 
3 
  
4. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities as a result of your physical health? (Circle one 
number on each line)  
 
 
All the 
time 
Most 
of the 
time 
Some 
of the 
time 
A little 
of the 
time 
None 
of the 
time 
A. Cut down on the amount of time you 
spend on work or other activities 
1 
2 
3 
4 
5 
B. Accomplished less than you would like 
1 
2 
3 
4 
5 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 42 of 45 
 
C. Were limited in the kind of work or other 
activities  
1 
2 
3 
4 
5 
D. Had difficulty performing the work or 
other activities (for example, it took extra 
effort) 
1 
2 
3 
4 
5 
 
5. During the past 4 weeks, how much of the time have you had any of the following problems 
with your work or other regular daily activities as a result of any emotional problems (such as 
feeling depressed or anxious)? (Circle one number on each line) 
 
 
All the 
time 
Most 
of the 
time 
Some 
of the 
time 
A little 
of the 
time 
None 
of the 
time 
A. Cut down on the amount of time you 
spend on work or other activities 
1 
2 
3 
4 
5 
B. Accomplished less than you would like 
1 
2 
3 
4 
5 
C. Did work or activities less carefully than 
usual  
1 
2 
3 
4 
5 
 
6. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your social activities with family, friends, neighbours, or groups? (Circle one) 
 
Not at all 
(1) 
Slightly 
(2) 
Moderately 
(3) 
Quite a bit 
(4) 
Extremely  
(5) 
 
7. How much bodily pain have you had during the past 4 weeks? (Circle one) 
 
None 
(1) 
Very Mild 
(2) 
Mild 
(3) 
Moderate  
(4) 
Severe 
(5) 
Very Severe 
(6) 
 
8. During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)? (Circle one) 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 43 of 45 
 
Not at all 
(1) 
Slightly 
(2) 
Moderately 
(3) 
Quite a bit 
(4) 
Extremely  
(5) 
 
9. These questions are about how you feel and how things have been with you during the past 4 
weeks. For each question, please give the one answer that comes closest to the way you have been 
feeling. How much of the time during the past 4 weeks… (Circle one number on each line) 
 
All the 
time 
Most 
of the 
time 
Some 
of the 
time 
A little 
of the 
time 
None 
of the 
time 
A. did you feel full of life? 
1 
2 
3 
4 
5 
B. have you been very nervous? 
1 
2 
3 
4 
5 
C. have you felt so down in the dumps 
nothing could cheer you up? 
1 
2 
3 
4 
5 
D. have you felt calm and peaceful? 
1 
2 
3 
4 
5 
E. did you have a lot of energy? 
1 
2 
3 
4 
5 
F. have you felt downhearted and 
depressed? 
1 
2 
3 
4 
5 
G. did you feel worn out? 
1 
2 
3 
4 
5 
H. have you been happy? 
1 
2 
3 
4 
5 
I. did you feel tired? 
1 
2 
3 
4 
5 
 
10. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting friends, relatives, etc.)? 
All of the Time 
 
(1) 
Most of the Time 
(2) 
Some of the 
Time 
(3) 
A Little of the 
Time 
(4) 
None of the 
Time 
(5) 
 
11. How TRUE or FALSE is each of the following statements for you? (Circle one number on each 
line) 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 44 of 45 
 
 
Definitely 
True 
Mostly 
True 
Don’t 
Know 
Mostly 
False 
Definitely 
False 
A. I seem to get sick a little easier than 
other people 
1 
2 
3 
4 
5 
B. I am as healthy as anybody I know 
1 
2 
3 
4 
5 
C. I expect my health to get worse 
1 
2 
3 
4 
5 
D. My health is excellent 
1 
2 
3 
4 
5 
 
23.4 Appendix 4:WPAI -CD 
The following questions ask about the effect of your Crohn’s disease on your ability to work 
and perform normal daily activities. Please provide answers or choose a number, as 
indicated. 
 
1. Are you currently in paid employment? 
 
If NO, choose “NO” and skip to question 6. 
 
 
_____NO  
  _____YES 
 
The next questions refer to the PAST SEVEN DAYS, not including today. 
 
2.  During the past seven days, how many hours did you miss from work because of 
problems ASSOCIATED WITH YOUR CROHN’S DISEASE? Include hours you missed 
on sick days, times you went in late, left early, etc., because of your Crohn’s disease. Do 
not include time you missed to participate in this study. 
 
_____HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of any 
other reason, such as annual leave, holidays, time off to participate in this study? 
 
_____HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS (If “0”, skip to question 6) 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2

REScUE -BIRD2018001 - V1.7-09Feb2022 
 
EudraCT number: 2018-004269-14 
confidential 
 
Page 45 of 45 
 
 
5. During the past seven days, how much did your Crohn’s disease affect your productivity 
WHILE YOU WERE WORKING? 
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual. If Crohn’s disease affected your work only a little, choose a low number. 
Choose a high number if Crohn’s disease affected your work a great deal. 
 
Crohn’s disease 
had no effect on 
my work 
 
 
 
 
 
 
 
 
 
 
 
Crohn’s disease 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CHOOSE A NUMBER 
 
6. 
During the past seven days, how much did your Crohn’s disease affect your ability to 
perform your normal daily activities, excluding your job? 
 
By normal activities, we mean the usual activities you perform, such as working around 
the house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could perform and times you accomplished 
less than you would like. If Crohn’s disease affected your activities only a little, choose a 
low number. Choose a high number if Crohn’s disease affected your activities a great 
deal. 
 
Crohn’s disease 
had no effect on 
my daily 
activities 
 
 
 
 
 
 
 
 
 
 
 
Crohn’s disease 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CHOOSE A NUMBER 
 
 
 
 
 
 
 
DocuSign Envelope ID: 1E501846-7F99-4A90-8348-5FD5A2EF5CD2