A 14 Week Phase 2b, Randomized, Double-Blind, Dose-Ranging Study to Determine the Pharmacokinetics, Efficacy, Safety and Tolerability of TEV-48574 in Adult Patients With Ulcerative Colitis or Crohn's Disease (RELIEVE UCCD)
Phase: PHASE2
Conditions: Crohn Disease, Colitis, Ulcerative
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

 
 
 
Clinical Study Protocol 
 
 
A 14-Week Phase 2b, RandomizEd, Double-BLind, Dose-Ranging Study to 
Determine the PharmacokInetics, Efficacy, Safety, and Tolerability of TEV-48574 
in Adult PatiEnts with Moderate to Severe Ulcerative Colitis or Crohn’s Disease 
(RELIEVE UCCD) 
 
 
Study Number TV48574-IMM-20036 
 
 
NCT05499130 
 
 
Protocol with Amendment 04 Approval Date: 08 July 2024 
 

Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
1 
 
  
Clinical Study Protocol Amendment 04 (JP05) (ES 01) (FR 01) 
Study Number TV48574-IMM-20036 
A 14-Week Phase 2b, RandomizEd, Double-BLind, Dose-Ranging Study to Determine the 
PharmacokInetics, Efficacy, Safety, and Tolerability of TEV-48574 in Adult PatiEnts with 
Moderate to Severe Ulcerative Colitis or Crohn’s Disease (RELIEVE UCCD) 
Short title: A Randomized, Double-Blind Study on Pharmacokinetics, Efficacy, Safety, and 
Tolerability of TEV-48574 in Adults with IBD 
Lay title: A Study to Test the Effect of TEV-48574 in Moderate to Severe Ulcerative Colitis 
or Crohn’s Disease 
Dose-Ranging Study (Phase 2b) 
IND number: 157634; 
NDA number: Not applicable; BLA number: Not applicable; 
EU CT number: 2024-511089-36-00 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
Protocol Approval Date: 03 February 2022 
Protocol with Amendment 01 Approval Date: 13 June 2022 
Protocol with Amendment 01 (JP 01) Approval Date: 15 August 2022 
Protocol with Amendment 01 (JP 02) Approval Date: 03 October 2022 
Protocol with Amendment 02 (JP 02) Approval Date: 13 January 2023 
Protocol with Amendment 02 (JP 02) (ES 01) Approval Date: 27 March 2023 
Protocol with Amendment 03 (JP 03) (ES 01) Approval Date: 28 June 2023 
Protocol Amendment 03 with Revision 01 (JP 03) (ES 01) Approval Date: 15 August 2023 
Protocol Amendment 03 with Revision 01 (JP 04) (ES 01) Approval Date: 21 September 
2023 
Protocol Amendment 04 (JP 05) (ES 01) (FR 01) Version Date: 08 July 2024 
 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
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Study TV48574-IMM-20036 
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region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs). 
Confidentiality Statement 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from the sponsor. 
©2024 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 
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DOCUMENT HISTORY  
 
Amendment 04 (JP 05) (ES 01) 
(FR 01) 
08 July 2024 
563* patients screened and 229* patients randomized to date 
Administrative Letter 02 
21 June 2024 
563* patients screened and 229* patients randomized to date 
Administrative Letter 01  
25 September 2023 
90 patients screened and 30 patients randomized to date 
Amendment 03 with Revision 01 
(JP 04) (ES 01) 
21 September 2023  
83 patients screened and 26 patients randomized to date 
Amendment 03 with Revision 01 
(JP 03) (ES 01) 
15 August 2023 
58 patients screened and 18 patients randomized to date 
Amendment 03 (JP 03) (ES 01) 
28 June 2023 
35 patients screened and 09 patients randomized to date 
Amendment 02 (JP 02) (ES 01) 
27 March 2023 
20 patients screened and 04 patients randomized to date  
Amendment 02 (JP 02) 
13 January 2023 
05 patients screened and 02 patients randomized to date 
Amendment 01 (JP 02) 
03 October 2022 
02 patients screened and 00 patients randomized to date 
Amendment 01 (JP 01) 
15 August 2022 
00 patients enrolled to date 
Amendment 01 
13 June 2022 
00 patients randomized/enrolled to date 
Original Protocol 
03 February 2022 
* Patient numbers as of 21 June 2024 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and the respective global administrative letters are provided in Section 17. 
The country specific amendments along with local administrative letters for France and Japan are 
provided in Appendix M. 
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INVESTIGATOR AGREEMENT  
Original Protocol Dated 03 February 2022 
Protocol with Amendment 01 Dated 13 June 2022 
Protocol with Amendment 01 (JP 01) Approval Date: 15 August 2022 
Protocol with Amendment 01 (JP 02) Approval Date: 03 October 2022 
Protocol with Amendment 02 (JP 02) Approval Date: 13 January 2023 
Protocol with Amendment 02 (JP 02) (ES 01) Approval Date: 27 March 2023 
Protocol with Amendment 03 (JP 03) (ES 01) Approval Date: 28 June 2023 
Protocol Amendment 03 with Revision 01 (JP 03) (ES 01) Approval Date: 15 August 2023 
Protocol Amendment 03 with Revision 01 (JP 04) (ES 01) Approval Date: 21 September 
2023 
Protocol Amendment 04 (JP 05) (ES 01) (FR 01) Version Date: 08 July 2024 
 
IND number: 157634; 
NDA number: Not applicable; BLA number: Not applicable; 
EU CT number: 2024-511089-36-00 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
A 14-Week Phase 2b, RandomizEd, Double-BLind, Dose-Ranging Study to Determine the 
PharmacokInetics, Efficacy, Safety, and Tolerability of TEV-48574 in Adult PatiEnts with 
Moderate to Severe Ulcerative Colitis or Crohn’s Disease (RELIEVE UCCD) 
Principal Investigator:  
 
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
I have read the protocol Amendment 04 (JP 05) (ES 01) (FR 01) and agree that it contains all 
necessary details for carrying out this study. I am qualified by education, experience, and 
training to conduct this clinical research study. The signature below constitutes agreement with 
this protocol and attachments, and provides assurance that this study will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to national or local legal and regulatory requirements and applicable regulations and 
guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
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reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations. 
Principal Investigator 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
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SPONSOR PROTOCOL APPROVAL 
Sponsor’s Authorized Representative 
 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
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COORDINATING INVESTIGATOR AGREEMENT  
Original Protocol Dated 03 February 2022 
Protocol with Amendment 01 Dated 13 June 2022 
Protocol with Amendment 01 (JP 01) Approval Date: 15 August 2022 
Protocol with Amendment 01 (JP 02) Approval Date: 03 October 2022 
Protocol with Amendment 02 (JP 02) Approval Date: 13 January 2023 
Protocol with Amendment 02 (JP 02) (ES 01) Approval Date: 27 March 2023 
Protocol with Amendment 03 (JP 03) (ES 01) Approval Date: 28 June 2023 
Protocol Amendment 03 with Revision 01 (JP 03) (ES 01) Approval Date: 15 August 2023 
Protocol Amendment 03 with Revision 01 (JP 04) (ES 01) Approval Date: 21 September 
2023 
Protocol Amendment 04 (JP 05) (ES 01) (FR 01) Version Date: 08 July 2024 
 
IND number: 157634; NDA number: Not applicable; BLA number: Not applicable; 
EU CT number: 2024-511089-36-00 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
A 14-Week Phase 2b, RandomizEd, Double-BLind, Dose-Ranging Study to Determine the 
PharmacokInetics, Efficacy, Safety, and Tolerability of TEV-48574 in Adult PatiEnts with 
Moderate to Severe Ulcerative Colitis or Crohn’s Disease (RELIEVE UCCD) 
I have read the protocol Amendment 04 (JP 05) (ES 01) (FR 01) and agree that it contains all 
necessary details for carrying out this study. I am qualified by education, experience, and 
training to conduct this clinical research study. The signature below constitutes agreement with 
this protocol and attachments, and provides assurance that this study will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to national and local legal and regulatory requirements and applicable regulations and 
guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations 
as well as all other national and international laws and regulations. In addition, I will assume the 
responsibility of the coordinating investigator according to a separate contract. 
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Coordinating Investigator 
 
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
 
Coordinating Investigator 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
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1. 
PROTOCOL SUMMARY  
1.1. 
Protocol Synopsis  
Protocol Title: A 14-Week Phase 2b, RandomizEd, Double-BLind, Dose-Ranging Study to 
Determine the PharmacokInetics, Efficacy, Safety, and Tolerability of TEV-48574 in Adult 
PatiEnts with Moderate to Severe Ulcerative Colitis or Crohn’s Disease (RELIEVE UCCD) 
Regulatory Agency Identifier Number: IND number: 157634; NDA number: Not applicable; 
BLA number: Not applicable; EU CT number: 2024-511089-36-00 
Rationale: Many patients with inflammatory bowel disease (IBD) do not respond, lose response, 
or are intolerant to currently available treatments for ulcerative colitis (UC) and Crohn’s disease 
(CD). Furthermore, some of the available therapeutic agents for IBD have been associated with 
significant safety issues. The anti- tumor necrosis factor (ligand) 1A (TL1A) activity of TEV-
48574 may have an anti-inflammatory and anti-fibrotic effect in patients with IBD, leading to 
improvement of their disease conditions, while demonstrating an acceptable safety profile. This 
study will determine the pharmacokinetics, efficacy, safety, and tolerability of 2 different doses 
of TEV-48574 subcutaneously (sc) administered every 2 weeks (Q2W) in adult patients with 
moderate to severe UC or CD. 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
The primary objective of the study 
is to characterize the efficacy of 
TEV-48574 subcutaneously (sc) 
administered every 2 weeks (Q2W) 
in adult patients with inflammatory 
bowel disease (IBD) (moderate to 
severe ulcerative colitis [UC] or 
Crohn’s disease [CD]), as assessed 
by induction of clinical remission 
(UC) and endoscopic response (CD) 
at week 14. 
The primary efficacy endpoint is response (yes or no) at week 14, where 
response in UC patients is defined as clinical remission and response in CD 
patients is defined as endoscopic response. Clinical remission and endoscopic 
response are determined as follows: 
• 
Clinical remission at week 14 in patients with moderate to severe UC. 
Clinical remission is a modified (9-point rectal bleeding, stool frequency, 
and endoscopy) Mayo score of ≤2 points, which is defined by:  
- 
stool frequency subscore of 0 or 1, 
- 
rectal bleeding subscore of 0, and  
- 
endoscopic subscore of 0 or 1, where a score of 1 does not include 
“friability”  
• 
Endoscopic response at week 14 in patients with moderate to severe CD, 
defined as a reduction in Simple Endoscopic Score for Crohn’s Disease 
(SES-CD) of at least 50% from baseline 
A secondary objective of the study 
is to evaluate the efficacy of 2 
different doses of TEV 48574 sc 
administered Q2W in adult patients 
with IBD (moderate to severe UC 
or CD) as assessed by multiple 
standard measures at week 14. 
UC: 
• 
Clinical response at week 14, defined as a decrease from baseline in the 
modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo 
score of at least 2 points AND at least a 30% reduction from baseline 
with either a decrease in rectal bleeding subscore of at least 1 or an 
absolute rectal bleeding subscore of less than or equal to 1 
• 
Endoscopic improvement defined as a Mayo endoscopic subscore of 0 or 
1 at week 14  
• 
Endoscopic remission defined as a Mayo endoscopic subscore of 0 at 
week 14  
• 
Clinical response defined as decrease from baseline of at least 50% in 2-
item patient-reported outcome (PRO2; rectal bleeding and stool 
frequency) at week 14 
• 
Clinical remission defined as score of rectal bleeding = 0 and stool 
frequency = 0 on the PRO2 scale at week 14 
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CD: 
• 
Clinical response defined as a ≥100-point decrease in Crohn’s Disease 
Activity Index (CDAI) score from baseline at weeks 4, 8, 12 and 14 
• 
Clinical remission defined as a CDAI score <150 at week 14  
• 
Clinical response defined as a decrease from baseline of at least 50% in 
PRO2 (PRO2 is defined as having 2 components, abdominal pain and 
stool frequency) at week 14  
• 
Clinical remission defined as abdominal pain ≤1 and stool frequency ≤3 
on the PRO2 scale at week 14  
• 
Endoscopic response defined as a decrease in modified multiplier (MM)-
SES-CD of >50% from baseline at week 14 
A secondary objective of the study 
is to evaluate the safety and 
tolerability of 2 different doses of 
TEV-48574 sc administered Q2W 
in adult patients with IBD 
(moderate to severe UC or CD). 
• 
Adverse events 
• 
Change from baseline in clinical laboratory test results (serum chemistry, 
hematology, and urinalysis) 
• 
Change from baseline in vital signs measurements (blood pressure, pulse 
rate, body temperature, and respiratory rate) 
• 
Change from baseline in 12-lead electrocardiogram (ECG) findings 
• 
Patients who stopped the investigational medicinal product (IMP) due to 
adverse events 
• 
Local tolerability at the injection site 
A secondary objective of the study 
is to evaluate the immunogenicity 
of 2 different doses of TEV-48574 
sc administered Q2W in adult 
patients with IBD (moderate to 
severe UC or CD). 
• 
Change from baseline in treatment-emergent anti-drug antibody (ADA) 
at weeks 2, 4, 8, 14, and follow-up visit 
• 
Presence of neutralizing ADA in ADA positive patients at weeks 2, 4, 8, 
14, and follow-up visit 
Overall Design: This is a Phase 2b, randomized, double-blind, dose-ranging study to determine 
the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with 
moderate to severe UC or CD.  The study will consist of a screening period of up to 6 weeks (42 
days), a 14-week treatment period, and a 4 week follow-up period. After the end of the 14 week 
treatment period, all patients may be offered the option to enter a long-term extension study, 
which is described in a separate protocol (TV48574-IMM-20038). If they choose to enter (sign 
the extension study informed consent form [ICF]) and will subsequently be randomized into the 
long-term extension study, they will not need to complete the follow-up visit in this study. All 
other patients will return to the site for a follow-up visit. 
Trial Population: Adult of male and female (without restrictions on gender), with a diagnosis of 
IBD: moderate to severe UC or CD. 
Number of Participants: Approximately 480 patients will be screened to achieve approximately 
240 randomized patients (approximately 120 patients with UC and 120 patients with CD). The 
sample size does not include patients that were randomized to the 1800 mg treatment group prior 
to Amendment 03 with Revision 01. 
Trial Arms and Duration:  Patients who meet all the inclusion criteria and none of the 
exclusion criteria will be randomly assigned to receive TEV‑48574 (single loading dose/6 
induction doses): 2250/900 mg, 2250/450 mg, or placebo to match TEV-48574, stratified by 
diagnosis (UC or CD) and previous exposure to advanced therapy for IBD (yes/no) (biologics, 
Janus kinase [JAK] inhibitors, and sphingosine-1-phosphate [S1P] receptor modulators). Prior to 
Amendment 03 with Revision 01, patients were randomly assigned to receive 1 of 4 treatment 
regimens (2250/1800 mg, 2250/900 mg, 2250/450 mg, or placebo to match TEV‑48574); these 
patients will continue to receive the same dose, volume, and rate of administration of the IMP to 
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which they were initially randomized and will remain blinded. The total duration of participation 
for each patient is planned to be up to 24 weeks. The study duration will be approximately 27 
months, from Quarter 3 (Q3) 2022 until approximately Quarter 4 (Q4) 2024. 
Data Monitoring/Other Committee: Independent Data Monitoring Committee (IDMC) has 
been established to monitor the study while it is ongoing, including periodic reviews of safety 
data, and prespecified analyses of efficacy -data. 
Ethical Considerations: The study was developed in a manner to protect patient safety. Overall, 
the risks for patients in this study are mitigated comprehensively and are considered adequate to 
justify the study. 
1.2. 
Trial Schema  
This figure applies only to patients randomized as of Amendment 04. 
Patients randomized prior to Amendment 03 with Revision 01 will continue to receive the same 
dose, volume, and rate of administration of the IMP to which they were initially randomized and 
will remain blinded. 
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Figure 1: 
Overall Program Schematic  
 
CD=Crohn’s disease; FU=follow-up; I/E=inclusion/exclusion; ID=induction dose; LD=loading dose; PBO=placebo; SES-CD=Simple Endoscopic Score for Crohn’s Disease; 
UC=ulcerative colitis. 
Note: After the end of the 14-week treatment period, all patients may be offered the option to enter a long-term extension study (to be described in a separate protocol [TV48574-
IMM-20038]). If they choose to enter (sign the extension study ICF) and will subsequently be randomized into the long-term extension study, they will not need to complete the 
follow-up visit in this study. All other patients will return to the site for a follow-up visit (day 127 [±3 days]). 
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1.3. 
Schedule of Activities  
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 7 (efficacy 
assessments), Section 8 (safety assessments), and Section 9 (pharmacokinetic and other 
assessments). Study procedures and assessments by visit are listed in Appendix A. 
Exclusionary laboratory values can be retested once during the screening period. If the retested 
laboratory value(s) remain(s) exclusionary, the subject will be considered a screen failure. 
Redrawing samples if previous samples were unable to be analyzed would not count as a retest 
since previous result was never obtained. 
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Table 1: 
Study Procedures and Assessments  
Study period 
Screening  
(-42 to -1) 
Induction period 
Follow-upa,b  
Early 
terminationb 
Treatment perioda 
Study visit 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study week 
Week -6 to -1 Week 0 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 
Week 18 
Study day 
Day -42 to -1 
Day 1 
Day 15 Day 29 Day 43 
Day 57 
Day 71 
Day 85 
Day 99 
Day 127 
Visit window 
N/A 
N/A 
±3 days based on previous visit 
±3 days based 
on previous 
visit 
Enrollment procedures 
Informed consentc  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
Vital signs measurementsd  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight (lb or kg) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Height (in or cm) 
X 
 
 
 
 
 
 
 
 
 
 
Medical procedures 
Full physical exam 
X 
 
 
 
 
 
 
 
X 
X 
X 
Brief physical exam 
 
 
 
X 
 
X 
 
X 
 
 
 
ECG (12-lead)e  
X 
 
 
X 
 
X 
 
 
X 
 
X 
Endoscopy 
Endoscopyf  
Xg 
 
 
 
 
 
 
 
X 
 
X 
Disease activity analysis 
Modified Mayo score 
(UC only) 
X 
 
 
 
 
 
X 
 
X 
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Study period 
Screening  
(-42 to -1) 
Induction period 
Follow-upa,b  
Early 
terminationb 
Treatment perioda 
Study visit 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study week 
Week -6 to -1 Week 0 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 
Week 18 
Study day 
Day -42 to -1 
Day 1 
Day 15 Day 29 Day 43 
Day 57 
Day 71 
Day 85 
Day 99 
Day 127 
Visit window 
N/A 
N/A 
±3 days based on previous visit 
±3 days based 
on previous 
visit 
Stool frequency and Rectal 
bleeding Mayo sub-scores 
(PRO2 UC) h  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Robarts Histopathology 
Index (UC only) 
X 
 
 
 
 
 
 
 
X 
 
X 
CDAI score (CD only) 
X 
 
 
X 
 
X 
X 
X 
 
X 
Stool frequency and 
Abdominal pain  
(PRO2 CD) h 
X 
  
X 
X 
X 
X 
X 
X 
X 
 
X 
SES-CD (CD only) 
X 
 
 
 
 
 
 
 
X 
 
X 
MM-SES-CD (CD only) 
X 
 
 
 
 
 
 
 
X 
 
X 
Laboratory assessments 
Stool sample tests for 
enteric pathogens 
(including stool culture and 
C difficile toxin assay)i  
X 
 
 
 
 
 
 
 
 
 
 
Infectious serologiesj  
X 
 
 
 
 
 
 
 
 
 
 
TB screening 
(QuantiFERON® TB Gold 
Test)k  
X 
 
 
 
 
 
 
 
 
 
 
FSH testing (to confirm 
postmenopausal status) 
X 
 
 
 
 
 
 
 
 
 
 
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Study period 
Screening  
(-42 to -1) 
Induction period 
Follow-upa,b  
Early 
terminationb 
Treatment perioda 
Study visit 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study week 
Week -6 to -1 Week 0 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 
Week 18 
Study day 
Day -42 to -1 
Day 1 
Day 15 Day 29 Day 43 
Day 57 
Day 71 
Day 85 
Day 99 
Day 127 
Visit window 
N/A 
N/A 
±3 days based on previous visit 
±3 days based 
on previous 
visit 
Pregnancy test (serum) in 
women of childbearing 
potential 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) in 
women of childbearing 
potential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory testsl  
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Urinalysism  
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
Pharmacodynamics/biomarkers 
Retained pharmacogenetic 
sample 
 
Xn  
 
 
 
 
 
 
 
 
 
Biomarker hsCRP 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Serum free and total TL1Ao  
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Stool sample for fecal 
calprotectin (FeCal) or 
other stool-derived markers 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Biopsy towards tissue 
transcriptomics 
X 
 
 
 
 
 
 
 
X 
 
X 
Serum measure of PDp  
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Serum measures of tissue 
condition 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
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Study period 
Screening  
(-42 to -1) 
Induction period 
Follow-upa,b  
Early 
terminationb 
Treatment perioda 
Study visit 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Study week 
Week -6 to -1 Week 0 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 
Week 18 
Study day 
Day -42 to -1 
Day 1 
Day 15 Day 29 Day 43 
Day 57 
Day 71 
Day 85 
Day 99 
Day 127 
Visit window 
N/A 
N/A 
±3 days based on previous visit 
±3 days based 
on previous 
visit 
Biomarker 
 
 
X 
X 
 
 
X 
 
 
X 
 
X 
Pharmacokinetics and immunogenicity 
Serum TEV-48574 
concentrationo,q  
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
ADA and neutralizing 
ADAo 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Trial treatment procedures 
Randomization (after all 
screening procedures 
complete and eligibility 
confirmed) 
 
X 
 
 
 
 
 
 
 
 
 
IMP administrationr  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event monitorings  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant 
medication and treatmentst  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local tolerability 
assessmentu  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a After the end of the 14-week treatment period, all patients may be offered the option to enter a long-term extension study (to be described in a separate protocol 
[TV48574-IMM-20038]). If they choose to enter (sign the extension study ICF) and will subsequently be randomized into the long-term extension study, they 
will not need to complete the follow-up visit in this study. All other patients will return to the site for a follow-up visit (day 127 [±3 days]). 
b EOS is defined as the last visit of the last patient. 
c A separate informed consent form will be provided for pharmacogenetics samples. 
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d Vital signs measurements include blood pressure, pulse rate, body temperature, and respiratory rate. Patients are to remain in a supine position for at least 
5 minutes prior to measuring blood pressure and pulse rate. If possible, blood pressure measurements should be completed on the same arm at each visit. Vital 
signs should be measured before scheduled blood draws and after the ECG assessment when applicable. 
e ECG assessments should precede vital sign assessments. ECGs should be performed in a supine position after 5 minutes rest. At screening, ECGs will be 
performed in triplicate, with each ECG taken within 1 to 5 minutes of the previous one. 
f For UC patients, endoscopy will include a flexible sigmoidoscopy only (colonoscopy may be performed instead for baseline endoscopy if not done in the prior 
12 months). For CD patients, endoscopy will include ileo-colonoscopy. 
g The endoscopy should be performed after key eligibility criteria have been met and within approximately 10 calendar days of randomization (day 1) to allow 
for central endoscopy scoring. The endoscopic subscore by the central reader must be available at baseline visit. The assessment by the central reader will be 
used to derive the modified Mayo and SES-CD scores for study eligibility. An endoscopy is also performed at visit 8 (week 14) or at the early termination visit 
when applicable. Biopsies will be collected at screening and week 14 or the early termination visit.  
h For PRO2, rectal bleeding and stool frequency (UC) and stool frequency and abdominal pain (CD) will be collected (entered) daily by the patient via a 
handheld e-diary. The baseline values are obtained at the last screening visit prior to randomization. 
i Additional testing (eg, ova and parasites) may be performed at the investigator’s clinical discretion. 
j Serology includes hepatitis B core antibody and surface antigen, hepatitis C virus, and human immunodeficiency virus types 1 or 2. Patients with HBcAb 
positive and HBsAg negative serology and undetectable Hepatitis B viral DNA at screening may have follow-up Hepatitis B viral DNA testing throughout their 
participation in the study. 
k If the QuantiFERON® TB Gold Test is deemed by the principal investigator to be a false positive, additional sample will be tested to confirm the diagnosis. 
l Clinical laboratory tests including serum chemistry and complete blood count (hematology). Patients should be fasting for at least 8 hours prior to safety 
laboratory assessments only at the screening, week 14, and early termination visits (ie, visits at which low density lipoprotein, high density lipoprotein, and 
triglycerides will be measured). Coagulation tests (PT/PTT/INR) will be performed at screening only or in case of suspected liver injury (see Appendix K). The 
hematocrit value measured at screening will be used to calculate the baseline CDAI score. Screening laboratory test abnormalities, if considered by the 
Investigator to be transient and inconsistent with the patient’s clinical condition, may be repeated once during the screening period for confirmation. 
m When sampling urine, menstruation status should be recorded for women of childbearing potential. 
n If sample has not been collected at this visit, it could also be collected at one of the following visits. 
o In cases of a suspected severe systemic hypersensitivity reaction (eg, anaphylaxis), serious adverse event, or immunogenicity-related adverse event, efforts 
should be made to collect additional sample(s) for immunogenicity, serum total and free TL1A, and serum concentration of TEV-48574. In cases of suspected 
or confirmed anaphylaxis, efforts should be made to collect samples for ADA determination as close to the onset of the event as possible, at resolution, and 
30 days after onset of the event. Confirmed ADA positive samples may be further evaluated for TEV-48574 neutralizing antibodies. 
p Proteomics and potentially autoantibodies (pANCA, ASCA). 
q At visits where IMP is administered, samples should be taken prior to IMP administration (ie, trough levels). 
r If during administration or during post-IMP administration observation the patient develops clinical symptoms or signs, vital signs should be collected and a 
physical exam (brief or full, at the discretion of the investigator) performed. The patient should be assessed for anaphylaxis/hypersensitivity reactions. All 
device-related adverse events, malfunctions, etc will be recorded and evaluated for their impact relative to the safety and efficacy of the IMP. 
s For each patient, adverse events will be captured from signature of the ICF to the end of study (ie, patient’s last visit). For those patients who enter the 
long-term extension study, adverse events will be recorded in the dose-ranging study CRF up until the date of extension study randomization (defined as the 
study completion date for the dose-ranging study). For those patients who screen fail the long-term extension study, adverse events will be recorded in the 
dose-ranging study up until the follow-up visit (day 127 [±3 days]) CRF. 
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t For each patient, concomitant medication data will be captured from signature of the ICF to the end of study (ie, patient’s last visit). For those patients who 
enter the long-term extension study, concomitant medication data will be recorded in the dose-ranging study CRF up until the date of extension study 
randomization (defined as the study completion date for the dose-ranging study). For those patients who screen fail the long-term extension study, concomitant 
medication data will be recorded in the dose-ranging study up until the follow-up visit (day 127 [±3 days]) CRF. 
u Pain will be assessed beginning, during (approximately midway through the infusion), and after the completion of IMP administration and 1 hour later. 
Administration site findings will be assessed after the completion of IMP administration and 1 hour later. Additionally, after the loading dose and first 
induction dose, assessments will also be performed 2 hours after the completion of IMP administration. Allowed time windows for the local tolerability 
assessments after the completion of the infusion are ±15 minutes. 
ADA=anti-drug antibody; ASCA=anti-Saccharomyces cerevisiae antibodies; C difficile=Clostridium difficile; CD=Crohn’s disease; CDAI=Crohn’s Disease 
Activity Index; CRF=case report form; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EOS=end of study; FSH=follicle-stimulating hormone; 
HBcAb=Hepatitis B core antibody; HBsAg=Hepatitis B surface antigen; hsCRP=high sensitivity C-reactive protein; ICF=informed consent form; 
IMP=investigational medicinal product; INR=international normalized ratio; MM-SES-CD=modified multiplier-Simple Endoscopic Score for Crohn’s Disease; 
N/A=not applicable; pANCA=perinuclear antineutrophil cytoplasmic antibodies;
; PD=pharmacodynamics; 
PRO2=2-item patient-reported outcome; PT=prothrombin time; PTT=partial thromboplastin time; Q2W=every 2 weeks; SES-CD=Simple Endoscopic Score for 
Crohn’s Disease; TB=tuberculosis; TL1A=tumor necrosis factor (ligand) 1A; UC=ulcerative colitis. 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
DOCUMENT HISTORY.................................................................................................................3 
INVESTIGATOR AGREEMENT...................................................................................................4 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................7 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Protocol Synopsis .........................................................................................................9 
1.2. 
Trial Schema ...............................................................................................................11 
1.3. 
Schedule of Activities .................................................................................................13 
LIST OF ABBREVIATIONS ........................................................................................................29 
2. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................33 
2.1. 
Introduction .................................................................................................................33 
2.1.1. 
Inflammatory Bowel Disease and Current Treatment Options ..................................33 
2.1.2. 
Relevance of Inhibition of TL1A Binding to Death Receptor 3 for 
Inflammatory Bowel Disease .....................................................................................35 
2.1.3. 
TEV-48574 and Inflammatory Bowel Disease ...........................................................36 
2.1.4. 
Purpose of Current Study ............................................................................................37 
2.2. 
Findings from Nonclinical and Clinical Studies .........................................................37 
2.2.1. 
Nonclinical Studies .....................................................................................................37 
2.2.2. 
Clinical Studies ...........................................................................................................38 
2.2.2.1. 
Phase 1 Study (TV48574-SAD-10126) ......................................................................38 
2.2.2.2. 
Phase 1 Study (TV48574-PK-10180) .........................................................................40 
2.2.2.3. 
Phase 2a Study (TV48574-AS-20031) .......................................................................41 
2.3. 
Known and Potential Benefits and Risks to Patients ..................................................41 
2.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................41 
2.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................42 
3. 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS ....................................43 
3.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................43 
3.1.1. 
Justification of Primary Endpoints .............................................................................44 
3.2. 
Primary Estimand .......................................................................................................45 
3.2.1. 
Supplementary Estimand ............................................................................................45 
3.3. 
Exploratory Objectives and Endpoints .......................................................................46 
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4. 
STUDY DESIGN .......................................................................................................48 
4.1. 
General Study Design and Study Schematic Diagram ...............................................48 
4.2. 
Planned Number of Patients and Countries ................................................................50 
4.3. 
Justification for Study Design and Selection of Population .......................................50 
4.4. 
Stopping Rules for the Study ......................................................................................51 
4.4.1. 
Individual Stopping Criteria .......................................................................................51 
4.4.1.1. 
Permanent Individual Withdrawn from IMP ..............................................................51 
4.4.1.2. 
Temporary Withholding of IMP .................................................................................53 
4.4.2. 
Study Stopping Criteria ..............................................................................................54 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................55 
5.1. 
Patient Inclusion Criteria ............................................................................................55 
5.2. 
Patient Exclusion Criteria ...........................................................................................57 
5.3. 
Withdrawal Criteria and Assessments/Procedures for the Patient .............................59 
5.4. 
Replacement of Patients .............................................................................................60 
5.5. 
Rescreening .................................................................................................................60 
5.6. 
Screening Failure ........................................................................................................60 
6. 
TREATMENTS ..........................................................................................................61 
6.1. 
Investigational Medicinal Products Used in the Study ...............................................61 
6.1.1. 
Test Investigational Medicinal Product ......................................................................61 
6.1.2. 
Placebo Investigational Medicinal Product ................................................................61 
6.1.3. 
Test and Placebo Investigational Medicinal Product Administration ........................62 
6.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products and Devices ........................................................63 
6.2.1. 
Preparation, Storage and Security ...............................................................................63 
6.2.2. 
Labeling ......................................................................................................................63 
6.2.3. 
Accountability .............................................................................................................64 
6.3. 
Justification for Investigational Medicinal Products ..................................................64 
6.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................64 
6.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................66 
6.3.3. 
Justification for Device Used for Administration .......................................................66 
6.4. 
Treatment After the End of the Study .........................................................................66 
6.5. 
Restrictions .................................................................................................................66 
6.5.1. 
Activity .......................................................................................................................66 
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6.5.2. 
Fasting.........................................................................................................................67 
6.5.3. 
Specific Food and Beverages ......................................................................................67 
6.5.4. 
Tobacco .......................................................................................................................67 
6.5.5. 
Blood Donation ...........................................................................................................67 
6.6. 
Prior and Concomitant Medication or Therapy ..........................................................67 
6.6.1. 
Prior Medications ........................................................................................................67 
6.6.2. 
Concomitant Medication(s) and Treatment(s) ............................................................67 
6.6.3. 
Permitted Inflammatory Bowel Disease Medications and Rescue 
Medications .................................................................................................................67 
6.6.4. 
Prohibited Medications and Therapies .......................................................................68 
6.7. 
Procedures for Monitoring Patient Compliance .........................................................69 
6.8. 
Randomization and Blinding ......................................................................................69 
6.9. 
Maintenance of Randomization and Blinding ............................................................69 
6.9.1. 
Maintenance of Randomization ..................................................................................69 
6.9.2. 
Blinding and Unblinding ............................................................................................69 
6.9.3. 
Independent Data Monitoring Committee ..................................................................70 
6.10. 
Total Blood Volume ...................................................................................................71 
7. 
ASSESSMENT OF EFFICACY ................................................................................72 
7.1. 
Assessments of Efficacy .............................................................................................72 
7.1.1. 
Modified Mayo Score (Ulcerative Colitis) .................................................................72 
7.1.2. 
Endoscopy ...................................................................................................................72 
7.1.2.1. 
Biopsy Collection .......................................................................................................72 
7.1.2.2. 
Simple Endoscopic Score for Crohn’s Disease ..........................................................73 
7.1.2.3. 
Modified Multiplier-Simple Endoscopic Score for Crohn’s Disease .........................73 
7.1.2.4. 
Robarts Histopathology Index (Ulcerative Colitis) ....................................................73 
7.1.2.5. 
Geboes Score (Ulcerative Colitis) ..............................................................................73 
7.1.2.6. 
Global Histologic Activity Score (Crohn’s Disease) ..................................................73 
7.1.3. 
Crohn’s Disease Activity Index ..................................................................................73 
7.1.4. 
Two-item Patient-Reported Outcome (Ulcerative Colitis and Crohn’s 
Disease) .......................................................................................................................74 
8. 
ASSESSMENT OF SAFETY .....................................................................................75 
8.1. 
Adverse Events and Adverse Device Effects .............................................................75 
8.1.1. 
Definition of an Adverse Event ..................................................................................75 
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8.1.2. 
Definition of an Adverse Device Effect .....................................................................76 
8.1.3. 
Recording and Reporting of Adverse Events .............................................................76 
8.1.4. 
Recording and Reporting of Adverse Device Effect ..................................................77 
8.1.5. 
Severity of an Adverse Event .....................................................................................79 
8.1.6. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device ..............................................................................................................79 
8.1.7. 
Serious Adverse Events and Serious Adverse Device Effects ...................................80 
8.1.7.1. 
Definition of a Serious Adverse Event .......................................................................80 
8.1.7.2. 
Definition of a Serious Adverse Device Effect ..........................................................81 
8.1.7.3. 
Expectedness ...............................................................................................................81 
8.1.8. 
Reporting a Serious Adverse Event ............................................................................82 
8.1.8.1. 
Investigator Responsibility .........................................................................................82 
8.1.8.2. 
Sponsor Responsibility ...............................................................................................83 
8.1.9. 
Reporting a Serious Adverse Device Effect ...............................................................83 
8.1.10. 
Protocol-Defined Adverse Events of Special Interest ................................................84 
8.1.10.1. 
Protocol-Defined Adverse Events of Special Interest that Require Reporting 
to Sponsor’s Global Patient Safety and Pharmacovigilance.......................................84 
8.1.10.2. 
Protocol-Defined Adverse Events of Special Interest that Do Not Require 
Reporting to Sponsor’s Global Patient Safety and Pharmacovigilance ......................85 
8.1.11. 
Protocol Deviations Because of an Adverse Event ....................................................85 
8.2. 
Assessment of Local Tolerability and Pain ................................................................86 
8.3. 
Pregnancy ...................................................................................................................87 
8.4. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................88 
8.5. 
Clinical Laboratory Tests ...........................................................................................89 
8.5.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................90 
8.5.2. 
Other Clinical Laboratory Tests .................................................................................90 
8.5.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................91 
8.5.2.2. 
Follicle-Stimulating Hormone ....................................................................................91 
8.6. 
Physical Examinations ................................................................................................91 
8.7. 
Vital Signs ..................................................................................................................91 
8.8. 
Electrocardiography ....................................................................................................92 
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9. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ 
PHARMACOGENETICS/IMMUNOGENICITY .....................................................93 
9.1. 
Pharmacokinetic Assessment ......................................................................................93 
9.2. 
Pharmacodynamics Assessment .................................................................................93 
9.3. 
Immunogenicity Testing .............................................................................................93 
9.4. 
Assessment of Exploratory Biomarkers .....................................................................94 
9.5. 
Pharmacogenetics .......................................................................................................95 
10. 
STATISTICS ..............................................................................................................96 
10.1. 
Sample Size and Power Considerations .....................................................................96 
10.2. 
Analysis Sets ...............................................................................................................97 
10.2.1. 
Intent-to-Treat Analysis Set ........................................................................................97 
10.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................97 
10.2.3. 
Safety Analysis Set .....................................................................................................98 
10.2.4. 
Pharmacokinetic Analysis Set ....................................................................................98 
10.2.5. 
Pharmacogenetic and Biomarker Analysis Set ...........................................................98 
10.2.6. 
Immunogenicity Analysis Set .....................................................................................98 
10.3. 
Data Handling Conventions ........................................................................................98 
10.3.1. 
Handling Withdrawals and Missing Data ...................................................................98 
10.4. 
Study Population .........................................................................................................98 
10.4.1. 
Patient Disposition ......................................................................................................98 
10.4.2. 
Demographic and Baseline Characteristics ................................................................99 
10.5. 
Efficacy Analysis ........................................................................................................99 
10.5.1. 
Primary Estimand .......................................................................................................99 
10.5.2. 
Primary Endpoints and Secondary Endpoints ............................................................99 
10.5.3. 
Exploratory Endpoints ................................................................................................99 
10.5.4. 
Planned Method of Analysis .......................................................................................99 
10.5.4.1. 
Primary Efficacy Analysis ..........................................................................................99 
10.5.4.2. 
Sensitivity Analysis ..................................................................................................100 
10.5.4.3. 
Supplementary Analysis ...........................................................................................100 
10.5.4.4. 
Secondary Efficacy Analysis ....................................................................................100 
10.5.4.5. 
Other Efficacy Analysis ............................................................................................100 
10.6. 
Multiple Comparisons and Multiplicity....................................................................100 
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10.7. 
Safety Analysis .........................................................................................................100 
10.8. 
Tolerability Analysis ................................................................................................101 
10.9. 
Population Pharmacokinetic, Pharmacodynamic, and 
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................101 
10.10. 
Pharmacogenetic Analysis ........................................................................................101 
10.11. 
Biomarker Analysis ..................................................................................................102 
10.12. 
Immunogenicity Analysis .........................................................................................102 
10.13. 
Planned Interim Analysis ..........................................................................................102 
10.14. 
Reporting Deviations from the Statistical Plan ........................................................103 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................104 
12. 
COMPLIANCE STATEMENT ................................................................................105 
13. 
DATA MANAGEMENT AND RECORD KEEPING ............................................106 
14. 
FINANCING AND INSURANCE ...........................................................................107 
15. 
PUBLICATION POLICY ........................................................................................108 
16. 
REFERENCES .........................................................................................................109 
17. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................113 
17.1. 
Amendment 04 Dated 08 July 2024 .........................................................................113 
17.2. 
Administrative Letter 02 Dated 21 June 2024 ..........................................................119 
17.3. 
Administrative Letter 01 Dated 15 August 2023 ......................................................122 
17.4. 
Amendment 03 with Revision 01 Dated 15 August 2023 ........................................124 
17.5. 
Amendment 03 Dated 28 June 2023 .........................................................................155 
17.6. 
Amendment 02 Dated 13 January 2023 ....................................................................201 
17.7. 
Amendment 01 Dated 13 June 2022 .........................................................................213 
APPENDIX A. STUDY PROCEDURES AND ASSESSMENTS BY VISIT ........................236 
APPENDIX B. QUALITY CONTROL AND QUALITY ASSURANCE ..............................241 
APPENDIX C. ETHICS ...........................................................................................................243 
APPENDIX D. BIRTH CONTROL METHODS .....................................................................244 
APPENDIX E. LOST TO FOLLOW-UP .................................................................................245 
APPENDIX F. PHARMACOGENETIC ASSESSMENTS .....................................................246 
APPENDIX G. PRODUCT COMPLAINTS ............................................................................247 
APPENDIX H. DATA MANAGEMENT AND RECORD KEEPING ...................................250 
APPENDIX I. PUBLICATION POLICY ................................................................................253 
APPENDIX J. LIST OF EXAMPLES OF OPPORTUNISTIC INFECTIONS .......................254 
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APPENDIX K. LIVER SAFETY: REQUIRED ACTIONS AND FOLLOW-UP 
ASSESSMENTS GUIDELINES ..............................................................................256 
APPENDIX L. OPERATING CHARACTERISTICS AND ASSUMPTIONS FOR 
FINAL AND INTERIM ANALYSIS ......................................................................257 
APPENDIX M. COUNTRY-SPECIFIC REQUIREMENTS...................................................260 
Country-Specific Requirements: France ......................................................................................261 
Country-Specific Requirements: Japan........................................................................................264 
Country-Specific Requirements: Spain........................................................................................275 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................14 
Table 2: 
Randomization Scheme ..............................................................................................48 
Table 3: 
Investigational Medicinal Products Used in the Study ...............................................62 
Table 4: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE ...............................................................................................................79 
Table 5: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device ................................................................................................80 
Table 6: 
Administration Site Finding Severity Assessment .....................................................87 
Table 7: 
Clinical Laboratory Tests ...........................................................................................89 
Table 8: 
Operating Characteristics of Interim and Final Analysis ...........................................96 
Table 9: 
Remission (UC), Response (CD) Rates Scenarios for Clinical Trial 
Simulations ...............................................................................................................257 
Table 10: Operating Characteristics for Interim and Final Analysis – All Scenarios ..............258 
Table 11: Posterior Probability of Adverse Events ...................................................................259 
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LIST OF FIGURES 
Figure 1: 
Overall Program Schematic ........................................................................................12 
Figure 2: 
TL1A/DR3 Signaling Interactions ..............................................................................36 
Figure 3: 
Decision Tree for Adverse Events and Adverse Device Effects Classification .........78 
Figure 4: 
Decision Tree for Device Deficiencies .....................................................................249 
Figure 5: 
Hepatitis B Testing Flow Chart ................................................................................274 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Term 
21CFR 
Title 21 Code of Federal Regulations 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
ADA 
anti-drug antibody 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ASCA 
anti-Saccharomyces cerevisiae antibodies 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the serum drug concentration-time curve from time 0 to the time of the last 
measurable drug concentration 
AUCτ 
area under the concentration-time curve over 1 dosing interval 
AZA 
azathioprine 
BLA 
Biological License Application 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CDEIS 
Crohn’s Disease Endoscopic Index of Severity  
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
apparent total body clearance after extravascular administration 
Cmax 
maximum observed drug concentration 
CMV 
cytomegalovirus 
COVID-19 
coronavirus disease 2019 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DR3 
death receptor 3  
DRF 
dose range finding 
DNA 
deoxyribonucleic acid 
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Abbreviation 
Term 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
EOS 
end-of-study  
EU 
European Union 
EudraCT 
European Clinical Trials 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HCG 
human chorionic gonadotropin 
hsCRP 
high sensitivity C-reactive protein 
HV 
healthy volunteers 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IL 
interleukin 
IMP 
investigational medicinal product 
IN 
Indigo naturalis 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
INR 
International Normalized Ratio 
ITT 
intent-to-treat 
iv 
intravenous 
JAK 
Janus kinase 
LoAC 
Loss of Asthma Control 
LSO 
local safety officer 
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Abbreviation 
Term 
mAb 
monoclonal antibody  
MAD 
multiple ascending dose 
MHLW 
Ministry of Health, Labour and Welfare 
mITT 
modified intent-to-treat 
MM 
modified multiplier 
NCI 
National Cancer Institute 
NCT 
National Clinical Trial 
NDA 
New Drug Application 
NOAEL 
no observable adverse effect level 
NRS-11 
11-point numeric rating scale 
pANCA 
perinuclear antineutrophil cytoplasmic antibodies  
PAH 
pulmonary arterial hypertension 
 
 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PDAESI 
protocol-defined adverse event of special interest 
PoC 
proof-of-concept  
PRO2 
2-item patient-reported outcome 
Q2W 
every 2 weeks 
Q3 
Quarter 3 
Q4  
Quarter 4 
RHI 
Robarts Histopathology Index 
RNA(s) 
ribonucleic acid(s) 
RTSM 
Randomization and Trial Supply Management 
S1P 
sphingosine-1-phosphate 
SAD 
single ascending dose 
sc 
subcutaneous(ly) 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
elimination half-life 
T2 
type 2 
TB 
tuberculosis 
TCR 
tissue cross-reactivity 
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Abbreviation 
Term 
Th 
T helper cell 
TL1A 
tumor necrosis factor (ligand) 1A 
tmax 
time to maximum observed serum drug concentration 
TNF 
tumor necrosis factor 
TNF-α 
tumor necrosis factor-alpha 
TNFSF15 
tumor necrosis factor (ligand) superfamily member 15 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
VC 
videoconference 
Vz/F 
apparent volume of distribution after extravascular administration 
WOCBP 
women of childbearing potential 
XML 
Extensible Markup Language 
 
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2. 
INTRODUCTION AND BACKGROUND INFORMATION  
2.1. 
Introduction  
2.1.1. 
Inflammatory Bowel Disease and Current Treatment Options  
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal 
(GI) tract that affects 5 million people worldwide. IBD presents as 1 of the 2 major forms, 
ulcerative colitis (UC) or Crohn’s disease (CD). In UC, the inflammation is confined to the 
mucosa of the colon, while in CD, the transmural inflammatory process can affect the entire GI 
tract from the mouth to the anus, even though it is preferentially located in the terminal ileum 
and/or right colon (in nearly 70% of forms). 
The incidence rates of UC have been reported as high as 24.3 and 19.2 per 100000 person-years 
in Europe and North America, respectively. The respective incidence rates for CD have been 
reported as high as 12.7 and 20.2 per 100000 person-years in Europe and North America, 
respectively. In terms of prevalence, Europe and North America have the highest reported 
prevalence values for IBD (Europe: UC, 505 per 100000 persons; CD, 322 per 100000 persons 
and North America: UC, 249 per 100000 persons; CD, 319 per 100000 persons) 
(Molodecky et al 2012). IBD (UC and CD) occurs more frequently in Caucasians and affects 
females more often than males. It is a lifelong condition with a serious effect on patients’ quality 
of life and has an increased prevalence with each decade of life (Betteridge et al 2013).  
The cause of IBD (UC and CD) is not yet known, but evidence has been accumulated to suggest 
that this is a multifactorial disease in which multiple environmental and genetic factors interact 
to trigger an excessive and deregulated mucosal immune response that is directed against normal 
components of the luminal flora and leads to the tissue damage (Fiocchi 2001). 
UC is a chronic GI inflammatory disorder that involves the surface mucosa, the crypt epithelium, 
and the submucosa of the colon. Patients with UC suffer from diarrhea, rectal bleeding, weight 
loss, abdominal pain, and fever (Friedman and Blumberg 2015). UC is characterized by a 
lifelong chronic course of remissions and exacerbations. In severe UC, the bowel wall may 
become thin, the mucosa may denude, and the inflammation may extend to the serosa leading to 
dilation, toxic megacolon, and perforation (Friedman and Blumberg 2015). Toxic megacolon 
commonly requires an urgent colectomy to avoid perforation, peritonitis, and sepsis. In 1 study, 
within 10 years of diagnosis, 19.9% of patients with UC had undergone colectomy 
(van Limbergen et al 2008). In addition, patients with UC have an increased risk of carcinoma 
when compared with the general population. The estimated risk of colorectal carcinoma 
increases as the duration and extent of disease increases from 2% of patients with UC for 
10 years, to 8% of patients with UC for 20 years, and to 18% of patients with UC for 30 years 
(Eaden et al 2001). 
CD is characterized by a significant variety of clinical phenotypes that are related to the chronic 
inflammation and fibrosis in the GI tract. The phenotypic manifestations of CD are clinically 
relevant due to differences in disease behavior and treatment options between these phenotypes. 
The clinical features of CD vary according to the disease phenotype (stricturing, penetrating, 
inflammatory [non-stricturing and non-penetrating], and perianal disease), but commonly include 
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chronic diarrhea, abdominal pain, and weight loss. The course of CD is epitomized by periods of 
relapse and remission with recurrent cycles of inflammation leading to development of 
complications such as strictures and intestinal fistulas (Adegbola et al 2018). 
The overall goal of treatment for patients with active UC is to induce and maintain remission and 
mucosal healing. Treatment of UC consists of anti-inflammatory and immunosuppressant 
therapies that are chosen to maximize efficacy while avoiding toxicity. The chosen therapy is 
therefore dependent on the patient’s disease severity and their response to therapy (Kornbluth 
and Sachar 2010, Ng and Kamm 2009). While agents used to treat mild to moderate UC are 
generally well tolerated, as the severity of UC disease increases, so do the potential toxicities of 
the medications required to manage the disease. Mild to moderate UC treatment typically starts 
with topical agents (5-aminosalicylic acid [5-ASA] or corticosteroids administered via 
suppository or enema). In patients unresponsive to local therapy or in patients with more severe 
or more extensive disease, systemic treatment with an oral 5-ASA, such as mesalamine, 
olsalazine, sulfasalazine, and balsalazide with or without antibiotics is commonly required 
(Rosenberg and Peppercorn 2010, Ng and Kamm 2009). 
Fifty percent (50%) to 75% of patients with mild to moderate UC improve when treated with 
5-ASA, and treatment with 5-ASA is generally safe and well tolerated (Friedman and Blumberg 
2015). For those patients who do not respond to treatment with 5-ASA or those with more 
severe, extensive disease at presentation, corticosteroids are generally the first-line treatment for 
inducing disease remission. Although effective in inducing disease remission, long-term 
treatment with corticosteroids is associated with multiple adverse effects including moon face, 
cataracts, acne, hypertension, diabetes, and psychosis in rare cases. Furthermore, 1 study 
demonstrated that although effective in induction of response, after 1 year, approximately 45% 
of patients who initially responded to corticosteroids have become steroid-dependent, and 5% 
required surgery the first year (Hyams et al 2006). For those patients who are unresponsive to or 
intolerant of corticosteroids, immunosuppressant drugs including azathioprine (AZA), 
6-mercaptopurine (6-MP), methotrexate, and cyclosporine, or biologics (such as anti-tumor 
necrosis factor [TNF] agents infliximab and adalimumab) are used to induce and/or maintain 
remission (Rosenberg and Peppercorn 2010, Kornbluth and Sachar 2010). These medications 
have multiple limitations including toxicities and a delay in onset of action; AZA and 6-MP take 
as long as 3 months to work. The use of AZA and 6-MP can result in neutropenia, pancytopenia, 
pancreatitis, nephrotoxicity, hepatotoxicity, and lymphoma in rare cases (Carter et al 2004, 
Bousvaros 2010, Chaparro et al 2009). 
Medical therapy for patients with CD is largely influenced by the type, site, and extent of lesions, 
as well as the presence of local and extraintestinal manifestations and activity of the disease. In 
general, patients with mild disease can be treated with high doses of mesalazine (5-ASA), while 
moderate to severe forms require the use of steroids. Immunosuppressant drugs, such as AZA, 
mercaptopurine, and methotrexate, are used to maintain remission either alone or in combination 
with biologics. This later group of compounds include the anti-TNF agents infliximab, 
adalimumab, and certolizumab (Friedman and Blumberg 2015).  
Anti-TNF agents are used to induce and maintain remission in IBD patients resistant to other 
therapies. Nearly 50% of patients respond to treatment, but remission can be induced in less than 
30% of patients (Fine et al 2019, Adegbola et al 2018). Moreover, response can wane with time, 
and treatment can associate with the development of severe side effects such as increased risk of 
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infections (particularly reactivation of latent tuberculosis [TB] and opportunistic fungal 
infections including disseminated histoplasmosis and coccidioidomycosis), acute liver injury due 
to reactivation of hepatitis B virus and to autoimmune effects and cholestasis, and the occurrence 
or exacerbations of immune-mediated pathologies (such as lupus and psoriasis) (Friedman and 
Blumberg 2015). Patients who do not respond to medical therapy are candidates for surgery, 
which, in many cases, is followed by recurrence of the disease. 
Despite the recent approvals of the new therapeutic option for IBD as the anti-integrin antibodies 
(vedolizumab) and anti-interleukin (IL)-12/23 (ustekinumab), and small molecule Janus kinase 
(JAK) inhibitor (tofacitinib), efficacy of all those drugs is limited to approximately 15% to 40% 
over placebo, depending on the stringency of the endpoint and rates of placebo response in the 
respective study (Misselwitz et al 2020). In addition, some of the therapeutic agents, for example 
tofacitinib, have been associated with significant safety issues: serious venous thromboembolism 
events including pulmonary embolism, some of which were fatal, and deep vein thrombosis; 
serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or 
other opportunistic pathogens; and lymphoma and other malignancies (XELJANZ SmPC 2021, 
XELJANZ PI 2021). 
In spite of the tremendous advances made in recent years in IBD therapeutics, many patients still 
do not respond, lose response, or are intolerant to currently available treatments for UC and CD. 
This, and the safety profiles of the current IBD therapies, support the notion that the 
development and implementation of highly effective drugs with favorable side effect profiles for 
patients is an important, unmet need. 
2.1.2. 
Relevance of Inhibition of TL1A Binding to Death Receptor 3 for Inflammatory 
Bowel Disease  
Tumor necrosis factor (ligand) 1A (TL1A) is a co-stimulatory molecule that enhances the 
activation of certain types of T cells. TL1A, which is produced primarily by dendritic cells and 
monocyte/macrophages, acts on different T cell types (Figure 2). TL1A additionally acts directly 
on death receptor 3 (DR3)+ fibroblasts to trigger profibrotic pathways. 
TL1A/DR3 signaling enhances proliferation and optimizes cytokine production by responding to 
lymphocytes, acting as a co-stimulatory signal that amplifies the primary responses. This 
function is of particular importance under conditions of sub-optimal lymphocyte stimulation but 
can also contribute to inflammatory pathology, especially in diseases with mucosal involvement, 
such as UC and CD. The response of all types of effector T cells (T helper cell [Th] 1, Th2, Th9, 
and Th17) can be enhanced by TL1A (Figure 2). 
Inhibiting TL1A binding to DR3 prevents activation of the DR3 signaling pathway. A 
therapeutic anti-TL1A antibody (PF-06480605) was found to be efficacious in patients with UC 
(Hassan-Zahraee et al 2020). The results of this proof-of-concept (PoC) clinical study provide 
support for the clinical and histological benefits of inhibition of TL1A/DR3 signaling in patients 
with UC (Danese et al 2021). The results of the study demonstrated an acceptable safety profile 
and statistically significant endoscopic improvement in participants with moderately to severely 
active UC. Similar findings were reported in a Phase 2 study in patients with moderate to severe 
UC. In this study, treatment with PRA-023 resulted in a statistically significant greater 
proportion of patients with clinical remission or endoscopic improvement compared with 
placebo with a well-tolerated and acceptable safety profile (Sands et al 2023). 
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Figure 2: 
TL1A/DR3 Signaling Interactions  
 
Source: Valatas et al 2019 (*modified). 
CD=cluster of differentiation; DC=dendritic cell; DR3=death receptor 3; IFN=interferon; IL=interleukin; 
ILC=innate lymphoid cell; NK=natural killer; NK-T=natural killer T; TGF=transforming growth factor; 
Th=T helper cell; TL1A=tumor necrosis factor (ligand) 1A; TNF=tumor necrosis factor; Treg=regulatory 
lymphocytes; UC=ulcerative colitis. 
Note: Although NK-T cells are designated as IL-4 and IL-13 producers in this figure, NK-T cells also produce 
significant amounts of IFN-γ, IL-9, IL-17, and IL-22. 
2.1.3. 
TEV-48574 and Inflammatory Bowel Disease  
TEV-48574 is a highly potent, fully human immunoglobulin G (IgG) subclass 1 (lambda) 
monoclonal antibody (mAb) with a molecular weight of 146 kDA that targets TL1A, encoded by 
the TNF superfamily member 15 (TNFSF15) gene. 
It is a neutralizing antibody that binds TL1A and inhibits its binding to its cognate signaling 
receptor, DR3, preventing activation of the DR3-signaling pathway. TEV-48574 also inhibits the 
binding of TL1A to decoy receptor 3 (DcR3), which is a natural antagonist of the TL1A-DR3 
interaction. TEV-48574 preferentially inhibits the TL1A-DR3 interaction over the TL1A-DcR3 
interaction. 
In colitis animal models, TEV-48574 has shown anti-inflammatory and anti-fibrotic effects 
during nonclinical studies. 
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Based on the TL1A/DR3 signaling interactions and the potential effects of TL1A inhibition on 
inflammation, the intended indications for UC and CD with TEV-48574 are for the treatment of 
adult patients with moderately to severely active UC who have had an inadequate response, loss 
of response, or intolerance to either conventional therapy or a biologic agent and/or JAK 
inhibitor; and for the treatment of adult patients with moderately to severely active CD who have 
had an inadequate response, loss of response, or intolerance to either conventional therapy or a 
biologic agent. 
2.1.4. 
Purpose of Current Study  
Many patients with IBD do not respond, lose response, or are intolerant to currently available 
treatments for UC and CD. Furthermore, some of the available therapeutic agents for IBD have 
been associated with significant safety issues. The anti-TL1A activity of TEV-48574 may have 
an anti-inflammatory and anti-fibrotic effect in patients with IBD, leading to improvement of 
their disease conditions, while demonstrating an acceptable safety profile. 
The purpose of the study is to determine the pharmacokinetics, efficacy, safety, and tolerability 
of 2 different doses of TEV-48574 subcutaneously (sc) administered every 2 weeks (Q2W) in 
adult patients with moderate to severe UC or CD. 
2.2. 
Findings from Nonclinical and Clinical Studies  
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure (IB). 
2.2.1. 
Nonclinical Studies  
A comprehensive set of in vitro and in vivo nonclinical studies was conducted to support TEV-
48574 long-term therapeutic use in humans. 
TEV-48574 bioavailability following a single sc administration was on average 93.0% in 
monkeys and 133.8% in rats (the higher than expected bioavailability observed in rats was 
possibly due to inter-animal variability and/or variability with the analytical method). A typical 
mAb pharmacokinetic profile was observed in monkeys; low volume of distribution indicating 
distribution is mainly limited to vasculature, no sex differences could be observed in exposure, 
and systemic exposure generally increased in a dose proportional manner. TEV-48574 displayed 
sc absorption with time to maximum observed serum drug concentration (tmax) of 48 hours 
followed by a gradual monophasic decline in serum levels and a terminal elimination half-life 
(t½) ranging between 155 and 177 hours. In rats, 90% of the animals developed anti-drug 
antibodies (ADAs) along with reduced exposure, while ADA prevalence was less than 20% in 
the repeat-dose non-Good Laboratory Practice (GLP) study in cynomolgus monkeys, with no 
major drop in exposure when ADAs were present. As such, the cynomolgus monkey was 
considered the only relevant species for long-term safety studies.  
The nonclinical safety program conducted with TEV-48574 consisted of a 6-week and a 6-month 
repeat-dose toxicity GLP study in the cynomolgus monkey. In addition to standard assessments, 
the 6-week study included cardiovascular and respiratory assessments and the 6-month study 
conducted in sexually mature animals included fertility assessments. These studies were 
preceded by single-dose pharmacokinetic and tolerability studies and 2-week dose range finding 
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(DRF) studies in rats and monkeys. In addition, in vitro tissue cross-reactivity (TCR) studies and 
cytokine release assays were conducted.  
The nonclinical safety program revealed no safety concerns. In the repeat-dose sc toxicology 
studies, there were no TEV-48574-related clinical observations, changes in body weights, food 
consumption, ophthalmology, and clinical pathology (hematology, coagulation, clinical 
chemistry, and urinalysis) following repeated administrations of TEV-48574. There were no 
TEV-48574-related changes in the numbers of circulating T lymphocytes, B lymphocytes, natural 
killer cells, and monocytes. There were no organ weight, or macroscopic or microscopic changes 
that could be attributed to TEV-48574. No TEV-48574-related effects were noted on blood 
pressure, electrocardiography, and respiratory rate nor on fertility parameters (menstrual cycle, 
testicular volume, echogenicity, and semen analysis). As no safety signal was observed in the 
studies, the no observable adverse effect level (NOAEL) was concluded to be the highest doses 
tested in the repeat-dose studies; 50 mg/kg for the rat (2-week study) and 100 mg/kg for the 
monkey (6-month study).  
Results obtained from in vitro TCR studies suggested that interactions of TEV-48574 with human 
tissues are unlikely. TEV-48574 is considered unlikely to induce a cytokine storm/cytokine 
syndrome as indicated by the low level of cytokine induction from human peripheral blood 
mononuclear cells in cytokine release assays. 
2.2.2. 
Clinical Studies  
2.2.2.1.Phase 1 Study (TV48574-SAD-10126)  
Study TV48574-SAD-10126 was a first-in-human (FIH), Phase 1, randomized, double-blind, 
placebo-controlled, parallel-group study to determine the safety, tolerability, pharmacokinetics, 
and immunogenicity of TEV-48574 in the following groups: 
• healthy volunteers (HV; single ascending dose [SAD] portion of the study: single sc 
administration of 1, 4, 12, 36, 90, 200, 400, and 1000 mg or placebo) 
• patients with asthma (multiple ascending dose [MAD] portion of the study: repeat sc 
administrations (3 sc administrations: 200 mg Q2W, 800 mg [loading dose]/600 mg 
[maintenance dose] Q2W, and 2300 mg [loading dose]/1600 mg [maintenance dose] 
Q2W, or placebo) 
Within each of the 8 dose cohorts in the SAD portion of the study, 8 healthy subjects were 
randomized to receive a single sc dose of TEV-48574 (6 subjects) or placebo (2 subjects). A total 
of 48 subjects received TEV-48574 and 16 subjects received placebo. In the MAD portion of the 
study, 36 patients with mild allergic asthma were assigned to 1 of 3 cohorts (12 patients per 
cohort). Within each cohort, the patients were randomly assigned to receive TEV-48574 
(9 patients) or placebo (3 patients). A total of 27 patients received TEV-48574 and 9 patients 
received placebo. The study was completed (last patient completed) on 26 February 2019. 
2.2.2.1.1. Pharmacokinetics  
In the SAD portion of the study, single sc doses of TEV-48574 at 1, 4, 12, 36, 90, 200, 400, and 
1000 mg were administered in HV. After 1- and 4-mg doses, all TEV-48574 serum 
concentrations were below the limit of quantitation.  
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The t½ of TEV-48574 in the SAD portion was similar across the studied dose range; generally 
exceeding 6.5 days in all SAD cohorts (range: approximately 6.5 to 9.6 days). TEV-48574 peak 
serum concentrations were typically reached between 72 and 96 hours postdose. Thereafter, 
TEV-48574 was eliminated gradually in a monophasic manner. For apparent total body 
clearance after extravascular administration (CL/F), mean estimates were similar across the dose 
range. The apparent volume of distribution after extravascular administration (Vz/F) was also 
similar across the dose range (8.24 to 15.13 L), indicating that TEV-48574 was mostly confined 
to the circulatory system. 
From 36 to 1000 mg, the increase in TEV-48574 exposure was greater than dose proportional. 
However, TEV-48574 half-life, CL/F, and Vz/F appeared similar across all SAD doses, which is 
suggestive of linear pharmacokinetics. Over the 200- to 1000-mg dose range, dose 
proportionality was observed. Therefore, the overall slightly greater than dose proportional 
results may be less relevant as only doses of 200 mg or greater were brought forward into the 
MAD portion. 
The pharmacokinetics of TEV-48574 was further characterized in patients with mild allergic 
asthma in the MAD portion of the study. Consistent with the results of the SAD portion in HV, 
the pharmacokinetics of TEV-48574 in patients was characterized by slow absorption. The t½ of 
TEV-48574 at steady state ranged from 8.3 to 8.7 days and was not impacted by dose level. Half-
life estimates appear similar to those for the SAD portion of the study, generally exceeded 
approximately 6.5 days in all cohorts. For CL/F, mean estimates were similar across the dose 
range tested in the MAD portion and were similar to the CL/F observed in the SAD portion. The 
Vz/F was similar across the studied dose range in the MAD portion (11.79 to 21.06 L), indicating 
that TEV-48574 was mostly confined to the circulatory system, consistent with what was 
observed in SAD portion of the study. 
Across the dose range tested in the MAD portion for single and multiple-dose administration, 
TEV-48574 peak (maximum observed drug concentration [Cmax]) and total (area under the 
concentration-time curve over 1 dosing interval [AUCτ]) systemic exposure increased with 
increasing dose. From 200 to 2300 mg on day 1 and from 200 to 1600 mg at steady state, the 
increase in TEV-48574 exposure was dose proportional, indicated by the 90% confidence 
interval (CI) for the estimated slope for Cmax and AUCτ including unity (1.0). 
Without a loading dose, there was weak accumulation following the first dose in cohort 1 in the 
MAD portion of the study (approximately 47%). After the loading dose administered to cohort 2, 
there was also weak accumulation (approximately 32%), suggesting that the loading dose may 
have been too low to achieve steady state as rapidly as intended, whereas the loading dose used 
for cohort 3 achieved steady-state conditions after the loading dose administration. Steady state 
was reached after the second dose for all dose regimens. 
2.2.2.1.2. Safety  
No deaths, serious adverse events, protocol-defined adverse events of special interest (PDAESIs; 
severe hypersensitivity reactions or anaphylaxis), or withdrawals due to adverse events were 
reported during the study. 
No adverse events consistent with immunosuppression (including opportunistic or unusual 
infections), cytopenias, or systemic reactions were reported, and no safety signal with 
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treatment-emergent ADA responses was observed. The nature and incidence of the adverse 
events were similar between doses and comparable with those for placebo. There were no 
dose-related trends and no clinically meaningful differences observed between the treatment 
groups for laboratory tests, vital signs, electrocardiograms (ECGs), and physical examination 
findings.  
The safety data of Study TV48574-SAD-10126 do not suggest any adverse drug reactions 
associated with TEV-48574 treatment except for transient nonserious injection site findings.  
2.2.2.1.3. Immunogenicity  
A subject/patient was classified as having a treatment-emergent ADA response if either: 1) a 
subject had a positive sample at any of the postdose time points, but not at the predose time 
point, or 2) a subject had positive samples at predose time point and 1 or more postdose time 
points, with at least a 4-fold increase in titers postdose relative to the predose sample ADA titers. 
(Note: Treatment-emergent ADA status was based on titer, but all ADA results in this document 
are presented as log10 titer.) 
Of the 48 subjects who received TEV-48574 in the SAD portion of the study, 23 subjects 
(47.9%) were identified as having a treatment-emergent ADA response. Treatment-emergent 
ADA responses were not associated with a safety signal. Treatment-emergent ADA responses 
were also observed in the cohorts that did not have measurable serum concentrations of 
TEV-48574 (cohorts 1 and 2, 1 and 4 mg TEV-48574, respectively). All ADAs occurred at 
200 mg or lower except for 1 patient who received 1000 mg developed 1 transient ADA (low 
titer) 43 days after the dose was administered, suggesting that there may be a trend toward 
immunological tolerance at higher doses. 
Three of 27 patients who received TEV-48574 (11% of patients tested) in the MAD portion were 
identified as having a positive treatment-emergent ADA response. All 3 patients were in cohort 1 
(200 mg). In these patients, the observed ADA log10 titer ranged from 0.6 to 2.5. One patient had 
treatment-emergent ADA responses at multiple time points starting by day 15, while the other 
2 patients were ADA positive only at the end-of-study (EOS) visit (day 92), approximately 
7 weeks after the last dose.  
For pharmacokinetics, the single evaluable treatment-emergent ADA positive patient had Cmax 
and area under the serum drug concentration-time curve from time 0 to the time of the last 
measurable drug concentration (AUC0-t) at steady state that were 86% and 93% lower, 
respectively, at day 15, and 82% and 97% lower, respectively, at day 29, when compared with 
geometric mean values of ADA negative patients. No treatment-emergent adverse events were 
reported for treatment-emergent ADA positive patients in the MAD portion of the study. 
2.2.2.2.Phase 1 Study (TV48574-PK-10180)  
Study TV48574-PK-10180 was a Phase 1 open-label, randomized, single-dose study to evaluate 
the pharmacokinetics, safety, immunogenicity, and tolerability of TEV-48574 in healthy 
Japanese and Caucasian subjects. There were 3 single dose cohorts. Healthy Japanese subjects 
were randomized to 1 of 2 dose levels of TEV-48574 (
 or 
 in cohort 1 or assigned to 
a dose of 
 TEV-48574 in cohort 2. Healthy Caucasian subjects were assigned to a dose 
of 
 in cohort 3. 
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The pharmacokinetic profile of TEV-48574 in Japanese subjects (n=24) was similar to 
pharmacokinetic profile in Caucasian subjects (n=8) across the absorption, distribution, and 
elimination phases; pharmacokinetic parameters in Japanese subjects were comparable to 
Caucasian subjects in the 
 dose cohorts and consistent with pharmacokinetic parameters 
in Caucasian subjects obtained from the TV48574-SAD-10126 study. The safety profile was 
consistent with that seen in the previous TEV-48574 studies with no evidence of any 
dose-related trends in adverse events in Japanese cohorts or differences between the Japanese 
and Caucasian subjects in any safety measures. 
2.2.2.3.Phase 2a Study (TV48574-AS-20031)  
Study TV48574-AS-20031 was a Phase 2a, PoC, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of TEV-48574 in adults with type 2 
(T2)-low/non-T2 severe uncontrolled asthma. This population of asthmatics is characterized by 
having an endotype and phenotype characterized by low peripheral eosinophil counts; sputum 
that contains neutrophils or is paucigranulocytic; a history of relatively late-onset asthma 
symptoms; an increased association with obesity; and a relative resistance to topical, oral, and/or 
parenterally administered corticosteroids. 
The study was initiated in Quarter 3 (Q3) of 2020. Approximately 124 to 174 patients (18 years 
of age and above) were planned to be enrolled, with the primary objective of the study to 
evaluate the effect of TEV-48574 compared with placebo on Loss of Asthma Control (LoAC). 
Patients were randomly assigned to receive a 
 of 
 and a maintenance dose 
of 
 TEV-48574 Q2W (1 
 and 7 maintenance doses), or placebo to match 
TEV-48574, in a 1:1 ratio, given sc via the KORU FreedomEdge® syringe infusion system Q2W 
over a 16-week treatment period for a total of 8 doses. 
A pre-specified interim futility analysis was conducted on 64 patients. Teva determined that the 
primary endpoint result, reduction in LoAC, met the decision rule for futility, meaning that the 
likelihood of a positive outcome of the completion of the study was small. Based on the results 
of the primary endpoint futility analysis, Teva decided to stop the study on 22 December 2021. 
A total of 65 patients were randomized into the study; 1 patient did not receive investigational 
medicinal product (IMP). No deaths occurred. Two treatment-emergent serious adverse events 
were reported; neither were assessed as related to the IMP by the investigator and sponsor. There 
were 28 patients who withdrew from the study due to LoAC. There were no early terminations 
due to adverse events. 
2.3. 
Known and Potential Benefits and Risks to Patients  
2.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)  
Given the targeted action of TEV-48574 on TL1A, and considering that the product is a mAb, 
immunosuppression (eg, higher risk for infections and malignancies or incomplete response to 
vaccines), systemic hypersensitivity, and immunogenicity may be considered potential risks of 
TEV-48574. None of these risks were observed in either portion of Study TV48574-SAD-10126, 
except for immunogenicity, predominantly in the low-dose level cohorts up to and including 
200 mg in single and repeat-dose settings. However, the observed immunogenicity was not 
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associated with safety signals; a single patient with decreased serum concentration of 
TEV-48574 associated temporally with a treatment-emergent ADA response in the MAD portion 
of the study in the 200 mg cohort. 
Transient, mostly mild injection site findings were evident in subjects/patients treated with 
TEV-48574. No risk was identified that would impact the safety of patients enrolled in clinical 
studies. 
The anti-TL1A activity of TEV-48574 may have an anti-inflammatory and anti-fibrotic effect in 
patients with IBD, leading to improvement of their disease conditions (see Section 2.1). 
In summary, the benefit and risk assessment for TEV-48574 is favorable following review of the 
outlined data. 
Additional information regarding benefits and risks to patients may be found in the IB. 
2.3.2. 
Overall Benefit and Risk Assessment for This Study  
This study will investigate the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 
in adult patients with IBD (UC or CD). As described in Section 2.1, such patients may benefit 
from the development of further therapy options. 
Based on the mechanism of action of TEV-48574 and that the exposure in patients with IBD is 
expected to be similar to the exposure demonstrated in HV and patients with asthma, the safety 
profile in the IBD population is expected to be comparable with that established in HV and 
patients with asthma. 
Management of the patients’ safety during the study that is expected to mitigate risk is detailed in 
Section 4 (investigational plan) and Section 8 (safety measurements and assessments); also refer 
to Section 10.13 for a description of the futility analysis, which will determine if recruitment 
should be stopped due to futility. 
In addition to the monitoring of individual patients, an Independent Data Monitoring Committee 
(IDMC), as described in Section 6.9.3, will review accumulating unblinded safety data. 
Overall, the risks for patients in this study are mitigated comprehensively and are considered 
adequate to justify the study.  
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3. 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
3.1. 
Primary and Secondary Study Objectives and Endpoints  
The primary and secondary study objectives and endpoints are: 
Objectives 
Endpoints 
The primary objective of the study is to 
characterize the efficacy of TEV-48574 sc 
administered Q2W in adult patients with 
IBD (moderate to severe UC or CD), as 
assessed by induction of clinical remission 
(UC) and endoscopic response (CD) at 
week 14. 
The primary efficacy endpoint is response (yes or no) at week 14, 
where response in UC patients is defined as clinical remission and 
response in CD patients is defined as endoscopic response. Clinical 
remission and endoscopic response are determined as follows: 
• 
Clinical remission at week 14 in patients with moderate to severe 
UC. Clinical remission is a modified (9-point rectal bleeding, stool 
frequency, and endoscopy) Mayo score of ≤2 points, which is 
defined by:  
o 
stool frequency subscore of 0 or 1, 
o 
rectal bleeding subscore of 0, and  
o 
endoscopic subscore of 0 or 1, where a score of 1 does 
not include “friability”  
• 
Endoscopic response at week 14 in patients with moderate to 
severe CD, defined as a reduction in Simple Endoscopic Score for 
Crohn’s Disease (SES-CD) of at least 50% from baseline 
A secondary objective of the study is to 
evaluate the efficacy of 2 different doses 
of TEV-48574 sc administered Q2W in 
adult patients with IBD (moderate to 
severe UC or CD) as assessed by multiple 
standard measures at week 14. 
The secondary efficacy endpoints to be measured in patients with 
moderate to severe UC are as follows: 
• 
Clinical response at week 14, defined as a decrease from 
baseline in the modified (9-point rectal bleeding, stool 
frequency, and endoscopy) Mayo score of at least 2 points 
AND at least a 30% reduction from baseline with either a 
decrease in rectal bleeding subscore of at least 1 or an 
absolute rectal bleeding subscore of less than or equal to 1 
• 
Endoscopic improvement defined as a Mayo endoscopic 
subscore of 0 or 1 at week 14  
• 
Endoscopic remission defined as a Mayo endoscopic subscore 
of 0 at week 14  
• 
Clinical response defined as decrease from baseline of at least 
50% in 2-item patient-reported outcome (PRO2; rectal 
bleeding and stool frequency) at week 14  
• 
Clinical remission defined as score of rectal bleeding = 0 and 
stool frequency = 0 on the PRO2 scale at week 14  
The secondary efficacy endpoints to be measured in patients with 
moderate to severe CD are as follows: 
• 
Clinical response defined as a ≥100-point decrease in Crohn’s 
Disease Activity Index (CDAI) score from baseline at weeks 
4, 8, 12 and 14 
• 
Clinical remission defined as a CDAI score <150 at week 14  
• 
Clinical response defined as a decrease from baseline of at 
least 50% in PRO2 (PRO2 is defined as having 2 components, 
abdominal pain and stool frequency) at week 14  
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Objectives 
Endpoints 
• 
Clinical remission defined as abdominal pain ≤1 and stool 
frequency ≤3 on the PRO2 scale at week 14  
• 
Endoscopic response defined as a decrease in modified 
multiplier (MM)-SES-CD of >50% from baseline at week 14  
A secondary objective of the study is to 
evaluate the safety and tolerability of 
2 different doses of TEV-48574 sc 
administered Q2W in adult patients with 
IBD (moderate to severe UC or CD). 
The safety and tolerability measures/parameters are as follows: 
• 
Adverse events 
• 
Change from baseline in clinical laboratory test results (serum 
chemistry, hematology, and urinalysis) 
• 
Change from baseline in vital signs measurements (blood 
pressure, pulse rate, body temperature, and respiratory rate) 
• 
Change from baseline in 12-lead electrocardiogram findings 
• 
Patients who stopped the investigational medicinal product 
due to adverse events 
• 
Local tolerability at the injection site 
A secondary objective of the study is to 
evaluate the immunogenicity of 
2 different doses of TEV-48574 sc 
administered Q2W in adult patients with 
IBD (moderate to severe UC or CD). 
The immunogenicity endpoints for this study are as follows: 
• 
Change from baseline in treatment-emergent anti-drug 
antibody (ADA) at weeks 2, 4, 8, 14, and follow-up visit 
• 
Presence of neutralizing ADA in ADA positive patients at 
weeks 2, 4, 8, 14, and follow-up visit 
3.1.1. 
Justification of Primary Endpoints  
The selected primary endpoint for patients with moderate to severe UC is clinical remission 
based on the modified Mayo score. The modified Mayo score evaluates UC stage based on the 
following 3 parameters: stool frequency, rectal bleeding, and endoscopic evaluation. Each 
parameter of the score ranges from 0 (normal or inactive disease) to 3 (severe activity) and the 
total score from 0 to 9, respectively. Determination of disease severity by the modified Mayo 
score is recommended by both the Food and Drug Administration (FDA) and the European 
Medicines Agency (Reinisch et al 2019). In addition, the selection of primary endpoints based on 
endoscopy increases the objectivity of the proposed approach. Endoscopy has been the gold 
standard for objective assessment of UC disease activity in clinical trials since 1956 (Truelove 
1956). The endoscopic component of the composite Mayo Clinic Score is used most commonly 
in clinical trials. There is evidence that the Mayo endoscopic subscore is a reliable measure 
(Samaan et al 2014). 
The selected primary endpoint for patients with moderate to severe CD is endoscopic response, 
defined as a reduction in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of at least 
50% from baseline. The assessment of CD activity is complicated by the heterogeneous nature of 
the disease. Signs and symptoms may also vary based on disease location, and endoscopic 
outcomes are currently favored in CD clinical trials. The most commonly used indices for 
endoscopic assessment of CD are the Crohn’s Disease Endoscopic Index of Severity (CDEIS) 
and SES-CD. The CDEIS and the SES-CD are similarly reliable and responsive instruments 
(Abreu et al 2020). The CDEIS and the SES-CD are closely correlated; however, CDEIS is time-
consuming, complicated, and not well suited for routine clinical practice (Sipponen et al 2010). 
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3.2. 
Primary Estimand  
The primary estimand in this study is defined by the following attributes: 
• Treatment: In both UC and CD indications, patients will be randomly assigned to 
receive any one of the study treatment regimens shown below, in a 1:1:1 ratio: 
− TEV-48574 2250 mg (single loading dose)/900 mg (6 induction doses) 
− TEV-48574 2250 mg (single loading dose)/450 mg (6 induction doses) 
− Matching placebo 
• Target population: The target population comprises patients with a diagnosis of 
moderate to severe UC or moderate to severe CD. 
• Variable: Response for the primary efficacy analysis is defined as clinical remission 
status at week 14 for UC patients or endoscopic response status at week 14 for CD 
patients. 
• Handling of intercurrent events: Intercurrent events addressed here are (a) use of 
rescue medication; (b) important protocol deviations; (c) UC or CD related surgery; and 
(d) treatment discontinuation. These intercurrent events will be addressed as follows: (a) 
Patients who used rescue medications prior to their week 14 evaluation of response 
(clinical remission in the UC indication or endoscopic response in the CD indication) will 
be reported as non-responders, ie, the composite variable strategy; (b) Patients 
experiencing any important protocol deviations, namely, use or changes in other 
medications, will be analyzed as if the deviation had not occurred, ie, treatment policy 
strategy; (c) Patients undergoing UC or CD related surgery will be treated as 
non-responders, ie, the composite strategy; and (d) Patients discontinuing treatment, 
regardless of the reason, will be treated as non-responders, ie, the composite strategy. 
• Population-level summary: The population-level summary of interest is the quantity 
Posterior Probability (𝑝𝑑,𝑖−𝑝0,𝑖> 0) estimated from a Bayesian Beta-Binomial model 
for the response rate (clinical remission rate for UC, or endoscopic response rate for CD), 
𝑝𝑑,𝑖 , where i=UC, CD and d =0,1,2 represent placebo, TEV-48574 low dose (450 mg 
Q2W), and TEV-48574 high dose (900 mg Q2W), respectively. 
3.2.1. 
Supplementary Estimand  
The supplementary estimand is defined by the following attributes: 
• Treatment: same as for the Primary Estimand. 
• Target population: same as for the Primary Estimand.  
• Variable: same as for the Primary Estimand. 
• Handling of intercurrent events: same as for the Primary Estimand. 
• Population-level summary: The population-level summary is difference in response 
rates of each TEV-48574 dose compared to placebo obtained from a logistic regression 
model fit separately to each indication, with dose as categorical variable. 
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3.3. 
Exploratory Objectives and Endpoints  
The exploratory objectives and endpoints are: 
Objectives 
Endpoints 
An exploratory objective of the study is 
to evaluate the efficacy of 2 different 
doses of TEV-48574 sc administered 
Q2W in adult patients with IBD 
(moderate to severe UC or CD) as 
assessed by multiple standard measures. 
The exploratory efficacy endpoints to be measured in patients with 
moderate to severe UC are as follows: 
• 
Clinical response defined as decrease from baseline of at least 
50% in 2-item patient-reported outcome (PRO2; rectal 
bleeding and stool frequency) at weeks 2, 4, 6, 8, 10, and 12 
• 
Clinical remission defined as score of rectal bleeding = 0 and 
stool frequency = 0 on the PRO2 scale at weeks 2, 4, 6, 8, 10, 
and 12 
• 
Histological remission defined as a Robarts Histopathology 
Index of ≤5 at week 14  
• 
Histological remission defined as Geboes index score ≤3.1 at 
week 14 
The exploratory efficacy endpoints to be measured in patients with 
moderate to severe CD are as follows: 
• 
Clinical response defined as a decrease from baseline of at 
least 50% in PRO2 (PRO2 is defined as having 2 components, 
abdominal pain and stool frequency) at weeks 2, 4, 6, 8, 10, 
and 12 
• 
Clinical remission defined as abdominal pain ≤1 and stool 
frequency ≤3 on the PRO2 scale at weeks 2, 4, 6, 8, 10, and 
12 
• 
Endoscopic remission defined as SES CD score of 0-2, or 
SES CD score of 0-4, with no individual sub score >1 at 
week 14  
• 
Histologic response defined as a ≥50% decrease in Global 
Histologic Activity Score from baseline at week 14 
An exploratory objective of the study is 
to evaluate the safety and tolerability of 2 
different doses of TEV-48574 sc 
administered Q2W in adult patients with 
IBD (moderate to severe UC or CD). 
• 
Use of concomitant medication 
• 
Device-related adverse events and malfunctions (for the 
commercial sc infusion system) 
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Objectives 
Endpoints 
An exploratory objective of this study is 
to evaluate association among exploratory 
biomarkers and clinical efficacy of 
TEV-48574 in adult patients with IBD 
(moderate to severe UC or CD). 
• 
Change from baseline at weeks 2, 4, 8, and 14 in 
protocol-specified serum-resident pharmacodynamic (PD) 
markers  
• 
Change from baseline in serum and/or gastrointestinal (GI) 
tissue markers of GI tissue condition (at weeks 2, 4, 8, and 14 
for serum; at week 14 for tissue) 
• 
Change from baseline at week 14 in GI tissue transcriptome 
• 
Change from baseline in fecal calprotectin or other 
stool-derived markers at weeks 2, 4, 8, and 14 
• 
Change from baseline in high sensitivity C-reactive protein at 
weeks 2, 4, 8, and 14 
• 
Change from baseline in serum free and total tumor necrosis 
factor (ligand) 1A at weeks 2, 4, 8, and 14 
• 
Change from baseline at week 14 in GI tissue TL1A 
expression 
• 
Change from baseline in UC-100 at week 14 in patients with 
moderate to severe UC 
• 
Change from baseline in 
 
 
 at weeks 2, 8, and 14 
An exploratory objective of the study is 
to obtain trough serum TEV-48574 
concentrations, to compare major 
pharmacokinetic characteristics between 
UC and CD patients with healthy 
volunteers and asthma patients, and, if 
data allows, to evaluate the 
pharmacokinetics/PD and/or exposure-
response relationship of different doses of 
TEV-48574 sc. 
• 
Trough serum TEV-48574 concentrations throughout the 
study (sparse sampling) 
• 
Population pharmacokinetic parameters (eg, clearance, 
volume of the central compartment, area under the 
concentration-time curve [AUC], maximum observed drug 
concentration, and trough drug concentration) 
• 
Population pharmacokinetic-PD parameters 
• 
Exposure-response parameters 
An exploratory objective of this study is 
to evaluate the effect of genetic 
polymorphisms on clinical efficacy in 
adult patients with IBD (moderate to 
severe UC or CD). 
• 
Primary and other efficacy endpoints  
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4. 
STUDY DESIGN  
4.1. 
General Study Design and Study Schematic Diagram  
This is a Phase 2b, randomized, double-blind, dose-ranging study to determine the 
pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate 
to severe UC or CD. The study will enroll adult patients (18 to 75 years of age, inclusive) of 
male and female sex (without restrictions on gender) with moderate to severe active UC or CD 
and who have demonstrated an inadequate response to, loss of response to, or intolerance to at 
least 1 of the following therapies: corticosteroids, immunosuppressants, or an advanced therapy 
for IBD including biologics (anti-TNF, anti-integrins, anti-IL-12/23 or anti-IL-23), JAK 
inhibitors, or sphingosine-1-phosphate (S1P) receptor modulators; and no more than 3 locally 
approved classes of biologics. 
The study will consist of a screening period of up to 6 weeks (42 days), a 14-week treatment 
period, and a 4-week follow-up period. 
Screening: After providing written informed consent, patients will be screened within 6 weeks 
(42 days) prior to randomization to confirm that they have met all the selection criteria for the 
study. At least 2 visits to the investigational site will be necessary to complete all screening 
procedures, including an endoscopy. The endoscopy should be performed after key eligibility 
criteria have been met and within approximately 10 calendar days of randomization (day 1) to 
allow for central endoscopy scoring. 
Randomization: Patients satisfying the eligibility criteria at the end of the screening period will 
be randomized in a 1:1:1 ratio (stratified by diagnosis [UC or CD] and previous exposure to 
advanced therapy for IBD (yes/no) (biologics, JAK inhibitors, and S1P receptor modulators) to 
1 of 3 treatment groups for the double-blind treatment period (Table 2). 
All study treatments will be administered in a double-blind fashion as 1 sc infusion Q2W. 
Table 2: 
Randomization Scheme 
Randomization ratio 
Planned approximate number 
randomized 
Treatment (Q2W) 
1 
40 UC + 40 CD 
TEV-48574 2250 mg (single loading dose)/900 mg 
(6 induction doses) 
1 
40 UC + 40 CD 
TEV-48574 2250 mg (single loading dose)/450 mg 
(6 induction doses) 
1 
40 UC + 40 CD 
Placebo 
CD=Crohn’s disease; Q2W=every 2 weeks; UC=ulcerative colitis. 
Patients randomized prior to Amendment 03 with Revision 01 will continue to receive the same 
dose, volume, and rate of administration of the IMP to which they were initially randomized and 
will remain blinded. 
Treatment and Follow-Up Period: During the 14-week treatment period, patients will visit the 
site Q2W on days 1, 15, 29, 43, 57, 71, and 85 (±3 days) for IMP administration (7 visits), as 
well as an end-of-treatment visit on day 99 (±3 days; week 14) (Table 1). After the end of the 
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14-week treatment period, all patients may be offered the option to enter a long-term extension 
study, which is described in a separate protocol (TV48574-IMM-20038). If they choose to enter 
(sign the extension study informed consent form [ICF]) and will subsequently be randomized 
into the long-term extension study, they will not need to complete the follow-up visit in this 
study. All other patients will return to the site for a follow-up visit (day 127 [±3 days]). For those 
patients who enter the long-term extension study, adverse events and concomitant medication 
data will be recorded in the dose-ranging study case report form (CRF) up until the date of 
extension study randomization (defined as the study completion date for the dose-ranging study). 
For those patients who screen fail the long-term extension study, adverse events and concomitant 
medication data will be recorded in the dose-ranging study up until the follow-up visit 
(day 127 [±3 days]) CRF. Patients who complete the last scheduled visit will be considered to 
have completed the study. 
Patients who withdraw from the study before completing the 14-week treatment period will 
complete the assessments for the early termination visit and will be encouraged to complete the 
follow-up period in the study. 
The end of study is defined as the last visit of the last patient. 
The total duration of patient participation in the study is planned to be up to 24 weeks for each 
individual patient. 
The study duration will be approximately 27 months, from Q3 2022 until approximately 
Q4 2024.  
Study procedures and assessments with respective time points are shown in Table 1.  
The overall study schematic diagram is shown in Figure 1. 
 
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4.2. 
Planned Number of Patients and Countries  
Approximately 480 patients will be screened to achieve approximately 240 randomized patients 
(approximately 120 patients with UC and 120 patients with CD). The sample size does not 
include patients that were randomized to the 1800 mg treatment group prior to Amendment 03 
with Revision 01. 
The study is planned to be conducted in North America, Europe, Africa, and Asia in 
approximately 200 investigational centers. The study is expected to start in Q3 2022 and last 
until approximately Q4 2024. 
4.3. 
Justification for Study Design and Selection of Population  
This study includes both patients with moderate to severe UC and patients with moderate to 
severe CD. 
The mucosal immune system components, including epithelial cells, innate and adaptive immune 
cells, cytokines, and chemokines, contribute to the pathogenesis of CD and UC 
(Wallace et al 2014). The fibrogenic factor TNF-like ligand 1A (TL1A, or TNF superfamily 
member 15) is one of such contributors (Shih et al 2014).  
Considering that increased cytokine production leads to chronic inflammation, inhibition of 
TL1A may be a therapeutic target for both UC and CD (Takedatsu et al 2008; Section 2.1.2). 
Preclinical studies in rodent colitis models and human cells have shown that the TEV-48574 can 
reduce tissue fibrosis, the number of fibroblasts, and clinical disease score (Clarke et al 2018). 
In addition to the pathophysiologic similarities between UC and CD, there is a commonality of 
the medications used to treat UC and CD. There are multiple classes approved for the treatment 
of patients with moderately to severely active UC and CD: 5-ASA, corticosteroids or 
immunosuppressant drugs, tumor necrosis factor-alpha (TNF-α) inhibitors, integrin inhibitors, 
and IL-12/23 inhibitors. The following approved mAbs have similar dose regimens for both UC 
and CD: 
• REMICADE® (infliximab; REMICADE SmPC 2021, REMICADE PI 2020). 
• HUMIRA® (adalimumab; HUMIRA SmPC 2020, HUMIRA PI 2021). 
• ENTYVIO® (vedolizumab; ENTYVIO SmPC 2021, ENTYVIO PI 2021). 
• STELARA® (ustekinumab; STELARA SmPC 2021, STELARA PI 2020). 
The individual product’s efficacy profiles share similarities across the 2 disease states. For 
example, in the induction phase of the Phase 3 clinical development program of ENTYVIO for 
the UC patient population, clinical remission described by a complete Mayo score of <2 with no 
individual score >1 at week 6 was 16.9% in the ENTYVIO cohort versus 5.4% in the placebo 
one (Feagan et al 2013). In comparison for the CD patient population, the clinical remission 
defined as Crohn’s Disease Activity Index (CDAI) <150 at week 6 was 14.5% in the ENTYVIO 
cohort and 6.8% in the placebo one (Sandborn et al 2013). Another example is related to the 
STELARA Phase 3 clinical development program for both UC and CD. Utilizing the 
above-described measures of clinical remission (Mayo score for UC and CDAI for CD), the 
efficacy in the UC study was 15.6% versus 5.3% for placebo at week 8 (Sands et al 2019) and 
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20.9% versus 7.3% at week 8 in the CD study (Feagan et al 2016). This information gives a 
reason to hypothesize that the TEV-48574 may exhibit the same pattern and provide similar 
efficacy in both UC and CD at the same dose levels with the same dosing regimen. 
There are many existing challenges associated with clinical study design and drug development 
in UC and CD. Current rates of patient recruitment for participation in Phase 2b UC and CD 
clinical studies are low. This situation is based on the significant number of clinical studies 
competing for recruitment of patients, as well as a reluctance to expose patients to placebo 
treatment considering the availability of multiple approved therapies. The timelines and invasive 
procedures contribute to an increased burden for patients, investigators, and industry sponsors 
(Abreu et al 2020). 
The basket design is designed to make full use of the hypothesized commonality of the 
anti-TL1A mechanism of action in patients with UC and CD. 
The basket DRF design offers the following efficiencies: 
• Provide data in both UC and CD populations in a single study to adequately support 
initiation of confirmatory studies 
• Operate under a single protocol, with opportunity for shared sites and Institutional 
Review Board (IRB) 
• Allow analyses and dose selections for UC and CD under consistent conditions 
• Investigate whether the same dosing regimen of TEV-48574 is efficacious for both UC 
and CD, as is the case with other approved mAbs for IBD 
Basket studies are prospectively designed studies typically conducted in Phase 2 to allow 
effective evaluation of therapeutic benefit of a single investigational treatment in multiple 
diseases or disease subtypes. In some instances, these designs have served as a basis for 
regulatory approval (Hyman et al 2015, Subbiah et al 2018). 
In summary, the commonality of the anti-TL1A mechanism of action in patients with UC and 
CD, the approved mAbs that have similar dose regimens for both UC and CD, and the 
opportunities for operational efficiencies make a basket design well suited for the planned study. 
Refer to Section 3.1.1 for the justification for the primary endpoint selection.  
Refer to Section 6.3 for justification for dose of test IMP, use of placebo IMP, and the device 
used for IMP administration. 
4.4. 
Stopping Rules for the Study  
4.4.1. 
Individual Stopping Criteria  
4.4.1.1.Permanent Individual Withdrawn from IMP  
IMP will be discontinued in the event of any of the following: 
• The patient develops a serious or severe infection that is: 
○ Life threatening 
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○ Requires intensive care unit admission 
○ Systemic opportunistic infection including tuberculosis (including pulmonary), 
cytomegalovirus (CMV; including CMV colitis), and listeriosis 
• The patient experiences a serious or severe hypersensitivity reaction following 
investigational medicinal product (IMP) administration, meeting the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria 3 to 4: 
○ Anaphylaxis 
○ Allergic reaction 
○ Serum sickness 
• The patient experiences a serious or severe Cytokine Release Syndrome following IMP 
administration, defined as CTCAE grade 3 to 4. 
• The patient is diagnosed with malignant neoplasm other than appropriately treated basal 
cell carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine 
cervix. 
• The patient experiences a serious adverse event where in the investigator, after 
consultation with the study sponsor’s medical expert, assesses there is a reasonable 
possibility that the serious adverse event may be caused by the IMP. 
• The patient becomes pregnant (see Section 8.3). 
• The patient requires prohibited medications or an increase from baseline of the 
medications for the treatment of UC and CD, including surgery for UC and CD (see 
Section 6.6.3 and Section 6.6.4). 
• Neutrophil count of: 
○ Absolute neutrophil count <0.5x109/L confirmed on repeat testing within 3 to 5 
days 
○ Absolute neutrophil count <1.0x109/L that lasts for 2 weeks (retested every 3 to 5 
days) or accompanied by fever ≥38.5°C 
• Lymphocyte count: 
○ Lymphocyte count <0.2x109/L confirmed on repeat testing within 3 to 5 days 
○ Lymphocyte count 0.2 to 0.5 x109/L that lasts for 2 weeks (retested every 3 to 5 
days) 
• Hemoglobin <8 g/dL or an absolute decrease of ≥3 g/dL from baseline (confirmed in 
repeated test) 
• Platelets <50x109/L (confirmed in repeated test) 
• Liver Chemistry Stopping and Increased monitoring criteria  
o  (Refer to Liver Safety Required Actions and Follow up Assessments section in 
Appendix K) 
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▪ alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5x 
upper limit of normal (ULN) 
▪ ALT or AST ≥3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%) 
▪ AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample or in 
combination with clinical jaundice or in combination of International 
Normalized Ratio (INR) >1.5 (not applicable for patients on 
anticoagulants) 
▪ ALT ≥3x ULN for 4 weeks 
▪ ALT ≥3x ULN and cannot be monitored weekly for 4 weeks 
• QTc >500 msec or change from baseline of QTc >60 msec 
4.4.1.2.Temporary Withholding of IMP  
IMP will be temporarily discontinued in the event of any of the following: 
• Mild or moderate infusion reactions (grade 1 to 2 according to CTCAE of “allergic 
reaction”) during the infusion. The infusion may be re-initiated, at the discretion of the 
investigator, at lower speed with or without appropriate premedication, if symptoms are 
resolved within 1 hour after the stop of infusion/injection. If symptoms return, IMP 
should be discontinued immediately and permanently. 
• A clinically significant infection that the investigator believes may be related to, or 
exacerbated by, ongoing treatment with the IMP, and none of the permanent stopping 
rules have been met. 
• Absolute neutrophil count <1.0x109/L 
○ Re-testing should be undertaken within 3 to 5 days, and should be re-tested every 
3 to 5 days until values have returned to >1.5x109/L, at which point dosing can be 
resumed. If the scheduled dose window is missed, re-initiation of study treatment 
intervention should be restarted as soon as possible but should not result in two 
consecutive doses being given less than 7 days apart.  
• ALT >3x ULN and <5x ULN and bilirubin <2x ULN, without symptoms believed to be 
related to liver injury or hypersensitivity, and who can be monitored weekly for 4 weeks 
may continue IMP after discussion with sponsor’s medical expert. If, after 4 weeks of 
monitoring, ALT <3x ULN and bilirubin <2x ULN, patient will be monitored twice 
monthly until liver chemistries normalize or return to within baseline. (Refer to Liver 
Safety Required Actions and Follow up Assessments section in Appendix K). 
The investigator must immediately inform Teva of these events, and repeat evaluations and 
testing must be conducted at an appropriate frequency until the event has resolved or stabilized, 
or until the patient is referred to the care of a healthcare professional. 
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4.4.2. 
Study Stopping Criteria  
The study may be prematurely terminated by the sponsor in case of an unacceptable risk, any 
relevant toxicity, or a negative change in the risk/benefit assessment. This might include the 
occurrence of AEs with a character, severity or frequency that is new in comparison to the 
existing risk profile. In addition, any data deriving from other clinical trials or toxicological 
studies which negatively influence the risk/benefit assessment might cause discontinuation or 
termination of the study. 
An IDMC will be established. The IDMC will make recommendations regarding study stopping 
based on criteria as described in Section 10.3 and Appendix L. The final decisions regarding 
modification to study conduct, including stopping, will be made by the study Sponsor, 
incorporating IDMC recommendations. 
Written notification documenting the reason for study termination by the Sponsor or principal 
investigator will be provided to investigators or the Sponsor, respectively, study participants, the 
IEC/IRB, and regulatory authorities. Study patients will be contacted, as applicable, and be 
informed of any changes to the study visit schedule. 
If the whole study will be stopped, the patients that are terminated early will be followed 
according to Withdrawal Criteria and Assessments/Procedures for the Patient (Section 5.3). 
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5. 
SELECTION AND WITHDRAWAL OF PATIENTS  
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix B). 
5.1. 
Patient Inclusion Criteria  
Patients may be randomized/enrolled in this study only if they meet all of the following criteria: 
a. Adults of male and female sex (without restrictions on gender) between 18 and 75 years 
of age, inclusive, at the time of informed consent. 
b. Diagnosis of UC or CD for ≥3 months. 
c. UC patients only: Patient with moderate to severe active UC as defined by the 
3-component modified Mayo score of 5 to 9, inclusive, with an endoscopic subscore of 
≥2 (from central reading). 
d. CD patients only: Patient with moderate to severe active CD as determined by a CDAI 
score of ≥220 and ≤450. 
e. CD patients only: SES-CD score of ≥6 (≥4 for isolated ileal disease). 
f. UC patients only: Active disease beyond the rectum (>15 cm of active disease at the 
screening endoscopy [sigmoidoscopy]). 
g. Patient must have inadequate response to, loss of response to, or intolerance to: 
− At least 1 of the following therapies: corticosteroids, immunosuppressants, or an 
approved advanced therapy for IBD including biologics (anti-TNF, anti-integrins, 
anti-IL-12/23, or anti-IL-23), JAK inhibitors, or S1P receptor modulators. No more 
than 3 locally approved classes of biologics. 
• Inadequate response to, loss of response to, or intolerance to corticosteroid 
treatment is defined as 1 or more of the following: 
− Steroid refractory: persistent symptoms of active disease despite treatment 
with at least one 4-week induction regimen that included a dose of ≥30 mg 
prednisone (oral) daily for at least 2 weeks or intravenous (iv) for at least 
1 week within the previous 5 years; 
− Steroid dependent: 2 failed attempts to taper steroids below a dose equivalent 
to 10 mg prednisone (oral) daily within the previous year; 
− Steroid intolerant: history of intolerance to corticosteroids (including, but not 
limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, 
insomnia, and infection) within the previous 5 years. 
• Inadequate response to, loss of response to, or intolerance to prior 
immunosuppressant treatment is defined by 1 or more of the following: 
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− Persistent signs and symptoms of active disease despite a history of at least 
1 regimen of oral AZA or 6-MP and/or methotrexate consistent with the 
regional standard of care; 
− History of intolerance to AZA, 6-MP, or methotrexate (including, but not 
limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function 
testing abnormalities, lymphopenia, thiopurine methyltransferase genetic 
mutation, and infection). 
• Inadequate response to, loss of response to, or intolerance to prior advanced 
therapy for IBD (biologics, JAK inhibitors, and S1P receptor modulators) defined 
as 1 or more of the following: 
− Loss of response: Persistent signs and symptoms of active disease despite at 
least one induction and one maintenance regimen of the locally approved 
regimen of anti-TNF, anti-integrins, anti-IL-12/23 or anti-IL-23 mAbs, JAK 
inhibitors, or S1P receptor modulators. 
− Inadequate response (primary non-response): Persistent signs and symptoms 
of active disease despite at least one induction regimen of the locally approved 
highest dosing regimen of anti-TNF, anti-integrins, anti-IL-12/23 or 
anti-IL-23 mAbs, JAK inhibitors, or S1P receptor modulators. 
− Intolerance: Discontinuation of anti-TNF, anti-integrins, anti-IL-12/23 or 
anti-IL-23 mAbs, JAK inhibitors, or S1P receptor modulators due to an 
adverse drug reaction as determined by treating physician. Such adverse drug 
reactions include, but are not limited to, nausea/vomiting, abdominal pain, 
pancreatitis, liver function testing abnormalities, lymphopenia, and infections. 
h. If patient is taking the following agents, patient must have been on a stable dose for the 
following specified period of time: oral 5-ASA or sulfasalazine stable dose for at least 
4 weeks prior to endoscopy, oral corticosteroids stable dose for at least 2 weeks prior to 
endoscopy, and 6-MP, AZA, or methotrexate stable dose for 4 weeks prior to endoscopy. 
i. The patient is able to communicate satisfactorily with the investigator and to participate 
in, and comply with, the requirements of the study. 
j. The patient is able to understand the nature of the study and any potential hazards 
associated with participating in the study. 
k. The patient must be willing and able to comply with study restrictions and to remain at 
the investigational center for the required duration during the study period, and willing to 
return to the investigational center for further visits, as applicable, and the follow-up 
procedures and assessments as specified in this protocol. 
l. Women of non-childbearing potential who are either surgically (documented 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or congenitally sterile 
as assessed by a physician, or 1-year postmenopausal (no menses for at least 12 months 
without an alternative medical cause plus a concentration of follicle-stimulating hormone 
[FSH] within the postmenopausal range [an increased concentration of FSH of more than 
35 IU/L] in women not using hormonal contraception or hormonal replacement therapy). 
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Women of childbearing potential (WOCBP) must have a negative β-human chorionic 
gonadotropin (HCG) test result and practice a highly effective method of birth control 
(methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly; Appendix D) prior to IMP administration and throughout the study or 50 
days after the last IMP dose, whichever is longer. 
m. Male patients (including vasectomized) with WOCBP partners (whether pregnant or not) 
must use condoms after the first IMP administration and throughout the study or until 
50 days after the last IMP dose, whichever is longer. 
5.2. 
Patient Exclusion Criteria  
Patients will not be randomized/enrolled in this study if they meet any of the following criteria: 
a. The patient has any concomitant conditions or treatments that could interfere with study 
conduct, influence the interpretation of study observations/results, or put the patient at 
increased risk during the study as judged by the investigator and/or the clinical study 
physician. 
b. Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease 
associated with colitis, or microscopic colitis. 
c. Patient has colonic dysplasia or neoplasia (with exception of dysplasia on a completely 
excised adenomatous polyp [not a sessile one]), toxic megacolon, primary sclerosing 
cholangitis, known non-passable colonic stricture, presence of colonic or small bowel 
stoma, presence of non-passable colonic or small bowel obstruction or resection 
preventing the endoscopy procedure, or fulminant colitis. 
d. Presence of active enteric infections (positive stool culture) or a history of serious 
infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks prior to 
the first screening visit. 
e. Patient anticipates requiring major surgery during this study. 
f. Hepatitis B core antibody (HBcAb) or surface antigen (HBsAg) positive. If HBcAb is 
positive and HBsAg negative, Hepatitis B viral deoxyribonucleic acid (DNA) will be 
done as reflective test, and, if undetectable, then not exclusionary. Hepatitis C antibody 
positive with detectable ribonucleic acids (RNAs). Positive human immunodeficiency 
virus types 1 or 2 at screening. 
g. Tested positive for TB at screening by the QuantiFERON® TB Gold Test (unless 
documentation of prior TB treatment is available) or had a history of untreated latent or 
active TB. 
h. A history of an opportunistic infection (eg, cytomegalovirus retinitis, Pneumocystis 
carinii, or aspergillosis). 
i. A history of more than 2 herpes zoster episodes in the last 5 years or multimetameric 
herpes zoster. 
j. A history of or ongoing chronic or recurrent serious infectious disease (eg, infected 
indwelling prosthesis or osteomyelitis). 
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k. Current or history of chronic liver or biliary disease (with the exception of Gilbert’s 
syndrome, asymptomatic gallstones or uncomplicated fatty liver disease) at screening or 
baseline ALT or AST >2x ULN or bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening. 
l. Absolute neutrophil count <1.5x109/L or Hemoglobin <9 g/dL or  
lymphocyte count <0.8x109/L or platelet count <100,000/mL  
m. The patient has QTc>480 ms 
n. Any acute infection which in the opinion of the investigator compromises the safety of 
the patient. 
o. The patient is currently pregnant or lactating or is planning to become pregnant or to 
lactate during the study or for at least 50 days after administration of the last dose of IMP 
in case of early termination. Any woman becoming pregnant during the study will be 
withdrawn from the study. 
p. The patient has a known hypersensitivity to the IMP and/or excipients. 
q. Presence of a transplanted organ. 
r. A history of malignancy within the last 5 years (exception: basal cell carcinoma or in situ 
carcinoma of the cervix if successful curative therapy occurred at least 12 months prior to 
screening or curatively resected papillary thyroid cancer). 
s. Patient is receiving any of the following therapies within the designated time period: 
− The patient is currently using any systemic immunosuppressant or 
immunomodulatory biologic or nonbiologic (other than those listed in inclusion 
criterion “h” and those that are used for IBD) within 30 days or 5 half-lives 
(whichever is longer) prior to the endoscopy. 
− >9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent within 
2 weeks prior to the endoscopy. 
− Topical (rectal) treatment of 5-ASA or intravenous, intramuscular (parenteral), or 
enema/suppository administration of corticosteroids within 2 weeks prior to the 
endoscopy. 
− Biologics including anti-TNF, anti-integrins, anti-IL-12/23, or anti-IL-23 within 
3 half-lives prior to randomization. 
− Small molecules including JAK inhibitors, or S1P receptor modulators, within 
5 half-lives or shorter washout duration if undetectable drug levels can be 
demonstrated prior to randomization. 
− Other investigational procedures or products, within 30 days or 5 half-lives of 
investigational product prior to the endoscopy, whichever is longer. 
− Live vaccine within 14 days prior to the first screening visit. Inactivated vaccines 
(including approved inactivated COVID-19 vaccines) should preferably be completed 
14 days before first IMP dosing. If administered during the study, it is recommended 
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to be at least 3 days before and after IMP administration, or as required by local 
country regulations. 
t. Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse. 
u. Patients with incurable diseases, persons in nursing homes, and patients incapable of 
giving written informed consent. 
5.3. 
Withdrawal Criteria and Assessments/Procedures for the Patient  
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), patients may completely withdraw from the study (ie, with no further study 
participation or contact) at any time for any reason. Patients may also discontinue IMP and 
remain in the study for assessments after consultation with the investigator and/or sponsor. The 
investigator and/or sponsor may also discontinue a patient from IMP and/or withdraw a patient 
from the study in any of the following events:  
• in the event of intercurrent illness, adverse events, pregnancy, or any other reason 
concerning the health or well-being of the patient that indicates to the investigator that 
continued participation is not in the best interest of the patient (see also Individual 
Stopping Rules can be found in Section 4.4.1);  
• if the patient is noncompliant with the study procedures and assessments or 
protocol-defined study restrictions or prohibited concomitant medication 
Patients who terminate the study should complete the safety and efficacy evaluations specified 
for early termination in the Study Procedures and Assessments schedule (Table 1) at the time 
they terminate study participation, and they will be encouraged to complete the follow-up period 
in the study. 
Investigators are to discuss patients who may be considering discontinuing IMP or withdrawing 
completely from the study with the sponsor as soon as the site becomes aware of the situation. 
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study or discontinuation from IMP. Results of any evaluations and observations, together with a 
narrative describing the reason(s) for withdrawal from the study or discontinuation from IMP, 
should be recorded in the source documents. The CRF should document the primary reason for 
withdrawal from the study or discontinuation from IMP. 
See Appendix E for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data. 
If an adverse event is the primary reason for discontinuation of IMP or withdrawal from the 
study, this should be documented in the source and in the CRF, including test results if 
applicable. Under these circumstances, monitoring should be continued until the event has 
resolved or stabilized, or until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made. 
The investigator should inform the sponsor as soon as possible of each patient who is being 
considered for withdrawal due to adverse events. Additional reports should be provided when 
requested. 
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A patient who withdraws from the study will have the following options regarding 
pharmacogenetic research:  
• Withdraw from the clinical study but accept that the DNA extracted from the patient’s 
blood will be retained and used in accordance with the patient’s original pharmacogenetic 
informed consent. 
• Withdraw from the clinical study and withdraw consent for pharmacogenetic research as 
well, in which case the DNA sample will be destroyed, and no further testing will take 
place. To initiate the sample destruction process, the investigator must notify the sponsor 
site contact to request sample destruction. The sponsor site contact will, in turn, contact 
the biomarker representative to execute sample destruction. If requested, the investigator 
will receive written confirmation from the sponsor that the sample has been destroyed. 
• Withdraw consent for pharmacogenetic research while remaining in the clinical study. In 
such a case, any DNA extracted from the patient’s blood will be destroyed. The sample 
destruction process will proceed as described above. 
5.4. 
Replacement of Patients  
A patient who is randomized but does not complete the treatment period will not be replaced. 
5.5. 
Rescreening  
If a patient needs to be rescreened, this should be discussed with the sponsor and/or designee. If 
a patient is a screen failure but at some point in the future is expected to meet the patient 
eligibility criteria, the patient may be rescreened only after consultation with the sponsor. 
Patients who are rescreened will be assigned a new patient number, will undergo the informed 
consent process, and will then start a new screening phase. 
5.6. 
Screening Failure  
Screen failure occurs when a patient who consents to participate in the clinical study is not 
subsequently randomized into the study because that patient did not meet the inclusion criteria or 
did meet the exclusion criteria.  
Selected information about patients who screen-fail will be collected to comply with reporting 
and publishing requirements. This information may include, but is not limited to, demography, 
detailed reasons for screening failure, eligibility criteria, and any serious adverse events. 
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6. 
TREATMENTS  
6.1. 
Investigational Medicinal Products Used in the Study  
An IMP is defined as the test IMP (TEV-48574) and matching placebo IMP to the test IMP. 
For patients randomized prior to Amendment 03 with Revision 01: 
The volume of the solution of each IMP (TEV-48574 and placebo) will be constant (15 mL 
loading dose volume and 12 mL induction dose volume) and will be administered as single sc 
administrations. 
Active IMP will be diluted with placebo to achieve the final delivered concentrations. Patients 
will receive the following regimens as a single sc administration Q2W using the 
 
 
, 
 
 
• TEV-48574 2250 mg (single loading dose)/1800 mg (6 induction doses) 
• TEV-48574 2250 mg (single loading dose)/900 mg (6 induction doses) 
• TEV-48574 2250 mg (single loading dose)/450 mg (6 induction doses) 
• Placebo to match TEV-48574 (single loading dose)/(Induction doses) 
For patients randomized as of Amendment 03 with Revision 01: 
The volume of the solution of each IMP (TEV-48574 and placebo) will be constant (15 mL 
loading dose volume and 6 mL induction dose volume) and will be administered as single sc 
administrations. 
Active IMP will be diluted with placebo to achieve the final delivered concentrations. Patients 
will receive the following regimens as a single sc administration Q2W using the 
 
 
, 
 
 
• TEV-48574 2250 mg (single loading dose)/900 mg (6 induction doses) 
• TEV-48574 2250 mg (single loading dose)/450 mg (6 induction doses) 
• Placebo to match TEV-48574 (single loading dose)/(Induction doses) 
6.1.1. 
Test Investigational Medicinal Product  
TEV-48574 for sc infusion is provided as a liquid solution with a concentration of 150 mg/mL. 
Refer to Table 3 for specific details regarding TEV-48574. Additional details may be found in 
the Pharmacy Manual and in the IB for TEV-48574.  
6.1.2. 
Placebo Investigational Medicinal Product  
Placebo IMP for sc infusion is provided as a liquid solution in the same formulation as 
TEV-48574, except for the absence of active protein. Refer to Table 3 for specific details 
regarding placebo IMP. 
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6.1.3. 
Test and Placebo Investigational Medicinal Product Administration  
TEV-48574 or placebo IMP will be administered using a commercial sc infusion system. For this 
study, the 
 will be utilized. This syringe infusion system 
is cleared for use in the US under a 510(k) K092313 and CE marked for use in the EU. This 
infusion system is indicated for the iv or sc infusion of medications and fluids in the hospital and 
clinics where the use of the pump can be supervised by a clinician. 
This system safely enables single-site sc administration of large volumes to avoid the need for 
multiple injections from individual syringes and is capable of administration of up to 60 mL 
syringe using a sc safety needle set. The system controls the rate of drug entry into the tissues 
surrounding the sc infusion site as well as the duration of infusion. The syringe infusion system 
is a mechanical or electromechanical syringe pump that pushes the syringe plunger at a constant 
rate throughout the infusion to infuse drug. 
A sterile disposable 20 mL syringe is utilized with the infusion systems and is connected to a 
subcutaneous needle set, via a luer lock connector, which has a 6mm needle length and delivers 
the IMP to the subcutaneous tissue. The subcutaneous needle set, which is used in conjunction 
with the pump and 20 mL syringe, is the KORU (RMS 12606) 26G 6mm single needle infusion 
set that is cleared under 510k (K102512) and is also CE marked. 
The infusion rate is fixed at 30 mL/hr for all sc infusions.  
For patients randomized prior to Amendment 03 with Revision 01: 
The expected infusion durations will therefore be 30 minutes for the 15 mL loading dose and 
24 minutes for the 12 mL induction doses. 
For patients randomized as of Amendment 03 with Revision 01: 
The expected infusion durations will therefore be 30 minutes for the 15 mL loading dose and 
12 minutes for the 6 mL induction doses. 
The sponsor has evaluated the suitability of these types of syringe infusion systems to deliver 
TEV-48574 and the compatibility of TEV-48574 with the appropriate syringe and tubing sets 
(drug fluid path) that will be used for sc delivery of TEV-48574. The evaluation included general 
device performance testing and drug compatibility/stability testing of the fluid path. The testing 
indicated that the drug product quality and characteristics were not affected by the use of a 
syringe infusion system, and the associated fluid path components and materials, and all drug 
critical quality attribute met specifications. The sponsor only intends to use this device for 
clinical purposes and will develop a yet to be defined device for commercial use. 
The device, syringe, and tubing and needle set to be used are documented in the study Pharmacy 
Manual. 
Table 3: 
Investigational Medicinal Products Used in the Study 
IMP name 
Test IMP 
Placebo IMP 
Trade name and INN, if 
applicable, or 
company-assigned number 
TEV-48574 
Placebo 
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IMP name 
Test IMP 
Placebo IMP 
Formulation 
10 mM histidine, 5% (w/v) sucrose, 100 
mM arginine-hydrochloride, 0.02% (w/v) 
polysorbate-80, pH 6.0. Liquid. Protein 
concentration: 150 mg/mL 
10 mM histidine, 5% (w/v) sucrose, 
100 mM arginine-hydrochloride, 
0.02% (w/v) polysorbate-80, pH 6.0. 
Liquid absent of protein 
Unit dose strengths/dosage 
levels 
450 mg/vial 
-- 
Route of administration 
sc administration using a commercial sc 
infusion system 
sc administration using a commercial 
sc infusion system 
Dosing instructions/dosing 
schedule/titration 
periods/treatment periods 
Refer to details in the Pharmacy Manual. 
Refer to details in the Pharmacy 
Manual. 
Packaging 
IMP will be provided in a type 1 clear glass 
vial with 20 mm butyl elastomer stopper 
and an aluminum crimp seal with a plastic 
flip off cap. 
Placebo IMP will be provided in a type 
1 clear glass vial with 20 mm butyl 
elastomer stopper and an aluminum 
crimp seal with a plastic flip off cap. 
Manufacturer 
Teva Branded Pharmaceutical Products 
R&D, Inc. 
 
 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
 
 
IMP=investigational medicinal product; INN=international nonproprietary name; sc=subcutaneous; 
w/v=weight/volume; USA=United States of America. 
6.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products and Devices  
6.2.1. 
Preparation, Storage and Security  
Prepared doses of TEV-48574 and placebo IMP will be kept for no more than 4 hours at 25ºC 
from time of opening the first vial, to completion of dose administration. Additional preparation 
details may be found in the Pharmacy Manual. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs. 
The IMPs (TEV-48574 and placebo IMP) must be stored at a controlled temperature 
(2°C to 8°C) in a secure area. The site should have a process for monitoring IMP storage 
temperature. 
6.2.2. 
Labeling  
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
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6.2.3. 
Accountability  
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and 
used in accordance with this protocol. 
Only patients enrolled (ie, randomized) in the study may receive IMPs, and only authorized staff 
at the investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center. 
The investigator is responsible for IMP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies.  
Further guidance and information are provided in the Pharmacy Manual. 
6.3. 
Justification for Investigational Medicinal Products  
6.3.1. 
Justification for Dose of Test Investigational Medicinal Product  
The justification listed herein refers to the study doses introduced in Amendment 03 with 
Revision 01 of the study protocol. In this study as of Amendment 03 with Revision 01, 
TEV-48574 will be administered as a single loading dose of 2250 mg followed by induction 
doses of 450 or 900 mg sc Q2W, for a total of 7 doses. Patients randomized prior to Amendment 
03 with Revision 01 will continue to receive the dose (including volume, rate, and duration) of 
IMP to which they were initially randomized to not disrupt potential response to treatment and 
maintain the integrity of the study (eg, blinding concerns and data analysis). 
The 2250 mg loading dose as part of the induction dose regimen has been selected to address the 
significant over-production of TL1A in the colon (Wenxiu et al 2021) within the first weeks of 
induction, and is supported by precedents from other mAbs with multiple autoimmune disease 
indications. In these products (HUMIRA SmPC 2020, HUMIRA PI 2021, REMICADE PI 2020, 
REMICADE SmPC 2021, STELARA SmPC 2021, STELARA PI 2020), it is often observed that 
a loading dose is included in the IBD therapeutic regimen but not in the other indications, and 
that the IBD dose levels are generally higher in comparison to the other indications. This may be 
partially explained by the antigen-dependent clearance pathway, often described as an “antigen 
sink.” It is known that receptor density influences the pharmacokinetics of mAbs. One potential 
explanation for the lack of response to TNF inhibitors is incomplete suppression of TNF-α 
activity because of insufficient serum drug concentrations to block the excess of TNF. A high 
inflammatory burden at baseline is associated with higher concentrations of TNF-α in both tissue 
and serum. Patients with a higher degree of systemic inflammation may therefore require greater 
amounts of drug to neutralize this excess of TNF-α (Ordas et al 2012). Specifically for this 
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target, it has been established that the TL1A/DR3 system is significantly up regulated in patients 
with IBD and chronic intestinal inflammation. Intestinal tissue samples from patients with CD 
and UC exhibit increased TL1A transcripts and protein expression, which correlated with the 
severity of inflammation (Valatas et al 2019). This may require greater amounts of TL1A 
inhibition to neutralize the increased TL1A expression in the IBD patient population. 
In line with this concept, a single loading dose of 2250 mg is used in this study. This dose level 
is within the range of doses safely administered to patients with asthma in the MAD portion of 
Study TV48574-SAD-10126 and in Study TV48574-AS-20031. 
The 2 induction dose strengths in this study as of Amendment 03 with Revision 01, were 
selected based on a combination of safety, preclinical evidence, and pharmacokinetic 
considerations and will enable selection for the next stage of clinical development by discerning 
clinically meaningful differences in the absence of pharmacologic or biomarker data to guide 
dose selection for the pivotal program. 
• Selection of the induction regimen of 450 mg or 900 mg Q2W TEV-48574 was done 
through the use of population pharmacokinetic modeling methodologies. These 
calculations were aimed to confirm that TEV-48574 induction doses resulted in similar 
exposures range as RVT-3101 (previously known as PF-06480605), another anti-TL1A 
antibody, which was tested at 50, 150, or 450 mg sc monthly in a Phase 2b study in UC 
(TUSCANY-2, National Clinical Trial [NCT] Number: NCT04090411). 
• Single/loading doses of up to 1000 mg and 2300 mg and repeated doses of up to 1600 mg 
Q2W were safely administered in Study TV48574-SAD-10126 and 
Study TV48574-AS-20031, respectively. The highest exposure to drug is expected in 
patients enrolled in this study is 900 mg Q2W. This dose is significantly lower than that 
tested in previous clinical trials for TEV-48574 where no safety signal was observed. 
Moreover, this dose is expected to result in exposures below those seen in GLP 
toxicology studies. Predictions obtained from a population pharmacokinetic model 
suggest a steady-state median value of 67.1 μg/mL (with 37.7 μg/mL and 125.8 μg/mL 
being the 5th and 95th percentile, respectively) for Cmax, and median value of 
690.8 days*μg/mL (with 309.8 days*μg/mL and 1449.6 days*μg/mL being the 5th and 
95th percentile, respectively) for AUCτ for the simulated 
 Q2W mg dose. The 
safety margins for the 
 Q2W dose based on population pharmacokinetic 
simulation exposure are ~20 and ~10 for Cmax and AUC, respectively. 
• As demonstrated in Study TV48574-SAD-10126, the potential for immunogenicity of 
TEV-48574 is increased in doses ≤200 mg in comparison to higher doses, deemed 
clinically relevant. No ADAs were detected at dose levels of 400 mg and above in 
single- and multiple-dose cohorts (except for a single patient in the 1000 mg cohort with 
an extremely low ADA titer detected at a single time point). Based on this consideration, 
the lowest dose of 450 mg Q2W is expected to have a low immunogenicity potential. 
• As per ICH E4 guidance, for a proper exposure-response characterization, the sponsor 
should choose doses that ensure adequate spread of attained concentrations in 
dose-response studies. The induction doses (TEV-48574 450 mg or TEV-48574 900 mg 
Q2W) will provide pharmacokinetic, PD, and response information which, together with 
other exposure-response data collected in the program, will enable selection of doses for 
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subsequent development. Doses tested in this study prior to Amendment 03 with 
Revision 01 introduction could provide additional supportive information. 
In summary, based on a combination of safety, pharmacokinetics, preclinical and clinical 
evidence, and disease-related considerations, the doses selected for this study are considered 
adequate to enable exploration of an efficacious dose and safe induction dosing regimen of 
TEV-48574 for patients with UC or CD. These doses are expected to establish a dose-response 
relationship, and to support an informed dose selection in future studies with TEV-48574 for 
each indication of UC and CD. 
6.3.2. 
Justification for Use of Placebo Investigational Medicinal Product  
A placebo-controlled design is scientifically appropriate as the use of a placebo-controlled design 
in this study will allow robust evaluation of any treatment effect of TEV-48574 and 
characterization of any potential adverse drug reactions. 
Patients will have close medical observation throughout the study. In addition, only patients for 
whom it is considered safe to participate in the study, in the opinion of the investigator, will be 
permitted to participate. 
6.3.3. 
Justification for Device Used for Administration  
The commercial sc infusion system selected for administration of TEV-48574 and placebo IMP 
is capable of delivering the desired volumes over a wide range of fluid administration rates to 
meet the needs of the clinical study. This system safely enables single-site sc administration of 
large volumes to avoid the need for multiple injections from individual syringes. 
6.4. 
Treatment After the End of the Study  
After the end of the 14-week treatment period, all patients may be offered the option to enter a 
long-term extension study (to be described in a separate protocol [TV48574-IMM-20038]). 
Otherwise, after the follow-up period, patients will be advised to return to their treating physician 
for appropriate treatment following completion of the study. 
6.5. 
Restrictions  
Patients will be required to comply with the following restrictions: 
6.5.1. 
Activity  
Patients must remain seated or in a supine position for safety reasons during each IMP 
administration and for 1 hour after each IMP administration. Patients will be allowed to use the 
restroom (escorted by investigational center personnel) during this time, as needed. 
Patients should avoid strenuous exercise for at least 4 hours prior to any clinic visit and for at 
least 4 hours after IMP administration. 
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6.5.2. 
Fasting  
Patients should be fasting for at least 8 hours prior to safety laboratory assessments only at the 
screening, week 14, and early termination visits (ie, visits at which low density lipoprotein, high 
density lipoprotein, and triglycerides will be measured). 
6.5.3. 
Specific Food and Beverages  
Patients are encouraged to keep their diet habits constant throughout the study. 
6.5.4. 
Tobacco  
Smoking can have an influence on the severity of UC and CD symptoms. For that reason, 
patients should keep their smoking habits constant throughout the study. Use of a nicotine patch 
should be recorded as a concomitant medication. 
6.5.5. 
Blood Donation  
Patients may not donate blood during this study. 
6.6. 
Prior and Concomitant Medication or Therapy  
6.6.1. 
Prior Medications  
All prior medications for IBD will be recorded in the source documentation and in the CRF. Any 
other prior therapy, medication (including nonprescription drugs, vitamins, and dietary or herbal 
supplements), or procedure a patient has had 4 weeks before screening through the end of the 
study will be recorded in the source documentation and in the CRF. Generic or trade name, 
indication, and dosage will be recorded. The sponsor will encode all therapy and medication 
according to the World Health Organization drug dictionary (WHO Drug). Assessment of 
concomitant and prior medications, including a complete history of all therapies for UC and CD 
received since diagnosis (including treatment response), and detailed UC and CD medications 
(including dose, frequency, and route) prior to the screening visit will be conducted. 
6.6.2. 
Concomitant Medication(s) and Treatment(s)  
All concomitant medication(s) and treatment(s) administered/taken during the study must be 
recorded with indication, daily dose, and start and stop dates of administration. All patients will 
be questioned about concomitant medication at each site visit. Medication(s) administered/taken 
following the first dose of IMP will be documented as concomitant medication(s). 
6.6.3. 
Permitted Inflammatory Bowel Disease Medications and Rescue Medications  
Permitted concomitant treatment for UC and CD must remain at a stable dose (no increase or 
decrease) during the study treatment period (except for decreases due to adverse events); if doses 
are increased, patients must be withdrawn from the study. The dose of any background 
medication for UC and CD should not be changed during the screening and double-blind 
treatment period. If a patient requires initiation of a new therapy for UC or CD, the patient 
should be withdrawn from the study, and appropriate treatment should be administered at the 
discretion of the investigator. 
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Patients will be allowed to use the following medications as detailed below: 
• Concomitant use of oral 5-ASA or sulfasalazine. Dose must be stable for at least 4 weeks 
prior to endoscopy and through week 14. If oral 5-ASA treatment has been recently 
discontinued, it must have been stopped for at least 2 weeks prior to endoscopy. 
• A stable dose of oral corticosteroids (prednisone equivalent of up to 20 mg/day; 
budesonide of up to 9 mg/day) for at least 2 weeks prior to endoscopy and through week 
14. If oral corticosteroids have been recently discontinued, they must have been stopped 
at least 2 weeks prior to endoscopy. Decreases in steroid use due to adverse events are 
allowed. 
• A stable dose of immunosuppressant drugs (methotrexate, 6-MP, or AZA consistent with 
regional standard of care) for 4 weeks prior to endoscopy and through week 14. 
Decreases due to adverse events are permitted. 
Following the week 14 visit if not continuing on to the long-term extension study, patients will 
no longer need to abstain from the medications that were prohibited or required no change in 
dose during the screening and induction period. Biologic treatment(s) should not be initiated 
during the follow-up period without discussion with the sponsor. 
6.6.4. 
Prohibited Medications and Therapies  
The following medications will be prohibited during this study: 
• Any live (attenuated) vaccines from 14 days prior to the first screening visit and 
throughout the study. 
• Topical (rectal) treatment of 5-ASA or intravenous, intramuscular (parenteral), or 
enema/suppository administration of corticosteroids within 2 weeks prior to endoscopy 
through week 14. 
• Prednisone dose of >20 mg/day or equivalent oral systemic corticosteroid from 2 weeks 
prior to endoscopy through week 14. 
• The patient is currently using any systemic immunosuppressant or immunomodulatory 
biologic or nonbiologic (other than those listed in inclusion criterion “h” and those that 
are used for IBD) within 30 days or 5 half-lives (whichever is longer) prior to the 
endoscopy. 
• Biologics including anti-TNF, anti-integrins, anti-IL-12/23, or anti-IL-23 within 
3 half-lives prior to randomization. 
• Small molecules including JAK inhibitors, or S1P receptor modulators, within 
5 half-lives or shorter washout duration if undetectable drug levels can be demonstrated 
prior to randomization. 
• Oral budesonide of >9 mg/day or equivalent from 2 weeks prior to endoscopy through 
week 14. 
• Patients requiring a surgical intervention for UC or CD will be discontinued from the 
study 
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6.7. 
Procedures for Monitoring Patient Compliance  
The investigator will be responsible for monitoring patient compliance with this protocol from 
the start of the screening period through the EOS visit. 
If the investigator or the sponsor determines that the patient is not in compliance with the study 
protocol, the investigator and the sponsor should determine whether the patient should be 
withdrawn from the study (Section 5.3). The Independent Ethics Committee 
(IEC)/IRB/competent authorities should be notified if required by local regulation. 
6.8. 
Randomization and Blinding  
This is a randomized, double-blind, placebo-controlled study. Patients who meet all the inclusion 
criteria and none of the exclusion criteria will be randomly assigned to receive TEV-48574 
(single loading dose/6 induction doses): 2250/900 mg, 2250/450 mg, or placebo to match 
TEV-48574, in a 1:1:1 ratio, stratified by diagnosis (UC or CD) and previous exposure to 
advanced therapy for IBD (yes/no) (biologics, JAK inhibitors, and S1P receptor modulators). 
Prior to Amendment 03 with Revision 01, patients were randomly assigned to receive 1 of 
4 treatment regimens (2250/1800 mg, 2250/900 mg, 2250/450 mg, or placebo to match 
TEV-48574); these patients will continue to receive the same dose, volume, and rate of 
administration of the IMP to which they were initially randomized and will remain blinded. 
Approximately 120 UC patients and 120 CD patients will be randomly assigned to the treatment 
groups by means of a computer-generated randomization list using interactive-response 
technology. The specifications for randomization will be under the responsibility and oversight 
of Teva Global Statistics. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the Randomization and Trial Supply Management (RTSM) system. The 
generation of the randomization list and management of the RTSM system will be done by a 
qualified service provider under the oversight of the responsible function at Teva. 
6.9. 
Maintenance of Randomization and Blinding  
6.9.1. 
Maintenance of Randomization  
Patient randomization codes will be securely maintained by the service provider contracted to 
generate the codes. At the time of analysis (interim analysis and after the end of study), after 
receiving unblinding request from Teva statistician, the service provider will provide the 
unblinded IMP assignment according to the processes defined in the relevant Standard Operating 
Procedure (SOP). 
6.9.2. 
Blinding and Unblinding  
Personnel who may be aware of IMP assignments will not be involved in the conduct of any 
study procedures or assessment of any adverse events. 
The patients and the site will be blinded until all patients complete the study, and the database is 
locked for final analysis for both indications. The sponsor study team will be blinded to 
treatment assignment until the database is locked for analysis of each indication. 
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Details regarding unblinding of an independent Teva team while maintaining the blind of the 
study, in case the final analysis is conducted for one indication while the other indication is 
ongoing, will be provided in a separate unblinding charter. 
Pharmacokinetic, PD and immunogenicity samples will be collected for bioanalysis during the 
study. Individuals responsible for sample bioanalysis and other responsible personnel may know 
who received test IMP and who received placebo IMP during the study. Personnel responsible 
for bioanalysis will be provided with the randomization code to facilitate the analysis. However, 
the personnel responsible for bioanalysis will not have access to clinical safety and efficacy data 
and will provide concentration data to other personnel in a manner that will not identify 
individual patients (ie, a dummy patient identifier will be linked to the concentration data of an 
individual patient).  
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations. Individual randomization 
codes, indicating the IMP assignment for each randomized patient, will be available to the 
investigator(s) or pharmacist(s) at the investigational center via the RTSM, both via telephone 
and internet. Breaking of the treatment code can always be performed by the investigator without 
prior approval by the sponsor; however, the sponsor should be notified following the breaking of 
the treatment code. The patient’s IMP assignment should not be revealed to the sponsor. 
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document. 
For an adverse event defined as a suspected unexpected serious adverse reaction (SUSAR) (ie, 
reasonable possibility; see Section 8.1.6), Global Patient Safety and Pharmacovigilance (GPSP) 
may independently request that the blind code be broken (on a case-by-case basis) to comply 
with regulatory requirements. The report will be provided in an unblinded manner for regulatory 
submission. If this occurs, blinding will be maintained for the investigator and for other 
personnel involved in the conduct of the study, and analysis and reporting of the data. 
Interim analyses as described in Section 10.13 will be performed throughout the study by 
unblinded analysis groups external to Teva and will be reviewed by an IDMC. 
6.9.3. 
Independent Data Monitoring Committee  
A single review committee (IDMC) will be established to monitor the study while it is ongoing, 
including periodic reviews of safety data, and pre-specified analyses of efficacy data, as 
described below. 
• The IDMC will include 2 Clinicians (external to Teva) with expertise in IBD and 
1 external Statistician. The names of the external IDMC members will be included in the 
IDMC charter. 
• The role of the IDMC will be to periodically monitor unblinded safety data to ensure the 
safety of study patients as well as efficacy data for pre-specified interim analysis, and 
make recommendations on study conduct. 
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• There will be an independent (external to the sponsor and the study team) statistical 
reporting team that will perform the planned unblinded analyses of interim efficacy and 
safety data for the IDMC to review. 
The IDMC charter will provide details regarding procedures to protect the scientific integrity of 
the trial, conduct of the interim analysis, dissemination of results, and decision criteria in 
addition to pre-specified study stopping rules for safety. 
Additional details on the procedures and conduct of the IDMC sessions will be described in the 
IDMC charter. 
6.10. 
Total Blood Volume  
The estimated maximum blood volume to be collected in this study is approximately 280 mL for 
each patient during the entire study. Details on blood volumes to be collected during the study 
are provided in the ICF and the Laboratory Manual. 
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7. 
ASSESSMENT OF EFFICACY  
7.1. 
Assessments of Efficacy  
The following efficacy assessments will be performed at the time points specified in Table 1. 
Endoscopy and histology assessments will be scored centrally. 
7.1.1. 
Modified Mayo Score (Ulcerative Colitis)  
The modified Mayo score evaluates UC stage based on the following 3 parameters: 
• stool frequency 
• rectal bleeding 
• endoscopic evaluation 
Each parameter of the score ranges from 0 (normal or inactive disease) to 3 (severe activity) and 
the total score from 0 to 9, respectively (Ulcerative Colitis: Clinical Trial Endpoints Guidance 
for Industry 2016, Naegeli et al 2018). 
7.1.2. 
Endoscopy  
Endoscopy will be performed at screening and week 14 or the early termination visit. 
Assessments and procedures performed during the endoscopy, including biopsy collection, 
SES-CD, and modified multiplier (MM)-SES-CD, are described below. 
7.1.2.1.Biopsy Collection  
For patients with CD, an ileo-colonoscopy will be performed at screening and week 14. During 
each endoscopy, a total of 11 to 18 mucosal biopsies will be obtained from the area with the 
greatest inflammation in each segment at screening and at the same location at week 14 or early 
termination. If ulceration is present, biopsies should be taken from the edge of the largest ulcer. 
If no ulceration is present, then biopsies should be taken from the most affected area of the 
segment. If the mucosa appears normal (eg, at follow-up), then random biopsies of the segment 
should be obtained.  
For patients with UC, a flexible sigmoidoscopy will be performed at screening and week 14 
(colonoscopy may be performed instead for baseline endoscopy if not done in the prior 
12 months). During each endoscopy, a total of 7 to 12 biopsies will be obtained from the area 
with the worst disease 15 to 25 cm from the anal verge. If ulceration is present, biopsies should 
be taken from the edge of the largest ulcer. If no ulceration is present, then biopsy should be 
taken from the most affected area. If mucosa appears normal (eg, at follow-up), then random 
biopsies should be taken from the area 15 to 25 cm from the anal verge. 
Endoscopic biopsies and will be evaluated by microscopic and histologic analyses, as well as for 
exploratory measures involving established and novel biomarkers of intestinal inflammation and 
fibrosis. There are several different approaches for obtaining these endoscopic biopsy samples, 
and the preferred procedures are described in the Laboratory Manual and Quick Reference Card.  
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Histology samples will be scored by qualified independent, blinded central readers and digitized 
to enable the use of digital pathology for histology endpoints adjudication and computational 
quantification of inflammation and fibrosis severity. Details of adjudication strategies will 
provided in the associated charter. 
7.1.2.2.Simple Endoscopic Score for Crohn’s Disease  
The SES-CD takes into account 4 parameters (presence of ulcers, percentage of ulcerated 
surfaces, affected surface, and presence of strictures) that need to be scored in 5 bowel segments 
(the rectum, sigmoid and left colon, transverse colon, right colon, and ileum) (Daperno et al 
2004). 
7.1.2.3.Modified Multiplier-Simple Endoscopic Score for Crohn’s Disease  
The MM-SES-CD is an endoscopic scoring tool, which takes into consideration each individual 
parameter’s prognostic value for achieving endoscopic remission while on active therapy (Narula 
et al 2021). 
7.1.2.4.Robarts Histopathology Index (Ulcerative Colitis)  
The Robarts Histopathology Index (RHI) final score is obtained by combining the subscores of 
4 main items: 
• chronic inflammatory infiltrate level (4 levels) 
• lamina propria neutrophils (4 levels) 
• neutrophils in the epithelium (4 levels) 
• erosion or ulceration (4 levels) 
The 4 components are classified from 0 to 3, yielding a final score that ranges between 0 and 33 
(Mosli et al 2017). 
7.1.2.5.Geboes Score (Ulcerative Colitis)  
Geboes score is a scoring system for microscopic disease activity that incorporates a number of 
histological items classified in 5 grades (Mosli et al 2014). 
7.1.2.6.Global Histologic Activity Score (Crohn’s Disease)  
The Global Histologic Activity Score consists of 8 items assessing acute and chronic 
inflammatory changes, epithelial damage, and the extent of inflammation (ie, the proportion of 
biopsy specimens affected). Each of the 8 items is scored, with the totals subsequently added 
together (D’Haens et al 1998). 
7.1.3. 
Crohn’s Disease Activity Index  
The CDAI (Yoshida 1999) consists of 8 factors added up after adjustment with a weighting 
factor: 
• Number of liquid or soft stools each day for 7 days × 2 
• Abdominal pain (graded from 0 to 3 on severity) each day for 7 days × 5 
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• General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 
7 days × 7 
• Presence of complications × 20 
• Taking Lomotil, Imodium, or opiates for diarrhea × 30 
• Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite) × 10 
• Hematocrit of <0.47 in men and <0.42 in women × 6 
• Percentage deviation from standard weight × 1 
7.1.4. 
Two-item Patient-Reported Outcome (Ulcerative Colitis and Crohn’s Disease)  
UC: The 2-item patient-reported outcome (PRO2) includes daily evaluation of the 2 subjected 
items of the Mayo score: stool frequency and rectal bleeding. Each parameter of the score ranges 
from 0 (normal or inactive disease) to 3 (severe activity) and the total score from 0 to 6, 
respectively (Dragasevic et al 2020, Jairath et al 2015). 
CD: PRO2 is the sum of the daily stool frequency (0 to 3) and abdominal pain (0 to 3) from the 
CDAI (Khanna et al 2015). 
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8. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, use of 
concomitant medication, local tolerability, and device-related adverse events and malfunctions. 
Device deficiencies that are not associated with an adverse event, as well as those that have the 
potential to cause a serious adverse event, are covered in Appendix G. 
There will be an IDMC to monitor safety in this study (Section 6.9.3). 
8.1. 
Adverse Events and Adverse Device Effects  
8.1.1. 
Definition of an Adverse Event  
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to TEV-48574. 
Accordingly, an adverse event can include any of the following:  
• a new condition or the worsening of a pre-existing condition  
• intercurrent illnesses  
• physical injuries and the mechanism that caused the injury  
• events possibly related to concomitant medication  
• drug or drug/device or device/device interactions  
• events occurring during diagnostic procedures or during any washout phase of this study 
• laboratory or diagnostic test abnormalities 
(Note: Abnormal laboratory or diagnostic test results at the screening visit that preclude a 
patient from entering the study or receiving study treatment are not considered adverse 
events.) 
IBD manifestations are efficacy variables for this study and should be captured on the relevant 
specific CRF; accordingly, these events should not be recorded as adverse events unless assessed 
as more severe than the patient’s usual disease course. Extraintestinal manifestations of the 
patient’s disease (eg, arthralgias, arthritis, or uveitis) that develop or worsen during the study 
should be reported as adverse events. IBD manifestations that are more severe than the patient’s 
usual course of disease and meet the criteria for a serious adverse event (eg, required 
hospitalization) should be reported as a serious adverse event. 
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8.1.2. 
Definition of an Adverse Device Effect  
An adverse device effect is an adverse event related to the use of an investigational medical 
device or a combination product. This includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device, including any event resulting from user error 
or from intentional misuse of the investigational medical device. This definition includes events 
related to the procedures involved. For users or other persons, this definition is restricted to 
events related to investigational medical devices. 
8.1.3. 
Recording and Reporting of Adverse Events  
For recording of adverse event, the study period is defined for each patient as the time period 
from signature of the ICF to the end of study (ie, patient’s last visit). Treatment-emergent 
adverse events are defined as adverse events that occurred after the first dose of IMP and/or 
device was administered through the end of the study. 
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP and/or device. For serious adverse events and PDAESI for expedited reporting to 
GPSP, the serious adverse event and PDAESI form must be completed and the serious adverse 
event and the PDAESI must be reported immediately (Section 8.1.8.1). The investigator does not 
need to actively monitor patients for new adverse events after the end of the study. 
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event or 
PDAESI for expedited reporting to GPSP, on the serious adverse event and PDAESI form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP and/or device or study 
procedure is made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP and/or device, treatment administered, and outcome for each adverse event 
must be recorded both on the source documentation and the CRF. 
The relationship of each adverse event to IMP (including to the device, if applicable), and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
as described below in Section 8.1.5. 
Further details are given in the Safety Monitoring Plan. 
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8.1.4. 
Recording and Reporting of Adverse Device Effect  
Adverse device effects (Figure 3) must be recorded on both the source documentation and the 
CRF.  
The investigator and sponsor will record all relevant information regarding every adverse device 
effect/serious adverse device effect and device deficiency.  
The investigator should make an initial determination whether the adverse event may be related 
to a device deficiency. 
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Figure 3: 
Decision Tree for Adverse Events and Adverse Device Effects Classification 
 
ADE=adverse device effect; AE=adverse event; CRF=case report form; IEC=Independent Ethics Committee; IRB=Institutional Review Board; SADE=serious 
adverse device effect; SAE=serious adverse event. 
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8.1.5. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded. The adverse event severity grading scale 
for the current version of the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE; version 5) will be used for assessing adverse event severity. 
Table 4 will be used for assessing severity for adverse events that are not specifically listed in the 
NCI CTCAE. 
Table 4: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living.a  
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. a,b  
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event (AE). 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the 
toilet, and taking medications, as performed by patients who are not bedridden. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. 
8.1.6. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device  
The relationship of an adverse event to the IMP and/or device is characterized as follows: 
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Table 5: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP and/or device. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP and/or device. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
IMP and/or device. 
• 
It does not reappear or worsen when the IMP and/or 
device is re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP and/or 
device cannot be ruled out with 
certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP and/or device. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP and/or device, yet an IMP 
and/or device relationship clearly exists. 
• 
It follows a known pattern of response to the IMP 
and/or device. 
IMP=investigational medicinal product. 
8.1.7. 
Serious Adverse Events and Serious Adverse Device Effects  
For recording of a serious adverse event or serious adverse device effect, the study period is 
defined for each patient as that time period from signature of the ICF to the end of study (ie, 
patient’s last visit). Serious adverse events or serious adverse device effects occurring in a 
patient after the end of study for that patient (ie, patient’s last visit) should be reported to the 
sponsor if the investigator becomes aware of them, following the procedures described in 
Section 8.1.8.1. 
8.1.7.1.Definition of a Serious Adverse Event  
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• results in death 
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• is a life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe 
• requires inpatient hospitalization or prolongation of existing hospitalization, which means 
that hospital inpatient admission or prolongation of hospital stay was required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events unless there was worsening of the pre-existing condition 
during the patient’s participation in this study. 
• results in persistent or significant disability/incapacity (refers to a substantial disruption 
of one’s ability to conduct normal life functions) 
• is a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention to 
prevent 1 of the outcomes listed in this definition. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or liver injury that meets the criteria for Hy's law; or the development 
of drug dependency or drug abuse. Note: Any suspected transmission of an infectious 
agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
8.1.7.2.Definition of a Serious Adverse Device Effect  
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (Section 8.1.7.1). 
8.1.7.3.Expectedness  
In this study, the reference safety information for determination of expectedness of suspected 
serious adverse reaction is included in the IB. A serious adverse event that is not included in the 
relevant reference safety information by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event.  
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events. 
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies. 
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8.1.8. 
Reporting a Serious Adverse Event  
8.1.8.1.Investigator Responsibility  
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the IMP, must be reported to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 
about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for new adverse events once this study has ended. 
Serious adverse events occurring after the patient has ended the study should be reported to the 
sponsor if the investigator becomes aware of them. 
The serious adverse event form should be sent to the local safety officer (LSO) or designee (as 
applicable, for example, a contract research organization [CRO] in a country without a sponsor 
LSO); the LSO will forward the report to the sponsor’s GPSP. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility) 
Additional information includes: 
• age and sex of patient 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event  
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
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− cause of death (whether or not the death was related to IMP) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form and/or Extensible Markup Language (XML) file to the 
LSO/CRO for local submission to the competent authorities, IEC/IRBs, and investigators, 
according to regulations. For studies in the European Economic Area, submission of SUSARs is 
done electronically to the EudraVigilance database (via EVWEB or by electronically using the 
E2B(R3) electronic ICSR form) by the GPSP. The investigator must ensure that the IEC/IRB is 
also informed of the event, in accordance with national and local regulations. 
Blinding will be maintained for all study personnel. Therefore, in case of a SUSAR, only the 
LSO/CRO unblinded personnel will receive the unblinded report for regulatory submission; the 
others will receive a blinded report. 
8.1.8.2.Sponsor Responsibility  
If a serious unexpected adverse event is believed to be related to the IMP (ie, Suspected 
Unexpected Serious Adverse Drug Reaction, SUSAR), the sponsor will take appropriate steps to 
notify all investigators participating in sponsored clinical studies of TEV-48574 and the 
appropriate competent authorities (and IEC/IRB, as appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• modifying the protocol and/or ICF 
• discontinuing or suspending the study 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-48574 
8.1.9. 
Reporting a Serious Adverse Device Effect  
The process and contact details for serious adverse device effect reporting are the same as for 
serious adverse event reporting provided in Section 8.1.8. 
Events shall be reported to the IEC/IRB by the investigator and to the regulatory authorities by 
the sponsor using the appropriate form according to national and local regulations. 
The investigator should use Appendix G to make an initial determination whether the serious 
adverse event may be related to a device deficiency. 
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8.1.10. 
Protocol-Defined Adverse Events of Special Interest  
Adverse events of special interest (AESIs)—which are not necessarily adverse drug reactions 
(ADRs) but are of special interest based on standard drug registration topics, safety findings 
from previous studies, potential risks associated with biologic immunomodulators, are listed 
below. 
8.1.10.1. Protocol-Defined Adverse Events of Special Interest that Require Reporting 
to Sponsor’s Global Patient Safety and Pharmacovigilance  
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s GPSP for evaluation: 
• systemic severe reactions (including anaphylaxis) 
• opportunistic or severe and/or serious infections 
• malignancies (including non-melanoma skin cancer) 
• liver injury 
• severe hematology abnormalities 
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (Section 8.1.8). Protocol-defined adverse events of special 
interest to be reported to GPSP can be either serious or nonserious, according to the criteria 
outlined in Section 8.1.7.1. Protocol-defined adverse events of special interest that occur before 
study drug administration and are not serious do not require reporting to GPSP.  
Systemic severe reactions (including anaphylaxis) 
In the event of suspected anaphylaxis while the patient is at the site, vital signs, including blood 
pressure, oxygen saturation, and respiration rate, should be measured. Blood samples to test 
TEV-48574 serum concentration, ADA, and free and total serum TL1A levels should be 
collected if possible. Collection of blood samples to test tryptase and/or histamine levels are 
encouraged if available locally at the time of the suspected hypersensitivity event. Other 
assessments may be performed at the discretion of the investigator. As a precaution, each site 
should have a resuscitation medication/equipment nearby. If a patient has symptoms of 
anaphylaxis or severe hypersensitivity, the administration of study drug must be discontinued 
permanently. In addition, information about all suspected anaphylaxis and hypersensitivity 
events will be recorded on the Suspected Anaphylaxis CRF, which is based on the 2006 Joint 
National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network 
Second Symposium on Anaphylaxis (Sampson et al 2006). These events should be reported to 
the Sponsor immediately (ie, no more than 24 hours after learning of the event). 
Opportunistic or severe and/or serious infections 
In the event of opportunistic or severe infections (CTCAE grade 3 to 4), the patient should not 
receive further study drug until the event has completely resolved. Study drug will be 
permanently stopped in case of infections following stopping criteria (see Section 4.4.1). Study 
drug may be restarted following consultation with the Medical Monitor. Treatment of infections 
should be initiated promptly according to standard of care and all efforts should be made to 
identify the infectious agent. Events should be reported to the Sponsor immediately (ie, no more 
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than 24 hours after learning of the event). Examples for opportunistic infections are included in 
Appendix J. 
Malignancies 
Any signs or symptoms that could be suggestive of malignancy should be promptly and 
aggressively evaluated. Patients who develop a malignancy (with the exception of an 
appropriately treated basal cell carcinoma or squamous cell carcinoma of the skin or in situ 
carcinoma of uterine cervix) should be withdrawn from study drug and must not receive 
additional doses of study drug. Malignancies should be reported to the Sponsor immediately (ie, 
no more than 24 hours after learning of the event). 
Liver injury 
If any of the following criteria occur, study drug should be withheld and additional monitoring 
and follow-up assessment will be required (as detailed in the Liver Safety Required Actions and 
Follow-up Assessments section in Appendix K): 
• ALT or AST ≥5x ULN 
• ALT or AST ≥3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• AST and/or ALT ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN 
measured in the same blood draw sample or in combination with clinical jaundice or 
INR>1.5 (not applicable for patients on anticoagulants) 
The additional information will be recorded on the Liver Event CRF. 
The most appropriate diagnosis or the abnormal laboratory values (if a diagnosis cannot be 
established) should be recorded on the Adverse Event eCRF (see Section 8.1.3) and reported to 
the Sponsor immediately (ie, no more than 24 hours after learning of the event). 
Severe hematology abnormalities 
Predefined confirmed hematology stopping criteria (see Section 4.4.1) should be re-tested every 
3 to 5 days until values have returned to above the hematological exclusion criteria threshold, at 
which point dosing can be resumed (however, two consecutive doses of IMP, should never be 
given less than 7 days apart).  
8.1.10.2. Protocol-Defined Adverse Events of Special Interest that Do Not Require 
Reporting to Sponsor’s Global Patient Safety and Pharmacovigilance  
The following are considered protocol-defined adverse events of special interest that do not need 
to be sent to the sponsor’s GPSP department (unless assessed as serious) and will be recorded 
only in the clinical database: 
• administration site reactions (as described in Section 8.2) 
8.1.11. 
Protocol Deviations Because of an Adverse Event  
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
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contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study. 
8.2. 
Assessment of Local Tolerability and Pain  
Local tolerability assessments should be performed at each administration of IMP (Table 1) and 
include administration site findings and pain. Administration site findings (erythema, 
ecchymosis, induration, tenderness, warmth, and swelling) will be assessed using the scales 
provided in Table 6. Pain at the administration site will be reported using a standardized 11-point 
numeric rating scale (NRS-11) for pain intensity, where 0 is “No pain” and 10 is “Worst possible 
pain.” Patients will be asked to respond to the following question: “How much pain do you feel 
at the drug injection site?” 
Pain will be assessed beginning, during (approximately midway through the infusion), and after 
the completion of IMP administration and 1 hour later. Administration site findings will be 
assessed after the completion of IMP administration and 1 hour later. Additionally, after the 
loading dose and first induction dose, assessments will also be performed 2 hours after the 
completion of IMP administration. Allowed time windows for the local tolerability assessments 
after the completion of the infusion are ±15 minutes.  
Severity of local tolerability symptoms should be assessed as described in Table 6. The surface 
diameter in millimeters should be recorded, and erythema, induration, and ecchymosis at the 
administration site will be graded according to the diameter measurements: absent, 5 mm to 
≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe). Erythema, ecchymosis, and 
induration under 5 mm in diameter should be assessed as absent. Care should be taken to avoid 
pressuring or squeezing the administration site while assessing induration via careful superficial 
palpation. 
In the case that findings do not resolve while the patient remains at the study center, additional 
evaluation should take place thereafter at each visit until resolution occurs. Administration sites 
may be photographed, including between visits to the study center, to provide visual 
representation in addition to comments in the source documents. Any features that could be used 
to identify the patient will not be captured on the photograph. Appropriate treatment for 
administration site finding or pain may be provided if necessary, in which case such treatments 
must be recorded as concomitant medication(s).  
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Table 6: 
Administration Site Finding Severity Assessment 
Test 
Response 
Erythema 
- Absent 
- Erythema surface diameter 5 to ≤50 mm (mild) 
- Erythema surface diameter >50 to ≤100 mm (moderate) 
- Erythema surface diameter >100 mm (severe) 
Ecchymosis 
- Absent 
- Ecchymosis surface diameter 5 to ≤50 mm (mild) 
- Ecchymosis surface diameter >50 to ≤100 mm (moderate) 
- Ecchymosis surface diameter >100 mm (severe) 
Induration 
- Absent 
- Induration surface diameter 5 to ≤50 mm (mild) 
- Induration surface diameter >50 to ≤100 mm (moderate) 
- Induration surface diameter >100 mm (severe) 
Tenderness 
Warmth 
Swelling 
- None 
- Mild 
- Moderate 
- Severe 
Administration site findings described in Table 6 and administration site pain will be recorded on 
specified CRF and will not require additional recording in the adverse events form. 
Administration site findings with characteristics that are not described in Table 6 (eg, 
lipoatrophy, necrosis, abscess) or fulfill seriousness criteria must be recorded and reported as 
adverse events or serious adverse events as specified in Section 8.1.3 and Section 8.1.8. 
8.3. 
Pregnancy  
Any female patient becoming pregnant during the screening period will be considered a screen 
failure and will not be allowed to rescreen.  
Any female patient becoming pregnant during the study will discontinue IMP. 
All pregnancies of women participating in the study and female partners of men participating in 
the study, if applicable, that occur during the study, or within 5 half-lives (50 days) of the last 
IMP administration, are to be reported immediately to the individual identified in the Clinical 
Study Personnel Contact Information section of this protocol, and the investigator must provide 
the sponsor (LSO/CRO) with the completed pregnancy form. The process for reporting a 
pregnancy is the same as that for reporting a serious adverse event but using the pregnancy form 
(Section 8.1.8). 
All female patients and female partners of men participating in the study (female partners of men 
participating in the study who become pregnant will be asked to sign an ICF) who become 
pregnant will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). If the pregnancy continues to term, the outcome (health of the infant up to 
8 weeks of age), including details of birth and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
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complication of pregnancy during the study and any complication of pregnancy that the 
investigator becomes aware of after withdrawal from the study will be reported as an adverse 
event or serious adverse event, as appropriate. 
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, 1 of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event (in addition to the 
pregnancy form). 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event (in addition to the pregnancy form). 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
8.4. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products  
Any administration of IMP that is not in accordance with the study protocol should be reported 
in the patients’ source documents, regardless of whether or not an adverse event occurs as a 
result. When meeting important protocol deviation criteria (Appendix B), all instances of 
incorrect IMP administration should be categorized as “Noncompliance to Investigational 
Medicinal Product (IMP).” 
The following are types of medication errors and special situations: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or administration of 
a medicinal product while in the control of the healthcare professional, patient, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized 
product information/study protocol. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP or placebo IMP), whether taken intentionally or unintentionally, 
in excess of that prescribed must be immediately reported to the sponsor. 
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in accordance 
with the authorized product information/study protocol. 
4. Abuse: Persistent or sporadic, intentional excessive use of IMP, which is accompanied by 
harmful physical or psychological effects. 
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information/study protocol. 
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation. 
7. Breastfeeding: Suspected adverse reactions, which occur in infants following exposure to a 
medicinal product from breast milk. 
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8.5. 
Clinical Laboratory Tests  
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to 1 of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event and monitored as described 
in Section 8.1.3. A laboratory or diagnostic test abnormality (once confirmed by repeated testing) 
that results in the withdrawal of the patient from the study; the temporary or permanent 
withdrawal of IMP or medical treatment, or further diagnostic work-up may be considered 
adverse events. If further diagnostic work-up of abnormal laboratory result leads to the 
investigator concluding that the initial abnormality was not clinically significant, it is at the 
investigator's discretion whether or not the laboratory result triggering the work-up is an adverse 
event. (Note: Abnormal laboratory or diagnostic test results at the screening visit(s) that preclude 
a patient from entering the study or receiving IMP are not considered adverse events.) 
Table 7: 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology and Coagulationa  
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
Blood urea nitrogen (BUN) 
Low density lipoprotein (LDL)b  
High density lipoprotein (HDL)b 
Triglyceridesb 
Urate 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactate dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (GGT) 
Alkaline phosphatase 
Bicarbonate 
Protein 
Albumin 
Total bilirubinc  
Hemoglobin 
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
• 
Neutrophils 
• 
Lymphocytes 
• 
Eosinophils 
• 
Monocytes 
• 
Basophils 
Prothrombin International Normalized 
Ratio (INR) 
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
• 
Bacteria 
• 
Erythrocytes 
• 
Leucocytes 
• 
Crystals 
• 
Casts 
a Coagulation tests will be performed at screening only. INR will be tested in case of a suspected liver injury (see 
Appendix K) 
b Only measured at the screening, week 14, and early termination visits (ie, visits at which patients are in a fasting 
state). 
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c Direct and indirect bilirubin will be measured if total bilirubin is elevated. 
8.5.1. 
Serum Chemistry, Hematology, and Urinalysis  
Clinical laboratory tests (serum chemistry, hematology and coagulation, urinalysis) will be 
performed at the time points detailed in Table 1. Patients should be fasting for at least 8 hours 
prior to safety laboratory assessments only at the screening, week 14, and early termination 
visits. Clinical laboratory tests will be performed using the central laboratory. Local laboratory 
testing can be used under extenuating circumstances and only following agreement with the 
sponsor. 
Screening laboratory test abnormalities, if considered by the Investigator to be transient and 
inconsistent with the patient’s clinical condition, may be repeated once during the screening 
period for confirmation. Redrawing samples if previous samples were unable to be analyzed 
would not count as a retest since previous result was never obtained. 
8.5.2. 
Other Clinical Laboratory Tests  
At screening, patients will be tested for HBcAb and HBsAg, antibodies to hepatitis C virus 
(reflex viral RNA testing if hepatitis C antibodies present), human immunodeficiency virus types 
1 or 2, and enteric pathogens (including stool culture and Clostridium difficile toxin assay; 
additional testing [eg, ova and parasites] may be performed at the investigator’s clinical 
discretion). 
If HBcAb is positive and HBsAg negative, hepatitis B viral DNA will be done as reflective test, 
and, if undetectable, then not exclusionary. 
Patients will also be tested for TB at screening (QuantiFERON® TB Gold Test). Patients with 
confirmed positive results will not be eligible to participate in the study (unless documentation of 
prior TB treatment is available).  
If the QuantiFERON® TB Gold Test is negative at screening, then the patient may proceed in the 
screening period. However, if the QuantiFERON® TB Gold Test is deemed by the principal 
investigator to be a false positive at screening, then a second sample should be drawn and the 
following steps taken: 
• If the second QuantiFERON® TB Gold Test is positive (ie, results match the first test), 
then the patient will be a screen failure. 
• If the second QuantiFERON® TB Gold Test is negative (ie, results do not match the first 
test), then a third sample should be drawn. 
− If the third QuantiFERON® TB Gold Test is positive (ie, results match the first test), 
then the patient will be a screen failure. 
− If the third QuantiFERON® TB Gold Test is negative (ie, results match the second 
test), then the patient may proceed in the screening period. 
In case of a suspected liver injury, additional laboratory tests will be required (see Appendix K).  
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8.5.2.1.Human Chorionic Gonadotropin Tests  
HCG tests in serum and in urine will be performed for women of childbearing potential at the 
time points detailed in Table 1. 
8.5.2.2.Follicle-Stimulating Hormone  
At screening, women who have been amenorrheic for at least 1 year without an alternative 
medical cause will have a serum FSH assessment to confirm postmenopausal status (an increased 
concentration of FSH of more than 35 IU/L in women not using hormonal contraception or 
hormonal replacement therapy). 
8.6. 
Physical Examinations  
Physical examinations will be performed at the time points detailed in Table 1. Any physical 
examination finding that is judged by the investigator as clinically significant (except at the 
initial screening visit, which will be captured as medical history) may be considered an adverse 
event, recorded on the CRF, and monitored as described in Section 8.1.3. Physical exam findings 
that are attributable to another adverse event would not be reported as separate adverse events. 
A full physical examination will include at a minimum the following organ systems: 
• General appearance 
• Head, eyes, ears, nose, mouth, and throat 
• Chest and lungs 
• Heart 
• Abdomen 
• Musculoskeletal 
• Skin 
• Extremities 
• Lymph nodes 
• Neurological 
Height and weight will be obtained at the at the time points detailed in Table 1. 
A brief physical examination will include at a minimum general appearance; head, eyes, ears, 
nose, mouth, and throat; chest and lung; heart and extremities (including pulses).  
8.7. 
Vital Signs  
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse rate) 
will be measured at the time points detailed in Table 1. Patients are to remain in a supine position 
for at least 5 minutes prior to measuring blood pressure and pulse rate. If possible, blood pressure 
measurements should be completed on the same arm at each visit. All vital signs results outside 
of the reference ranges will be judged by the investigator as belonging to 1 of the following 
categories: 
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• abnormal and not clinically significant 
• abnormal and clinically significant 
For any abnormal vital sign value, the measurement should be repeated as soon as possible. Any 
vital sign value that is judged by the investigator as clinically significant will be recorded both on 
the source documentation and the CRF as an adverse event and monitored as described in 
Section 8.1.3. 
8.8. 
Electrocardiography  
A 12-lead ECG will be recorded at the time points detailed in Table 1. ECGs should be 
performed in a supine position after 5 minutes rest. 
ECG review and assessment will be done both by the investigators and by a centralized ECG 
reading vendor. 
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
1 of the following categories: 
• abnormal and not clinically significant  
• abnormal and clinically significant 
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit[s]) will be considered an adverse event, recorded on the source documentation 
and in the CRF, and monitored as described in Section 8.1.3. 
Where triplicate measurements are required (at screening), each ECG will be taken within 1 to 
5 minutes of the previous one. 
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9. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ 
PHARMACOGENETICS/IMMUNOGENICITY  
9.1. 
Pharmacokinetic Assessment  
Blood samples will be collected via venipuncture at the time points detailed in Table 1 for 
measurements of serum concentration of TEV-48574. At visits where IMP is administered, 
samples should be taken prior to IMP administration (ie, trough levels). 
Additionally, efforts should be made to determine serum concentration of TEV-48574 in cases of 
suspected severe, systemic hypersensitivity reaction, or anaphylaxis; serious adverse event; or 
immunogenicity-related adverse events. 
The dates and times of IMP administration and the date and time point (24-hour clock time) of 
each pharmacokinetic sample will be recorded both on the source documentation and the CRF. 
Samples will be analyzed for concentration of TEV-48574 using an appropriate validated 
method. Incurred sample reanalysis may be performed. Blood samples from patients who 
received placebo will not be analyzed. 
Blood volumes are provided in the ICF and Laboratory Manual. Details on sample handling, 
storage, shipment, and analysis are provided in the Laboratory Manual. 
9.2. 
Pharmacodynamics Assessment  
All PD potential parameters tested in this study are exploratory markers and are described in 
Section 9.4. 
9.3. 
Immunogenicity Testing  
Blood samples for ADA testing will be collected via venipuncture at the time points detailed in 
Table 1. Details on sample handling, storage, shipment, and analysis are provided in the 
Laboratory Manual. 
Additionally, efforts should be made to collect ADA samples in cases of suspected severe, 
systemic hypersensitivity reaction, or anaphylaxis; serious adverse event; or 
immunogenicity-related adverse events. In cases of suspected or confirmed anaphylaxis, efforts 
should be made to collect samples as close to the onset of the event as possible, at resolution, and 
30 days after onset of the event. Antibodies to TEV-48574 will be evaluated in serum samples. 
All samples collected for detection of antibodies to TEV-48574 may also be evaluated for 
TEV-48574 serum concentration to facilitate interpretation of the antibody data. Confirmed 
ADA positive samples may be further evaluated for TEV-48574 neutralizing antibodies. 
The dates and times of IMP administration and the date and time point of each immunogenicity 
sample will be recorded both on the source documentation and the CRF. 
The detection and characterization of antibodies to TEV-48574 will be performed using 
validated assay methods. Blood samples from patients who received placebo will not be analyzed 
by the ADA assay. 
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A patient will be classified as having a treatment-emergent ADA response if either: 1) the patient 
had a positive sample at any of the time points after first dose of IMP but not at the time point 
before first dose of IMP, or 2) the patient had positive samples before first dose of IMP and 1 or 
more time points after first dose of IMP, with at least a 4-fold increase in titers after first dose 
relative to the sample ADA titers before first dose. Where possible, the impact of the presence of 
ADAs on pharmacokinetics and clinical safety will be evaluated. 
Samples may be stored if permitted by the ICF and local regulations after the last patient’s last 
visit for the study at a facility selected by the sponsor to enable further analysis of immune 
responses to TEV-48574. 
9.4. 
Assessment of Exploratory Biomarkers  
Potential exploratory biomarker objectives include characterization of TEV-48574 responders, 
identification of tissue-, fecal-, and blood-based-resident proteomic or transcriptomic biomarkers 
indicative of TEV-48574 mechanism of action and PD, development of scalable tools to identify 
likely responders in future studies, and elucidation of TL1A-mediated pathway(s) that drive IBD 
in responders within the target patient population. 
The following exploratory biomarker assessments will be pursued from samples collected at 
indicated time points (Table 1): 
• Serum free and total TL1A levels will be measured using qualified/validated assay 
methods. Tissue TL1A protein expression will also be assessed. 
• Serum proteomic markers assertive of PD and mechanism of action effects will be 
pursued by singleplex or multiplex assays. 
 
will be collected and may be analyzed for evaluation of target engagement, PD, and 
mechanism of action. 
• Serum level of autoantibodies involved in IBD, such as perinuclear antineutrophil 
cytoplasmic antibodies (pANCA) or anti-Saccharomyces cerevisiae antibodies (ASCA), 
could also be measured to test the correlation with the response to TEV-48574 
• Serum and tissue markers of GI tissue condition (eg, fibrosis/remodeling) will be 
assessed by transcriptomic and/or specific proteomic assays. 
• GI transcriptome will be assessed from biopsies by RNASeq to characterize TEV-48574-
mediated responses or TEV-48574-responsive patients. 
• Fecal calprotectin or other stool-derived markers as a tissue proximal marker of GI 
inflammation  
• High sensitivity C-reactive protein (hsCRP) as a peripheral marker of inflammation 
• UC-100 score (1+16 × Mayo stool frequency subscore [0 to 3]+6 × Mayo endoscopic 
subscore [0 to 3]+1 × RHI score [0 to 33]); ranges from 1 (no disease activity) to 100 
(severe disease activity) (Jairath et al 2019) 
Details of the specimen collection, processing, and handling requirements are provided in the 
Laboratory Manual. 
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Residual biopsy, fecal, and blood samples, after appropriate analysis to support this study, may 
be stored at a Teva-secured facility for up to 15 years towards future analysis related to 
TEV-48574 or IBD if permitted by the ICF and local regulations. 
Exploratory biomarker analyses may be presented in a separate analytical plan and report at the 
end of the study. 
9.5. 
Pharmacogenetics  
Pharmacogenetic analyses will be performed on samples of patients who signed the dedicated 
informed consent. The candidate genes that will be analyzed may be related or hypothesized to 
be related to pharmacokinetics, safety features, drug mechanism of action, or related to study 
diseases. The final list of genes to be evaluated will be determined at the time of analysis to be 
able to account for the most current research. The planned pharmacogenetic analysis and results 
of other potential genetic factors will be detailed in a separate document that will encompass the 
latest scientific advances related to this evaluation. 
For information regarding pharmacogenetic assessments, see Appendix F. 
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10. 
STATISTICS  
This section describes the statistical analysis methods for this study. Further details on analysis 
methods will be described in the Statistical Analysis Plan. Any changes or additions from the 
planned analysis methods described in the protocol will be disclosed in the Statistical Analysis 
Plan and in the clinical study report (CSR). 
10.1. 
Sample Size and Power Considerations  
A total study sample size of 240 patients is planned, with 120 patients (40 patients per dose arm) 
each for the 2 indications of UC and CD. 
The sample size does not include patients that were randomized to the 1800 mg treatment group 
prior to Amendment 03 with Revision 01. 
Assumptions: 
The clinical remission and endoscopic response rates assumed in the sample size and related 
operating characteristics computations are as follows: 
• Clinical remission rates in UC indication: 8% for placebo; 30% for TEV-48574 low- and 
high-dose groups, respectively 
• Endoscopic response rates in CD indication: 12% for placebo; 34% for TEV-48574 low- 
and high-dose groups, respectively 
Simulation-based operating characteristics for the analysis of the primary efficacy variable using 
a Bayesian Beta Binomial model are presented in Table 8. This model uses a posterior 
probability cutoff of <0.30 for the assessment of futility at the interim analysis and a posterior 
probability cutoff of ≥0.90 to declare success at the final analysis.  
For UC, the family-wise false-positive rate (ie, probability of making at least 1 false-positive 
conclusion under the null assumption for both doses) is 13%, and the probability of declaring 
success for at least 1 dose group is 98%, under the assumptions above.  
For CD, the family-wise false-positive rate is 16%, and the probability of declaring success for at 
least 1 dose is 95%, under the assumptions above. 
Table 8: 
Operating Characteristics of Interim and Final Analysis 
 
UC 
CD 
% Futile at interim 
analysis 
% Successful at end of 
trial 
% Futile at interim 
analysis  
% Successful at end of 
trial 
TEV-48574 doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both 
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both 
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
Null 
25% 
24% 
11% 
8% 
8% 
13% 
24% 
24% 
12% 
9% 
10% 
16% 
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UC 
CD 
% Futile at interim 
analysis 
% Successful at end of 
trial 
% Futile at interim 
analysis  
% Successful at end of 
trial 
TEV-48574 doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both 
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both 
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
Intermediate 
efficacy both 
doses 
4% 
4% 
1% 
61% 
61% 
77% 
4% 
4% 
1% 
59% 
59% 
76% 
Efficacy  
both doses 
1% 
1% 
<1% 
91% 
91% 
98% 
1% 
1% 
<1% 
87% 
87% 
95% 
CD=Crohn’s disease; Q2W=every 2 weeks; UC=ulcerative colitis. 
Note: Beta-Binomial model with non-informative prior; posterior probability futility cutoff: <0.30; final analysis 
posterior probability cutoff of ≥0.90.  
Note: Operating characteristics based on 500,000 simulations. 
Under a less optimistic scenario where the placebo response rates remain the same while the 
clinical remission rate in the UC indication is reduced to 20% for both doses, and the endoscopic 
response rate in the CD indication is reduced to 25% for both doses, the probability of declaring 
success in at least 1 dose is 77% for UC and 76% for CD. 
Details regarding the statistical decision criteria and Bayesian model, as well as operating 
characteristics in case only 1 active dose is effective are provided in Appendix L. 
For comparison, a frequentist logistic regression analysis with 40 patients per dose per indication 
would provide at least 90% power using a Mantel-Haenszel test with a 1-sided Type 1 error rate 
of 10% and the assumptions about response rate specified above. This power does not take into 
account the planned futility analysis. 
10.2. 
Analysis Sets  
10.2.1. 
Intent-to-Treat Analysis Set  
The intent-to-treat (ITT) analysis set for each indication (UC or CD) will include all randomized 
patients. 
In the ITT analysis set, patients will be categorized by treatment to which patients were 
randomized, regardless of which treatment they actually received. 
Data collected from patients after treatment discontinuation will be included in the ITT analysis 
set. 
10.2.2. 
Modified Intent-to-Treat Analysis Set  
The modified intent-to-treat (mITT) analysis set for each indication (UC or CD) is a subset of the 
ITT analysis set including only patients who receive at least 1 dose of placebo, TEV-48574 
450 mg (low dose), or TEV-48574 900 mg (high dose). 
In the mITT analysis set, patients will be categorized by treatment to which patients were 
randomized, regardless of which treatment they actually receive. 
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10.2.3. 
Safety Analysis Set  
The safety analysis set for each indication (UC or CD) will include all randomized patients who 
receive at least 1 dose of IMP. 
In the safety analysis set, patients will be categorized by treatment actually received, regardless 
of the treatment to which they were randomized, unless otherwise specified. 
10.2.4. 
Pharmacokinetic Analysis Set  
All patients in the safety analysis set who have at least 1 measurable concentration of 
TEV-48574 will be included in the pharmacokinetic analysis set. 
10.2.5. 
Pharmacogenetic and Biomarker Analysis Set  
All patients in the safety analysis set who provided consent for pharmacogenetic or biomarker 
sampling will be included in the analysis of pharmacogenetic or biomarker data. 
10.2.6. 
Immunogenicity Analysis Set  
The immunogenicity analysis set will include all patients in the safety set who receive 
TEV-48574 and who have at least 1 reportable immunogenicity result. 
10.3. 
Data Handling Conventions  
For all variables, only the observed data from the patients will be used in the statistical analyses; 
ie, there is no plan to estimate missing data, unless otherwise specified. Detailed data imputation 
rules will be described in the Statistical Analysis Plan. 
10.3.1. 
Handling Withdrawals and Missing Data  
The mITT analysis set will be used for efficacy analyses. UC patients who did not complete 
evaluation for clinical remission at week 14 will be reported as non-remitters. CD patients who 
did not complete evaluation for endoscopic response at week 14 will be reported as non-
responders. 
10.4. 
Study Population  
The ITT analysis set (Section 10.2.1) will be used for all study population summaries. 
Summaries will be presented by treatment group, pooled TEV-48574, and all patients, separately 
by indication (UC or CD) and pooled (UC and CD). 
10.4.1. 
Patient Disposition  
Data from patients screened; patients screened but not randomized and reason for not 
randomized; patients who are randomized/enrolled; patients randomized/enrolled but not treated 
and reason; patients in the ITT, safety, and other analysis sets; patients who complete the study; 
patients who withdraw from the study; and patients who discontinue IMP will be summarized 
using descriptive statistics. Data from patients who withdraw from the study or discontinue IMP 
will also be summarized by reason for withdrawal using descriptive statistics. 
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10.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics, including detailed IBD history, general medical 
history, prior medications and therapies, and ECG findings, will be examined to assess the 
comparability of the treatment groups by treatment, underlying disease, and all patients using 
descriptive statistics. For continuous variables, descriptive statistics (number [n], mean, standard 
deviation, median, minimum, and maximum) will be provided. For categorical variables, patient 
counts and percentages will be provided. Categories for missing data will be presented if 
necessary. 
10.5. 
Efficacy Analysis  
10.5.1. 
Primary Estimand  
Refer to Section 3.2 for the primary estimand for UC patients and CD patients. 
10.5.2. 
Primary Endpoints and Secondary Endpoints  
Refer to Section 3.1 for primary and secondary endpoints. 
10.5.3. 
Exploratory Endpoints  
Refer to Section 3.3 for exploratory endpoints. 
10.5.4. 
Planned Method of Analysis  
The mITT analysis set (Section 10.2.2) will be used as the primary analysis set for all efficacy 
analyses. Summaries will be presented by treatment group, underlying disease, and for all 
patients. 
Note that patients that were randomized to the 1800 mg treatment group are excluded from the 
mITT analysis set. Efficacy endpoints for these patients will be analyzed using descriptive 
statistics, in separate summary tables. 
10.5.4.1. Primary Efficacy Analysis  
A Beta-binomial model with a non-informative Beta(1,1) prior will be used to analyze the 
primary response endpoint, clinical remission (for UC) or endoscopic response (for CD), 
hereafter denoted as “response”. The model will be fit separately for each dose within each 
indication.  
Inference will be based on posterior distribution of the response rates. A TEV-48574 dose will be 
declared successful at the final analysis if the posterior probability that the response rate in the 
TEV-48574 dose is higher than the response rate in the placebo arm is ≥0.90. Put another way, 
the success criterion for each dose within indication can be written as: 
Posterior Probability (TEV-48574 response rate – placebo response rate >0) ≥0.90 
The following quantities will be presented: 
• Posterior means of the response rates for TEV-48574 high dose (900 mg Q2W), 
TEV-48574 low dose (450 mg Q2W) and placebo  
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• 95% credible intervals for difference in response rates (TEV-48574 doses – placebo) 
• For each TEV-48574 dose, Posterior Probability (TEV-48574 dose – placebo response 
rate >0)  
For further details, see Appendix L. 
10.5.4.2. Sensitivity Analysis  
Tipping point analysis will be performed to test the robustness of the primary analysis to the 
imputation of patients that discontinue the study or have missing week 14 modified Mayo score 
(UC patients) or SES-CD (CD patients) data as non-responders. 
10.5.4.3. Supplementary Analysis  
A supplementary analysis for the primary efficacy variable (defined in the supplementary 
estimand) will be performed using a logistic regression model fit separately to each indication 
with the following fixed effects: dose (as categorical variable), previous exposure to advanced 
IBD therapy (yes/no), and baseline modified Mayo score (UC patients) or SES-CD (CD 
patients). Each comparison of TEV-48574 dose versus placebo will be tested (one-sided) at a 
nominal significance level of α=0.1. 
In addition, a Cochran-Mantel-Haenszel (CMH) test for pairwise comparisons between the active 
dose groups and placebo will be performed separately for UC and CD. Nominal p-values will be 
presented for each of the comparisons. 
10.5.4.4. Secondary Efficacy Analysis  
All secondary efficacy endpoints will be analyzed separately for the UC and CD indications. For 
each binary endpoint, a logistic regression model similar to the supplementary model described 
in Section 10.5.4.3 with the respective baseline measurement will be used. For each comparison 
of TEV-48574 dose versus placebo, the differences in proportions, odds ratios, associated 95% 
CIs, and nominal p-value will be reported.  
10.5.4.5. Other Efficacy Analysis  
Consistency of treatment effect across baseline, demographic covariates, and subgroups may be 
explored. The variables, corresponding models, and relevant details will be pre-specified in the 
Statistical Analysis Plan. 
10.6. 
Multiple Comparisons and Multiplicity  
No adjustments to control the false-positive rate will be made for the preplanned multiple 
comparisons/endpoints analyses for the protocol-specified endpoints. 
10.7. 
Safety Analysis  
Safety analyses will be performed on the safety analysis set (Section 10.2.3). 
Safety assessments and time points are provided in Table 1. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
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analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to test IMP and/or device (ie, 
reasonable possibility) (defined as related or with missing relationship) (overall and by severity), 
serious adverse events, serious adverse device effects, and adverse events and adverse device 
effects causing withdrawal from the study. Summaries will be presented by treatment group, 
underlying disease, and for all patients. Patient listings of serious adverse events, serious adverse 
device effects, and adverse events and adverse device effects leading to withdrawal will be 
presented. 
The frequency of each score measuring local tolerability, including an NRS-11 for pain intensity, 
at the injection site(s) will be listed and summarized for each time point. 
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. Values will be compared with predefined criteria to identify potentially clinically 
significant values or changes, and such values will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. 
For continuous variables, descriptive statistics (number [n], mean, standard deviation, median, 
minimum, and maximum) will be provided for actual values and change from baseline to each 
time point. For categorical variables, patient counts and percentages will be provided. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR. 
10.8. 
Tolerability Analysis  
Tolerability will be assessed by the number (%) of patients who fail to complete the study due to 
adverse events. 
10.9. 
Population Pharmacokinetic, Pharmacodynamic, and 
Pharmacokinetic/Pharmacodynamic Analysis  
All patients in the safety analysis set who have at least 1 measurable concentration of 
TEV-48574 will be included in the analysis of pharmacokinetic data. Serum concentrations will 
be expressed in mass per volume units. All concentrations below the limit of quantification or 
missing data will be labeled as such in the concentration data listings. TEV-48574 concentration 
data will be summarized by visit and treatment group. 
A population pharmacokinetic analysis will be performed, and, if feasible, a pharmacokinetic/PD 
analysis of relevant PD variables and/or exposure-response analysis of relevant efficacy or safety 
endpoints may be performed and reported in a separate pharmacometrics report. 
10.10. 
Pharmacogenetic Analysis  
Exploratory analyses may be undertaken to describe the relationship between genetic 
polymorphisms (single-nucleotide polymorphisms) and treatment effects of TEV-48574. 
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10.11. 
Biomarker Analysis  
Exploratory analyses may be undertaken to study the treatment effects of TEV-48574 on hsCRP, 
fecal calprotectin, autoantibodies, and other potential TL1A-mediated blood-based biomarkers. 
Free and Total TL1A serum levels: Concentration data and change from baseline may be 
individually listed and summarized using descriptive statistics, and, when possible may be 
presented by treatment group, dose level, and nominal time point.  
TL1A tissue expression: When feasible, level of expression at baseline may be listed and 
summarized. 
Analysis of baseline TL1A free and/or total levels and baseline tissue TL1A level may be 
performed as a subpopulation analysis of treatment effects. Moreover, the level of specific 
autoantibodies, such as pANCA or ASCA, could also be considered. 
Other potential emerging fecal, blood-based-resident proteomic, and tissue transcriptomic 
biomarkers reflective of PD, mechanism of action, and GI tissue condition may also be assessed. 
 will be collected and may also be analyzed.  
An attempt may be made to correlate pharmacokinetic parameters with biomarkers. 
These analyses may be reported in a separate report and may have a separate pre-specified 
analysis plan. These analyses may not be reported in the CSR. 
10.12. 
Immunogenicity Analysis  
Immunogenicity analyses will be performed. Listing(s) of patients with positive ADA sample(s) 
will be provided. Summaries may be provided if appropriate. 
Treatment-emergent ADA responses and the impact of the presence of ADAs on 
pharmacokinetics and clinical safety may be assessed. Confirmed ADA positive samples may be 
further characterized (eg, testing for presence of neutralizing ADA) as needed. 
Refer to Section 9.3 for the definition of treatment-emergent ADA response in this study. 
10.13. 
Planned Interim Analysis  
Interim analyses for safety and efficacy are planned for this study. An interim efficacy/futility 
analysis is planned in each indication (UC and CD) when approximately 50% of patients in the 
indication have completed the 14-week primary efficacy readout time point or had the 
opportunity to do so. This is expected to yield approximately 20 evaluable patients per treatment 
group for each indication in the interim analysis.  
Due to study recruitment acceleration or other operational considerations, the interim analysis for 
efficacy/futility will not be conducted as it will be impractical and have limited utility.  
In the interim analysis, the same Bayesian Beta-Binomial model described in the primary 
analysis model will be used to analyze the primary efficacy response variable for each dose 
within each indication. The futility criterion for each dose is: 
• Posterior probability (TEV-48574 response rate – placebo response rate >0) <0.30 
Refer to Table 10 and Appendix L for operating characteristics of the interim and final analysis. 
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In addition to futility, efficacy criteria, which is nonbinding, will be incorporated for the purpose 
of internal decision making for further development planning. Details of the efficacy criteria will 
be provided in the Statistical Analysis Plan. 
Additionally periodic analysis of safety data will be done during the study. Analyses will focus 
on the following events: 
• Incidence of serious adverse events 
• Incidence of CTCAE grade 3 or grade 4 events 
• Incidence of opportunistic infections and severe and/or serious infections 
• Incidence of anaphylaxis 
A Bayesian continuous monitoring approach will be employed for the above events, looking at 
the posterior probability for the incidence being greater on active treatment relative to placebo. A 
posterior probability exceeding 0.85 to 0.9 will trigger consideration for stopping the study or 
individual dose arms within the study. 
All interim analyses will be performed by an external, independent, unblinded reporting team. 
The results of all interim analyses will be reviewed by an IDMC comprised of external medical 
and statistical experts. The IDMC will make recommendations regarding study conduct after 
evaluation of the totality of the data. Recommendations include, but are not limited to, dropping 
of a dose arm, termination of an indication, or termination of the study. The details regarding the 
statistical analysis methods will be provided in the Statistical Analysis Plan. The IDMC charter 
will provide details regarding procedures to protect the scientific integrity of the study, conduct 
of the interim analysis, dissemination of results, and decision criteria. 
Individuals who may not be blinded include the bioanalytical scientists, pharmacometrician, and 
external biostatisticians (who are part of the unblinded analysis groups that are not directly 
involved in study conduct), as well as the IDMC members. 
Additional Analyses: 
As part of the interim analysis for efficacy/futility, additional analyses may be provided to the 
IDMC upon request or as deemed necessary by the sponsor. 
Pharmacokinetic and PD analysis may be provided to the IDMC upon request. Population 
pharmacokinetic and PD analysis will be performed by an external analysis group independent of 
the study team. The process to ensure the study integrity, the maintenance of the double blind, 
and the responsibilities of the external members and relevant study personnel will be described in 
the IDMC charter. The details regarding the population pharmacokinetic or PD analysis will be 
described in the pharmacometric analysis plan. 
10.14. 
Reporting Deviations from the Statistical Plan  
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the Statistical Analysis Plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations. 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE  
Refer to Appendix B for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection. 
Details are given in the Study Manual. 
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12. 
COMPLIANCE STATEMENT  
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for Good Clinical Practice E6 and International Organization for Standardization 
14155: Clinical investigation of medical devices for human subjects – Good clinical practice, as 
applicable, and any applicable national and local laws and regulations (eg, Title 21 Code of 
Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Clinical 
Trial Directive 2001/20/EC, EU Medical Device Regulation 2017/745, EU Clinical Trial 
Regulation No 536/2014, as applicable). Any episode of noncompliance will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMPs as described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities. 
See Appendix C for the ethics expectations of informed consent, competent authorities and IEC 
and IRB, confidentiality regarding study patients, and requirements for registration of the clinical 
study. 
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13. 
DATA MANAGEMENT AND RECORD KEEPING  
See Appendix H for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents. 
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14. 
FINANCING AND INSURANCE  
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered. 
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are eg, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 
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15. 
PUBLICATION POLICY  
See Appendix I for information regarding the publication policy. 
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16. 
REFERENCES  
Abreu M, Sandborn W; IOIBD Defining Endpoints and Biomarkers in Inflammatory Bowel 
Disease Writing Group. Defining endpoints and biomarkers in inflammatory bowel disease: 
moving the needle through clinical trial design. Gastroenterology 2020;159:2013-18. 
Adegbola S, Sahnan K, Warusavitarne J, Hart A, Tozer P. Anti-TNF therapy in Crohn’s disease. 
Int J Mol Sci 2018;19:2244. 
Betteridge J, Armbruster S, Maydonovitch C, Veerappan G. Inflammatory bowel disease 
prevalence by age, gender, race, and geographic location in the U.S. military health care 
population. Inflamm Bowel Dis 2013;19:1421-7. 
Bousvaros A. Use of immunomodulators and biologic therapies in children with inflammatory 
bowel disease. Expert Rev Clin Immunol 2010;6(4):659-66. 
Carter M, Lobo A, Travis S. Guidelines for the management of inflammatory bowel disease in 
adults. Gut 2004;53(Suppl V):V1-16. 
Chaparro M, Trapero-Marugan M, Morena-Otero R, Gisbert J. Azathioprine plus ribavirin 
treatment and pancytopenia. Ailment Pharmacol Ther 2009;30:962-3. 
Clarke A, Poulton L, Shim D, Mabon D, Butt D, Pollard M, et al. An anti-TL1A antibody for the 
treatment of asthma and inflammatory bowel disease. mAbs 2018;10(4):664-77. 
Danese S, Klopocka M, Scherl E, Romatowski J, Allegretti J, Peeva E, et al. Anti-TL1A 
antibody PF 06480605 safety and efficacy for ulcerative colitis: a phase 2a single-arm study. 
Clinical Gastroenterology and Hepatology 2021;11 S1542-3565(21)00614-5. 
Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and 
validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. 
Gastrointest Endosc 2004; 60(4):505-12. 
D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent 
Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 
1998;114(2):262-7. 
Dragasevic S, Sokic-Milutinovic A, Stojkovic Lalosevic M, Milovanovic T, Djuranovic S, 
Jovanovic I, etc. Correlation of patient-reported outcome (PRO-2) with endoscopic and 
histological features in ulcerative colitis and Crohn’s disease patients. Gastroenterol Res Pract 
2020;2020:2065383. 
Eaden J, Abrams K, Mayberry J. The risk of colorectal cancer in ulcerative colitis: a meta-
analysis. Gut 2001;48:526-35. 
ENTYVIO (vedolizumab). US Prescribing Information. Takeda Pharmaceuticals; 2021. 
ENTYVIO SmPC. Takeda Pharma A/S. Revised 22 March 2021 
https://ec.europa.eu/health/documents/community-register/html/h923.htm 
Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab 
as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369(8):699-710.  
VV-00492862 v6.0

 
Placebo-Controlled Study-IBD 
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Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as 
induction and maintenance therapy for Crohn's Disease. N Engl J Med 2016;375(20):1946-60.  
Fine S, Papamichael K, Cheifetz A. Etiology and management of lack of loss of response to anti-
tumor necrosis factor therapy in patients with inflammatory bowel disease. Gastroenterology and 
Hepatology 2019;15(12):656-65. 
Fiocchi C. TGF-beta/Smad signaling defects in inflammatory bowel disease: mechanisms and 
possible novel therapies for chronic inflammation. J Clin Invest 2001;108(4):523-6. 
Friedman S, Blumberg R. Inflammatory Bowel Disease. In: Faci K, Longo H, Loscalzo J, 
editors. Harrison’s Principles of Internal Medicine, 19th Edition. 2015:1947-65. 
Hassan-Zahraee M, Ye Z, Xi L, Baniecki ML, Li X, Farin W, et al. P446 Transcriptional and 
microbial biomarkers of response to anti-TL1A therapy in ulcerative colitis: the Phase 2a 
TUSCANY study. J Crohn’s Colitis 2020;14:S401-2. 
HUMIRA (adalimumab). US Prescribing Information. AbbVie Inc.; 2021. 
HUMIRA SmPC. AbbVie Deutschland GmbH & Co.KG. Revised 20 November 2020. 
https://ec.europa.eu/health/documents/community-register/html/h256.htm 
Hyams J, Markowitz J, Lerer T, Griffiths A, Mack D, Bousvaros A, et al. The natural history of 
corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4:1118-
23. 
Hyman D, Puzanov I, Subbiah V, Faris J, Chau I, Blay JY, et al. Vemurafenib in multiple 
nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726-36. 
Jairath V, Khanna R, Zou GY, Stitt L, Mosli M, Vandervoort MK, et al. Development of interim 
patient-reported outcome measures for the assessment of ulcerative colitis disease activity in 
clinical trials. Aliment Pharmacol Ther 2015;42(10):1200-10. 
Jairath V, Jeyarajah J, Zou G, Parker CE, Olson A, Khanna R, et al. A composite disease activity 
index for early drug development in ulcerative colitis: development and validation of the UC-100 
score. Lancet Gastroenterol Hepatol 2019;4(1):63-70. 
Khanna R, Zou G, D’Haens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. A 
retrospective analysis: the development of patient reported outcome measures for the assessment 
of Crohn’s disease activity. Aliment Pharmacol Ther 2015;41(1):77-86. 
Kornbluth A, Sachar D. Ulcerative colitis practice guidelines in adults: American college of 
gastroenterology, practice parameters committee. Am J Gastroenterol 2010;105:501-23. 
Misselwitz B, Juillerat P, Sulz MC, Siegmund B, Brand S; Swiss IBDnet, an official working 
group of the Swiss Society of Gastroenterology. Emerging treatment options in inflammatory 
bowel disease: Janus kinases, stem cells, and more. Digestion 2020;101 Suppl 1:69-82. 
Molodecky N, Shian Soon I, Rabi D, Ghali W, Ferris M, Chernoff G, et al. Increasing incidence 
and prevalence of the inflammatory bowel diseases with time, based on systematic review. 
Gastroenterology 2012;142:46-54. 
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D’Haens G, Khanna R, et al. Development and 
validation of a histological index for UC. Gut 2017;66(1):50-58. 
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Mosli MH, Feagan BG, Sandborn WJ, Dʼhaens G, Behling C, Kaplan K, et al. Histologic 
evaluation of ulcerative colitis: a systematic review of disease activity indices. Inflamm Bowel 
Dis 2014;20(3):564-75. 
Naegeli A, Zhang X, Hunter T, Hoskin B, Middleton C, Hetherington J, et al. Full, partial, or 
modified: understanding relationships between permutations of the Mayo score in real-world 
ulcerative colitis patients. Am J Gastroenterol 2018;113:S384. 
Narula N, Wong ECL, Colombel JF, Sandborn WJ, Marshall JK, Daperno M, et al. Predicting 
endoscopic remission in Crohn's disease by the modified multiplier SES-CD (MM-SES-CD). 
Gut 2021;0:1-10. 
Ng S, Kamm M. Therapeutics strategies for the management of ulcerative colitis. Inflamm 
Bowel Dis 2009;15:935-50. 
Ordas I, Mould DR, Feagan BG, SandbornWJ. Anti-TNF monoclonal antibodies in 
inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 
2012;91:635–46. 
Reinisch W, Gottlieb K, Colombel JF, Danese S, Panaccione R, Panes J, et al. Comparison of the 
EMA and FDA Guidelines on Ulcerative Colitis Drug Development. Clin Gastroenterol Hepatol 
2019;17(9):1673-1679.e1. 
REMICADE (infliximab). US Prescribing Information. Janssen Biologics B.V.; 2020. 
REMICADE SmPC. Janssen Biologics B.V. Revised 15 November 2021. 
https://ec.europa.eu/health/documents/community-register/html/h116.htm 
Rosenberg L, Peppercorn M. Efficacy and safety of drugs for ulcerative colitis. Expert Opin 
Drug Saf 2010;9(4):573-92. 
Samaan MA, Mosli MH, Sandborn WJ, Feagan BG, DʼHaens GR, Dubcenco E, et al. A 
systematic review of the measurement of endoscopic healing in ulcerative colitis clinical trials: 
recommendations and implications for future research. Inflamm Bowel Dis 2014;20(8):1465-71. 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006;117(2):391-7. 
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab 
as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369(8):711-21.  
Sands B, Peyrin-Biroulet L, Danese S, Rubin DT, Vermeire S, Laurent O, et al. PRA023 
Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely 
Active UC: Phase 2 ARTEMIS-UC Study Results [abstract]. J Crohns Colitis 2023;17:i56-i59. 
Sands BE, Sandborn WJ, Panaccione R, OʼBrien CD, Zhang H, Johanns J, et al. Ustekinumab as 
induction and maintenance therapy for ulcerative colitis. N Engl J Med 2019;381(13):1201-14.  
Shih D, Zheng L, Zhang X, Zhang H, Kanazawa Y, Ichikawa R, et al. Inhibition of a novel 
fibrogenic factor Tl1a reverse established colonic fibrosis. Mucosal Immunol 2014;7(6):1492-
1503. 
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Sipponen T, Nuutinen H, Turunen U, Färkkilä M. Endoscopic evaluation of Crohnʼs disease 
activity: comparison of the CDEIS and the SES-CD. Inflamm Bowel Dis 2010;16(12):2131-6. 
STELARA (austekinumab). US Prescribing Information. Janssen; 2020.  
STELARA SmPC. Janssen-Cilag International NV. Revised 12 November 2021. 
https://ec.europa.eu/health/documents/community-register/html/h494.htm 
Subbiah V, Kreitman R, Wainberg Z, Cho JY, Schellens J, Soria J, et al. Dabrafenib and 
trametinib treatment in patients with locally advanced or metastatic BRAF V600–mutant 
anaplastic thyroid cancer. J Clin Oncol 2018;36(1):7-13. 
Takedatsu H, Michelsen K, Wei B, Landers C, Thomas L, Dhall D, et al. TL1A (TNFSF15) 
regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 
activation. Gastroenterology 2008;135:552-67. 
Truelove SC. Treatment of ulcerative colitis with local hydrocortisone. Br Med J 
1956;2(5004):1267-72. 
Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry. US Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER). August 2016. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/ulcerative-colitis-clinical-trial-endpoints-guidance-industry. 
Valatas V, Kollos G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): a co-stimulatory 
system of cytokines with diverse functions in gut mucosal immunity. Front Immunol 
2019;10:583. 
Van Limbergen J, Russell R, Drummond H, Aldhous M, Round N, Nimmo E, et al. Definition of 
phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 
2008;135:1114-22. 
Wallace K, Zheng L, Kanazawa Y, Shih D. Immunopathology of inflammatory bowel disease. 
World J Gastroneterol 2014;20(1):6-21. 
Wenxiu J, Mingyue Y, Fei H, Yuxin L, Mengyao W, Chenyang L, et al. Effect and Mechanism 
of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related 
Intestinal Fibrosis. Mediators Inflamm. 2021 Jun 25;2021:5927064. 
XELJANZ (tofacitinib). US Prescribing Information. Pfizer; 2021. 
XELJANZ SmPC. Pfizer Europe MAEEIG. Revised 15 November 2021. 
https://ec.europa.eu/health/documents/community-register/html/h1178.htm 
Yoshida EM. The Crohn’s Disease Activity Index, its derivatives and the Inflammatory Bowel 
Disease Questionnaire: a review of instruments to assess Crohn’s disease. Can J Gastroenterol 
1999;13(1):65-73. 
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17. 
SUMMARY OF CHANGES TO PROTOCOL  
17.1. 
Amendment 04 Dated 08 July 2024  
The protocol was amended for the following reasons: 
• To update the protocol in line with CTR following the study transition to CTR: 
− Replacing the Eudra CT number with EU CT number 
−  Shortening the information in the study synopsis to approximately 2 pages 
− To add a statement to clarify clinical study is conducted in compliance with EU 
Number 536/2014 [CTR Annex I 17 (a);  
− To add statement to clarify sponsors obligation in compliance with EU CTR Articles 
52 through 54 
• To add criterion for not performing the planned IA for futility/efficacy taking into 
consideration the practicality of such analyses in relation to study recruitment 
acceleration or other operational considerations. 
• To extend the study period to approximately 27 months, from Q3 2022 until 
approximately Q3 Q4 2024. 
• To incorporate within the protocol changes from the following administrative letters: 
− TV48574-IMM-20036 Administrative Letter 01 (dated 25 September 2023) 
− TV48574-IMM-20036 Administrative Letter 02 (dated 21 June 2024) 
− TV48574-IMM-20036 Administrative Letter 01 for Japan (JP) (dated 12 March 2024) 
− TTV48574-IMM-20036 Administrative Letter 01 for France (FR) (dated 11 March 
2024) 
All changes to the protocol body are listed below in the table, and are reflected in the synopsis, 
as applicable. Minor editorial changes (typos, punctuation, etc.) have been made to the protocol 
(and protocol synopsis, as appropriate).  
 
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Original text with changes shown 
New wording 
Reason/Justification for change 
Title Page 
EudraCT number: 2021 006881 19; EU CT 
number: 2024-511089-36-00 
EU CT number: 2024-511089-36-00 
Number changed following the transition of the 
study from the EU CTD to EU CTR  
This clinical study will be conducted in 
accordance with current Good Clinical Practice 
(GCP) as directed by the provisions of the 
International Council for Harmonisation (ICH); 
ISO 14155: Clinical investigation of medical 
devices for human subjects  Good clinical 
practice, as applicable; United States (US) Code of 
Federal Regulations (CFR), and European Union 
(EU) Directives and Regulations (as applicable in 
the region of the study); national country 
legislation; the protocol; and the sponsor’s 
Standard Operating Procedures (SOPs). 
This clinical study will be conducted in 
accordance with current Good Clinical Practice 
(GCP) as directed by the provisions of the 
International Council for Harmonisation (ICH); 
United States (US) Code of Federal Regulations 
(CFR), and European Union (EU) Directives and 
Regulations (as applicable in the region of the 
study); national country legislation; the protocol; 
and the sponsor’s Standard Operating Procedures 
(SOPs). 
Removed text that is not relevant for this protocol. 
CLINICAL STUDY PROTOCOL SYNOPSIS 1. PROTOCOL SUMMARY 
See new wording column. 
Original Clinical Study Protocol Synopsis was 
renamed to Protocol Summary, condensed to 2 
pages, and relocated to Section 1. Protocol 
Summary section created with the following 
sections: 
Protocol Synopsis (information from previous 
synopsis condensed to just a few pages), Trial 
Schema (study schematic figure moved from the 
study design section of the protocol), and Schedule 
of Activities (moved from the study design section 
of the protocol). 
Document must be compliant with CTR in Europe. 
 
All subsequent sections have been renumbered. 
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New wording 
Reason/Justification for change 
See new wording column. 
1.1 Protocol Synopsis 
… 
Trial Arms and Duration: …The study duration 
will be approximately 27 months, from Q3 2022 
until approximately Q4 2024. 
Subsection 1.1 created in compliance with CTR in 
Europe. 
 
Study duration extended due to increase in the 
initially estimated recruitment rate duration. 
(change incorporated from TV48574-IMM-20036 
Administrative Letter 02 (dated 21 June 2024)). 
All subsequent tables have been renumbered as 
applicable. 
Section 1.2. Trial Schema  
See new wording column. 
Figure 1 (Overall Program Schematic) relocated 
from Section 4.1 (General Study Design and Study 
Schematic Diagram)  
Subsection 1.2 created in compliance with ICH 
M11. 
All subsequent tables have been renumbered as 
applicable. 
Section 1.3. Schedule of Activities 
See new wording column. 
Table 4 (Study Procedures and Assessments) was 
relocated from Section 4.5 (Schedule of Study 
Procedures and Assessments) and renumbered as 
Table 1. 
Subsection 1.3 created in compliance with ICH 
M11. 
Subsequent tables have been renumbered as 
applicable. 
4.1. General Study Design and Study Schematic Diagram  
See new wording column. 
Figure 2 Overall Study Schematic Diagram moved 
from the study design section of the protocol to 
newly created subsection 1.2 Trial Schema,  
 
Figure 2 Overall Study Schematic Diagram has 
been changed to Figure 1 Overall Program 
Schematic. 
Figure 2 Overall Study Schematic Diagram moved 
to newly created subsection 1.2 Trial Schema in 
compliance with ICH M11 template.  
All subsequent figures have been renumbered. 
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New wording 
Reason/Justification for change 
… 
The study duration will be approximately 24 27 
months, from Q3 2022 until approximately Q3 
Q4 2024.  
… 
The study duration will be approximately 27 
months, from Q3 2022 until approximately 
Q4 2024.  
Increase in the initially estimated recruitment 
duration. 
(change incorporated from TV48574-IMM-20036 
Administrative Letter 02 dated 21 June 2024) 
Section 4.2 Planned Number of Patients and Countries 
The study is expected to start in Q3 2022 and last 
until approximately Q3 Q4 2024. 
The study is expected to start in Q3 2022 and last 
until Q4 2024. 
Study duration extended due to increase in the 
initially estimated recruitment duration. 
(change incorporated from TV48574-IMM-20036 
Administrative Letter 02 dated 21 June 2024) 
3.5.4.5 Schedule of Study Procedures and Assessments 
See new wording column. 
Schedule of Activities Table 2 moved from the 
study design section of the protocol to newly 
created subsection 1.3 Schedule of Activities. 
Schedule of Activities have been changed to Table 
1. All subsequent tables from 1 to 3 have been 
renumbered. 
Schedule of Activities Table 2 moved to newly 
created subsection 1.3 Schedule of Activities in 
compliance with ICH M11. 
 
All subsequent tables have been renumbered as 
applicable. 
Pain will be assessed beginning, during (~15 
minutes after the start of (approximately midway 
through the infusion), and after the completion of 
IMP administration and 1 hour later. 
Table 4,Table 1 Footnote “u” and  
7.2 8.2 Assessment of Local Tolerability and Pain 
Pain will be assessed beginning, during 
(approximately midway through the infusion), and 
after the completion of IMP administration and 1 
hour later. 
Table 1 Footnote “u” and 
8.2 Assessment of Local Tolerability and Pain and 
For patients randomized as of Amendment 03 with 
Revision 01, reduction in IMP volume 
administered at Visits 2 to 7 described in Section 
5.1.3 results in a decreased infusion time.  The 
volume of IMP was decreased from a 12 mL 
induction dose volume to a 6 mL induction dose 
volume, and the duration of the infusion therefore 
decreased from 24 minutes to 12 minutes. Since 
the infusion rate only lasts 12 minutes, it is not 
possible to perform this assessment at ~15 
minutes, and therefore updated to assess pain 
during approximately midpoint of the infusion. 
(change incorporated from TV48574-IMM-20036 
Administrative letter 02 (dated 21 June 2024))  
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Reason/Justification for change 
Section 7.1.2.1 Biopsy Collection 
For patients with CD, an ileo-colonoscopy will be 
performed at screening and week 14. During each 
endoscopy, a total of 16 11 to 18 mucosal biopsies 
will be obtained from the area with the greatest 
inflammation in each segment at screening and at 
the same location at week 14 or early termination.  
 
For patients with UC, a flexible sigmoidoscopy 
will be performed at screening and week 14 
(colonoscopy may be performed instead for 
baseline endoscopy if not done in the prior 
12 months). During each endoscopy, a total of 8 7 
to 12 biopsies will be obtained from the area with 
the worst disease 15 to 25 cm from the anal verge. 
For patients with CD, an ileo-colonoscopy will be 
performed at screening and week 14. During each 
endoscopy, a total of 11 to 18 mucosal biopsies 
will be obtained from the area with the greatest 
inflammation in each segment at screening and at 
the same location at week 14 or early termination.  
 
For patients with UC, a flexible sigmoidoscopy 
will be performed at screening and week 14 
(colonoscopy may be performed instead for 
baseline endoscopy if not done in the prior 
12 months). During each endoscopy, a total of 7 to 
12 biopsies will be obtained from the area with the 
worst disease 15 to 25 cm from the anal verge. 
The number of total biopsies was reduced to 
reduce the patient’s burden. 
(changes incorporated from TV48574-IMM-20036 
Administrative letter 01 (dated 25 September 
2023) 
 
Section 8.1.8.1. Investigator Responsibility 
For all countries, the sponsor’s GPSP will 
distribute the Council for International 
Organizations of Medical Sciences (CIOMS) 
form/MedWatch/ and/or Extensible Markup 
Language (XML) file to the LSO/CRO for local 
submission to the competent authorities, 
IEC/IRBs, and investigators, according to 
regulations. For studies in the European 
Economic Area, submission of SUSARs is done 
electronically to the EudraVigilance database 
(via EVWEB or by electronically using the 
E2B(R3) electronic ICSR form) by the GPSP. 
The investigator must ensure that the IEC/IRB is 
also informed of the event, in accordance with 
national and local regulations. 
For all countries, the sponsor’s GPSP will 
distribute the Council for International 
Organizations of Medical Sciences (CIOMS) form 
and/or Extensible Markup Language (XML) file to 
the LSO/CRO for local submission to the 
competent authorities, IEC/IRBs, and 
investigators, according to regulations. For studies 
in the European Economic Area, submission of 
SUSARs is done electronically to the 
EudraVigilance database (via EVWEB or by 
electronically using the E2B(R3) electronic ICSR 
form) by the GPSP. The investigator must ensure 
that the IEC/IRB is also informed of the event, in 
accordance with national and local regulations. 
 Updated to be compliant with European Union 
safety reporting requirements and the EU CTR. 
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Reason/Justification for change 
10.13 Planned Interim Analysis 
Interim analyses for safety and efficacy are 
planned for this study. An interim efficacy/futility 
analysis is planned in each indication (UC and 
CD) when approximately 50% of patients in the 
indication have completed the 14-week primary 
efficacy readout time point or had the opportunity 
to do so. This is expected to yield approximately 
20 evaluable patients per treatment group for each 
indication in the interim analysis. Due to study 
recruitment acceleration or other operational 
considerations, the interim analysis for 
efficacy/futility will not be conducted as it will be 
impractical and have limited utility. 
Interim analyses for safety and efficacy are 
planned for this study. An interim efficacy/futility 
analysis is planned in each indication (UC and 
CD) when approximately 50% of patients in the 
indication have completed the 14-week primary 
efficacy readout time point or had the opportunity 
to do so. This is expected to yield approximately 
20 evaluable patients per treatment group for each 
indication in the interim analysis. Due to study 
recruitment acceleration or other operational 
considerations, the interim analysis for 
efficacy/futility will not be conducted as it will be 
impractical and have limited utility. 
Due to the accelerated recruitment, performing IA 
for futility/high efficacy is not pragmatic as all 
participants will have almost completed the 
treatment period at the time of the IA. There is no 
impact on the safety and rights of the patients in 
the study as there are no changes to the planned 
safety monitoring as specified in the protocol, 
including the monthly IAs for safety and the 
planned safety IDMC meetings. Additionally, the 
study integrity and blinding are preserved and the 
statistical operating characteristics (e.g., type II 
error rate under the assumption of efficacy) are not 
impacted. 
(change incorporated from TV48574-IMM-20036 
Administrative letter 02 (dated 21 June 2024)) 
 
Appendix A Departments and Institutions 
See new wording column. 
Appendix A was deleted.  
All subsequent appendices renumbered. 
To remove protected personal data that should not 
be displayed. 
APPENDIX M: COUNTRY-SPECIFIC REQUIREMENTS 
See new wording column. 
Added Administrative Letter 01 Dated 12 March 
2024 for Japan. 
To clarify concomitant use of permitted Chinese 
herbal supplements is associated with global 
inclusion criterion “h”. 
(change incorporated from Administrative Letter 
01 for Japan (JP) (dated 12 March 2024)) 
See new wording column. 
Added Administrative Letter 01 Dated 11 March 
2024 for France. 
To clarify patient enrolled in France will not be 
offered the option to enter the long-term extension 
study (TV48574-IMM-20038). 
(change incorporated from Administrative Letter 
01 for France (FR) (dated 11 March 2024)) 
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17.2. 
Administrative Letter 02 Dated 21 June 2024  
 
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17.3. 
Administrative Letter 01 Dated 15 August 2023  
 
 
 
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17.4. 
Amendment 03 with Revision 01 Dated 15 August 2023  
Amendment 03 of the protocol was revised for the following reasons:  
• To clarify that all patients randomized prior to Amendment 03 Revision 01 will continue 
to receive the same dose, volume, and rate of administration of the IMP to which they 
were initially randomized and will remain blinded. 
• To clarify induction dose volume: 
− All patients randomized prior to Amendment 03 with Revision 01 will receive 12 mL 
induction dose volume. 
− All patients randomized as of Amendment 03 with Revision 01 will receive 6 mL 
induction dose volume. 
• To clarify all randomized patients in this study may enroll in the long-term extension 
study. 
• To adjust the secondary and exploratory study objectives: 
− Moved the following UC secondary endpoints to exploratory endpoints 
○ Clinical response defined as decrease from baseline of at least 50% in 2-item 
PRO2 (rectal bleeding and stool frequency) at weeks 2, 4, 6, 8, 10, and 12 
○ Clinical remission defined as score of rectal bleeding = 0 and stool frequency = 0 
on the PRO2 scale at weeks 2, 4, 6, 8, 10, and 12 
○ Histological remission defined as a Robarts Histopathology Index of ≤5 at 
week 14  
○ Histological remission defined as Geboes index score ≤3.1 at week 14 
○ Use of concomitant medication 
○ Device-related adverse events and malfunctions (for the commercial sc infusion 
system) 
− Moved the following CD secondary endpoints to exploratory endpoints 
○ Clinical response defined as a decrease from baseline of at least 50% in PRO2 
(PRO2 is defined as having 2 components, abdominal pain and stool frequency) at 
weeks 2, 4, 6, 8, 10, and 12 
○ Clinical remission defined as abdominal pain ≤1 and stool frequency ≤3 on the 
PRO2 scale at weeks 2, 4, 6, 8, 10, and 12 
○ Endoscopic remission defined as SES CD score of 0-2, or SES CD score of 0-4, 
with no individual sub score >1 at week 14  
○ Histologic response defined as a ≥50% decrease in Global Histologic Activity 
Score from baseline at week 14 
○ Use of concomitant medication 
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○ Device-related adverse events and malfunctions (for the commercial sc infusion 
system) 
− Added/amended the following exploratory objectives: 
○ Added the change from baseline in 
 at 
weeks 2, 8, and 14 
○ Included the potential of other fecal/stool-derived biomarkers to be tested and 
analyzed, ie, change from baseline in fecal calprotectin or other stool-derived 
markers at weeks 2, 4, 8, and 14) 
• To update the planned number of countries and investigational centers participating in the 
study 
• To modify the justification of dose of test IMP 
• To modify the hemoglobin value threshold in exclusion criterion l from <8 to <9 g/dL 
• To replace exclusion criterion n, which is specific for COVID-19 infection, with any 
acute infection that may compromise the safety of the patient 
• To remove the procedures and assessments of COVID-19 symptoms from all visits, 
including Appendix K (Management of Study Activities during COVID-Outbreaks)  
• To add urine pregnancy testing at weeks 2, 6, and 10 
• To add biomarker sample collection and potential exploratory analysis of 
 at 
weeks 0, 2, 8, 14, and early termination 
• To potentially investigate additional fecal/stool derived-biomarkers 
• To revise the total blood volume collected per patient from 240 mL to 280 mL to account 
for the 
 sample collections 
• To revise the duration of the follow-up window from ±14 days to ±3 days 
• To clarify all prior medications for IBD will be captured in the source documentation and 
CRF 
• To clarify biopsies for patients with CD will be obtained at week 14 or early termination 
from the same area as the screening biopsy 
• To clarify the total study sample size of 240 patients does not include patients that were 
randomized to the 1800 mg treatment group prior to Amendment 03 with Revision 01 
• To update the statistical futility cutoff from <0.55 to <0.30 
• To clarify the interim analysis will be conducted when approximately 50% of patients in 
the indication have completed the 14-week primary efficacy readout or had the 
opportunity to do so 
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc.) have been made to 
the protocol (and protocol synopsis, as appropriate). Table 1  (Study Procedures and 
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Assessments) and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect 
changes described below. 
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New wording 
Reason/Justification for 
change 
Section 1.1.2 Relevance of Inhibition of TL1A Binding to Death Receptor 3 for Inflammatory Bowel Disease 
Inhibiting TL1A binding to DR3 prevents activation of the DR3 
signaling pathway. A therapeutic anti-TL1A antibody (PF-
06480605) was found to be efficacious in patients with UC 
(Hassan-Zahraee et al 2020). The results of this proof-of-
concept (PoC) clinical study provide support for the clinical and 
histological benefits of inhibition of TL1A/DR3 signaling in 
patients with UC (Danese et al 2021). The results of the study 
demonstrated an acceptable safety profile and statistically 
significant endoscopic improvement in participants with 
moderately to severely active UC. 
Similar findings were reported in a Phase 2 study in patients 
with moderate to severe UC. In this study, treatment with 
PRA-023 resulted in a statistically significant greater 
proportion of patients with clinical remission or endoscopic 
improvement compared with placebo with a well-tolerated and 
acceptable safety profile (Sands et al 2023). 
… 
Inhibiting TL1A binding to DR3 prevents activation of the 
DR3 signaling pathway. A therapeutic anti-TL1A antibody 
(PF-06480605) was found to be efficacious in patients with UC 
(Hassan-Zahraee et al 2020). The results of this proof-of-
concept (PoC) clinical study provide support for the clinical 
and histological benefits of inhibition of TL1A/DR3 signaling 
in patients with UC (Danese et al 2021). The results of the 
study demonstrated an acceptable safety profile and statistically 
significant endoscopic improvement in participants with 
moderately to severely active UC. 
Similar findings were reported in a Phase 2 study in patients 
with moderate to severe UC. In this study, treatment with PRA-
023 resulted in a statistically significant greater proportion of 
patients with clinical remission or endoscopic improvement 
compared with placebo with a well-tolerated and acceptable 
safety profile (Sands et al 2023). 
… 
To provide additional 
support on the role of TL1A 
in IBD and the rationale for 
the study. 
Section 1.2.2.1.3 Immunogenicity  
… 
Of the 48 subjects who received TEV-48574 in the SAD portion 
of the study, 23 subjects (47.9%) were identified as having a 
treatment-emergent ADA response. Treatment-emergent ADA 
responses were not associated with a safety signal. Treatment-
emergent ADA responses were also observed in the cohorts that 
did not have measurable serum concentrations of TEV-48574 
(cohorts 1 and 2, 1 and 4 mg TEV-48574, respectively). The 
higher dose cohorts 7 (400 mg) and 8 (1000 mg) had the lowest 
numbers of subjects with treatment emergent ADA responses 
All ADAs occurred at 200 mg or lower except for 1 patient 
who received 1000 mg developed 1 transient ADA (low titer) 
43 days after the dose was administered, suggesting that there 
may be a trend toward immunological tolerance at higher doses. 
Three of 27 patients who received TEV-48574 (11% of patients 
tested) in the MAD portion were identified as having a positive 
… 
Of the 48 subjects who received TEV-48574 in the SAD 
portion of the study, 23 subjects (47.9%) were identified as 
having a treatment-emergent ADA response. Treatment-
emergent ADA responses were not associated with a safety 
signal. Treatment-emergent ADA responses were also observed 
in the cohorts that did not have measurable serum 
concentrations of TEV-48574 (cohorts 1 and 2, 1 and 4 mg 
TEV-48574, respectively). All ADAs occurred at 200 mg or 
lower except for 1 patient who received 1000 mg developed 
1 transient ADA (low titer) 43 days after the dose was 
administered, suggesting that there may be a trend toward 
immunological tolerance at higher doses. 
Three of 27 patients who received TEV-48574 (11% of patients 
tested) in the MAD portion were identified as having a positive 
treatment-emergent ADA response. All 3 patients were in 
Clarification. 
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Reason/Justification for 
change 
treatment-emergent ADA response. All 3 patients were in 
cohort 1 (200 mg). In these patients, the observed ADA log10 
titer ranged from 0.6 to 2.5. One patient had treatment-emergent 
ADA responses at multiple time points starting by day 15, while 
the other 2 patients were ADA positive only at the end-of-study 
(EOS) visit (day 92), approximately 7 weeks after the last dose.  
… 
cohort 1 (200 mg). In these patients, the observed ADA log10 
titer ranged from 0.6 to 2.5. One patient had treatment-
emergent ADA responses at multiple time points starting by 
day 15, while the other 2 patients were ADA positive only at 
the end-of-study (EOS) visit (day 92), approximately 7 weeks 
after the last dose.  
… 
Section 1.2.2.2 Phase 1 Study (TV48574-PK-10180) 
New section added; see new wording column. 
Study TV48574-PK-10180 was a Phase 1 open-label, 
randomized, single-dose study to evaluate the 
pharmacokinetics, safety, immunogenicity, and tolerability of 
TEV-48574 in healthy Japanese and Caucasian subjects. There 
were 3 single dose cohorts. Healthy Japanese subjects were 
randomized to 1 of 2 dose levels of TEV-48574 (
 or 
) in cohort 1 or assigned to a dose of 
 TEV-
48574 in cohort 2. Healthy Caucasian subjects were assigned to 
a dose of 
 in cohort 3. 
The pharmacokinetic profile of TEV-48574 in Japanese 
subjects (n=24) was similar to pharmacokinetic profile in 
Caucasian subjects (n=8) across the absorption, distribution, 
and elimination phases; pharmacokinetic parameters in 
Japanese subjects were comparable to Caucasian subjects in the 
 dose cohorts and consistent with pharmacokinetic 
parameters in Caucasian subjects obtained from the TV48574-
SAD-10126 study. The safety profile was consistent with that 
seen in the previous TEV-48574 studies with no evidence of 
any dose-related trends in adverse events in Japanese cohorts or 
differences between the Japanese and Caucasian subjects in any 
safety measures. 
The CSR for Study 
TV48574-PK-10180 has 
been completed; therefore, a 
brief summary of the study 
results has been added. 
Section 1.2.2.3 Phase 2a Study (TV48574-AS-20031) 
… 
A pre-specified interim futility analysis was conducted on 
64 patients for the first 40 patients who have completed the 
treatment period, experienced LoAC, or withdrawn from the 
study completely. Teva determined that the primary endpoint 
… 
A pre-specified interim futility analysis was conducted on 
64 patients. Teva determined that the primary endpoint result, 
reduction in LoAC, met the decision rule for futility, meaning 
that the likelihood of a positive outcome of the completion of 
Correction. 
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Reason/Justification for 
change 
result, reduction in LoAC, met the decision rule for futility, 
meaning that the likelihood of a positive outcome of the 
completion of the study was small. Based on the results of the 
primary endpoint futility analysis, Teva decided to stop the 
study on 22 December 2021. 
A total of 65 patients have been were randomized into the 
study; 1 patient did not receive investigational medicinal 
product (IMP). No deaths occurred. 
the study was small. Based on the results of the primary 
endpoint futility analysis, Teva decided to stop the study on 22 
December 2021. 
A total of 65 patients were randomized into the study; 1 patient 
did not receive investigational medicinal product (IMP). No 
deaths occurred. 
Section 1.3.2 Overall Benefit and Risk Assessment for This Study 
… 
Management of the patients’ safety during the study that is 
expected to mitigate risk is detailed in Section 3 (investigational 
plan) and Section 7 (safety measurements and assessments); 
also refer to Section 9.13 for a description of the futility 
analysis, which will determine if recruitment should be stopped 
due to futility. Management of study activities during 
coronavirus disease 2019 (COVID 19) outbreaks is detailed in 
Appendix K. 
… 
… 
Management of the patients’ safety during the study that is 
expected to mitigate risk is detailed in Section 3 
(investigational plan) and Section 7 (safety measurements and 
assessments); also refer to Section 9.13 for a description of the 
futility analysis, which will determine if recruitment should be 
stopped due to futility. 
… 
Experience of the current 
stage of the pandemic does 
not support the contingent 
restrictions of COVID-19. 
Section 2.1 Primary and Secondary Study Objectives and Endpoints 
The secondary efficacy endpoints to be measured in patients 
with moderate to severe UC are as follows: 
… 
• 
Clinical response defined as decrease from baseline of 
at least 50% in 2-item patient-reported outcome 
(PRO2; rectal bleeding and stool frequency) at weeks 
2, 4, 6, 8, 10, 12 and 14  
• 
Clinical remission defined as score of rectal bleeding = 
0 and stool frequency = 0 on the PRO2 scale at weeks 
2, 4, 6, 8, 10, 12 and 14 
• 
Histological remission defined as a Robarts 
Histopathology Index of ≤5 at week 14  
• 
Histological remission defined as Geboes index score 
The secondary efficacy endpoints to be measured in patients 
with moderate to severe UC are as follows: 
… 
• 
Clinical response defined as decrease from baseline of 
at least 50% in 2-item patient-reported outcome 
(PRO2; rectal bleeding and stool frequency) at 
week 14  
• 
Clinical remission defined as score of rectal bleeding 
= 0 and stool frequency = 0 on the PRO2 scale at 
week 14 
The secondary efficacy endpoints to be measured in patients 
with moderate to severe CD are as follows: 
… 
• 
Correction 
Only week 14 is 
the primary 
endpoint for 
clinical response 
and clinical 
remission; 
therefore, moved 
other time points to 
exploratory 
analysis. 
• 
Sample size is 
likely 
underpowered to 
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Reason/Justification for 
change 
≤3.1 at week 14.  
The secondary efficacy endpoints to be measured in patients 
with moderate to severe CD are as follows: 
… 
• 
Endoscopic remission defined as SES CD score of 0-2, 
or SES CD score of 0-4, with no individual sub score 
>1 at week 14  
• 
Clinical response defined as a decrease from baseline 
of at least 50% in PRO2 (PRO2 is defined as having 
2 components, abdominal pain and stool frequency) at 
weeks 2, 4, 6, 8, 10, 12 and 14  
• 
Clinical remission defined as abdominal pain ≤1 and 
stool frequency ≤3 on the PRO2 scale at weeks 2, 4, 6, 
8, 10, 12 and 14  
… 
• 
Histologic response defined as a ≥50% decrease in 
Global Histologic Activity Score from baseline at week 
14 
• 
Clinical response defined as a decrease from baseline 
of at least 50% in PRO2 (PRO2 is defined as having 
2 components, abdominal pain and stool frequency) at 
week 14  
• 
Clinical remission defined as abdominal pain ≤1 and 
stool frequency ≤3 on the PRO2 scale at week 14 
… 
show a clinically 
meaningful 
difference for 
endoscopic 
remission; 
therefore, 
endpoints moved to 
exploratory 
analysis. 
Section 2.3 Exploratory Objectives and Endpoints 
Endpoints 
See new wording column. 
Moved the following efficacy endpoints from secondary to 
exploratory objectives to evaluate 2 different doses of 
TEV-48574 sc administered Q2W in adult patients with IBD: 
UC: 
• 
Clinical response defined as decrease from baseline of 
at least 50% in 2-item patient-reported outcome 
(PRO2; rectal bleeding and stool frequency) at 
weeks 2, 4, 6, 8, 10, and 12 
• 
Clinical remission defined as score of rectal bleeding 
= 0 and stool frequency = 0 on the PRO2 scale at 
weeks 2, 4, 6, 8, 10, and 12 
• 
Histological remission defined as a Robarts 
Histopathology Index of ≤5 at week 14 
• 
Histological remission defined as Geboes index score 
• 
Correction 
Only week 14 is 
the primary 
endpoint for 
clinical response 
and clinical 
remission; 
therefore, moved 
other time points to 
exploratory 
analysis. 
• 
Sample size is 
likely 
underpowered to 
show a clinically 
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Reason/Justification for 
change 
≤3.1 at week 14 
CD: 
• 
Clinical response defined as a decrease from baseline 
of at least 50% in PRO2 (PRO2 is defined as having 2 
components, abdominal pain and stool frequency) at 
weeks 2, 4, 6, 8, 10, and 12 
• 
Clinical remission defined as abdominal pain ≤1 and 
stool frequency ≤3 on the PRO2 scale at weeks 2, 4, 6, 
8, 10, and 12 
• 
Endoscopic remission defined as SES CD score of 
0-2, or SES CD score of 0-4, with no individual sub 
score >1 at week 14  
• 
Histologic response defined as a ≥50% decrease in 
Global Histologic Activity Score from baseline at 
week 14 
Moved the following safety and tolerability endpoints from 
secondary to exploratory objectives for both UC and CD to 
evaluate 2 different doses of TEV-48574 sc administered Q2W 
in adult patients with IBD: 
• 
Use of concomitant medication 
• 
Device-related adverse events and malfunctions (for 
the commercial sc infusion system) 
meaningful 
difference for 
endoscopic 
remission; 
therefore, 
endpoints moved to 
exploratory 
analysis. 
• 
Concomitant 
medication and 
device-related 
adverse event 
endpoints are not 
part of the main 
safety analysis. 
Endpoints 
See new wording column. 
• 
Added the following endpoint for the exploratory 
objective of evaluating association among exploratory 
biomarkers and clinical efficacy of TEV-48574: 
− 
Change from baseline in 
 
 
 at weeks 2, 8, 
and 14 
• 
Amended the fecal calprotectin endpoint as follows to 
include potential testing/analysis for other 
stool-derived markers  
− 
change from baseline in fecal calprotectin or other 
• 
 
 
 
 
 
 
• 
Other fecal 
biomarkers may be 
investigated to 
study the treatment 
effect of 
TEV-48574. 
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Reason/Justification for 
change 
stool-derived markers at weeks 2, 4, 8, and 14) 
An exploratory objective of the study is to obtain trough serum 
TEV-48574 concentrations, to compare major pharmacokinetic 
characteristics between UC and CD patients with healthy 
volunteers and asthma patients, and, if data allows, to evaluate 
the pharmacokinetics/pharmacodynamics PD and/or exposure-
response relationship of 2 different doses of TEV-48574 sc. 
An exploratory objective of the study is to obtain trough 
serum TEV-48574 concentrations, to compare major 
pharmacokinetic characteristics between UC and CD patients 
with healthy volunteers and asthma patients, and, if data allows, 
to evaluate the pharmacokinetics/PD and/or exposure-response 
relationship of different doses of TEV-48574 sc. 
The 1800 mg dose may be 
considered for exploratory 
analyses, if data allows. 
Section 3.1 General Study Design and Study Schematic Diagram 
… 
Randomization: Patients satisfying the eligibility criteria at the 
end of the screening period will be randomized in a 1:1:1 ratio 
(stratified by diagnosis [UC or CD] and previous exposure to 
advanced therapy for IBD (yes/no) (biologics, JAK inhibitors, 
and S1P receptor modulators) to 1 of 3 treatment groups for the 
double-blind treatment period (Table 3). 
… 
Patients randomized prior to Amendment 03 with Revision 01 
will continue to receive the same dose, volume, and rate of 
administration of the IMP to which they were initially 
randomized and will remain blinded. 
… 
Treatment and Follow-Up Period: During the 14-week treatment 
period, patients will visit the site Q2W on days 1, 15, 29, 43, 57, 
71, and 85 (±3 days) for IMP administration (7 visits), as well 
as an end-of-treatment visit on day 99 (±3 days; week 14) 
(Table14). After the end of the 14-week treatment period, all 
patients may be offered the option to enter a long-term 
extension study, (to be which is described in a separate protocol 
(TV48574-IMM-20038). If they choose to enter (sign the 
extension study informed consent form [ICF]) and will 
subsequently be randomized into the long-term extension study, 
they will not need to complete the follow-up visit in this study. 
All other patients will return to the site for a follow-up visit (day 
127 [±14 3 days]). For those patients who enter the long-term 
extension study, adverse events and concomitant medication 
… 
Randomization: Patients satisfying the eligibility criteria at the 
end of the screening period will be randomized in a 1:1:1 ratio 
(stratified by diagnosis [UC or CD] and previous exposure to 
advanced therapy for IBD (yes/no) (biologics, JAK inhibitors, 
and S1P receptor modulators) to 1 of 3 treatment groups for the 
double-blind treatment period (Table 3). 
… 
Patients randomized prior to Amendment 03 with Revision 01 
will continue to receive the same dose, volume, and rate of 
administration of the IMP to which they were initially 
randomized and will remain blinded. 
… 
Treatment and Follow-Up Period: During the 14-week 
treatment period, patients will visit the site Q2W on days 1, 15, 
29, 43, 57, 71, and 85 (±3 days) for IMP administration 
(7 visits), as well as an end-of-treatment visit on day 99 
(±3 days; week 14) (Table14). After the end of the 14-week 
treatment period, all patients may be offered the option to enter 
a long-term extension study, which is described in a separate 
protocol (TV48574-IMM-20038). If they choose to enter (sign 
the extension study informed consent form [ICF]) and will 
subsequently be randomized into the long-term extension study, 
they will not need to complete the follow-up visit in this study. 
All other patients will return to the site for a follow-up visit 
(day 127 [±3 days]). For those patients who enter the long-term 
extension study, adverse events and concomitant medication 
Clarification. 
• 
Patients 
randomized prior 
to Amendment 03 
with Revision 01 
will continue to 
receive the dose 
(including volume, 
rate, and duration) 
of IMP to which 
they were initially 
randomized to not 
disrupt potential 
response to 
treatment and 
maintain the 
integrity of the 
study (eg, blinding 
concerns and data 
analysis).  
• 
All patients 
randomized in this 
study may be 
eligible for 
enrollment in the 
long-term 
extension study. 
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Reason/Justification for 
change 
data will be recorded in the dose-ranging study case report form 
(CRF) up until the date of extension study randomization 
(defined as the study completion date for the dose-ranging 
study). For those patients who screen fail the long-term 
extension study, adverse events and concomitant medication 
data will be recorded in the dose-ranging study up until the 
follow-up visit (day 127 [±14 3 days]) CRF. Patients who 
complete the last scheduled visit will be considered to have 
completed the study. 
… 
The end of study is defined as the last visit of the last patient. 
The total duration of patient participation in the study is 
planned to be up to 24 weeks for each individual patient. 
The study duration will be approximately 24 months, from Q3 
2022 until approximately Q3 2024. 
… 
data will be recorded in the dose-ranging study case report form 
(CRF) up until the date of extension study randomization 
(defined as the study completion date for the dose-ranging 
study). For those patients who screen fail the long-term 
extension study, adverse events and concomitant medication 
data will be recorded in the dose-ranging study up until the 
follow-up visit (day 127 [±14 3 days]) CRF. Patients who 
complete the last scheduled visit will be considered to have 
completed the study. 
… 
The end of study is defined as the last visit of the last patient. 
The total duration of patient participation in the study is 
planned to be up to 24 weeks for each individual patient. 
The study duration will be approximately 24 months, from Q3 
2022 until approximately Q3 2024. 
… 
• 
Added the total 
duration of patient 
participation. 
Figure 2 Overall Study Schematic Diagram 
See new wording column. 
Figure 2 was modified as described below. 
• 
Added a note to indicate the figure only applies to 
patients randomized as of Amendment 03 with 
Revision 01. Patients randomized prior to Amendment 
03 with Revision 01 will continue to receive the same 
dose, volume, and rate of administration of the IMP to 
which they were initially randomized and will remain 
blinded. 
• 
Clarified that all patients randomized in this study may 
enroll in the long-term extension study. 
• 
Revised the duration of follow-up window from 
±14 days to ±3 days. 
• 
Clarification. 
- Patients 
randomized prior 
to Amendment 03 
with Revision 01 
will continue to 
receive the dose 
(including volume, 
rate, and duration) 
of IMP to which 
they were initially 
randomized to not 
disrupt potential 
response to 
treatment and 
maintain the 
integrity of the 
study (eg, blinding 
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Reason/Justification for 
change 
concerns and data 
analysis). 
- All patients 
randomized in this 
study may be 
eligible for 
enrollment in the 
long-term 
extension study. 
• 
To provide a 
uniform variation 
of visits throughout 
the study, the 
follow-up window 
duration was 
updated to ±3 days. 
Section 3.2 Planned Number of Patients and Countries 
Approximately 480 patients will be screened to achieve 
approximately 240 randomized patients (approximately 
120 patients with UC and 120 patients with CD). The sample 
size does not include patients that were randomized to the 
1800 mg treatment group prior to Amendment 03 with 
Revision 01. 
The study is planned to be conducted in North America the 
United States of America (USA), Europe, Africa, and Asia in 
approximately 100 200 investigational centers. The study is 
expected to start in Q3 2022 and last until approximately Q3 
2024. 
Approximately 480 patients will be screened to achieve 
approximately 240 randomized patients (approximately 
120 patients with UC and 120 patients with CD). The sample 
size does not include patients that were randomized to the 
1800 mg treatment group prior to Amendment 03 with 
Revision 01. 
The study is planned to be conducted in North America, 
Europe, Africa, and Asia in approximately 200 investigational 
centers. The study is expected to start in Q3 2022 and last until 
approximately Q3 2024. 
Clarification. 
• 
The planned total 
study sample size 
does not include 
patients 
randomized to the 
1800 mg treatment 
group.  
• 
Revised USA to 
North America for 
consistency of 
continental regions. 
• 
Added Africa to 
the list of regions 
where the study is 
being conducted. 
• 
Updated the 
estimated number 
of investigational 
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centers 
participating in this 
study from 100 to 
200. 
Section 3.5 Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are 
presented in Table14. Detailed descriptions of each method of 
procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 
(pharmacokinetic and other assessments). Study procedures and 
assessments by visit are listed in Appendix B. 
Exclusionary laboratory values can be retested once during 
the screening period. If the retested laboratory value(s) 
remain(s) exclusionary, the subject will be considered a screen 
failure. Redrawing samples if previous samples were unable to 
be analyzed would not count as a retest since previous result 
was never obtained. 
Study procedures and assessments with their time points are 
presented in Table14. Detailed descriptions of each method of 
procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 
(pharmacokinetic and other assessments). Study procedures and 
assessments by visit are listed in Appendix B. 
Exclusionary laboratory values can be retested once during the 
screening period. If the retested laboratory value(s) remain(s) 
exclusionary, the subject will be considered a screen failure. 
Redrawing samples if previous samples were unable to be 
analyzed would not count as a retest since previous result was 
never obtained. 
Clarification. 
Section 3.5 Schedule of Study Procedures and Assessments, Table 1 
See new wording column. 
Table 1 Study Procedures and Assessments was modified as 
follows: 
• 
Added biomarker 
 collections at weeks 0, 2, 8, 
14, and early termination. 
• 
Revised the duration of follow-up window from 
±14 days to ±3 days. 
• 
Removed the assessment of COVID-19 symptoms 
inquiry from all visits. 
• 
Specified stool samples may be collected for other 
stool-derived markers at weeks 0, 2, 4, 8, 14, 18 and 
early termination. 
• 
Added urine pregnancy testing at weeks 2, 6, and 10. 
• 
Footnote a updated to clarify all patients in this study 
may enroll in the long-term extension study and to 
revise the duration of the follow-up window from ±14 
• 
 collection 
added for better 
evaluation of target 
engagement, PD, 
and mechanism of 
action. 
• 
To provide a 
uniform variation 
of visits throughout 
the study, the 
follow-up window 
duration was 
updated to ±3 days. 
• 
Experience of the 
current stage of the 
pandemic does not 
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days to ±3 days. 
• 
Footnote e was deleted since assessment of 
COVID-19 symptoms inquiry removed from all visits; 
subsequent footnotes were renumbered. 
• 
Footnote h updated to define baseline (ie, last 
screening visit prior to randomization) for PRO2, 
rectal bleeding and stool frequency for UC and stool 
frequency and abdominal pain for CD. 
• 
Footnote l updated to clarify the hematocrit value 
measured at screening will be used to calculate the 
baseline CDAI score. 
• 
Footnote s updated to revise the duration of the 
follow-up window from ±14 days to ±3 days. 
• 
Footnote t updated to revise the duration of the follow-
up window from ±14 days to ±3 days. 
support the 
contingent 
restrictions of 
COVID-19. 
• 
Clarification.  
- All patients 
randomized in this 
study may be 
eligible for 
enrollment in the 
long-term 
extension study. 
- Specified the 
definition of 
baseline for PRO2. 
- Specified the 
hematocrit value 
measured at 
screening will be 
used to calculate 
the baseline CDAI 
score. 
• 
Other fecal 
biomarkers may be 
investigated to 
study the treatment 
effect of 
TEV-48574. 
• 
Urine pregnancy 
test added to visits 
2, 4, and 6 to align 
with IMP 
administration 
every 2 weeks. 
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Section 4.2 Patient Exclusion Criteria 
Criterion l 
Absolute neutrophil count <1.5x109/L or Hemoglobin <89 g/dL 
or  
lymphocyte count <0.8x109/L or platelet count <100,000/mL  
Criterion l 
Absolute neutrophil count <1.5x109/L or Hemoglobin <9 g/dL 
or  
lymphocyte count <0.8x109/L or platelet count <100,000/mL  
Correction. 
Criterion n 
Patients with confirmed infection with COVID 19 within 
6 weeks prior to the screening visit, or with residual COVID 19 
symptoms (“long COVID 19”). Patients with active 
documented or suspected COVID 19 infection within 4 weeks 
of randomization or asymptomatic positive severe acute 
respiratory syndrome coronavirus 2 (SARS CoV 2) polymerase 
chain reaction (PCR) test within 2 weeks of randomization are 
excluded. Any acute infection which in the opinion of the 
investigator compromises the safety of the patient. 
Criterion n 
Any acute infection which in the opinion of the investigator 
compromises the safety of the patient. 
Experience of the current 
stage of the pandemic does 
not support the contingent 
restrictions of COVID-19. 
Section 4.6 Screening Failure 
Screen failure occurs when a patient who consents to participate 
in the clinical study is not subsequently randomized into the 
study because that patient did not meet the inclusion criteria or 
did meet the exclusion criteria. Patients will be allowed to 
screen fail twice before no longer being considered for 
enrollment in the clinical study. 
… 
Screen failure occurs when a patient who consents to 
participate in the clinical study is not subsequently randomized 
into the study because that patient did not meet the inclusion 
criteria or did meet the exclusion criteria. 
… 
Correction.  
Section 5.1 Investigational Medicinal Products Used in the Study 
An IMP is defined as the test IMP (TEV-48574) and matching 
placebo IMP to the test IMP. 
For patients randomized prior to Amendment 03 with Revision 
01: 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 
12 mL induction dose volume) and will be administered as 
single sc administrations. 
An IMP is defined as the test IMP (TEV-48574) and matching 
placebo IMP to the test IMP. 
For patients randomized prior to Amendment 03 with Revision 
01: 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 
12 mL induction dose volume) and will be administered as 
single sc administrations. 
Clarification.  
• 
Twelve (12) mL is 
the induction dose 
volume associated 
with the 1800 mg 
dose and has a 
24-minute infusion 
duration; therefore, 
all patients 
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Active IMP will be diluted with placebo to achieve the final 
delivered concentrations. Patients will receive the following 
regimens as a single sc administration Q2W using the 
 
, 
 
 
• 
TEV-48574 2250 mg (single loading dose)/1800 mg (6 
induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/900 mg 
(6 induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/450 mg 
(6 induction doses) 
• 
Placebo to match TEV-48574 (single loading 
dose)/(Induction doses) 
For patients randomized as of Amendment 03 03 with 
Revision 01: 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 
6 mL induction dose volume) and will be administered as single 
sc administrations. 
… 
Active IMP will be diluted with placebo to achieve the final 
delivered concentrations. Patients will receive the following 
regimens as a single sc administration Q2W using the 
 
, 
 
 
• 
TEV-48574 2250 mg (single loading dose)/1800 mg 
(6 induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/900 mg (6 
induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/450 mg (6 
induction doses) 
• 
Placebo to match TEV-48574 (single loading 
dose)/(Induction doses) 
For patients randomized as of Amendment 03 with Revision 
01: 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 
6 mL induction dose volume) and will be administered as 
single sc administrations. 
… 
randomized prior 
to Amendment 03 
with Revision 01 
(doses of 
2250/1800 mg, 
2250/900 mg, 
2250/450 mg, or 
placebo) will 
continue to receive 
the 12 mL 
induction volume 
over 24 minutes to 
maintain study 
blind.  
• 
Six (6) mL is the 
induction dose 
volume associated 
with the 900 mg 
dose and has a 
12-minute infusion 
duration; therefore, 
all patients 
randomized as of 
Amendment 03 
with Revision 01 
will receive the 
6 mL induction 
volume over 
12 minutes to 
maintain study 
blind. 
Section 5.1.3 Test and Placebo Investigational Medicinal Product Administration 
… 
The infusion rate is fixed at 30 mL/hr for all sc infusions. 
For patients randomized prior to Amendment 03 03 with 
… 
The infusion rate is fixed at 30 mL/hr for all sc infusions. 
For patients randomized prior to Amendment 03 with Revision 
Clarification. 
• 
Twelve (12) mL is 
the induction dose 
volume associated 
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Revision 01: 
The expected infusion durations will therefore be 30 minutes 
for the 15 mL loading dose and 24 minutes for the 12 mL 
induction doses. 
For patients randomized as of Amendment 03 03 with 
Revision 01: 
The expected infusion durations will therefore be 30 minutes for 
the 15 mL loading dose and 12 minutes for the 6 mL induction 
doses. 
… 
01: 
The expected infusion durations will therefore be 30 minutes 
for the 15 mL loading dose and 24 minutes for the 12 mL 
induction doses. 
For patients randomized as of Amendment 03 with Revision 
01: 
The expected infusion durations will therefore be 30 minutes 
for the 15 mL loading dose and 12 minutes for the 6 mL 
induction doses. 
… 
with the 1800 mg 
dose and has a 
24-minute infusion 
duration; therefore, 
all patients 
randomized prior 
to Amendment 03 
with Revision 01 
(doses of 
2250/1800 mg, 
2250/900 mg, 
2250/450 mg, or 
placebo) will 
continue to receive 
the 12 mL 
induction volume 
over 24 minutes to 
maintain study 
blind. 
• 
Six (6) mL is the 
induction dose 
volume associated 
with the 900 mg 
dose and has a 
12-minute infusion 
duration; therefore, 
all patients 
randomized as of 
Amendment 03 
with Revision 01 
will receive the 
6 mL induction 
volume over 
12 minutes to 
maintain study 
blind. 
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Section 5.3.1 Justification for Dose of Test Investigational Medicinal Product 
See new wording column. 
This text in this section was deleted and replaced as follows: 
The justification listed herein refers to the study doses 
introduced in Amendment 03 with Revision 01 of the study 
protocol. In this study as of Amendment 03 with Revision 01, 
TEV-48574 will be administered as a single loading dose of 
2250 mg followed by induction doses of 450 or 900 mg sc 
Q2W, for a total of 7 doses. Patients randomized prior to 
Amendment 03 with Revision 01 will continue to receive the 
dose (including volume, rate, and duration) of IMP to which 
they were initially randomized to not disrupt potential response 
to treatment and maintain the integrity of the study (eg, 
blinding concerns and data analysis). 
… 
Removal of the 1800 mg 
Q2W treatment arm. 
Section 5.4 Treatment After the End of the Study 
After the end of the 14-week treatment period, all patients may 
be offered the option to enter a long-term extension study (to be 
described in a separate protocol [TV48574-IMM-20038]). 
After the end of the 14-week treatment period, all patients may 
be offered the option to enter a long-term extension study (to be 
described in a separate protocol [TV48574-IMM-20038]). 
Clarification.  
All patients randomized in 
this study may be eligible 
for enrollment in the long-
term extension study. 
Section 5.6.1 Prior Medications 
All prior medications for IBD will be recorded in the source 
documentation and in the CRF. Any other prior or 
concomitant therapy, medication (including nonprescription 
drugs, vitamins, and dietary or herbal supplements), or 
procedure a patient has had 4 weeks before screening through 
the end of the study will be recorded in the source 
documentation and in the CRF. 
… 
All prior medications for IBD will be recorded in the source 
documentation and in the CRF. Any other prior therapy, 
medication (including nonprescription drugs, vitamins, and 
dietary or herbal supplements), or procedure a patient has had 4 
weeks before screening through the end of the study will be 
recorded in the source documentation and in the CRF.  
… 
Clarification. 
All prior medications for 
IBD will be captured in the 
source documentation and 
CRF. 
Section 5.8 Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. 
Patients who meet all the inclusion criteria and none of the 
This is a randomized, double-blind, placebo-controlled study. 
Patients who meet all the inclusion criteria and none of the 
Clarification. 
• 
Patients 
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exclusion criteria will be randomly assigned to receive 
TEV-48574 (single loading dose/6 induction doses): 
2250/900 mg, 2250/450 mg, or placebo to match TEV-48574, in 
a 1:1:1 ratio, stratified by diagnosis (UC or CD) and previous 
exposure to advanced therapy for IBD (yes/no) (biologics, JAK 
inhibitors, and S1P receptor modulators). 
Prior to Amendment 03 with Revision 01, patients were 
randomly assigned to receive 1 of 4 treatment regimens 
(2250/1800 mg, 2250/900 mg, 2250/450 mg, or placebo to 
match TEV-48574); these patients will continue to receive the 
same dose, volume, and rate of administration of the IMP to 
which they were initially randomized and will remain blinded. 
Approximately 120 UC patients and 120 CD patients will be 
randomly assigned to the treatment groups by means of a 
computer-generated randomization list using interactive-
response technology. The specifications for randomization will 
be under the responsibility and oversight of Teva Global 
Statistics. 
The patients and the site will be blinded until all patients 
complete the study, and the database is locked for final analysis 
for both indications. The sponsor will be blinded to treatment 
assignment until the database is locked for analysis of each 
indication. Prior to unblinding, the sponsor will establish a 
separate blinded study team supporting the conduct of the study 
until the database is locked for final analysis for both 
indications. 
… 
exclusion criteria will be randomly assigned to receive 
TEV-48574 (single loading dose/6 induction doses): 
2250/900 mg, 2250/450 mg, or placebo to match TEV-48574, 
in a 1:1:1 ratio, stratified by diagnosis (UC or CD) and previous 
exposure to advanced therapy for IBD (yes/no) (biologics, JAK 
inhibitors, and S1P receptor modulators). 
Prior to Amendment 03 with Revision 01, patients were 
randomly assigned to receive 1 of 4 treatment regimens 
(2250/1800 mg, 2250/900 mg, 2250/450 mg, or placebo to 
match TEV-48574); these patients will continue to receive the 
same dose, volume, and rate of administration of the IMP to 
which they were initially randomized and will remain blinded. 
Approximately 120 UC patients and 120 CD patients will be 
randomly assigned to the treatment groups by means of a 
computer-generated randomization list using interactive-
response technology. The specifications for randomization will 
be under the responsibility and oversight of Teva Global 
Statistics. 
… 
randomized prior 
to Amendment 03 
with Revision 01 
will continue to 
receive the dose 
(including volume, 
rate, and duration) 
of IMP to which 
they were initially 
randomized to not 
disrupt potential 
response to 
treatment and 
maintain the 
integrity of the 
study (eg, blinding 
concerns and data 
analysis). 
• 
Specifications of 
blinding moved to 
Section 5.9.2 
(Blinding and 
Unblinding). 
Section 5.9.1 Maintenance of Randomization 
 
 
Patient randomization codes will be securely maintained in a 
secure location at by the service provider contracted to generate 
the codes. At the time of analysis (interim analysis and after the 
end of study), after receiving unblinding request from Teva 
statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant 
Standard Operating Procedure (SOP). 
Patient randomization codes will be securely maintained by the 
service provider contracted to generate the codes. At the time 
of analysis (interim analysis and after the end of study), after 
receiving unblinding request from Teva statistician, the service 
provider will provide the unblinded IMP assignment according 
to the processes defined in the relevant Standard Operating 
Procedure (SOP). 
Clarification. 
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Section 5.9.2 Blinding and Unblinding 
For information about pPersonnel who may be aware of IMP 
assignments, see Section 5.8. These individuals will not be 
involved in the conduct of any study procedures or assessment 
of any adverse events. 
The patients and the site will be blinded until all patients 
complete the study, and the database is locked for final 
analysis for both indications. The sponsor study team will be 
blinded to treatment assignment until the database is locked 
for analysis of each indication.  
Details regarding unblinding of an independent Teva team 
while maintaining the blind of the study, in case efficacy 
threshold is met at the interim analysis, and in case the final 
analysis is conducted for one indication while the other 
indication is ongoing, will be provided in a separate unblinding 
charter. 
… 
Personnel who may be aware of IMP assignments will not be 
involved in the conduct of any study procedures or assessment 
of any adverse events. 
The patients and the site will be blinded until all patients 
complete the study, and the database is locked for final analysis 
for both indications. The sponsor study team will be blinded to 
treatment assignment until the database is locked for analysis of 
each indication.  
Details regarding unblinding of an independent Teva team 
while maintaining the blind of the study, in case the final 
analysis is conducted for one indication while the other 
indication is ongoing, will be provided in a separate unblinding 
charter. 
… 
Consolidated blinding 
procedures in a single 
section of the protocol. 
Section 5.9.3 Independent Data Monitoring Committee 
A single review committee (IDMC) will be established to 
monitor the study while it is ongoing, including periodic 
reviews of safety data, and pre-specified analyses of efficacy 
data, as described below. 
• 
The IDMC will include 2 Clinicians (external to Teva) 
with expertise in IBD and 1 external Statistician. The 
names of the external IDMC members will be included 
in the IDMC charter. In addition to the IDMC, there 
will be an independent (external to the sponsor and the 
study team) statistical reporting team that will perform 
the planned unblinded analyses of interim efficacy and 
safety data for the IDMC to review. 
• 
The role of the IDMC will be to periodically monitor 
unblinded safety data to ensure the safety of study 
patients as well as efficacy data for pre-specified 
interim analysis, and make recommendations on study 
A single review committee (IDMC) will be established to 
monitor the study while it is ongoing, including periodic 
reviews of safety data, and pre-specified analyses of efficacy 
data, as described below. 
• 
The IDMC will include 2 Clinicians (external to Teva) 
with expertise in IBD and 1 external Statistician. The 
names of the external IDMC members will be 
included in the IDMC charter. 
• 
The role of the IDMC will be to periodically monitor 
unblinded safety data to ensure the safety of study 
patients as well as efficacy data for pre-specified 
interim analysis, and make recommendations on study 
conduct. 
• 
There will be an independent (external to the sponsor 
and the study team) statistical reporting team that will 
Clarification.  
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conduct. In addition, the IDMC will review pre
specified analyses of efficacy data to make 
recommendations to the sponsor regarding futility or 
the possible acceleration of Phase 3 planning. 
• 
There will be an independent (external to the sponsor 
and the study team) statistical reporting team that will 
perform the planned unblinded analyses of interim 
efficacy and safety data for the IDMC to review. 
… 
perform the planned unblinded analyses of interim 
efficacy and safety data for the IDMC to review. 
… 
Section 5.10 Total Blood Volume 
The estimated maximum blood volume to be collected for each 
patient in this study is approximately 20 mL per visit and 
approximately 240 280 mL for each patient during the entire 
study. Details on blood volumes to be collected during the study 
are provided in the ICF and the Laboratory Manual. 
The estimated maximum blood volume to be collected in this 
study is approximately 280 mL for each patient during the 
entire study. Details on blood volumes to be collected during 
the study are provided in the ICF and the Laboratory Manual. 
Total blood volume was 
increased to account for the 
added biomarker 
 
collections. 
Section 6.1.2.1 Biopsy Collection 
For patients with CD, an ileo-colonoscopy will be performed at 
screening and week 14. During each endoscopy, a total of 16 to 
18 mucosal biopsies will be collected and handled as outlined 
below. Mucosal biopsies will be obtained from the area with the 
greatest inflammation in each segment at screening and at the 
same location at week 14 or early termination. If ulceration is 
present, biopsies should be taken from the edge of the largest 
ulcer. If no ulceration is present, then biopsies should be taken 
from the most affected area of the segment. If the mucosa 
appears normal (eg, at follow-up), then random biopsies of the 
segment should be obtained.  
… 
Ileal (for CD) and multiple colonic tissue sampling will be 
obtained by eEndoscopic biopsies and will be evaluated by 
microscopic and histologic analyses, as well as for exploratory 
measures involving established and novel biomarkers of 
intestinal inflammation and fibrosis. There are several different 
approaches for obtaining these endoscopic biopsy samples, and 
For patients with CD, an ileo-colonoscopy will be performed at 
screening and week 14. During each endoscopy, a total of 16 to 
18 mucosal biopsies will be obtained from the area with the 
greatest inflammation in each segment at screening and at the 
same location at week 14 or early termination. If ulceration is 
present, biopsies should be taken from the edge of the largest 
ulcer. If no ulceration is present, then biopsies should be taken 
from the most affected area of the segment. If the mucosa 
appears normal (eg, at follow-up), then random biopsies of the 
segment should be obtained.  
… 
Endoscopic biopsies and will be evaluated by microscopic and 
histologic analyses, as well as for exploratory measures 
involving established and novel biomarkers of intestinal 
inflammation and fibrosis. There are several different 
approaches for obtaining these endoscopic biopsy samples, and 
the preferred procedures are described in the Laboratory 
Manual and Quick Reference Card. 
Clarification. 
To describe the time of 
obtaining biopsy and its 
location in patients with 
CD. 
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the preferred procedures are described in the Laboratory Manual 
and Quick Reference Card. 
… 
… 
Section 7.3 Pregnancy 
… 
If the pregnancy in the woman participating in the study and/or 
the female partners of men participating in the study does not 
continue to term, 1 of the following actions will be taken: 
• 
For a spontaneous abortion, report as a serious adverse 
event (in addition to the pregnancy form). 
• 
For an elective abortion due to developmental 
anomalies, report as a serious adverse event (in 
addition to the pregnancy form). 
… 
… 
If the pregnancy in the woman participating in the study and/or 
the female partners of men participating in the study does not 
continue to term, 1 of the following actions will be taken: 
• 
For a spontaneous abortion, report as a serious adverse 
event (in addition to the pregnancy form). 
• 
For an elective abortion due to developmental 
anomalies, report as a serious adverse event (in 
addition to the pregnancy form). 
… 
Clarification. 
Section 7.5.1 Serum Chemistry, Hematology, and Urinalysis 
… 
Screening laboratory test abnormalities, if considered by the 
Investigator to be transient and inconsistent with the patient’s 
clinical condition, may be repeated once during the screening 
period for confirmation. Redrawing samples if previous 
samples were unable to be analyzed would not count as a 
retest since previous result was never obtained. 
… 
Screening laboratory test abnormalities, if considered by the 
Investigator to be transient and inconsistent with the patient’s 
clinical condition, may be repeated once during the screening 
period for confirmation. Redrawing samples if previous 
samples were unable to be analyzed would not count as a retest 
since previous result was never obtained. 
Clarification. 
Section 7.5.2 Other Clinical Laboratory Tests 
… 
At screening, patients with clinical symptoms that may indicate 
COVID 19 infection and/or patients who, in the investigator’s 
opinion, were at high risk of exposure to COVID 19 within 
6 weeks before screening or during screening will be tested for 
active COVID 19 infection. Patients who test positive will be 
excluded. COVID 19 testing will be available at the central 
laboratory. Locally performed COVID 19 testing results will 
also be accepted.  
… 
Not applicable; text was deleted. 
,,, 
Experience of the current 
stage of the pandemic does 
not support the contingent 
restrictions of COVID-19. 
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… 
Section 8.4 Assessment of Exploratory Biomarkers 
Potential exploratory biomarker objectives include 
characterization of TEV-48574 responders, identification of 
tissue-, fecal-, and serum blood-based-resident proteomic or 
transcriptomic biomarkers indicative of TEV-48574 mechanism 
of action and pharmacodynamics PD, development of scalable 
tools to identify likely responders in future studies, and 
elucidation of TL1A-mediated pathway(s) that drive IBD in 
responders within the target patient population. 
The following exploratory biomarker assessments will be 
pursued from samples collected at indicated time points (Table 
1): 
• 
Serum free and total TL1A levels will be measured 
using qualified/validated assay methods. Tissue TL1A 
protein expression will also be assessed. 
• 
Serum proteomic markers assertive of 
pharmacodynamics PD and mechanism of action 
effects will be pursued by singleplex or multiplex 
assays. 
 
will be collected and may be analyzed for evaluation 
of target engagement, PD, and mechanism of action. 
… 
• 
Fecal calprotectin or other stool-derived markers as a 
tissue proximal marker of GI inflammation  
… 
Residual biopsy, fecal, and serum blood samples, after 
appropriate analysis to support this study, may be stored at a 
Teva-secured facility for up to 15 years towards future analysis 
related to TEV-48574 or IBD if permitted by the ICF and local 
regulations. 
… 
Potential exploratory biomarker objectives include 
characterization of TEV-48574 responders, identification of 
tissue-, fecal-, and blood-based-resident proteomic or 
transcriptomic biomarkers indicative of TEV-48574 
mechanism of action and PD, development of scalable tools to 
identify likely responders in future studies, and elucidation of 
TL1A-mediated pathway(s) that drive IBD in responders within 
the target patient population. 
The following exploratory biomarker assessments will be 
pursued from samples collected at indicated time points (Table 
1): 
• 
Serum free and total TL1A levels will be measured 
using qualified/validated assay methods. Tissue TL1A 
protein expression will also be assessed. 
• 
Serum proteomic markers assertive of PD and 
mechanism of action effects will be pursued by 
singleplex or multiplex assays. 
 
will be collected and may 
be analyzed for evaluation of target engagement, PD, 
and mechanism of action. 
… 
• 
Fecal calprotectin or other stool-derived markers as a 
tissue proximal marker of GI inflammation  
… 
Residual biopsy, fecal, and blood samples, after appropriate 
analysis to support this study, may be stored at a Teva-secured 
facility for up to 15 years towards future analysis related to 
TEV-48574 or IBD if permitted by the ICF and local 
regulations. 
… 
• 
The biomarker 
 was added 
for better 
evaluation of target 
engagement, PD, 
and mechanism of 
action. 
• 
Other fecal 
biomarkers may be 
investigated to 
study the treatment 
effect of 
TEV48574. 
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Original text with changes shown 
New wording 
Reason/Justification for 
change 
Section 9.1 Sample Size and Power Calculations 
A total study sample size of 240 patients is planned, with 
120 patients (40 patients per dose arm) each for the 
2 indications of UC and CD. 
The sample size does not include patients that were 
randomized to the 1800 mg treatment group prior to 
Amendment 03 with Revision 01. 
… 
Simulation-based operating characteristics for the analysis of 
the primary efficacy variable using a Bayesian Beta Binomial 
model are presented in Table 10. This model uses a posterior 
probability cutoff of <0.55 <0.30 for the assessment of futility at 
the interim analysis and a posterior probability cutoff of ≥0.90 
to declare success at the final analysis.  
For UC, the family-wise false-positive rate (ie, probability of 
making at least 1 false-positive conclusion under the null 
assumption for both doses) is 13%, and the probability of 
declaring success for at least 1 dose group is 97% 98%, under 
the assumptions above.  
For CD, the family-wise false-positive rate is 15% 16%, and the 
probability of declaring success for at least 1 dose is 95%, under 
the assumptions above. 
… 
Under a less optimistic scenario where the placebo response 
rates remain the same while the clinical remission rate in the UC 
indication is reduced to 20% for both doses, and the endoscopic 
response rate in the CD indication is reduced to 25% for both 
doses, the probability of declaring success in at least 1 dose is 
75% 77% for UC and 74% 76% for CD. 
… 
A total study sample size of 240 patients is planned, with 
120 patients (40 patients per dose arm) each for the 
2 indications of UC and CD. 
The sample size does not include patients that were randomized 
to the 1800 mg treatment group prior to Amendment 03 with 
Revision 01. 
… 
Simulation-based operating characteristics for the analysis of 
the primary efficacy variable using a Bayesian Beta Binomial 
model are presented in Table 10. This model uses a posterior 
probability cutoff of <0.30 for the assessment of futility at the 
interim analysis and a posterior probability cutoff of ≥0.90 to 
declare success at the final analysis.  
For UC, the family-wise false-positive rate (ie, probability of 
making at least 1 false-positive conclusion under the null 
assumption for both doses) is 13%, and the probability of 
declaring success for at least 1 dose group is 98%, under the 
assumptions above.  
For CD, the family-wise false-positive rate is 16%, and the 
probability of declaring success for at least 1 dose is 95%, 
under the assumptions above. 
… 
Under a less optimistic scenario where the placebo response 
rates remain the same while the clinical remission rate in the 
UC indication is reduced to 20% for both doses, and the 
endoscopic response rate in the CD indication is reduced to 
25% for both doses, the probability of declaring success in at 
least 1 dose is 77% for UC and 76% for CD. 
… 
• 
Clarification. 
The planned total 
study sample size 
does not include 
patients 
randomized to the 
1800 mg treatment 
group. 
• 
The cutoff for the 
interim assessment 
of futility was 
reduced to align 
with priorities of 
the business to 
minimize the risk 
of falsely stopping 
an effective 
compound at the 
interim analysis. 
Table 10 (Operating Characteristics of Interim and Final 
Analysis) 
See new wording column. 
Table 10 (Operating Characteristics of Interim and Final 
Analysis) was revised as described below: 
• 
Simulations updated based on updated futility cutoff 
and number of expected evaluable patients for the 
The operating 
characteristics were revised 
based on the updated futility 
cutoff of <0.30 and the 
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New wording 
Reason/Justification for 
change 
interim analysis  
• 
Modified the futility cutoff in the footnotes 
assumed number of 
evaluable patients to be 
included in the interim 
analysis. 
Section 9.5.4 Planned Method of Analysis 
The mITT analysis set (Section 9.2.2) will be used as the 
primary analysis set for all efficacy analyses. Summaries will 
be presented by treatment group, underlying disease, and for all 
patients. 
Note that patients that were randomized to the 1800 mg 
treatment group are excluded from the mITT analysis set. 
Efficacy endpoints for these patients will be analyzed using 
descriptive statistics, in separate summary tables. 
The mITT analysis set (Section 9.2.2) will be used as the 
primary analysis set for all efficacy analyses. Summaries will 
be presented by treatment group, underlying disease, and for all 
patients. 
Note that patients that were randomized to the 1800 mg 
treatment group are excluded from the mITT analysis set. 
Efficacy endpoints for these patients will be analyzed using 
descriptive statistics, in separate summary tables. 
A small number of patients 
had been randomized to the 
1800 mg Q2W treatment 
arm at the time of sponsor 
decision to discontinue 
development of this dose. 
As this number of patients 
will not provide sufficient 
data to test the study 
hypotheses, the 1800 mg 
Q2W treatment arm will be 
summarized descriptively 
and not contribute to the 
primary analysis results of 
the study. 
Section 9.11 Biomarker Analysis 
Exploratory analyses may be undertaken to study the treatment 
effects of TEV-48574 on hsCRP, fecal calprotectin, 
autoantibodies, and other potential TL1A-mediated serum 
blood-based biomarkers. 
… 
Other potential emerging fecal, serum blood-based-resident 
proteomic, and tissue transcriptomic biomarkers reflective of 
pharmacodynamic PD, mechanism of action, and GI tissue 
condition may also be assessed. 
 
will be collected and may be analyzed. 
… 
Exploratory analyses may be undertaken to study the treatment 
effects of TEV-48574 on hsCRP, fecal calprotectin, 
autoantibodies, and other potential TL1A-mediated blood-
based biomarkers. 
… 
Other potential emerging fecal, blood-based-resident 
proteomic, and tissue transcriptomic biomarkers reflective of 
PD, mechanism of action, and GI tissue condition may also be 
assessed. 
 will be 
collected and may be analyzed. 
… 
• 
Clarification.  
Other potential 
exploratory fecal 
biomarkers may be 
assessed. 
• 
 collection 
added for better 
evaluation of target 
engagement, PD, 
and mechanism of 
action. 
Section 9.13. Planned Interim Analysis 
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Original text with changes shown 
New wording 
Reason/Justification for 
change 
Interim analyses for safety and efficacy are planned for this 
study. An interim efficacy/futility analysis is planned in each 
indication (UC and CD) when at least approximately 50% of 
patients in the indication have completed the 14-week primary 
efficacy readout time point or had the opportunity to do so. This 
is expected to yield approximately 20 evaluable patients per 
treatment group for each indication in the interim analysis. 
In the interim analysis, the same Bayesian Beta-Binomial model 
described in the primary analysis model will be used to analyze 
the primary efficacy response variable for each dose within each 
indication. The futility criterion for each dose is: 
Posterior probability (TEV-48574 response rate – placebo 
response rate > 0) <0.55 <0.30 
… 
In addition to futility, efficacy criteria, which is nonbinding, 
will be incorporated for the purpose of internal decision making 
and planning purposes for further development planning. The 
criteria are non binding, purely for purposes of accelerating 
planning for subsequent trials, and will not trigger any 
recommendations on trial conduct. Details of the efficacy 
criteria will be provided in the Statistical Analysis Plan. 
… 
Interim analyses for safety and efficacy are planned for this 
study. An interim efficacy/futility analysis is planned in each 
indication (UC and CD) when approximately 50% of patients 
in the indication have completed the 14-week primary efficacy 
readout time point or had the opportunity to do so. This is 
expected to yield approximately 20 evaluable patients per 
treatment group for each indication in the interim analysis. 
In the interim analysis, the same Bayesian Beta-Binomial 
model described in the primary analysis model will be used to 
analyze the primary efficacy response variable for each dose 
within each indication. The futility criterion for each dose is: 
Posterior probability (TEV-48574 response rate – placebo 
response rate >0) <0.30 
… 
In addition to futility, efficacy criteria, which is nonbinding, 
will be incorporated for the purpose of internal decision making 
for further development planning. Details of the efficacy 
criteria will be provided in the Statistical Analysis Plan. 
… 
• 
Clarification. 
- The timing of the 
interim 
efficacy/futility 
analysis is at 
approximately 50% 
for each indication. 
- The interim 
efficacy criteria are 
considered 
nonbinding. 
• 
The cutoff for the 
interim assessment 
of futility was 
reduced to align 
with priorities of 
the business to 
minimize the risk 
of falsely stopping 
an effective 
compound at the 
interim analysis. 
Section 15 References 
See new wording column. 
The following references were added: 
• 
Sands B, Peyrin-Biroulet L, Danese S, Rubin DT, 
Vermeire S, Laurent O, et al. PRA03 Demonstrated 
Efficacy and Favorable Safety as Induction Therapy 
for Moderately to Severely Active UC: Phase 2 
ARTEMIS-UC Study Results [abstract]. J Crohns 
Colitis 2023;17:i56-i59. 
• 
Wenxiu J, Mingyue Y, Fei H, Yuxin L, Mengyao W, 
Chenyang L, et al. Effect and Mechanism of TL1A 
Expression on Epithelial-Mesenchymal Transition 
during Chronic Colitis-Related Intestinal Fibrosis. 
• 
Added references 
as used source of 
information in 
support of the 
proposed study. 
• 
Deleted literature 
references that are 
no longer 
applicable to 
support the study. 
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Original text with changes shown 
New wording 
Reason/Justification for 
change 
Mediators Inflamm 2021;5927064. 
The following references were deleted: 
• 
Back I, Marcon S, Gaino N, Vulcano D, Dorna M, 
Sassaki L. Body composition in patients with Crohn’s 
disease and ulcerative colitis. Arq Gastroenterol 
2017;54(2):109-114. 
• 
Dirks N, Meibohm B. Population pharmacokinetics of 
therapeutic monoclonal antibodies. Clin 
Pharmacokinet 2010;49:633-59. 
• 
Dong J, Chen Y, Tang Y, Xu F, Yu C, Li Y et al. 
Body mass index is associated with inflammatory 
bowel disease: a systematic review and meta-analysis. 
PLoS ONE 2015;10(12): e0144872. 
• 
Fasanmade AA, Adedokun OJ, Ford J, Hernandez D, 
Johanns J, Hu C, et al. Population pharmacokinetic 
analysis of infliximab in patients with ulcerative 
colitis. Eur J Clin Pharmacol 2009;65:1211–28. 
• 
Flores A, Burstein E, Cipher DJ, Feagins LA. Obesity 
in inflammatory bowel disease: a marker of less severe 
disease. Dig Dis Sci 2015;60:2436–45. 
• 
Johnson AM, Harmsen WS, Aniwan S, Tremaine WJ, 
Abu Dayyeh BK, Loftus EV. Prevalence and impact 
of obesity on disease-specific outcomes in a 
population-based cohort of patients with ulcerative 
colitis. J Crohn’s Colitis 2021;15(11):1816-23.. 
• 
Kapel N, Meillet D, Favennec L, Magne D, Raichvarg 
D, Gobert JG. Evaluation of intestinal clearance and 
faecal excretion of alpha 1-antiproteinase and 
immunoglobulins during Crohn’s disease and 
ulcerative colitis. Eur J Clin Chem Clin 1992;30:197–
202. 
• 
Lobo ED, Hansen RJ, Balthasar JP. Antibody 
pharmacokinetics and pharmacodynamics. J Pharm 
Sci 2004;93(11):2645-68.  
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Original text with changes shown 
New wording 
Reason/Justification for 
change 
• 
Mascelli MA, Zhou H, Sweet R, Getsy J, Davis HM, 
Graham M, et al. Molecular, biologic, and 
pharmacokinetic properties of monoclonal antibodies: 
impact of these parameters on early clinical 
development. J Clin Pharmacol 2007;47(5):553-65.  
• 
Neelakantan S, Martin SW, Li G, Hung K, Chandra 
DE, Rath N, et al. Population 
pharmacokinetic/pharmacodynamic modeling of PF-
06480605, an anti-TL1A antibody, in healthy subjects 
and ulcerative colitis patients [poster abstract]. 
Presented at Population Approach Group Europe 
(PAGE) 2019 meeting; June 11-14, 2019; Stockholm, 
Sweden [Abstract published online]. 
• 
Nic Suibhne T, Raftery TC, McMahon O, Walsh C, 
O’Morain C, O’Sullivan M. High prevalence of 
overweight and obesity in adults with Crohn’s disease: 
associations with disease and lifestyle factors. J 
Crohn’s Colitis 2013;7(7):e241–e248. 
• 
Singh S, Dulai PS, Zarrinpar A, Ramamoorthy S, 
Sandborn WJ. Obesity in IBD: epidemiology, 
pathogenesis, disease course and treatment outcomes. 
Nat Rev Gastroenterol Hepatol 2017;14:110–21. 
• 
GUIDANCE ON THE MANAGEMENT OF 
CLINICAL TRIALS DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC Version 4, 
04/02/2021. Available at: 
https://ec.europa.eu/health/sites/health/files/files/eudra
lex/vol-10/guidanceclinicaltrials_covid19_en.pdf 
Appendix B. Study Procedures and Assessments by Visit 
1. Procedures for Screening (week -6 to week -1, days -42 to -1) 
• 
coronavirus disease 2019 (COVID-19) symptoms 
inquiry 
 
2. Procedures During Administration of Investigational 
1. Procedures for Screening (week -6 to week -1, days -42 
to -1) 
• 
NA; text for COVID-19 inquiry was deleted 
 
2. Procedures During Administration of Investigational 
• 
Experience of the 
current stage of the 
pandemic does not 
support the 
contingent 
restrictions of 
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New wording 
Reason/Justification for 
change 
Medicinal Product (Double-Blind Treatment Period) 
a. Visit 1 (week 0, day 1) 
• 
COVID-19 symptoms inquiry 
• 
Stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
• 
biomarker 
 
 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 
([±3 days based on previous visit]) 
• 
COVID-19 symptoms inquiry 
• 
pregnancy test (urine) in women of childbearing 
potential) 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers (visit 2 only) 
• 
biomarker 
(visit 2 only) 
 
c. Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 
([±3 days based on previous visit]) 
• 
COVID-19 symptoms inquiry 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers (visits 3 and 5 only) 
• 
biomarker 
 (visit 5 only) 
 
d. Visit 8 (week 14, day 99 [±3 days based on previous visit]) 
• 
COVID 19 symptoms inquiry 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
• 
biomarker 
 
 
3. Follow-up (visit 9, week 18, day 127 [±14 3 days based on 
previous visit]) 
Medicinal Product (Double-Blind Treatment Period) 
a. Visit 1 (week 0, day 1) 
• 
NA; text for COVID-19 inquiry was deleted 
• 
Stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
• 
biomarker 
 
 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 
([±3 days based on previous visit]) 
• 
NA; text for COVID-19 inquiry was deleted 
• 
pregnancy test (urine) in women of childbearing 
potential) 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers (visit 2 only) 
• 
biomarker 
 (visit 2 only) 
 
c. Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 
([±3 days based on previous visit]) 
• 
NA; text for COVID-19 inquiry was deleted 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers (visits 3 and 5 only) 
• 
biomarker 
 (visit 5 only) 
 
d. Visit 8 (week 14, day 99 [±3 days based on previous visit]) 
• 
NA; text for COVID-19 inquiry was deleted 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
• 
biomarker 
 
 
3. Follow-up (visit 9, week 18, day 127 [±3 days based on 
previous visit]) 
COVID19. 
• 
Urine pregnancy 
test added to visits 
2, 4, and 6 to align 
with IMP 
administration 
every 2 weeks. 
• 
collection 
added for better 
evaluation of target 
engagement, PD, 
and mechanism of 
action. 
• 
Other fecal 
biomarkers may be 
investigated to 
study the treatment 
effect of 
TEV48574. 
• 
To provide a 
uniform variation 
of visits throughout 
the study, the 
followup window 
duration was 
updated to ±3 days. 
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New wording 
Reason/Justification for 
change 
• 
COVID-19 symptoms inquiry 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
• 
NA; text for COVID-19 inquiry was deleted 
• 
stool sample for fecal calprotectin (FeCal) or other 
stool-derived markers 
Appendix C. Quality Control and Quality Assurance 
… 
Study Monitoring 
… 
In case of an emergency situation (eg, the COVID-19 
pandemic), where trial monitors may not be able to access the 
investigational centers for on-site visits, investigational centers 
will be monitored remotely, where allowed, and in accordance 
with global and/or local regulations. 
… 
Audit and Inspection 
… 
The investigator must accept that competent authorities and 
sponsor representatives may conduct inspections and audits to 
verify compliance with GCP guidelines. 
In case of an emergency situation (eg, the COVID-19 
pandemic), where auditors may not be able to access the 
investigational centers for on-site visits, investigational centers 
will be audited remotely, where allowed, and in accordance 
with global and/or local regulations. 
… 
Study Monitoring 
… 
In case of an emergency situation (eg, the COVID-19 
pandemic), where trial monitors may not be able to access the 
investigational centers for on-site visits, investigational centers 
will be monitored remotely, where allowed, and in accordance 
with global and/or local regulations. 
… 
Audit and Inspection 
… 
The investigator must accept that competent authorities and 
sponsor representatives may conduct inspections and audits to 
verify compliance with GCP guidelines. 
In case of an emergency situation (eg, the COVID-19 
pandemic), where auditors may not be able to access the 
investigational centers for on-site visits, investigational centers 
will be audited remotely, where allowed, and in accordance 
with global and/or local regulations. 
Clarification. 
The procedures related to 
emergency situations of 
monitoring and site audits 
were originally included in 
Appendix K. With the 
deletion of Appendix K, 
these details were moved to 
Appendix C. 
Appendix K. Management of Study Activities During COVID-19 Outbreaks 
See new wording column. 
Not applicable. Appendix K was deleted and subsequent 
appendices were renumbered, as applicable. 
Experience of the current 
stage of the pandemic does 
not support the contingent 
restrictions of COVID-19. 
Appendix M. Operating Characteristics and Assumptions for Final and Interim Analysis 
… 
Number of Patients at the Interim Analysis: 
… 
Number of Patients at the Interim Analysis: 
• 
Clarification.  
The timing of the 
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Reason/Justification for 
change 
The interim analysis for each indication is planned when at least 
approximately 50% of patients in the indication have completed 
the 14-week primary efficacy readout or had the opportunity to 
do so. Operating characteristics were obtained from simulations 
assuming that exactly 21 20 patients per arm in the 
corresponding indication will be included in the interim 
analysis. Since the analysis is separate for each indication, no 
assumptions on the expected difference in recruitment rate 
between UC and CD are required. 
… 
Statistical Futility Cutoff – Interim Analysis: 
The same Bayesian Beta-Binomial model described in the 
primary analysis model will be used for the interim futility 
analysis for each dose within each indication. A TEV-48574 
dose will be declared futile at the interim analysis if the 
posterior probability that the response rate in the TEV-48574 
dose is higher than the response rate in the placebo arm is <0.55 
<0.30, ie, the futility criterion for each dose within indication is: 
Posterior Probability (TEV-48574 response rate – placebo 
response rate >0) <0.55 <0.30 
… 
These simulations demonstrate that the probability of a false 
positive result is ≤1516% for each indication, while the 
probability of declaring success for at least 1 dose within each 
indication under the efficacy assumption for both doses is 
≥95%.  
The futility threshold was selected to control the probability to 
declare an effective dose to be futile at a maximum of 71%, 
while making the correct decision in the null with a probability 
of at least 60approximately 25%. 
The interim analysis for each indication is planned when 
approximately 50% of patients in the indication have completed 
the 14-week primary efficacy readout or had the opportunity to 
do so. Operating characteristics were obtained from simulations 
assuming that exactly 20 patients per arm in the corresponding 
indication will be included in the interim analysis. Since the 
analysis is separate for each indication, no assumptions on the 
expected difference in recruitment rate between UC and CD are 
required. 
… 
Statistical Futility Cutoff – Interim Analysis: 
The same Bayesian Beta-Binomial model described in the 
primary analysis model will be used for the interim futility 
analysis for each dose within each indication. A TEV-48574 
dose will be declared futile at the interim analysis if the 
posterior probability that the response rate in the TEV-48574 
dose is higher than the response rate in the placebo arm is 
<0.30, ie, the futility criterion for each dose within indication 
is: 
Posterior Probability (TEV-48574 response rate – placebo 
response rate >0) <0.30 
… 
These simulations demonstrate that the probability of a false 
positive result is ≤16% for each indication, while the 
probability of declaring success for at least 1 dose within each 
indication under the efficacy assumption for both doses is 
≥95%.  
The futility threshold was selected to control the probability to 
declare an effective dose to be futile at a maximum of 1%, 
while making the correct decision in the null with a probability 
of approximately 25%. 
interim 
efficacy/futility 
analysis is at 
approximately 50% 
for each indication. 
• 
The cutoff for the 
interim assessment 
of futility was 
reduced to align 
with priorities of 
the business to 
minimize the risk 
of falsely stopping 
an effective 
compound at the 
interim analysis. 
Table 12 (Operating Characteristics of Interim and Final 
Analysis – All Scenarios)  
See new wording column 
Table 12 (Operating Characteristics of Interim and Final 
Analysis – All Scenarios) was revised as described below: 
• 
Simulations updated based on updated futility cutoff 
and number of expected evaluable patients for the 
The operating 
characteristics were revised 
based on the updated futility 
cutoff of <0.30 and the 
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Reason/Justification for 
change 
interim analysis  
• 
Modified the futility cutoff in the footnotes 
assumed number of 
evaluable patients to be 
included in the interim 
analysis. 
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17.5. 
Amendment 03 Dated 28 June 2023  
The protocol was amended for the following reasons:  
• To remove the 1800 mg Q2W treatment arm. Based on recent PD data along with 
pharmacokinetic predictions, the induction dose of 1800 mg Q2W is projected to exceed 
the exposure needed to demonstrate clinical effect and as such is being removed. 
− This reduces the total number of treatment groups to 3 (2 doses of TEV-48574 
[450 and 900 mg Q2W] and placebo). 
− This reduces the induction volume of solution for each IMP dose from 12 mL to 
6 mL, and adjusts the duration time of the 6 mL infusion to 12 minutes. 
• To change the timing of the planned interim analysis to at least 50% of patients per 
indication and add non-binding analysis of efficacy. 
• To amend the primary and secondary objectives to characterize the efficacy instead of 
dose response of TEV-48574 since there are only 2 active treatment arms. 
• To update the primary and supplementary estimands, and the statistical methods and 
analysis sections of the protocol to address revisions to the primary analysis model, 
sample size and operating characteristics. 
• To revise the definition of endoscopic response for the primary CD endpoint as a 
reduction from baseline in SES-CD from “>50%” to “of at least 50%”.  
• To remove the CDAI assessments and analysis at weeks 2, 6, and 10. 
• To clarify the stratification factors for randomization are diagnosis (UC and CD) and 
previous exposure to advanced therapy for IBD. 
• To modify clinical laboratory sample collection as follows: 
− Added a clinical laboratory sample collection at week 12. 
− Clarified screening laboratory tests may be repeated once during the screening period 
at the discretion of the Investigator. 
− Removed lymphocytes atypical as an analyte for clinical laboratory testing. 
− Added local laboratory testing can be used under extenuating circumstances and only 
following agreement with the sponsor. 
• Added a weight measurement at week 14. 
• To correct the total blood volume collected per patient from 200 mL to 240 mL. 
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• To revise study entry criteria as follows: 
− Inclusion criterion g: Amended definition of inadequate response, loss of response, or 
intolerance to treatment to include at least 1 therapy for IBD and no more than 
3 locally approved classes of biologics; included IL-23 class therapy as a locally 
approved classes and biologics; aligned permitted doses of AZA, 6-MP, and 
methotrexate with regional standard of care. 
− Exclusion criterion c: Clarified dysplasia on a completely excised adenomatous polyp 
(not a sessile one) is permitted. 
− Exclusion criterion f: Clarified Hepatitis B and Hepatitis C virus testing procedures at 
screening. 
− Exclusion criterion g: Clarified patients with a positive TB test at screening are 
eligible to participate if documentation of prior TB treatment is available. 
− Exclusion criterion i: Modified to 2 episodes of herpes zoster episodes in the last 
5 years as exclusionary instead of a history of 1 episode. 
− Exclusion criterion k: Clarified that screening or baseline clinical laboratory value for 
ALT or AST should not exceed 2x ULN. 
− Exclusion criterion n: Clarified patients will be excluded from participation into the 
study if confirmed COVID-19 infection within 6 weeks before the screening visit or 
has residual symptoms (“long COVID-19”), within 4 weeks before randomization, or 
within 2 weeks before randomization if asymptomatic PCR test positive. 
− Exclusion criterion r: Included curatively resected papillary thyroid cancer as an 
exception for history of malignancy within the last 5 years. 
− Exclusion criterion s: Added anti-IL-23 as a prohibited biologic if administered 
within 3 half-lives prior to randomization 
− Exclusion criterion u: Clarified informed consent must be provided in written form. 
− Exclusion criterion v: Removed restriction that patients cannot be an employee or an 
immediate relative of an employee of the sponsor or of any of the clinical 
investigational centers participating in the study. 
• To remove COVID-19 infection as a criterion for withdrawal of IMP. 
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc.) have been made to the 
protocol (and protocol synopsis, as appropriate). Table 1 (Study Procedures and Assessments) 
and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect changes described 
below.
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Reason/Justification for change 
Document History 
Amendment 02 (JP 02) (ES 01) 
27 March 2023 
20 patients screened and 10 04 patients randomized to date 
Amendment 02 (JP 02) (ES 01) 
27 March 2023 
20 patients screened and 04 patients randomized to date 
Correction to number of patients 
enrolled as of 27 March 2023. 
Sponsor Protocol Approval 
Sponsor’s Authorized Representative 
 
 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Sponsor’s Authorized Representative 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Transfer of sponsor responsibility. 
Section 1.1.3 TEV-48574 and Inflammatory Bowel Disease 
In both asthma and colitis animal models, TEV-48574 has 
shown anti-inflammatory and anti-fibrotic effects during 
nonclinical studies. 
In colitis animal models, TEV-48574 has shown 
anti-inflammatory and anti-fibrotic effects during 
nonclinical studies. 
Removed reference of asthma 
findings in nonclinical rat models 
as it is not relevant for this study 
in IBD. 
Section 1.1.4 Purpose of Current Study 
The purpose of the study is to determine the pharmacokinetics, 
efficacy, safety, and tolerability of 3 2 different doses regimens 
of TEV-48574 subcutaneously (sc) administered every 2 weeks 
(Q2W) in adult patients with moderate to severe UC or CD 
The purpose of the study is to determine the 
pharmacokinetics, efficacy, safety, and tolerability of 
2 different doses of TEV-48574 subcutaneously (sc) 
administered every 2 weeks (Q2W) in adult patients with 
moderate to severe UC or CD 
Removal of the 1800 mg Q2W 
treatment arm. 
Section 1.3.2 Overall Benefit and Risk Assessment for This Study 
… 
The basket design of this study allows a lower number of 
patients to be studied (as compared to 2 parallel, independent 
studies of UC and CD), further reducing the total exposure in 
this population. 
… 
Not applicable; text was deleted. 
Deleted description of basket 
design as it is not relevant for the 
overall assessment of benefit and 
risk of the study or of TEV-48574 
in patients with IBD. 
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Section 2.1 Primary and Secondary Study Objectives and Endpoints 
The primary objective of the study is to characterize the dose 
response efficacy of TEV-48574 sc administered Q2W and to 
evaluate the efficacy in adult patients with IBD (IBD with 
moderate to severe UC or CD), as assessed by induction of 
clinical remission (UC) and endoscopic response (CD) at week 
14. 
The primary objective of the study is to characterize the 
efficacy of TEV-48574 sc administered Q2W in adult 
patients with IBD (IBD with moderate to severe UC or 
CD), as assessed by induction of clinical remission (UC) 
and endoscopic response (CD) at week 14. 
Removal of the 1800 mg Q2W 
treatment arm. 
Primary endpoint: CD 
Endoscopic response at week 14 in patients with moderate to 
severe CD, defined as a reduction in Simple Endoscopic Score 
for Crohn’s Disease (SES-CD) of > at least 50% from baseline 
Primary endpoint: CD 
Endoscopic response at week 14 in patients with 
moderate to severe CD, defined as a reduction in Simple 
Endoscopic Score for Crohn’s Disease (SES-CD) of at 
least 50% from baseline 
To align with FDA 2022 draft 
guidance “Crohn’s Disease: 
Developing Drugs for Treatment” 
(Apr 2022). 
A secondary objective of the study is to evaluate the efficacy 
and dose response of 3 2 different doses regimens of 
TEV-48574 sc administered Q2W in adult patients with IBD 
(moderate to severe UC or CD) as assessed by multiple 
standard measures at week 14. 
A secondary objective of the study is to evaluate the 
efficacy of 2 different doses of TEV-48574 sc 
administered Q2W in adult patients with IBD (moderate 
to severe UC or CD) as assessed by multiple standard 
measures at week 14. 
Removal of the 1800 mg Q2W 
treatment arm. 
Secondary endpoint: CD 
Clinical response defined as a ≥100-point decrease in Crohn’s 
Disease Activity Index (CDAI) score from baseline at weeks 2, 
4, 6, 8, 10, 12 and 14 
Secondary endpoint: CD 
Clinical response defined as a ≥100-point decrease in 
Crohn’s Disease Activity Index (CDAI) score from 
baseline at weeks 4, 8, 12 and 14 
To reduce patient burden 
associated with additional blood 
draws for the hematocrit 
component of CDAI. 
A secondary objective of the study is to evaluate the safety 
and tolerability of 3 2 different doses regimens of TEV-48574 
sc administered Q2W in adult patients with IBD (moderate to 
severe UC or CD). 
A secondary objective of the study is to evaluate the 
safety and tolerability of 2 different doses of TEV-48574 
sc administered Q2W in adult patients with IBD 
(moderate to severe UC or CD). 
Removal of the 1800 mg Q2W 
treatment arm. 
A secondary objective of the study is to evaluate the 
immunogenicity of 3 2 different doses regimens of TEV-48574 
sc administered Q2W in adult patients with IBD (moderate to 
severe UC or CD). 
A secondary objective of the study is to evaluate the 
immunogenicity of 2 different doses of TEV-48574 sc 
administered Q2W in adult patients with IBD (moderate 
to severe UC or CD). 
Removal of the 1800 mg Q2W 
treatment arm. 
Section 2.1.1 Justification of Primary Endpoints 
… 
… 
To align with FDA 2022 draft 
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The selected primary endpoint for patients with moderate to 
severe CD is endoscopic response, defined as a reduction in 
Simple Endoscopic Score for Crohn’s Disease (SES-CD) of > 
at least 50% from baseline. 
… 
The selected primary endpoint for patients with moderate 
to severe CD is endoscopic response, defined as a 
reduction in Simple Endoscopic Score for Crohn’s 
Disease (SES-CD) of at least 50% from baseline. 
… 
guidance “Crohn’s Disease: 
Developing Drugs for Treatment” 
(Apr 2022). 
Section 2.2 Primary Estimand 
• 
Treatment: In both UC and CD groups indications, 
patients will be randomly assigned to receive any one of 
the study treatment regimens shown below, in a 1:1:1:1 
ratio: 
- 
TEV 48574 2250 mg (single loading dose)/1800 mg 
(6 induction doses) 
- 
TEV-48574 2250 mg (single loading dose)/900 mg (6 
induction doses) 
- 
TEV-48574 2250 mg (single loading dose)/450 mg (6 
induction doses) 
- 
Matching placebo 
• 
Treatment: In both UC and CD indications, patients 
will be randomly assigned to receive any one of the 
study treatment regimens shown below, in a 1:1:1 
ratio: 
- 
TEV-48574 2250 mg (single loading dose)/900 
mg (6 induction doses) 
- 
TEV-48574 2250 mg (single loading dose)/450 
mg (6 induction doses) 
- 
Matching placebo 
Removal of the 1800 mg Q2W 
treatment arm. 
• 
Handling of intercurrent events: Intercurrent events 
addressed here are (a) use of rescue medication; (b) 
important protocol deviations; (c) UC or CD related 
surgery; and (d) treatment discontinuation. These 
intercurrent events will be addressed as follows: (a) 
Patients who used rescue medications prior to their week 
14 evaluation of response (clinical remission in the UC 
group indication and prior to the week 14 evaluation of or 
endoscopic response in the CD group indication) will be 
reported as non-responders, ie, the composite variable 
strategy; (b) Patients experiencing any important protocol 
deviations, namely, use or changes in other medications, 
will be analyzed as if the deviation had not occurred, ie, 
treatment policy strategy; (c) Patients undergoing UC or 
CD related surgery will be treated as non-responders, ie, 
the composite strategy; and (d) Patients discontinuing 
• 
Handling of intercurrent events: Intercurrent 
events addressed here are (a) use of rescue 
medication; (b) important protocol deviations; (c) 
UC or CD related surgery; and (d) treatment 
discontinuation. These intercurrent events will be 
addressed as follows: (a) Patients who used rescue 
medications prior to their week 14 evaluation of 
response (clinical remission in the UC indication or 
endoscopic response in the CD indication) will be 
reported as non-responders, ie, the composite 
variable strategy; (b) Patients experiencing any 
important protocol deviations, namely, use or 
changes in other medications, will be analyzed as if 
the deviation had not occurred, ie, treatment policy 
strategy; (c) Patients undergoing UC or CD related 
surgery will be treated as non-responders, ie, the 
Correction. 
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treatment, regardless of the reason, will be treated as non-
responders, ie, the composite strategy 
composite strategy; and (d) Patients discontinuing 
treatment, regardless of the reason, will be treated as 
non-responders, ie, the composite strategy 
… 
• 
Population-level summary: The population-level 
summary of interest is the quantity Posterior Probability 
(pd,i-p0,i>0) estimated from a Bayesian Beta-Binomial 
model for the response rate (clinical remission rate for 
UC, or endoscopic response rate for CD), pd,i, where 
i=UC, CD and d=0,1,2 represent placebo, TEV-48574 
low dose (450 mg Q2W), and TEV-48574 high dose (900 
mg Q2W), respectively. hierarchical 3 parameter Emax 
model (with E_(0,i),ED_(50,i) and E_(max,i),i=1,2 for 
UC,CD) for the logit of response rate. p_(d,i)  denotes 
either the clinical remission (for UC) or endoscopic 
response rate (for CD) and doses d =0,1,2,3 represent 
placebo, low, mid, and high doses of TEV-48574. 
… 
• 
Population-level summary: The population-level 
summary of interest is the quantity Posterior 
Probability (pd,i-p0,i>0) estimated from a Bayesian 
Beta-Binomial model for the response rate (clinical 
remission rate for UC, or endoscopic response rate 
for CD), pd,i, where i=UC, CD and d=0,1,2 represent 
placebo, TEV-48574 low dose (450 mg Q2W), and 
TEV-48574 high dose (900 mg Q2W), respectively. 
Updated definition of primary 
estimand and corresponding 
analysis methods following the 
removal of the 1800 mg Q2W 
treatment arm and change in the 
primary analysis. 
Section 2.2.1 Supplementary Estimand 
A supplementary analysis using a frequentist logistic 
regression dose response model that incorporates separate 
dose response lines for each patient population (UC and CD) 
will be used in support of the supplementary estimand below.  
The supplementary estimand is defined by the following 
attributes: 
• 
Treatment: same as for the Primary Estimand. 
• 
Target population: same as for the Primary Estimand.  
• 
Variable: same as for the Primary Estimand. 
• 
Handling of intercurrent events: same as for the Primary 
Estimand. 
• 
Population-level summary: The population-level 
summary is difference in response rates of each 
TEV-48574 dose compared to placebo obtained from a 
logistic regression model fit separately to each 
The supplementary estimand is defined by the following 
attributes: 
• 
Treatment: same as for the Primary Estimand. 
• 
Target population: same as for the Primary 
Estimand.  
• 
Variable: same as for the Primary Estimand. 
• 
Handling of intercurrent events: same as for the 
Primary Estimand. 
• 
Population-level summary: The population-level 
summary is difference in response rates of each 
TEV-48574 dose compared to placebo obtained from 
a logistic regression model fit separately to each 
indication, with dose as categorical variable. 
Updated definition of 
supplementary estimand and 
corresponding analysis methods 
following the removal of the 1800 
mg Q2W treatment arm and 
change in the primary analysis. 
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indication, with dose as categorical variable. 
A logistic regression analysis of response at week 14 will be 
performed. The population level summary will be provided by 
the estimated slope terms specific to each patient population 
from this model. 
Section 2.3 Exploratory Objectives and Endpoints 
An exploratory objective of the study is to obtain trough 
serum TEV-48574 concentrations, to compare major 
pharmacokinetic (PK) characteristics between UC and CD 
patients with healthy volunteers and asthma patients, and, if 
data allows, to evaluate the 
pharmacokinetics/pharmacodynamics and/or exposure-
response relationship of 3 2 different doses regimens of 
TEV-48574 sc. 
An exploratory objective of the study is to obtain trough 
serum TEV-48574 concentrations, to compare major 
pharmacokinetic characteristics between UC and CD 
patients with healthy volunteers and asthma patients, and, 
if data allows, to evaluate the 
pharmacokinetics/pharmacodynamics and/or exposure-
response relationship of 2 different doses of TEV-48574 
sc. 
Removal of the 1800 mg Q2W 
treatment arm. 
Section 3.1 General Study Design and Study Schematic Diagram 
This is a Phase 2b, randomized, double-blind, dose-ranging 
study to determine the pharmacokinetics, efficacy, safety, and 
tolerability of TEV-48574 in adult patients with moderate to 
severe UC or CD. The study will enroll adult patients (18 to 75 
years of age, inclusive) of male and female sex (without 
restrictions on gender) with moderate to severe active UC or 
CD and who have demonstrated an inadequate response to, loss 
of response to, or intolerance of to at least 1 of the following 
therapies: agents corticosteroids, immunosuppressants, or an 
advanced therapy for IBD including biologics (anti-TNF, 
anti-integrins, anti-IL-12/23 or anti-IL-23), JAK inhibitors, 
or sphingosine-1-phosphate (S1P) receptor modulators; and 
no more than 3 locally approved classes of biologics.and no 
more than 2 classes of biologics: corticosteroids, 
immunosuppressant drugs, and/or tumor necrosis factor-alpha 
(TNF-α) antagonist therapy, anti-integrins, anti-IL-12/23, JAK 
inhibitors, and/or sphingosine-1-phosphate (S1P) receptor 
modulators (see Section 4.1 for definitions of these terms). 
This is a Phase 2b, randomized, double-blind, dose-
ranging study to determine the pharmacokinetics, 
efficacy, safety, and tolerability of TEV-48574 in adult 
patients with moderate to severe UC or CD. The study 
will enroll adult patients (18 to 75 years of age, inclusive) 
of male and female sex (without restrictions on gender) 
with moderate to severe active UC or CD and who have 
demonstrated an inadequate response to, loss of response 
to, or intolerance to at least 1 of the following therapies: 
corticosteroids, immunosuppressants, or an advanced 
therapy for IBD including biologics (anti-TNF, anti-
integrins, anti-IL-12/23) or anti-IL-23, JAK inhibitors, or 
sphingosine-1-phosphate (S1P) receptor modulators; and 
no more than 3 locally approved classes of biologics. 
• 
Included IL-23 as it is a 
newly approved class for 
treatment for IBD and will 
be considered a similar class 
as the IL-12/23. 
• 
Updated to no more than 3 
classes of biologics to 
potentially increase the 
patient pool for enrollment. 
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Randomization: 
Patients satisfying the eligibility criteria at the end of the 
screening period will be randomized in a 1:1:1:1 ratio 
(stratified by diagnosis [UC or CD] and previous exposure to 
advanced therapy for IBD (yes/no), failure of (biologics, and 
small molecules including JAK inhibitors, and S1P receptor 
modulators for UC) or naive to biologics and small molecule 
therapy) to 1 of 4 3 treatment groups for the double-blind 
treatment period (Table 3). 
Randomization: 
Patients satisfying the eligibility criteria at the end of the 
screening period will be randomized in a 1:1:1 ratio 
(stratified by diagnosis [UC or CD] and previous 
exposure to advanced therapy for IBD (yes/no) 
(biologics, JAK inhibitors, and S1P receptor modulators) 
to 1 of 3 treatment groups for the double-blind treatment 
period (Table 3). 
Clarification. 
Table 3: Randomization Scheme 
See new wording column. 
Table 3 Randomization Scheme was modified as follows: 
• 
Row removed for 1800 mg treatment arm. 
• 
Number of patients to be randomized modified 
from 35 to 40 for each indication (UC and CD) 
for the remaining 3 treatments arms. 
Updated the sample size 
following the removal of the 1800 
mg Q2W treatment arm. 
Figure 2 Overall Study Schematic Diagram 
See new wording column. 
Figure 2 was modified as described below. 
• 
Removed 1800 mg treatment arm from the UC 
and CD patient groups 
• 
Changed the sample size for each treatment arm 
from 35 to 40 and total sample size for each 
indication from 140 to 120 patients 
• 
Changed screening estimate from 570 to 
480 patients 
• 
Removed description of analysis model 
Modified Figure 2 to include 
updates to the sample size and 
primary analysis following the 
removal of the 1800 mg Q2W 
treatment arm. 
Section 3.2 Planned Number of Patients and Countries 
Approximately 570 480 patients will be screened to achieve 
approximately280 240 randomized patients (approximately 
Approximately 480 patients will be screened to achieve 
approximately 240 randomized patients (approximately 
Updated the sample size 
following the removal of the 1800 
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140 120 patients with UC and 140 120 patients with CD). 
… 
120 patients with UC and 120 patients with CD). 
… 
mg Q2W treatment arm. 
Section 3.3 Justification for Study Design and Selection of Population 
… 
The basket DRF design offers the following efficiencies: 
… 
• 
Enable information sharing between UC and CD doses, 
thereby enhancing the inferential quotient in a single trial 
as compared with independent analyses/trials for UC and 
CD. 
• 
Allow a lower number of patients to be studied (as 
compared to 2 parallel, independent studies of UC and 
CD), further reducing the total exposure in this population. 
Basket studies are prospectively designed studies typically 
conducted in Phase 2 to allow effective evaluation of 
therapeutic benefit of a single investigational treatment in 
multiple diseases or disease subtypes. In some instances, these 
designs have served as a basis for regulatory approval (Hyman 
et al 2015, Subbiah et al 2018). 
Bayesian hierarchical models are used to analyze the data and 
generally demonstrate a robust control of the family-wise (type 
1) error rate (Kaizer et al 2019) when compared to a simple 
pooling or an independence approach for analysis of a range of 
outcomes. The operating characteristics for various scenarios 
(ie, treatment effect for doses, indications) can be explored 
using simulation studies. Further, such designs permit interim 
evaluations (efficacy and/or futility) of the accumulating data.  
An overall primary efficacy analysis incorporating all data 
from both indications will be performed using a Bayesian 
hierarchical model. . 
In this Phase 2 dose-range study, a functional relationship 
(namely Emax model) between the doses is assumed. While 
there are many options for specifying these relationships (ie, 
… 
The basket DRF design offers the following efficiencies: 
… 
Basket studies are prospectively designed studies 
typically conducted in Phase 2 to allow effective 
evaluation of therapeutic benefit of a single 
investigational treatment in multiple diseases or disease 
subtypes. In some instances, these designs have served as 
a basis for regulatory approval (Hyman et al 2015, 
Subbiah et al 2018). 
In summary, the commonality of the anti-TL1A 
mechanism of action in patients with UC and CD, the 
approved mAbs that have similar dose regimens for both 
UC and CD, and the opportunities for operational 
efficiencies make a basket design well suited for the 
planned study. 
… 
Removed description of the Emax 
analysis since no longer 
applicable following removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
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Emax, logistic, exponential etc.), the Emax model (with Hill 
parameter close to 1) has been shown to provide a good fit 
across a range of pharmaceutical studies (Thomas et al 2014). 
Additionally, as demonstrated in Gajewski et al (2019), the 
Emax model performs adequately when non-monotonicity is not 
expected, thereby resulting in a higher likelihood of identifying 
the correct dose. Further, previously conducted phase 2 trial for 
Tofacitinib (Sandborn et al 2013) has implemented such an 
approach to characterize the dose response and to identify 
efficacious doses via Emax models. 
In summary, the commonality of the anti-TL1A mechanism of 
action in patients with UC and CD, the approved mAbs that 
have similar dose regimens for both UC and CD, and the 
opportunities for operational and inferential efficiencies make 
a basket design well suited for the planned study. 
… 
Section 3.4.1.1 Permanent Individual Withdrawn from IMP 
… 
• 
The patient experiences coronavirus disease 2019 
(COVID 19) infection. 
… 
Not applicable; event of COVID-19 was deleted as a 
criterion for withdrawal from IMP. 
Experience of the current stage of 
the pandemic does not support the 
contingent restrictions of COVID-
19. 
Section 3.5 Schedule of Study Procedures and Assessments, Table 1 
See new wording column.  
Table 1 Study Procedures and Assessments was modified 
as follows: 
• 
CDAI assessments removed at weeks 2, 6, 
and 10 
• 
Weight measurement added at week 14 
• 
Clinical laboratory assessments added at 
week 12 
• 
Removed specified 
assessment of CDAI to 
reduce patient burden 
associated with additional 
blood draws for the 
hematocrit component of 
CDAI. 
• 
Correction to include weight 
as a measurement for CDAI 
at week 14. 
• 
Correction to add the 
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collection of laboratory 
assessments at week 12. 
Footnote e 
At screening, patients with clinical symptoms that may indicate 
COVID-19 infection, and/or patients who, in the investigator’s 
opinion, were at high risk of exposure to COVID-19 within 6 
weeks before screening or during screening, will be tested for 
active COVID-19 infection. Patients who test positive will be 
excluded. After day 1, if a patient exhibits clinical symptoms 
during the study that may indicate COVID 19 infection, the 
patient will be tested for active COVID-19 infection. If the 
patient tests positive, the patient will be discontinued from 
IMP and will need to visit the clinical site again for an early 
termination visit after recovery. 
Footnote e 
At screening, patients with clinical symptoms that may 
indicate COVID-19 infection, and/or patients who, in the 
investigator’s opinion, were at high risk of exposure to 
COVID-19 within 6 weeks before screening or during 
screening, will be tested for active COVID-19 infection. 
Patients who test positive will be excluded. 
Experience of the current stage of 
the pandemic does not support the 
contingent restrictions of COVID-
19. 
Footnote g 
For UC patients, endoscopy will include a flexible 
sigmoidoscopy only (colonoscopy may be performed instead 
for baseline endoscopy if not done in the prior 12 months). 
For CD patients, endoscopy will include ileo-colonoscopy. 
Footnote g 
For UC patients, endoscopy will include a flexible 
sigmoidoscopy only (colonoscopy may be performed 
instead for baseline endoscopy if not done in the prior 
12 months). For CD patients, endoscopy will include 
ileo-colonoscopy. 
Clarification. 
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Footnote k 
Serology includes hepatitis B core antibody and surface 
antigen, hepatitis C virus, and human immunodeficiency virus 
types 1 or 2. Patients with HBcAb positive and HBsAg 
negative serology and undetectable Hepatitis B viral DNA at 
screening may have follow-up Hepatitis B viral DNA testing 
throughout their participation in the study. 
Footnote k 
Serology includes hepatitis B core antibody and surface 
antigen, hepatitis C virus, and human immunodeficiency 
virus types 1 or 2. Patients with HBcAb positive and 
HBsAg negative serology and undetectable Hepatitis B 
viral DNA at screening may have follow-up Hepatitis B 
viral DNA testing throughout their participation in the 
study. 
Clarification. 
Footnote m 
Clinical laboratory tests includinge serum chemistry and 
complete blood count (hematology). Patients should be fasting 
for at least 8 hours prior to safety laboratory assessments only 
at the screening, week 14, and early termination visits (ie, 
visits at which low density lipoprotein, high density 
lipoprotein, and triglycerides will be measured). Coagulation 
tests (PT/PTT/INR) will be performed at screening only or in 
case of suspected liver injury (see Appendix M). Screening 
laboratory test abnormalities, if considered by the 
Investigator to be transient and inconsistent with the 
patient’s clinical condition, may be repeated once during the 
screening period for confirmation. 
Footnote m 
Clinical laboratory tests including serum chemistry and 
complete blood count (hematology). Patients should be 
fasting for at least 8 hours prior to safety laboratory 
assessments only at the screening, week 14, and early 
termination visits (ie, visits at which low density 
lipoprotein, high density lipoprotein, and triglycerides 
will be measured). Coagulation tests (PT/PTT/INR) will 
be performed at screening only or in case of suspected 
liver injury (see Appendix M). Screening laboratory test 
abnormalities, if considered by the Investigator to be 
transient and inconsistent with the patient’s clinical 
condition, may be repeated once during the screening 
period for confirmation. 
To confirm validity of out of 
range laboratory result(s). 
Section 4.1 Patient Inclusion Criteria 
Criterion g. 
Patient must have inadequate response to, loss of response to, 
or intolerance of to: 
- aAt least 1 of the following therapies agents: corticosteroids, 
immunosuppressants, or an approved advanced therapy for 
IBD including biologics (anti-TNF, anti-integrins, anti-
IL-12/23, or anti-IL-23), JAK inhibitors, or S1P receptor 
modulators.and nNo more than 2 3 locally approved classes of 
Criterion g. 
Patient must have inadequate response to, loss of 
response to, or intolerance to: 
- At least 1 of the following therapies: corticosteroids, 
immunosuppressants, or an approved advanced therapy 
for IBD including biologics (anti-TNF, anti-integrins, 
anti-IL-12/23, or anti-IL-23), JAK inhibitors, or S1P 
receptor modulators. No more than 3 locally approved 
• 
Included IL-23 as it is a 
newly approved class for 
treatment for IBD and will 
be considered a similar class 
as the IL-12/23. 
• 
Removed doses of AZA, 
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biologics: corticosteroids, immunosuppressant drugs, and/or 
TNF α antagonist therapy, anti integrins, anti IL 12/23, JAK 
inhibitors, and/or S1P receptor modulators. 
… 
• 
Inadequate response to, loss of response to, or 
intolerance to prior immunosuppressant treatment is 
defined by 1 or more of the following: 
- 
Persistent signs and symptoms of active disease 
despite a history of at least one 12 week 
1 regimen of oral AZA (≥2 to 2.5 mg/kg/day) or 
6-MP (≥1 to 1.5 mg/kg/day) and/or methotrexate 
(≥25 mg/week) consistent with the regional 
standard of care; 
… 
Inadequate response to, loss of response to, or intolerance to 
prior advanced therapy for IBD (biologics, JAK inhibitors, 
and S1P receptor modulators) or small molecules defined as 1 
or more of the following: 
- 
Loss of response: Persistent signs and symptoms 
of active disease despite at least one induction 
and one maintenance regimen of the locally 
approved regimen of anti-TNF inhibitors, 
anti-integrins, anti-IL-12/23 or anti-IL-23 
monoclonal antibodiesmAbs, JAK inhibitors, or 
S1P receptor modulators. 
- 
Inadequate response (primary non-response): 
Persistent signs and symptoms of active disease 
despite at least one induction regimen of the 
locally approved highest dosing regimen of anti-
TNF inhibitors, anti-integrins, anti-IL-12/23 or 
anti-IL-23 mAbs, JAK inhibitors, or S1P 
receptor modulators. 
- 
Intolerance: Discontinuation of anti-TNF 
inhibitors, anti-integrins, anti-IL-12/23 or 
anti-IL-23 monoclonal antibodies mAbs, JAK 
classes of biologics. 
… 
• 
Inadequate response to, loss of response to, or 
intolerance to prior immunosuppressant 
treatment is defined by 1 or more of the 
following: 
- 
Persistent signs and symptoms of active 
disease despite a history of at least 
1 regimen of oral AZA or 6-MP and/or 
methotrexate consistent with the regional 
standard of care; 
… 
Inadequate response to, loss of response to, or intolerance 
to prior advanced therapy for IBD (biologics, JAK 
inhibitors, and S1P receptor modulators) defined as 1 or 
more of the following: 
- 
Loss of response: Persistent signs and 
symptoms of active disease despite at least 
one induction and one maintenance regimen 
of the locally approved regimen of anti-
TNF, anti-integrins, anti-IL-12/23 or anti-
IL-23 mAbs, JAK inhibitors, or S1P 
receptor modulators. 
- 
Inadequate response (primary non-
response): Persistent signs and symptoms of 
active disease despite at least one induction 
regimen of the locally approved highest 
dosing regimen of anti-TNF, anti-integrins, 
anti-IL-12/23 or anti-IL-23 mAbs, JAK 
inhibitors, or S1P receptor modulators. 
- 
Intolerance: Discontinuation of anti-TNF, 
anti-integrins, anti-IL-12/23 or anti-IL-23 
mAbs, JAK inhibitors, or S1P receptor 
modulators due to an adverse drug reaction 
as determined by treating physician. Such 
6-MP, and methotrexate to 
align with regional standards 
of care. 
• 
Updated to no more than 
3 classes to potentially 
increase the patient pool for 
enrollment. 
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inhibitors, or S1P receptor modulators due to an 
adverse drug reaction as determined by treating 
physician. Such adverse drug reactions include, 
but are not limited to, nausea/vomiting, 
abdominal pain, pancreatitis, liver function 
testing abnormalities, lymphopenia, and 
infections. 
adverse drug reactions include, but are not 
limited to, nausea/vomiting, abdominal 
pain, pancreatitis, liver function testing 
abnormalities, lymphopenia, and infections. 
Section 4.2 Patient Exclusion Criteria 
Criterion c. 
Patient has colonic dysplasia or neoplasia (with exception of 
dysplasia on a completely excised adenomatous polyp [not a 
sessile one]), toxic megacolon, primary sclerosing cholangitis, 
known non-passable colonic stricture, presence of colonic or 
small bowel stoma, presence of non-passable colonic or small 
bowel obstruction or resection preventing the endoscopy 
procedure, or fulminant colitis. 
Criterion c. 
Patient has colonic dysplasia or neoplasia (with exception 
of dysplasia on a completely excised adenomatous polyp 
[not a sessile one]), toxic megacolon, primary sclerosing 
cholangitis, known non-passable colonic stricture, 
presence of colonic or small bowel stoma, presence of 
non-passable colonic or small bowel obstruction or 
resection preventing the endoscopy procedure, or 
fulminant colitis. 
Clarification. If dysplasia or 
neoplasm on an adenomatous 
polyp can be demonstrated to 
have been completely resected by 
polypectomy, and wide tissue 
margins are shown to be free of 
any dysplastic or neoplastic tissue, 
then the excision can therefore be 
considered to have been curative 
and the patient does not need to be 
excluded from study participation. 
Criterion f. 
A patient is Hepatitis B core antibody (HBcAb) or surface 
antigen (HBsAg) positive,. and/or If HBcAb is positive and 
HBsAg negative, Hepatitis B viral deoxyribonucleic acid 
(DNA) will be done as reflective test, and, if undetectable, 
then not exclusionary. Hepatitis C antibody positive with 
detectable ribonucleic acids (RNAs),. or pPositive human 
immunodeficiency virus types 1 or 2 at screening. 
Criterion f. 
Hepatitis B core antibody (HBcAb) or surface antigen 
(HBsAg) positive. If HBcAb is positive and HBsAg 
negative, Hepatitis B viral deoxyribonucleic acid (DNA) 
will be done as reflective test, and, if undetectable, then 
not exclusionary. Hepatitis C antibody positive with 
detectable ribonucleic acids (RNAs). Positive human 
immunodeficiency virus types 1 or 2 at screening. 
Clarification. 
Criterion g. 
Tested positive for TB at screening by the QuantiFERON® TB 
Gold Test (unless documentation of prior TB treatment is 
available) or had a history of untreated latent or active TB. 
Criterion g. 
Tested positive for TB at screening by the 
QuantiFERON® TB Gold Test (unless documentation of 
prior TB treatment is available) or had a history of 
untreated latent or active TB. 
Clarification. 
Criterion i. 
A history of more than 12 herpes zoster episodes in the last 
Criterion i. 
A history of more than 2 herpes zoster episodes in the 
The mechanism of action of 
aTL1A is involved in 
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5 years or multimetameric herpes zoster. 
last 5 years or multimetameric herpes zoster. 
amplification of immune 
response; therefore, does not 
require such a rigid restriction. 
Criterion k. 
Current or history of chronic liver or biliary disease (with the 
exception of Gilbert’s syndrome, asymptomatic gallstones or 
uncomplicated fatty liver disease) at screening or baseline or 
alanine aminotransferase (ALT) or AST >2x upper limit of 
normal (ULN) and or bilirubin >1.5x ULN (isolated bilirubin 
>1.5x ULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%) at screening. 
Criterion k. 
Current or history of chronic liver or biliary disease (with 
the exception of Gilbert’s syndrome, asymptomatic 
gallstones or uncomplicated fatty liver disease) at 
screening or baseline ALT or AST >2x ULN or bilirubin 
>1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%) at 
screening. 
Clarification. 
Criterion n. 
Patients with clinical symptoms that may indicate confirmed 
infection with coronavirus disease 2019 (COVID-19) 
infection, and/or patients who, in the investigator’s opinion, 
were at high risk of exposure to COVID 19 within 6 weeks 
before prior to the screening or during screening visit, will be 
tested for active COVID 19 infection and will be excluded if 
they test positive for COVID 19. Patients who were admitted 
to an intensive care unit during a prior COVID 19 infection, 
patients who contracted or recovered from COVID 19 less than 
6 weeks prior to screening, or patients or with residual 
COVID-19 symptoms (“long-term COVID-19”). Patients with 
active documented or suspected COVID-19 infection within 
4 weeks of randomization or asymptomatic positive severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
polymerase chain reaction (PCR) test within 2 weeks of 
randomization symptoms are excluded from the study. 
Criterion n. 
Patients with confirmed infection with COVID-19 within 
6 weeks prior to the screening visit, or with residual 
COVID-19 symptoms (“long COVID-19”). Patients with 
active documented or suspected COVID-19 infection 
within 4 weeks of randomization or asymptomatic 
positive severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) polymerase chain reaction (PCR) test 
within 2 weeks of randomization are excluded. 
Experience of the current stage of 
the pandemic does not support the 
contingent restrictions of COVID-
19. 
Criterion r. 
A history of malignancy within the last 5 years (exception: 
basal cell carcinoma or in situ carcinoma of the cervix if 
successful curative therapy occurred at least 12 months prior to 
screening or curatively resected papillary thyroid cancer). 
Criterion r. 
A history of malignancy within the last 5 years 
(exception: basal cell carcinoma or in situ carcinoma of 
the cervix if successful curative therapy occurred at least 
12 months prior to screening or curatively resected 
papillary thyroid cancer). 
Clarification. 
Criterion s. 
Criterion s. 
Included IL-23 as it is a newly 
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Patient is receiving any of the following therapies within the 
designated time period: 
… 
- 
Biologics including anti-TNF inhibitors, 
anti-integrins inhibitors, and anti-IL-12/23, or 
anti-IL-23 inhibitors within 3 half-lives prior to 
randomization. 
… 
Patient is receiving any of the following therapies within 
the designated time period: 
… 
- 
Biologics including anti-TNF, 
anti-integrins, anti-IL-12/23, or anti-IL-23 
within 3 half-lives prior to randomization. 
… 
approved class for treatment for 
IBD and will be considered a 
similar class as the IL-12/23. 
Criterion u. 
Patients with incurable diseases, persons in nursing homes, and 
patients incapable of giving written informed consent 
Criterion u. 
Patients with incurable diseases, persons in nursing 
homes, and patients incapable of giving written informed 
consent 
Clarification. 
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Criterion v. 
The patient is either an employee or an immediate relative of 
an employee of the sponsor or of any of the clinical 
investigational centers participating in the study. 
Criterion v. 
Not applicable; exclusion criterion was deleted.  
Criterion is an unlikely restriction 
for this study. 
Section 5.1 Investigational Medicinal Products Used in the Study 
… 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 12 
6 mL induction dose volume) and will be administered as 
single sc administrations. 
… 
Patients will receive the following regimens as a single sc 
administration Q2W using the 
 
 
, 
 
 
• 
TEV 48574 2250 mg (single loading dose)/1800 mg 
(6 induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/900 mg (6 
induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/450 mg (6 
induction doses) 
• 
Placebo to match TEV-48574 (single loading 
dose)/(Iinduction doses) 
… 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume 
and 6 mL induction dose volume) and will be 
administered as single sc administrations. 
… 
Patients will receive the following regimens as a single sc 
administration Q2W using the 
 
 
, 
 
 
• 
TEV-48574 2250 mg (single loading dose)/900 
mg (6 induction doses) 
• 
TEV-48574 2250 mg (single loading dose)/450 
mg (6 induction doses) 
• 
Placebo to match TEV-48574 (single loading 
dose)/(induction doses) 
• 
12 mL is the volume 
associated with the 1800 mg 
dose. The highest dose is 
now 900 mg and is 
associated with 6 mL 
induction volume. 
• 
Removal of the 1800 mg 
Q2W treatment arm. 
Section 5.1.3 Test and Placebo Investigational Medicinal Product Administration  
… 
The infusion rate is fixed at 30 mL/hr for all sc infusions. The 
expected infusion durations will therefore be 30 minutes for 
the 15 mL loading dose and 24 12 minutes for the 12 6 mL 
induction doses. 
… 
The infusion rate is fixed at 30 mL/hr for all sc infusions. 
The expected infusion durations will therefore be 30 
minutes for the 15 mL loading dose and 12 minutes for 
the 6 mL induction doses. 
12 mL is the volume associated 
with the 1800 mg dose. The 
highest dose is now 900 mg and is 
associated with 6 mL induction 
volume. 
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… 
… 
Section 5.3.1 Justification for Dose of Test Investigational Medicinal Product 
In this study, TEV-48574 will be administered as a single 
loading dose of 2250 mg followed by induction doses of 
450 or, 900, or 1800 mg sc Q2W, for a total of 7 doses. 
… 
Furthermore, in preclinical rat models of asthma and colitis, 
good efficacy improvement in disease outcomes, including 
fibrosis, was observed at TEV-48574 doses of 3 mg/kg and 
above, with reductions in efficacy at doses below 1 mg/kg. 
This suggests that TEV 48574 would have a similar range of 
efficacious doses in asthma and IBDs. 
… 
The 3 2 induction dose strengths in this study were selected 
based on a combination of safety, preclinical evidence, and 
pharmacokinetic considerations and will enable an 
identification of a minimal potential efficacy dose and a 
comprehensive exposure response relationship characterization 
to support dose selection for the next stage of clinical 
development. As wide a range of The 2 doses are as is 
compatible with practicality and patient safety was and were 
selected to discern clinically meaningful differences as 
currently there are no pharmacologic or biomarker data to give 
sufficient guidance as to dose. 
With regard to safety, TEV-48574 exposure in patients with 
UC or CD is not expected to exceed that of asthma patients and 
HV, and therefore, the suggested 
 level 
 
and the highest 
 level 
 are 
supported by both nonclinical and available clinical safety 
data. The dose of 
 is 12.5% higher than the top 
repeated dose 
 previously safely administered in 
Study TV48574 SAD 10126 and administered in Study 
TV48574 AS 20031 in patients with asthma. This change is 
driven by the change in IMP formulation from 100 mg/mL to 
150 mg/mL, resulting in overall lower volumes of 
In this study, TEV-48574 will be administered as a single 
loading dose of 2250 mg followed by induction doses of 
450 or 900 mg sc Q2W, for a total of 7 doses. 
… 
Furthermore, in preclinical rat models of colitis, 
improvement in disease outcomes, including fibrosis, 
was observed at TEV-48574 doses of 3 mg/kg and above. 
… 
The 2 induction dose strengths in this study were selected 
based on a combination of safety, preclinical evidence, 
and pharmacokinetic considerations and will enable 
selection for the next stage of clinical development. The 
2 doses are compatible with practicality and patient 
safety and were selected to discern clinically meaningful 
differences as currently there are no pharmacologic or 
biomarker data to give sufficient guidance as to dose. 
With regard to safety, TEV-48574 exposure in patients 
with UC or CD is not expected to exceed that of asthma 
patients and HV, and therefore, the suggested 
 
level 
 and the highest 
 level 
 are supported by both nonclinical and available 
clinical safety data. 
… 
Selection of 
 as the highest dose provides an 
opportunity to maximize exposure within the safe range 
in case such increased clearance phenomenon 
materializes for TEV-48574. 
… 
In addition, it was established that the pharmacokinetics 
of TEV-48574 was linear at doses ≥400 mg. Based on 
these considerations, the low dose of 
 is used in 
the current study to optimize the safety profile, exposure, 
• 
Removal of the 1800 mg 
Q2W treatment arm. 
• 
Removed reference of 
asthma findings in 
preclinical rat models as it is 
not relevant for this study in 
IBD. 
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administration but risking the accuracy of administration of the 
 dose, which would result in a volume of 10.667 mL. 
Therefore, a dose of 
 (12 mL administration volume) 
is selected. The sponsor considers this difference to be 
marginal in the context of the inherent pharmacokinetic 
variability of TEV-48574 of ≥40% for different 
pharmacokinetic parameters and still contained well within the 
nonclinical safety margins. Based on dose linear 
pharmacokinetics and a simple equivalence calculation, the 
safety margins for the 
 dose versus exposure 
parameters retrieved from the 100 mg/kg sc dose in 
cynomolgus monkeys (highest NOAEL reported) are 9.8 and 
10.4 for Cmax and area under the concentration time curve 
(AUC), respectively. 
Predictions obtained from the established population 
pharmacokinetic model based on the observed data from Study 
TV48574 SAD 10126 suggest the steady state median value of 
145.8 μg/mL (with 62.9 μg/mL and 299.6 μg/mL being the 5th 
and 95th percentile, respectively) for Cmax, and median value of 
1372 days*μg/mL (with 562.6 days*μg/mL and 
2936.5 days*μg/mL being the 5th and 95th percentile, 
respectively) for AUCτ for the simulated 
 
The safety margins for the 
 dose based on 
population pharmacokinetic simulation exposure are 9.5 and 
4.9 for Cmax and AUC, respectively. 
… 
Selection of 
 as the highest dose provides an 
opportunity to maximize exposure within the safe range in case 
such increased clearance phenomenon materializes for TEV-
48574. 
… 
In addition, it was established that the pharmacokinetics of 
TEV-48574 was linear at doses ≥400 mg. Based on these 
considerations, the lowest dose of 
 is used in the current 
study to optimize the safety profile, exposure, and future 
pharmacokinetic/pharmacodynamic relationship 
and future pharmacokinetic/ pharmacodynamic 
relationship characterization of TEV-48574. 
… 
For drugs with high pharmacokinetic variability, a 
greater spread of exposures could be chosen. Therefore, 
the 2 doses were selected to provide sufficient exposure 
separation between the highest and the lowest potentially 
therapeutic dose. 
Additional supportive evidence is provided by the 
findings of a completed Phase 2b study in patients with 
UC that evaluated another anti-TL1A mAb (RVT-3101, 
previously known as PF--06480605). 
Neelakantan and colleagues analyzed the totality of 
observed pharmacokinetic data from RVT-3101 studies 
in HV (Phase 1) and patients with UC (Phase 2a) 
(Neelakantan et al 2019). The available data included 
various dose levels from both iv and sc administrations. 
Their results suggest that the pharmacokinetics of 
RVT-3101 displayed the typical attributes of a mAb, with 
a half-life of around 20 days, approximately 67% 
bioavailability, and with no observable differences 
between the subject populations. Weight at baseline was 
the only identifiable factor that influenced the drug 
exposure, and its influence was incorporated as a 
covariate on drug elimination rate. 
The exposure comparison between TEV-48574 and 
RVT-3101 using population pharmacokinetic modelling 
and simulation approaches was performed. The suggested 
TEV-48574 
 were benchmarked with 
those reported to be administered in the Phase 2b study 
of RVT-3101, and the analyses suggest comparable 
concentrations for the 2 dose levels. Due to the 
differences in half-lives between the 2 compounds, 
average drug exposure over time was used as a 
comparative metric. 
… 
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characterization of TEV-48574 in this study. 
… 
For drugs with high pharmacokinetic variability, a greater 
spread of doses exposures could be chosen. Therefore, the 
2 doses were an intermediate dose of 900 mg providing 2-fold 
difference between the tested dose strengths that is considered 
reasonable for proper exposure response characterization was 
selected to provide sufficient exposure separation between the 
highest and the lowest potentially therapeutic dose. 
Additional supportive evidence is provided by the findings of 
a completed Phase 2b study in patients with UC that 
evaluated another anti-TL1A mAb (RVT-3101, previously 
known as PF-06480605), an anti TL1A mAb currently under 
investigation in a Phase 2b study in patients with UC. 
Neelakantan and colleagues analyzed the totality of observed 
pharmacokinetic data from RVT-3101 PF-06480605 studies in 
HV (Phase 1) and patients with UC (Phase 2a) (Neelakantan et 
al 2019). The available data included various dose levels from 
both iv and sc administrations. Their results suggest that the 
pharmacokinetics of RVT-3101 PF 06480605 displayed the 
typical attributes of a mAb, with a half-life of around 20 days, 
approximately 67% bioavailability, and with no observable 
differences between the subject populations. Weight at baseline 
was the only identifiable factor that influenced the drug 
exposure, and its influence was incorporated as a covariate on 
drug elimination rate. 
The exposure comparison between TEV-48574 and RVT-3101 
PF 06480605 using population pharmacokinetic modelling and 
simulation approaches was performed. The suggested 
TEV-48574 
 were benchmarked with those 
reported to be administered in the Phase 2b study of RVT-3101 
PF 06480605, and the analyses suggest comparable 
concentrations for the all 3 2 dose levels. Due to the 
differences in half-lives between the 2 compounds, average 
drug exposure over time was used as a comparative metrics. 
… 
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Section 5.6.3 Permitted Inflammatory Bowel Disease Medications and Rescue Medications 
… 
Patients will be allowed to use the following medications as 
detailed below: 
… 
A stable dose of immunosuppressant drugs (methotrexate, ≤25 
mg intramuscular or sc once weekly or ≤15 mg per os once 
weekly; 6-MP, ≤1.5 mg/kg/day; or AZA ≤2.5 mg/kg/day 
consistent with regional standard of care) for 4 weeks prior 
to endoscopy and through week 14. Decreases due to adverse 
events are permitted. 
… 
Patients will be allowed to use the following medications 
as detailed below: 
… 
A stable dose of immunosuppressant drugs 
(methotrexate, 6-MP, or AZA consistent with regional 
standard of care) for 4 weeks prior to endoscopy and 
through week 14. Decreases due to adverse events are 
permitted. 
Removed doses of AZA, 6-MP, 
and methotrexate to align with 
regional standards of care. 
Section 5.6.4 Prohibited Medications and Therapies 
The following medications will be prohibited during this study: 
… 
• 
Biologics including anti-TNF inhibitors, anti-integrins 
inhibitors, and anti-IL-12/23, or anti-IL-23 inhibitors 
within 3 half-lives prior to randomization. 
… 
The following medications will be prohibited during this 
study: 
… 
• 
Biologics including anti-TNF, anti-integrins, 
anti-IL-12/23, or anti-IL-23 within 3 half-lives 
prior to randomization. 
… 
Included IL-23 as it is a newly 
approved class for treatment for 
IBD and will be considered a 
similar class as the IL-12/23. 
Section 5.8 Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. 
Patients who meet all the inclusion criteria and none of the 
exclusion criteria will be randomly assigned to receive 
TEV-48574 (single loading dose/6 induction doses): 
2250/1800 mg, 2250/900 mg, 2250/450 mg, or placebo to 
match TEV-48574, in a 1:1:1:1 ratio, stratified by diagnosis 
(UC or CD) and previous exposure to advanced therapy for 
IBD (yes/no), failure of (biologics, and small molecules, 
including JAK inhibitors, and S1P receptor modulators for UC) 
or naive to biologics and small molecule therapy. 
Approximately 140 120 UC patients and 140 120 CD patients 
will be randomly assigned to the treatment groups by means of 
This is a randomized, double-blind, placebo-controlled 
study. Patients who meet all the inclusion criteria and 
none of the exclusion criteria will be randomly assigned 
to receive TEV-48574 (single loading dose/6 induction 
doses): 2250/900 mg, 2250/450 mg, or placebo to match 
TEV-48574, in a 1:1:1 ratio, stratified by diagnosis (UC 
or CD) and previous exposure to advanced therapy for 
IBD (yes/no) (biologics, JAK inhibitors, and S1P 
receptor modulators). 
Approximately 120 UC patients and 120 CD patients will 
be randomly assigned to the treatment groups by means 
of a computer-generated randomization list using 
• 
Clarification. 
• 
Updated the sample size 
following the removal of the 
1800 mg Q2W treatment 
arm. 
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a computer-generated randomization list using interactive-
response technology. 
… 
The study patients, sponsor, and the clinical team at the site 
will be blinded to treatment assignment until the database is 
locked for analysis and the site will be blinded until all 
patients complete the study, and the database is locked for 
final analysis for both indications. The sponsor will be 
blinded to treatment assignment until the database is locked 
for analysis of each indication. Prior to unblinding, the 
sponsor will establish a separate blinded study team 
supporting the conduct of the study until the database is 
locked for final analysis for both indications. 
… 
interactive-response technology. 
… 
The patients and the site will be blinded until all patients 
complete the study, and the database is locked for final 
analysis for both indications. The sponsor will be blinded 
to treatment assignment until the database is locked for 
analysis of each indication. Prior to unblinding, the 
sponsor will establish a separate blinded study team 
supporting the conduct of the study until the database is 
locked for final analysis for both indications. 
… 
Section 5.9.2 Blinding and Unblinding 
… 
Details regarding unblinding of Teva team while maintaining 
the blind of the study, in case efficacy threshold is met at the 
interim analysis, and in case the final analysis is conducted 
for one indication while the other indication is ongoing, will 
be provided in a separate unblinding charter. 
… 
… 
Details regarding unblinding of Teva team while 
maintaining the blind of the study, in case efficacy 
threshold is met at the interim analysis, and in case the 
final analysis is conducted for one indication while the 
other indication is ongoing, will be provided in a separate 
unblinding charter. 
… 
Clarification. 
Section 5.9.3 Independent Data Monitoring Committee 
A single review committee (IDMC) will be established to 
assess futility and monitor safety datathe study while the 
studyit is ongoing, including periodic reviews of safety data, 
and pre-specified analyses of efficacy data, as described 
below. 
… 
• 
The role of the IDMC will be to periodically monitor 
unblinded safety data to ensure the safety of study 
patients, review the planned interim futility analysis, 
and make recommendations on study conduct. In 
A single review committee (IDMC) will be established to 
monitor the study while it is ongoing, including periodic 
reviews of safety data, and pre-specified analyses of 
efficacy data, as described below. 
… 
• 
The role of the IDMC will be to periodically 
monitor unblinded safety data to ensure the 
safety of study patients, and make 
recommendations on study conduct. In addition, 
the IDMC will review pre-specified analyses of 
Modification to accommodate the 
change in the interim analysis to 
include non-binding analysis of 
high efficacy. 
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addition, the IDMC will review pre-specified 
analyses of efficacy data to make recommendations 
to the sponsor regarding futility or the possible 
acceleration of Phase 3 planning. 
The IDMC charter will provide details regarding procedures to 
protect the scientific integrity of the trial, conduct of the 
interim analysis, dissemination of results, and decision criteria 
based on the futility analysis in addition to pre-specified study 
stopping rules for safety. 
…. 
efficacy data to make recommendations to the 
sponsor regarding futility or the possible 
acceleration of Phase 3 planning. 
The IDMC charter will provide details regarding 
procedures to protect the scientific integrity of the trial, 
conduct of the interim analysis, dissemination of results, 
and decision criteria in addition to pre-specified study 
stopping rules for safety. 
…. 
Section 5.10 Total Blood Volume 
The estimated maximum blood volume to be collected for each 
patient in this study is approximately 20 mL per visit and 
approximately 200 240 mL for each patient during the entire 
study. 
The estimated maximum blood volume to be collected 
for each patient in this study is approximately 20 mL per 
visit and approximately 240 mL for each patient during 
the entire study. 
Correction to include serum 
measures of tissue condition in the 
calculation of total blood volume. 
Section 6.1.2.1 Biopsy Collection 
… 
Biopsies will be used for measures of histologic disease and 
exploratory biomarker assays. Ileal (for CD) and multiple 
colonic tissue sampling will be obtained by endoscopic 
biopsies and will be evaluated by microscopic and histologic 
analyses, as well as for exploratory measures involving 
established and novel biomarkers of intestinal inflammation 
and fibrosis. There are several different approaches for 
obtaining these endoscopic biopsy samples, and the preferred 
procedures are described in the Laboratory Manual and 
Quick Reference Card.  
… 
… 
Ileal (for CD) and multiple colonic tissue sampling will 
be obtained by endoscopic biopsies and will be evaluated 
by microscopic and histologic analyses, as well as for 
exploratory measures involving established and novel 
biomarkers of intestinal inflammation and fibrosis. There 
are several different approaches for obtaining these 
endoscopic biopsy samples, and the preferred procedures 
are described in the Laboratory Manual and Quick 
Reference Card. 
… 
Clarification. 
Section 7.5 Clinical Laboratory Tests, Table 9 
See new wording column. 
Table 9 Clinical Laboratory Tests was updated as 
follows: 
• 
Hematology and Coagulation 
Laboratory does not measure this 
analyte. 
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− 
Lymphocytes atypical was removed as a 
laboratory test. 
Section 7.5.1 Serum Chemistry, Hematology, and Urinalysis 
… 
Clinical laboratory tests will be performed using the central 
laboratory. Local laboratory testing can be used under 
extenuating circumstances and only following agreement 
with the sponsor. 
Screening laboratory test abnormalities, if considered by the 
Investigator to be transient and inconsistent with the 
patient’s clinical condition, may be repeated once during the 
screening period for confirmation. 
… 
Clinical laboratory tests will be performed using the 
central laboratory. Local laboratory testing can be used 
under extenuating circumstances and only following 
agreement with the sponsor. 
Screening laboratory test abnormalities, if considered by 
the Investigator to be transient and inconsistent with the 
patient’s clinical condition, may be repeated once during 
the screening period for confirmation. 
Clarification. 
Section 7.5.2 Other Clinical Laboratory Tests 
At screening, patients will be tested for HBcAb and HBsAg, 
antibodies to hepatitis C virus (reflex viral RNA testing if 
hepatitis C antibodies present), human immunodeficiency 
virus types 1 or 2, and enteric pathogens (including stool 
culture and Clostridium difficile toxin assay; additional testing 
[eg, ova and parasites] may be performed at the investigator’s 
clinical discretion). 
If HBcAb is positive and HBsAg negative, hepatitis B viral 
DNA will be done as reflective test, and, if undetectable, then 
not exclusionary. 
Patients will also be tested for TB at screening 
(QuantiFERON® TB Gold Test). Patients with confirmed 
positive results will not be eligible to participate in the study 
(unless documentation of prior TB treatment is available). 
… 
At screening, patients will be tested for HBcAb and 
HBsAg, antibodies to hepatitis C virus (reflex viral RNA 
testing if hepatitis C antibodies present), human 
immunodeficiency virus types 1 or 2, and enteric 
pathogens (including stool culture and Clostridium 
difficile toxin assay; additional testing [eg, ova and 
parasites] may be performed at the investigator’s clinical 
discretion). 
If HBcAb is positive and HBsAg negative, hepatitis B 
viral DNA will be done as reflective test, and, if 
undetectable, then not exclusionary. 
Patients will also be tested for TB at screening 
(QuantiFERON® TB Gold Test). Patients with confirmed 
positive results will not be eligible to participate in the 
study (unless documentation of prior TB treatment is 
available). 
… 
Clarification. 
… 
At screening, patients with clinical symptoms that may indicate 
… 
At screening, patients with clinical symptoms that may 
indicate COVID-19 infection and/or patients who, in the 
Experience of the current stage of 
the pandemic does not support the 
contingent restrictions of COVID-
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COVID-19 infection and/or patients who, in the investigator’s 
opinion, were at high risk of exposure to COVID-19 within 
6 weeks before screening or during screening will be tested for 
active COVID-19 infection. Patients who test positive will be 
excluded. After day 1, if a patient exhibits clinical symptoms 
during the study that may indicate COVID-19 infection, the 
patient will be tested for active COVID 19 infection. If the 
patient tests positive, the patient will be discontinued from 
IMP and will need to visit the clinical site again for an early 
termination visit after recovery. 
… 
investigator’s opinion, were at high risk of exposure to 
COVID-19 within 6 weeks before screening or during 
screening will be tested for active COVID-19 infection. 
Patients who test positive will be excluded.  
… 
19. 
Section 8.4 Assessment of Exploratory Biomarkers 
… 
Details of the specimen collection, processing, and handling 
requirements are provided in the study reference m Laboratory 
Manual. 
 
All biopsy and fecal samples collected in this study will be 
utilized to support study specific endpoints, and any residual 
samples will be destroyed. Residual biopsy, fecal, and serum 
samples, after appropriate analysis to support this study, may 
be stored at a Teva-secured facility for up to 155 years towards 
future analysis related to TEV-48574 or IBD if permitted by 
the ICF and local regulations. 
… 
… 
Details of the specimen collection, processing, and 
handling requirements are provided in the Laboratory 
Manual. 
 
Residual biopsy, fecal, and serum samples, after 
appropriate analysis to support this study, may be stored 
at a Teva-secured facility for up to 15 years towards 
future analysis related to TEV-48574 or IBD if permitted 
by the ICF and local regulations. 
… 
Correction. 
Section 9.1 Sample Size and Power Considerations 
A total study sample size of 280 240 patients is planned, with 
140 120 patients (3540 patients per dose arm) each for the 
2 disease groups indications of UC and CD. 
Assumptions: 
The clinical remission and endoscopic response rates assumed 
in the sample size and related operating characteristics 
computations are as follows: 
A total study sample size of 240 patients is planned, with 
120 patients (40 patients per dose arm) each for the 
2 indications of UC and CD. 
Assumptions: 
The clinical remission and endoscopic response rates 
assumed in the sample size and related operating 
characteristics computations are as follows: 
Updated the sample size 
calculation following the removal 
of the 1800 mg Q2W treatment 
arm. 
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• 
Clinical remission rates in UC group indication: 8% 
for placebo and low-dose; 30% for TEV-48574 
lowmid- and high-dose groups, respectively 
• 
Endoscopic response rates in CD group indication: 
12% for placebo and low-dose; 34% for TEV-48574 
low mid- and high-dose groups, respectively 
Simulation-based operating characteristics for the analysis of 
the primary efficacy variable using a Bayesian Beta Binomial 
hierarchical 3 parameter Emax model for the interim and final 
analysis are presented in Table 10,. This model uses with a 
posterior probability futility cutoff of <0.55 for the assessment 
of futility at the interim analysis each disease group, and final 
success a posterior probability cutoff of ≥0.86 90, are 
presented in Table 10 to declare success at the final analysis. 
For UC, Tthe family-wise false-positive rate (ie, probability of 
making at least 1 false-positive conclusion under the global 
null assumption for both doses) is no more than 12%13%, and 
the probability of declaring success for at least 1 dose group is 
97%both UC and CD groups is 94%, under the assumptions 
stated above.  
For CD, the family-wise false-positive rate is 15%, and the 
probability of declaring success for at least 1 dose is 95%, 
under the assumptions above. 
… 
Under a less optimistic scenario for mid  and high dose groups, 
when where the placebo response rates remain the same 
while the clinical remission rate in the UC group indication is 
reduced to 20% (from 30%) for both doses, and the 
endoscopic response rate in the CD group indication is 
reduced to 25% (from 34%) for both doses, while maintaining 
the identical response rates for placebo and low dose (in both 
UC and CD groups), the probability of declaring success in at 
least 1 dose both UC is 75% for UC and CD groups is about 
6974% for CD. 
• 
Clinical remission rates in UC indication: 8% 
for placebo; 30% for TEV-48574 low- and high-
dose groups, respectively 
• 
Endoscopic response rates in CD indication: 
12% for placebo; 34% for TEV-48574 low- and 
high-dose groups, respectively 
Simulation-based operating characteristics for the 
analysis of the primary efficacy variable using a 
Bayesian Beta Binomial model are presented in Table 10. 
This model uses a posterior probability futility cutoff of 
<0.55 for the assessment of futility at the interim analysis 
and a posterior probability cutoff of ≥0.90 to declare 
success at the final analysis. 
For UC, the family-wise false-positive rate (ie, 
probability of making at least 1 false-positive conclusion 
under the null assumption for both doses) is 13%, and the 
probability of declaring success for at least 1 dose group 
is 97%, under the assumptions above.  
For CD, the family-wise false-positive rate is 15%, and 
the probability of declaring success for at least 1 dose is 
95%, under the assumptions above. 
… 
Under a less optimistic scenario where the placebo 
response rates remain the same while the clinical 
remission rate in the UC indication is reduced to 20% for 
both doses, and the endoscopic response rate in the CD 
indication is reduced to 25% for both doses, the 
probability of declaring success in at least 1 dose is 75% 
for UC and 74% for CD. 
Details regarding the statistical decision criteria and 
Bayesian model, as well as operating characteristics in 
case only 1 active dose is effective are provided in 
Appendix N.  
For comparison, a frequentist logistic regression analysis 
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Details regarding the statistical decision criteria and Bayesian 
hierarchical model, as well as operating characteristics 
including priors and hyper priors used in the computation of 
the operating characteristics, in case only 1 active dose is 
effective are provided in Appendix N. The operating 
characteristics under additional scenarios, including discordant 
scenarios where the treatment is effective only in one disease 
group, are presented in Appendix N. 
For comparison, an independent (by UC, CD indication)a 
frequentist logistic regression analysis, 140 with 40 patients 
per dose per indication would provides at least 90% power 
using a Mantel-Haenszel test with a 1-sided Type I error rate 
of 10% as determined by 1 sided Cochran Armitage trend test 
with and the assumptions of the true clinical remission and 
endoscopic about response rates specified under 
“Assumptions” above. This power does not take into account 
the planned futility analysis. 
with 40 patients per dose per indication would provide at 
least 90% power using a Mantel-Haenszel test with a 
1-sided Type 1 error rate of 10% and the assumptions 
about response rate specified above. This power does not 
take into account the planned futility analysis.  
Table 10 (Operating Characteristics of Interim and Final 
Analysis 
See new wording column. 
Table 10 was revised as described below: 
• 
Simulations updated based on Beta-Binomial 
model 
• 
Modified the futility cutoffs in the footnotes 
The interim and final analysis 
rules with a corresponding update 
to the operating characteristics 
were revised following the 
removal of the 1800 mg Q2W 
treatment arm and change in the 
primary analysis model. 
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Section 9.2.2 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set for each 
indication (UC or CD) is a subset of the ITT analysis set 
including only patients who receive at least 1 dose of placebo, 
TEV-48574 450 mg (low dose), or TEV-48574 900 mg (high 
dose)IMP. 
… 
The modified intent-to-treat (mITT) analysis set for each 
indication (UC or CD) is a subset of the ITT analysis set 
including only patients who receive at least 1 dose of 
placebo, TEV-48574 450 mg (low dose), or TEV-48574 
900 mg (high dose). 
… 
Removal of the 1800 mg Q2W 
treatment arm. 
Section 9.2.4 Per-Protocol Analysis Set 
The per protocol (PP) analysis set for each indication (UC or 
CD) is a subset of the mITT analysis set including only 
patients without important protocol deviations. 
In the PP analysis set, patients will be categorized by treatment 
patients actually received, regardless of the treatment to which 
they were randomized. 
Not applicable; the analysis set was deleted. 
No longer applicable for the study 
design. 
Section 9.4 Study Population 
The mITT analysis set (Section 9.2.1) will be used for all 
efficacy study population summaries unless otherwise 
specified. Summaries will be presented by treatment group, 
pooled TEV-48574, and all patients, separately by indication 
(UC or CD) and pooled (UC and CD).Efficacy summaries will 
be presented separately by indication (UC or CD). The safety 
analysis set will be used for all safety summaries unless 
otherwise specified. Safety summaries will be presented 
separately by indication (UC or CD) and pooled (UC and CD). 
The ITT analysis set (Section 9.2.1) will be used for all 
study population summaries. Summaries will be 
presented by treatment group, pooled TEV-48574, and all 
patients, separately by indication (UC or CD) and pooled 
(UC and CD). 
Correction to describe analysis of 
study population. 
Section 9.5.4.1 Primary Efficacy Analysis 
A Beta-binomial model with a non-informative Beta(1,1) 
prior will be used to analyze the primary response endpoint, 
clinical remission (for UC) or endoscopic response (for CD), 
hereafter denoted as “response”. The model will be fit 
separately for each dose within each indication.  
An Emax dose response model will be used to analyze the 
primary efficacy variable (defined in the primary estimand). 
Notation and distributional assumptions are as follows: 
A Beta-binomial model with a non-informative Beta(1,1) 
prior will be used to analyze the primary response 
endpoint, clinical remission (for UC) or endoscopic 
response (for CD), hereafter denoted as “response”. The 
model will be fit separately for each dose within each 
indication.  
Inference will be based on posterior distribution of the 
response rates. A TEV-48574 dose will be declared 
The previous Bayesian 
hierarchical Emax dose-response 
model is not applicable following 
the removal of the 1800 mg Q2W 
treatment arm. The simple 
beta-binomial model fit separately 
to each dose within each 
indication, with a final cutoff of 
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• 
Y represents response  
• 
 𝜃𝑑,𝑖 denotes the log odds of response  
− 
d = 0, 1, 2, 3 denote placebo, low, medium, and 
high doses  
− 
i = 1, 2 correspond to UC, CD 
• 
 Y ~ Ber (𝑎𝑛𝑡𝑖𝑙𝑜𝑔𝑖𝑡(𝜃𝑑,𝑖) ) 
The 3-parameter Emax model for dose response is given by: 
𝜃𝑑,𝑖= 𝐸0,𝑖+ (𝐸𝑚𝑎𝑥,𝑖 . 𝑑) 
(𝐸𝐷50,𝑖+ 𝑑) 
  
For each i = 1,2 , the parameters are as follows:  
• 
𝐸0,𝑖 is the average placebo response 
• 
𝐸𝑚𝑎𝑥,𝑖 represents the maximum effect of the drug 
• 
𝐸𝐷50,𝑖 is the dose corresponding to half the effect of 
𝐸𝑚𝑎𝑥,𝑖  
A Bayesian hierarchical model will be employed to model the 
data and estimate these parameters. A common underlying 
prior distribution is assumed for the same parameters across 
the 2 models for UC and CD. The hierarchical model borrows 
information across disease groups (UC, CD), shrinking the 
estimates of the model parameters for the 2 disease groups 
towards a common mean. The borrowing of information 
improves precision associated with the estimates of the 
parameters. A smaller variance (ie, 1/precision) in the common 
prior increases information borrowed, whereas a larger 
variance would mean that the estimates are largely impacted by 
the data within the disease group.  
Inference will be based on posterior distribution of the 
response rates. A TEV-48574 dose will be declared successful 
successful at the final analysis if the posterior probability 
that the response rate in the TEV-48574 dose is higher 
than the response rate in the placebo arm is ≥0.90. Put 
another way, the success criterion for each dose within 
indication can be written as:  
Posterior Probability (TEV-48574 response rate – 
placebo response rate > 0) ≥0.90 
The following quantities will be presented: 
• 
Posterior means of the response rates for 
TEV-48574 high dose (900 mg Q2W), 
TEV-48574 low dose (450 mg Q2W) and 
placebo  
• 
95% credible intervals for difference in response 
rates (TEV-48574 doses – placebo) 
• 
For each TEV-48574 dose, Posterior Probability 
(TEV-48574 dose – placebo response rate >0)  
For further details, see Appendix N. 
≥0.90, was selected based on 
operating characteristics. 
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at the final analysis if the posterior probability that the 
response rate in the TEV-48574 dose is higher than the 
response rate in the placebo arm is ≥0.90. Put another way, 
the success criterion for each dose within indication can be 
written as:these parameters and summarized as follows for 
each indication (UC, CD):  
Posterior Probability (TEV-48574 response rate – placebo 
response rate > 0) ≥0.90 
The following quantities will be presented: 
• 
Posterior means and/or medians of the response rates 
for TEV-48574 high dose (900 mg Q2W), 
TEV-48574 low dose (450 mg Q2W) doses,and 
placebo  
• 
95% credible intervals for difference in response rates 
(TEV-48574 doses – placebo) 
• 
For each TEV-48574 dose, Posterior Probability 
(TEV-48574 dose – placebo response rate > 0)  
• 
Posterior Probability (Emax > 0) 
For further details, see Appendix N. provides details 
regarding prior and hyper-prior distributions for the Bayesian 
hierarchical (Emax) model in addition to operating 
characteristics under various assumptions of remission (UC), 
response rates (CD).  
Section 9.5.4.2 Sensitivity Analysis 
Tipping point analysis will be performed to test the 
robustness of the primary analysis to the imputation of 
patients that discontinue the study or have missing week 14 
modified Mayo score (UC patients) or SES-CD (CD patients) 
data as non-responders. 
The following sensitivity analyses will be performed for the 
primary efficacy analysis: (a) replication of the primary 
Tipping point analysis will be performed to test the 
robustness of the primary analysis to the imputation of 
patients that discontinue the study or have missing 
week 14  modified Mayo score (UC patients) or SES-CD 
(CD patients) data as non-responders. 
Updated sensitivity analysis. 
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analysis using the PP analysis set and (b) an analysis to test the 
robustness of the missing at random assumption (made in the 
primary analysis) by using an alternate approach (ie, different 
from non-responder imputation) to handle missing data. Details 
will be provided in the Statistical Analysis Plan. 
Section 9.5.4.3 Supplementary Analysis 
A supplementary analysis for the primary efficacy variable 
(defined in the supplementary estimand) will be performed 
using a logistic regression model fit separately to each 
indication with the following fixed effects: dose (as 
categorical variable), indication, dose by indication 
interaction, randomization stratification factors, previous 
exposure to advanced IBD therapy (yes/no), and baseline 
modified Mayo score (UC patients) or SES-CD (CD 
patients).response. Separate dose response lines will be 
derived for each of the 2 disease groups. The (slope) 
coefficient corresponding to dose within an indication will be 
estimated and Each comparison of TEV-48574 dose versus 
placebo will be tested (one-sided) for statistical significance at 
a nominal significance level of α=alpha of0.1. 
The following additional analyses will be undertaken to  
examine the robustness of the primary efficacy analysis results: 
In addition, a Cochran-Mantel-Haenszel (CMH) test for 
pairwise comparisons between the active dose groups and 
placebo will be performed separately for UC and CD. Nominal 
p-values will be presented for each of the comparisons. 
• 
Bayesian Emax dose-response model fit separately (ie, 
no borrowing) for UC and CD. Inferences presented 
for the primary efficacy analysis will be re-produced 
for this approach. 
• 
Frequentist Emax dose response model fit separately 
for UC and CD. Response rates of TEV 48574 doses, 
placebo and 95% confidence intervals for difference 
A supplementary analysis for the primary efficacy 
variable (defined in the supplementary estimand) will be 
performed using a logistic regression model fit separately 
to each indication with the following fixed effects: dose 
(as categorical variable), previous exposure to advanced 
IBD therapy (yes/no), and baseline modified Mayo score 
(UC patients) or SES-CD (CD patients). Each 
comparison of TEV-48574 dose versus placebo will be 
tested (one-sided) at a nominal significance level of 
α=0.1. 
In addition, a Cochran-Mantel-Haenszel (CMH) test for 
pairwise comparisons between the active dose groups and 
placebo will be performed separately for UC and CD. 
Nominal p-values will be presented for each of the 
comparisons. 
Updated supplementary analyses 
following the removal of the 1800 
mg Q2W treatment arm and 
change in the primary analysis. 
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in response rates (TEV 48574 doses  placebo), along 
with summaries of model parameters will be 
presented 
• 
Logistic regression model with fixed effects for dose, 
randomization stratification factors and baseline 
response fit separately for UC and CD. 
Section 9.5.4.4 Secondary Efficacy Analysis 
All secondary efficacy endpoints will be analyzed separately 
for the UC and CD disease groups indications. For each 
binary endpoint, Aa logistic regression model similar to the 
supplementary model described in Section 9.5.4.3 will be used 
with the following fixed effects: dose, randomization 
stratification factors, and with the respective baseline 
measurement will be used. For each comparison of 
TEV-48574 dose versus placebo, the differences in 
proportions, Oodds ratios (for each of the TV48574 doses 
versus placebo), associated 95% CIs, and nominal p-values 
will be reported.  
All secondary efficacy endpoints will be analyzed 
separately for the UC and CD indications. For each 
binary endpoint, a logistic regression model similar to the 
supplementary model described in Section 9.5.4.3 with 
the respective baseline measurement will be used. For 
each comparison of TEV-48574 dose versus placebo, the 
differences in proportions, odds ratios, associated 95% 
CIs, and nominal p-value will be reported.  
Clarification. 
Section 9.13 Planned Interim Analysis 
Interim analyses for safety and efficacy are planned for this 
study. An interim efficacy/futility analysis for futility is 
planned in each disease group indication (UC and CD) when at 
least 44 50% of patients (approximately 30%) in that group the 
indication have completed the 14-week primary efficacy 
readout or had the opportunity to do so. 
In the interim analysis, the same Bayesian Beta-Binomial 
hierarchical Emax dose-response model used as described in the 
primary analysis model will be used to analyze the primary 
efficacy response variable (clinical remission for UC and 
endoscopic response for CD, hereafter denoted as “response”) 
for each dose within each disease group indication. The 
futility criterion for each disease group dose is: 
Interim analyses for safety and efficacy are planned for 
this study. An interim efficacy/futility analysis is planned 
in each indication (UC and CD) when at least 50% of 
patients in the indication have completed the 14-week 
primary efficacy readout or had the opportunity to do so. 
In the interim analysis, the same Bayesian Beta-Binomial 
model described in the primary analysis model will be 
used to analyze the primary efficacy response variable 
for each dose within each indication. The futility criterion 
for each dose is: 
• 
Posterior probability (TEV-48574 response rate 
– placebo response rate > 0) <0.55 
Refer to Table 12 and Appendix N for operating 
• 
The interim analysis timing, 
method, and cutoff were 
updated following the 
change in the primary 
analysis model and the 
corresponding operating 
characteristics. 
• 
Efficacy analysis added to 
allow the sponsor timely 
assessment for futility and 
efficacy. 
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• 
If the pPosterior probability 
 𝑃(𝐸𝑚𝑎𝑥,𝑖> 0|𝑖𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎)for disease group i is 
<0.55, then the corresponding disease group is 
futile.(TEV-48574 response rate – placebo response 
rate > 0) < 0.55 
An analysis of each disease group independently will be 
performed at the interim analysis for the disease group as a 
supporting analysis, as follows: 
• 
A Beta-Binomial model with a non-informative prior 
Beta(1,1) will be fitted to the response rate π in each 
treatment group d in the disease group i, and the 
posterior probability that the response rate in each 
active group is higher than the response rate in the 
placebo group, 𝑃( 𝜋𝑑,𝑖> 𝜋0,𝑖), will be calculated.  
Refer to Table 12 and Appendix N for operating characteristics 
of the interim and final analysis. 
In addition to futility, an efficacy criteria will be incorporated 
for the purpose of internal decision making and planning 
purposes. The criteria are non-binding, purely for purposes 
of accelerating planning for subsequent trials, and will not 
trigger any recommendations on trial conduct. Details of the 
efficacy criteria will be provided in the Statistical Analysis 
Plan. 
… 
All interim analyses will be performed by an external, 
independent, unblinded reporting team. The results of all 
interim analyses will be reviewed by an IDMC comprised of 
external medical and statistical experts. The IDMC will make a 
recommendations regarding study conduct after evaluation of 
the totality of available safety the data. Recommendations 
include, but are not limited to, dropping of a dose arm, 
termination of an indication, or termination of the study. The 
details regarding the statistical analysis methods will be 
characteristics of the interim and final analysis. 
In addition to futility, efficacy criteria will be 
incorporated for the purpose of internal decision making 
and planning purposes. The criteria are non-binding, 
purely for purposes of accelerating planning for 
subsequent trials, and will not trigger any 
recommendations on trial conduct. Details of the efficacy 
guideline will be provided in the Statistical Analysis 
Plan. 
… 
All interim analyses will be performed by an external, 
independent, unblinded reporting team.The results of all 
interim analyses will be reviewed by an IDMC 
comprised of external medical and statistical experts. The 
IDMC will make recommendations regarding study 
conduct after evaluation of the totality of the data. 
Recommendations include, but are not limited to, 
dropping of a dose arm, termination of an indication, or 
termination of the study. The details regarding the 
statistical analysis methods will be provided in the 
Statistical Analysis Plan. The IDMC charter will provide 
details regarding procedures to protect the scientific 
integrity of the study, conduct of the interim analysis, 
dissemination of results, and decision criteria. 
… 
Additional Analyses: 
As part of the interim analysis for efficacy/futility, 
additional analyses may be provided to the IDMC upon 
request or as deemed necessary by the sponsor. 
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provided in the Statistical Analysis Plan. The IDMC charter 
will provide details regarding procedures to protect the 
scientific integrity of the study, conduct of the interim analysis, 
dissemination of results, and decision criteria based on the 
futility analysis. 
… 
Additional Analyses: 
As part of the interim analysis for efficacy/futility, additional 
analyses may be provided to the IDMC upon request or as 
deemed necessary by the sponsor. the primary efficacy 
endpoints may be analyzed by the presence of TEV 48574 
ligand or other relevant biomarkers. 
Additional endpoints may also be provided to the IDMC as 
part of the interim analyses for futility.  
Section 15 References 
… 
• 
Gajewski BJ, Meinzer C, Berry SM, et al. Bayesian 
hierarchical EMAX model for dose-response in early 
phase efficacy clinical trials. Stat Med. 
2019;38(17):3123-3138. 
... 
• 
Kaizer A, Koopmeiners J, Kane M, Roychoudhury S, 
Hong D, Hobbs B, et al. Basket designs: statistical 
considerations for oncology trials. JCO Precision 
Oncology 2019;3:1 9. 
… 
• 
Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an 
oral Janus kinase inhibitor, in active ulcerative colitis. 
Not applicable; the 3 references were deleted: 
References were removed as they 
are no longer applicable to 
support the study, including the 
statistical analysis methods due to 
removal of the 1800 mg Q2W 
treatment arm. 
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N Engl J Med. 2012;367(7):616 624. 
… 
• 
Thomas N, Sweeney K, & Somayaji V Meta analysis 
of clinical dose response in a large drug development 
portfolio. Statistics in 
--- 
Appendix A. Departments and Institutions 
Sponsor’s Authorized Representative 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
Sponsor’s Authorized Representative 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
Transfer of sponsor 
responsibilities. 
Appendix B. Study Procedures and Assessments by Visit 
2. Procedures During Administration of Investigational 
Medicinal Product (Double-Blind Treatment Period) 
 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 ([±3 
days based on previous visit]) 
• 
CDAI score (CD only) 
 
c. Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 ([±3 
2. Procedures During Administration of Investigational 
Medicinal Product (Double-Blind Treatment Period) 
 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 
([±3 days based on previous visit]) 
Not applicable; CDAI assessment was deleted at weeks 
2, 6, and 10. 
 
c. Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 
• 
To reduce patient burden 
associated with additional 
blood draws for the 
hematocrit component of 
CDAI. 
• 
CDAI is being collected at 
week 12; therefore, a clinical 
laboratory collection was 
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days based on previous visit]) 
• 
clinical laboratory tests (visits 3 and 5 only) 
 
d. Visit 8 (week 14, day 99 [±3 days based on previous visit]) 
• 
weight measurement 
([±3 days based on previous visit]) 
Clinical laboratory test added at visit 7; performed at 
visits 3, 5, and 7 
 
d. Visit 8 (week 14, day 99 [±3 days based on previous 
visit]) 
Weight measurement added at visit 8. 
added at visit 7. 
• 
CDAI is being collected at 
week 14; therefore, weight 
measurement was added at 
visit 8. 
4. Early Termination 
The procedures and assessments performed at the early 
termination visit are identical to those performed at the visit 8 
(week 14 visit; see item “d” above), except that weight is 
measured as well. If a patient develops COVID-19 during the 
course of the trial this is not an indication for early 
termination. 
4. Early Termination 
The procedures and assessments performed at the early 
termination visit are identical to those performed at the 
visit 8 (week 14 visit; see item “d” above), except that 
weight is measured as well. If a patient develops 
COVID-19 during the course of the trial this is not an 
indication for early termination. 
Experience of the current stage of 
the pandemic does not support the 
contingent restrictions of COVID-
19. 
Appendix K. Management of Study Activities During COVID-19 Outbreaks 
Section 1.3. Known and Potential Benefits and Risks to 
Patients 
… 
It should be noted that patients diagnosed with active or 
residual COVID-19 or who were hospitalized in the intensive 
care unit during COVID-19 infection would not be included in 
the study as they would meet exclusion criteriona “a” and did 
not meet inclusion criterion“k”. 
… 
If a patient exhibits clinical symptoms during the study that 
may indicate COVID 19 infection, the patient will be tested for 
active COVID 19 infection. If the patient tests positive, the 
patient will be discontinued from the IMP and will attend an 
early termination visit once recovered. Remote assessment of 
safety via teleconference (TC) and/or videoconference (VC), 
with VC being the preferred method, is recommended until the 
patient attends for the early termination visit. 
Section 3.1. General Study Design and Study Schematic 
Section 1.3. Known and Potential Benefits and Risks to 
Patients 
… 
It should be noted that patients diagnosed with active or 
residual COVID-19 or who were hospitalized in the 
intensive care unit during COVID-19 infection would not 
be included in the study as they would meet exclusion 
criterion “a” and did not meet inclusion criterion “k”. 
… 
• 
Correction to denote 
eligibility criterion “a” as 
part of the inclusion criteria. 
• 
Experience of the current 
stage of the pandemic does 
not support the contingent 
restrictions of COVID-19. 
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Diagram; Section 3.5. Schedule of Study Procedures and 
Assessments 
In the event of an emergency situation (eg, COVID 19 
outbreaks), in case a patient cannot return to the clinic for the 
scheduled visits (eg, due to quarantine, isolation, patient’s 
concern, active COVID-19 infection, or closure of the site 
clinic), the patient will be discontinued from the IMP, 
scheduled adverse event and concomitant medication 
monitoring will be continued, and the patient will attend an 
early termination visit when that becomes possible. Remote 
assessment of safety via TC and/or VC, with VC being the 
preferred method, is recommended until the patient attends the 
early termination visit. All other tests (including safety labs, 
pharmacokinetics, anti drug antibody, and biomarkers [if 
applicable and only in patients who do not have active 
COVID-19 infection]) are to be conducted once the patient can 
return to the study center for the early termination visit. 
In the event that a patient completes the screening procedures 
but cannot come to the site for visit 1 (eg, due to quarantine, 
isolation, patient’s concern, or closure of the site clinic), it may 
be possible to extend the duration of the screening period on a 
case by case basis, following discussion between the 
investigator and the sponsor study physician. Rescreening of 
the patient will also be allowed. 
These measures will be implemented on a case by case basis, 
and only when and where they are warranted due to the 
emergency situation. Preferably, the full protocol instructions 
will be followed whenever the modified instructions are not 
required. 
… 
Section 4.4. Replacement of Patients 
In the event of an emergency situation (eg, COVID 19 
outbreaks), the number of patients to be randomized may be 
increased to ensure the targeted number of completers per arm. 
Section 6. Assessment of Efficacy 
In the event of an emergency situation (eg, COVID 19 
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outbreaks), in case a patient cannot return to the clinic for the 
scheduled visits (eg, due to quarantine, isolation, patient's 
concern, active COVID 19 infection, or closure of the site 
clinic), the patient will be discontinued from IMP, remote 
monitoring will continue, and the patient will attend for an 
early termination visit when that becomes possible. 
These measures will be implemented on a case by case basis, 
and only when and where they are warranted due to the 
emergency situation. Preferably, the full protocol instructions 
will be followed whenever the modified instructions are not 
required. 
… 
Section 7.5. Clinical Laboratory Tests 
For early termination patients (patients who cannot be 
administered the IMP), all required samples scheduled for 
early termination will be collected once the patient can return 
to the study center. 
Section 9.5.5. Planned Method of Analysis 
Sensitivity and supplementary analyses will be conducted to 
evaluate the impact of the change to remote monitoring 
(TC/VC visits) and the impact of COVID-19 on primary 
efficacy measurements. The analysis will include subgroup 
analysis (eg, pre , during, and post COVID 19 outbreak, where 
each patient will be classified into 1 of the levels), a 
multivariate model (eg, Cox regression with time dependent 
covariates for COVID 19 and/or use of remote monitoring), 
and/or imputation methodology for patients’ attrition due to the 
COVID 19, as appropriate and if data permit. Details of the 
supplementary and sensitivity analyses will be presented in the 
Statistical Analysis Plan or addendum thereof, following a 
blinded review meeting prior to database lock. 
… 
Appendix N. Operating Characteristics and Assumptions for Final and Interim Analysis 
Final Analysis and Interim Futility Analysis  
Final Analysis and Interim Futility Analysis  
Operating characteristics 
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A Beta-binomial model with a non-informative Beta(1,1) 
prior will be used to analyze the primary response endpoint, 
clinical remission (for UC) or endoscopic response (for CD), 
hereafter denoted as “response”. The model will be fit 
separately for each dose within each indication. 
Primary analysis will be based on the 3-parameter Emax model 
for dose response, as explained in Section 9.5 (where d = 0, 1, 
2, 3 for placebo, low, mid, and high doses and i = 1, 2 for UC, 
CD). 
θd,i = 𝐸0,𝑖+ (𝐸𝑚𝑎𝑥,𝑖 . 𝑑) 
𝐸𝐷50,𝑖+ 𝑑 
Assumptions: 
The priors used in the Bayesian hierarchical (Emax) model are 
given by: 
𝐸0,𝑖 ~ 𝑁(𝜇𝐸0, 𝜎𝐸0
2 ) ,   
𝐸𝑚𝑎𝑥,𝑖 ~ 𝑁(𝜇𝐸𝑚𝑎𝑥, 𝜎𝐸𝑚𝑎𝑥
2
) ,   
𝐸𝐷50,𝑖 ~ ℎ𝑎𝑙𝑓 𝐶𝑎𝑢𝑐ℎ𝑦 (0, 5)  
Also assume the following hyper prior distributions: 
𝜇𝐸0 ~ 𝑁(0, 102) , 𝜇𝐸𝑚𝑎𝑥 ~ 𝑁(0, 102), 
𝜎𝐸0
2  ~  ℎ𝑎𝑙𝑓 𝐶𝑎𝑢𝑐ℎ𝑦 (0, 2), 𝜎𝐸𝑚𝑎𝑥
2
 ~  ℎ𝑎𝑙𝑓 𝐶𝑎𝑢𝑐ℎ𝑦 (0, 2) 
 
Given the lack of information on dose response of TEV 48574 
in UC and CD indications, the prior distributions are non
informative and are chosen to encompass the range of plausible 
values for the model parameters and to optimize the power 
under various scenarios while controlling the type I error rate. 
Various scenarios for remission (UC), response rates (CD) are 
assumed as outlined in Table 11 to investigate the operating 
characteristics. 
A Beta-binomial model with a non-informative Beta(1,1) 
prior will be used to analyze the primary response 
endpoint, clinical remission (for UC) or endoscopic 
response (for CD), hereafter denoted as “response”. The 
model will be fit separately for each dose within each 
indication. 
Assumptions: 
Various scenarios for remission (UC), response rates 
(CD) are assumed as outlined in Table 11 to investigate 
the operating characteristics. 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
Final Analysis and Interim Futility Analysis  
Table 11 (Remission (UC), Response (CD) Rates Scenarios for 
Clinical Trial Simulations) 
Final Analysis and Interim Futility Analysis  
Table 11 was revised as described below: 
• 
Remove the low dose 
• 
Remove the scenarios low efficacy; efficacy 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
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UC, Null CD; and Null UC, Efficacy CD 
• 
Removed footnote ”a” and note to table 
describing the deleted scenarios noted above 
and change in the primary 
analysis model. 
Number of Patients at the Interim Analysis: 
The interim analysis for each indication is planned when at 
least 44 50% of patients (approximately 30%) in that group the 
indication have completed the 14-week primary efficacy 
readout or had the opportunity to do so. Operating 
characteristics were obtained from simulations assuming that 
exactly 11 21 patients per arm in the corresponding disease 
group indication will be included in the interim analysis. Since 
the analysis is separate for each indication, no assumptions 
on Due to the expected difference in recruitment rate between 
UC and CD are required., it is assumed that at the time of the 
interim analysis for UC, data from ~20 patients (5 patients per 
arm) in CD will be available; at the time of the interim analysis 
for CD, data from ~96 patients (24 patients per arm) in UC will 
be available if UC was not stopped for futility at the UC 
interim analysis. 
Statistical Decision Criteria – Final Analysis: 
A TEV-48574 dose will be declared successful at the final 
analysis if the posterior probability that the response rate in 
the TEV-48574 dose is higher than the response rate in the 
placebo arm is ≥0.90, ie, the success criterion for each dose 
within indication is: 
Posterior Probability (TEV-48574 response rate – placebo 
response rate > 0) ≥0.90 
The trial will be deemed positive if at least 1 dose of TEV
48574 is demonstrated to be better than placebo in the primary 
efficacy analysis for UC, CD. The corresponding statistical 
decision criteria translate to: 
• 
𝑝𝑑,𝑖> 𝑝0,𝑖 , (where 𝑝𝑑,𝑖 denotes the probability of 
response for dose d ) 
Number of Patients at the Interim Analysis: 
The interim analysis for each indication is planned when 
at least 50% of patients in the indication have completed 
the 14-week primary efficacy readout or had the 
opportunity to do so. Operating characteristics were 
obtained from simulations assuming that 
exactly 21 patients per arm in the corresponding 
indication will be included in the interim analysis. Since 
the analysis is separate for each indication, no 
assumptions on the expected difference in recruitment 
rate between UC and CD are required. 
Statistical Decision Criteria – Final Analysis: 
A TEV-48574 dose will be declared successful at the 
final analysis if the posterior probability that the response 
rate in the TEV-48574 dose is higher than the response 
rate in the placebo arm is ≥0.90, ie, the success criterion 
for each dose within indication is: 
Posterior Probability (TEV-48574 response rate – 
placebo response rate > 0) ≥0.90 
Statistical Futility Cutoff – Interim Analysis: 
The same Bayesian Beta-Binomial model described in 
the primary analysis model will be used for the interim 
futility analysis for each dose within each indication. A 
TEV-48574 dose will be declared futile at the interim 
analysis if the posterior probability that the response rate 
in the TEV-48574 dose is higher than the response rate in 
the placebo arm is <0.55, ie, the futility criterion for each 
dose within indication is: 
• 
Posterior Probability (TEV-48574 response rate 
– placebo response rate > 0) <0.55 
Operating Characteristics: 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
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• 
This occurs if and only if θd,i > θ0,i 
• 
This will occur if and only if 𝐸𝑚𝑎𝑥,𝑖> 0. 
To elaborate, 
θd,i − θ0,i measures the difference in log odds of response 
between TEV 48574 doses and placebo. In particular for any 
dose d = 1, 2, 3: 
• 
θd,i
 θ0,i > 0 if and only if  
(𝐸𝑚𝑎𝑥,𝑖 .𝑑) 
𝐸𝐷50,𝑖+𝑑> 0,
which equates to  𝐸𝑚𝑎𝑥,𝑖> 0  
• 
𝑝𝑑,𝑖 is uniquely identified by a corresponding value of 
the log odds, θd,i ( 𝑝𝑑,𝑖= exp(θd,i)/(1 + exp(θd,i))  
Thus, if the Posterior Probability P (𝐸𝑚𝑎𝑥,𝑖>
0 | 𝑓𝑢𝑙𝑙 𝑑𝑎𝑡𝑎) exceeds the pre specified threshold of 0.86, the 
study will have met the criterion for success. The threshold 
was selected to achieve optimal operating characteristics for 
the assumed scenarios. 
Statistical Futility Cutoff – Interim Analysis: 
The same Bayesian Beta-Binomial model described in the 
primary analysis model will be used for the interim futility 
analysis for each dose within each indication. A TEV-48574 
dose will be declared futile at the interim analysis if the 
posterior probability that the response rate in the TEV-48574 
dose is higher than the response rate in the placebo arm is 
<0.55, ie, the futility criterion for each dose within indication 
is: 
• 
Posterior Probability (TEV-48574 response rate – 
placebo response rate > 0) <0.55 
The Bayesian hierarchical Emax model will be used in the 
futility analysis of each disease group (UC and CD). For each 
interim analysis, the available data from the patients that 
completed 14 weeks or early terminated, in both treatment 
groups, will be used. However, the futility decision will be for 
Clinical trial simulations were performed under the 
assumptions for the interim and primary analysis to 
generate the operating characteristics (presented in Table 
12), for a target sample size of 40 patients per arm in 
each indication, and an interim analysis for futility for 
each indication at 21 patients per arm in the indication. 
The posterior probability futility cutoff is <0.55 for each 
indication and final success posterior probability cutoff is 
≥0.90. 
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the disease group under investigation, ie, at the UC interim 
analysis only futility of UC will be tested, and vice versa. 
The futility decision rule is:  
If the posterior probability 𝑃(𝐸𝑚𝑎𝑥,𝑖> 0|𝑖𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎) for 
disease group i is <0.55, then the corresponding disease group 
is futile. The threshold was selected to achieve optimal 
operating characteristics for the null and efficacy scenarios. 
Operating Characteristics: 
Clinical trial simulations were performed under the 
assumptions for the interim and primary analysis to generate 
the operating characteristics (presented in Table 12), for a 
target sample size of 35 40 patients per arm in each indication, 
and an interim analysis for futility for each indication at 11 21 
patients per group arm in the indication. The posterior 
probability futility cutoff is <0.55 for each disease group 
indication and final success posterior probability cutoff is 0.86 
≥0.90. 
For all scenarios presented in Table 12, it is assumed that the 
Emax model is used for decision making in the interim analysis. 
Operating Characteristics:  
Table 12 (Simulation based Operating Characteristics for 
Interim and Final Analysis All Scenarios) 
See new wording column. 
Operating Characteristics:  
Table 12 (Operating Characteristics for Interim and Final 
Analysis – All Scenarios) was revised as described 
below: 
• 
Simulations updated based on Beta-Binomial 
model 
• 
Removed the scenarios low efficacy; efficacy 
UC, Null CD; and Null UC, Efficacy CD 
• 
Updated the number of simulations performed 
in the footnote 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
Operating Characteristics:  
These simulations demonstrate that the probability of a false 
positive result is ≤15%no more than 12% for the trial each 
indication, with while the probability of declaring success for 
at least 1 dose within each indication both UC and CD disease 
Operating Characteristics:  
These simulations demonstrate that the probability of a 
false positive result is ≤15% for each indication, while 
the probability of declaring success for at least 1 dose 
within each indication under the efficacy assumption for 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
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groups under the high efficacy assumption for both doses is 
≥at 9495%.  
The futility threshold was selected to control the probability 
to declare an effective dose to be futile at a maximum of 7%, 
while making the correct decision in the null with a 
probability of at least 60%. 
Since the analysis is done separately for each dose and each 
indication, the probability to demonstrate efficacy in one dose 
is not affected by the other dose. Moreover, no inflation of 
the Type 1 error rate is expected in hypothetical The 
discordant scenarios where TEV-48574 is effective in 
1 indication but not in the other of Efficacy UC, Null CD and 
Null UC, Efficacy CD result in a higher rate of positive trials 
for the null indication as compared to the other relevant 
concordant scenarios.  
Clinical trial simulations were also performed under these 
assumptions for the primary analysis only (without interim 
analysis) to generate the operating characteristics (shown in 
Table 13) with a posterior probability threshold of 0.86 and 35 
patients per (dose) arm for each of UC, CD disease groups. 
both doses is ≥95%.  
The futility threshold was selected to control the 
probability to declare an effective dose to be futile at a 
maximum of 7%, while making the correct decision in 
the null with a probability of at least 60%. 
Since the analysis is done separately for each dose and 
each indication, the probability to demonstrate efficacy in 
one dose is not affected by the other dose. Moreover, no 
inflation of the Type 1 error rate is expected in 
hypothetical discordant scenarios where TEV-48574 is 
effective in 1 indication but not in the other. 
analysis model. 
Table 13 (Simulation-based Operating Characteristics for 
Primary Analysis with n = 35/arm for UC, CD: Success 
CriterionPosterior Probability (𝐸𝑚𝑎𝑥,𝑖> 0 |𝑓𝑢𝑙𝑙 𝑑𝑎𝑡𝑎) >
0.86, 𝑖= 1,2 𝑓𝑜𝑟 𝑈𝐶, 𝐶𝐷) was deleted 
Not applicable; Table 13 was deleted and subsequent 
in-text tables were renumbered, as applicable. 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
Operating Characteristics:  
These simulations demonstrate that the probability of a false 
positive is no more than 15% for the trial, with the probability 
of declaring success for both UC and CD groups at about 99%. 
Further simulations to assess the impact of varying degrees of 
borrowing (shrinkage) on the same dose response scenarios are 
tabulated below in Table 14. These simulations are for the final 
analysis only, without an interim analysis. 
Operating Characteristics:  
Not applicable; this section was deleted. 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
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Table 14 (Additional Simulation-based Operating 
Characteristics for Primary Analysis with n = 35/arm for UC, 
CD: Success Criterion  Posterior Probability (𝑬𝒎𝒂𝒙,𝒊>
𝟎 |𝒇𝒖𝒍𝒍 𝒅𝒂𝒕𝒂) > 𝟎. 𝟖𝟔, 𝒊= 𝟏, 𝟐 𝒇𝒐𝒓 𝑼𝑪, 𝑪𝑫) was deleted. 
Not applicable; Table 14 was deleted. 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
Operating Characteristics:  
These additional simulations demonstrate that:  
• 
The family-wise error rate remains close to 15% in 
instances of increased borrowing (ie, half 
Cauchy(0, 0.5)) or low borrowing (ie, under half 
Cauchy(0, 6)).  
• 
Under increased borrowing, the discordant scenarios 
result in a higher rates of positive results for CD as 
compared to lower borrowing (ie, under half Cauchy 
(0, 6) or under half Cauchy (0, 2) in Table 13).  
Further simulations provided below involve independent (ie, 
by UC, CD) analyses using: 
• 
Bayesian Emax model  no borrowing between UC and 
CD with same posterior probability threshold  
 
Success criteria (applied separately to each 
population): posterior  
Prob(Difference in Response proportions for 
TEV 48574 dose  Placebo > 0|data) > 0.86 
• 
Response Proportion Difference between active dose 
groups and placebo (frequentist framework) 
− 
Success Criterion: at least one Agresti-Caffo 90% 
CI for difference in proportions (relative to 
placebo) has lower limit > 0  
• 
Cochran Armitage Trend test (one sided increasing at 
Operating Characteristics:  
Not applicable; this section was deleted. 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
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type I error rate = 0.15).  
− 
Success Criterion: p-value for 1-sided Cochran-
Armitage test of increasing trend is < 0.15 
These simulations are for the final analysis only, without an 
interim analysis (Table 15). 
Table 15 (Operating Characteristics with n=35/group for 
Separate Analysis of UC and CD [ie, No Borrowing]) was 
deleted. 
Not applicable; Table 15 was deleted. 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
Operating Characteristics:  
Comparing these simulations with the primary analysis, it can 
be noted that  
• 
In the complete null case, the proposed primary 
analysis (hierarchical Emax with borrowing) provides 
stronger control of the family wise type I error rate 
(<14% ) than the independent (by indication) analyses 
• 
In the scenario #2 (employed in powering the study), 
the proposed primary analysis (hierarchical Emax with 
borrowing) gains a small amount in power relative to 
the separate (by UC, CD) Bayesian Emax model and 
Cochran-Armitage trend test, and a measurable 
advantage in power over the analysis of difference in 
proportions 
• 
In the discordant scenario #3, as expected, the 
separate (ie, by UC, CD) analyses for all three models 
result in a lower false positive rate for CD relative to 
the primary analysis. 
Operating Characteristics:  
Not applicable; this section was deleted 
Operating characteristics 
throughout Appendix N were 
revised following the removal of 
the 1800 mg Q2W treatment arm 
and change in the primary 
analysis model. 
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Reason/Justification for change 
• 
Regardless of the scenarios considered, one observes 
that the Emax model provides consistent operating 
characteristics as compared to Difference in 
proportions or Cochran-Armitage test, thus increasing 
the likelihood of identifying the dose correctly for 
Phase 3 confirmatory trials. 
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17.6. 
Amendment 02 Dated 13 January 2023  
The protocol was amended for the following reasons:  
• Revise the definition of endoscopic response for the primary CD endpoint as a reduction 
in Simple Endoscopic Score for Crohn’s Disease (SES-CD) of >50% from baseline 
• Amend the primary estimand to include the same strategy to handle the intercurrent event 
of treatment discontinuation regardless of the reason  
• Amend the primary estimand to include the intercurrent event of CD surgery 
• Clarify collection procedures for adverse events and concomitant medication for patients 
rolling over into the long-term extension study 
• Add serious infections to the list of protocol-defined adverse events of special interest 
• Redefine the patient population cut-off point for the futility analysis from “at least 50%” 
to “at least 44 patients (approximately 30%)” 
• Revise the futility analysis and futility rule with a corresponding update to the operating 
characteristics in Appendix N 
• Update the safety stopping rules to be based on totality of safety data rather than solely 
on the proposed study stopping rules 
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc.) have been made to the 
protocol (and protocol synopsis, as appropriate). Table 1 (Study Procedures and Assessments) 
has been revised to reflect changes described below.  
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Section 2.1 Primary and Secondary Study Objectives and Endpoints 
Primary endpoint: CD 
Endoscopic response at week 14 in patients with moderate to 
severe CD, defined as a reduction from baseline in Simple 
Endoscopic Score for Crohn’s Disease (SES-CD) of at least >50% 
from baseline 
Primary Endpoint: CD 
Endoscopic response at week 14 in patients with moderate to 
severe CD, defined as a reduction in Simple Endoscopic 
Score for Crohn’s Disease (SES-CD) of >50% from baseline 
Health authority (FDA) advice and 
information request dated 
29Nov2022 – update to >50% 
reduction from baseline in SES-CD 
as primary CD endpoint. 
Section 2.1.1 Justification of Primary Endpoints 
… 
The selected primary endpoint for patients with moderate to severe 
CD is endoscopic response, defined as a reduction from baseline in 
Simple Endoscopic Score for Crohn’s Disease (SES-CD) of at 
least >50% from baseline. 
… 
The selected primary endpoint for patients with moderate to 
severe CD is endoscopic response, defined as a reduction in 
Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 
>50% from baseline. 
Health authority (FDA) advice and 
information request dated 
29Nov2022 – update to >50% 
reduction from baseline in SES-CD 
as primary CD endpoint. 
Section 2.2 Primary Estimand 
… 
Handling of intercurrent events: Intercurrent events addressed here 
are (a) use of rescue medication; and (b) important protocol 
deviations; (c) UC only: or CD related surgery; and (d) treatment 
discontinuation due to lack of efficacy or adverse events. These 
intercurrent events will be addressed as follows: (a) Patients who 
used rescue medications prior to their week 14 evaluation of 
response (clinical remission in the UC group and prior to the week 
14 evaluation of endoscopic response in the CD group) will be 
reported as non-responders, ie, the composite variable strategy; 
and (b) Patients experiencing any important protocol deviations, 
namely, use or changes in other medications, will be analyzed as if 
the deviation had not occurred, ie, treatment policy strategy; (c) 
UC only: Patients undergoing UC or CD related surgery will be 
treated as non-responders, ie, the composite strategy; and (d) 
Patients discontinuing treatment due to lack of efficacy or adverse 
events, regardless of the reason, will be treated as non-
responders, ie, the composite strategy. 
… 
Handling of intercurrent events: Intercurrent events 
addressed here are (a) use of rescue medication; (b) 
important protocol deviations; (c) UC or CD related surgery; 
and (d) treatment discontinuation. These intercurrent events 
will be addressed as follows: (a) Patients who used rescue 
medications prior to their week 14 evaluation of response 
(clinical remission in the UC group and prior to the week 14 
evaluation of endoscopic response in the CD group) will be 
reported as non-responders, ie, the composite variable 
strategy; (b) Patients experiencing any important protocol 
deviations, namely, use or changes in other medications, will 
be analyzed as if the deviation had not occurred, ie, 
treatment policy strategy; (c) Patients undergoing UC or CD 
related surgery will be treated as non-responders, ie, the 
composite strategy; and (d) Patients discontinuing treatment, 
regardless of the reason, will be treated as non-responders, 
ie, the composite strategy. 
Treatment discontinuation: 
Health authority (FDA) advice and 
information request dated 
29Nov2022 – use the same strategy 
to handle the intercurrent event of 
treatment discontinuation regardless 
of the reason. 
 
CD-related surgery: Correction as 
surgery is applicable to both disease 
groups. 
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Section 3.1 General Study Design and Study Schematic Diagram 
… 
Treatment and Follow-Up Period:  
During the 14-week treatment period, patients will visit the site 
Q2W on days 1, 15, 29, 43, 57, 71, and 85 (±3 days) for IMP 
administration (7 visits), as well as an end-of-treatment visit on 
day 99 (±3 days; week 14) (Table 1). After the end of the 14-week 
treatment period, patients may be offered the option to enter a 
long-term extension study (to be described in a separate protocol). 
If they choose to enter (sign the extension study informed consent 
form [ICF]) and will subsequently be randomized into the 
long-term extension study, they will not need to complete the 
follow-up visit in this study. All other patients will return to the 
site for a follow-up visit (day 127 [±14 days]). For those patients 
who enter the long-term extension study, adverse events and 
concomitant medication data will be recorded in the dose-
ranging study case report form (CRF) up until the date of 
extension study randomization (defined as the study completion 
date for the dose-ranging study). For those patients who screen 
fail the long-term extension study, adverse events and 
concomitant medication data will be recorded in the dose-
ranging study up until the follow-up visit (day 127 [±14 days]) 
CRF. Patients who complete the last scheduled follow-up visit 
will be considered to have completed the study. 
… 
Treatment and Follow-Up Period:  
During the 14-week treatment period, patients will visit the 
site Q2W on days 1, 15, 29, 43, 57, 71, and 85 (±3 days) for 
IMP administration (7 visits), as well as an end-of-treatment 
visit on day 99 (±3 days; week 14) (Table 1). After the end 
of the 14-week treatment period, patients may be offered the 
option to enter a long-term extension study (to be described 
in a separate protocol). If they choose to enter (sign the 
extension study informed consent form [ICF]) and will 
subsequently be randomized into the long-term extension 
study, they will not need to complete the follow-up visit in 
this study. All other patients will return to the site for a 
follow-up visit (day 127 [±14 days]). For those patients who 
enter the long-term extension study, adverse events and 
concomitant medication data will be recorded in the dose-
ranging study case report form (CRF) up until the date of 
extension study randomization (defined as the study 
completion date for the dose-ranging study). For those 
patients who screen fail the long-term extension study, 
adverse events and concomitant medication data will be 
recorded in the dose-ranging study up until the follow-up 
visit (day 127 [±14 days]) CRF. Patients who complete the 
last scheduled visit will be considered to have completed the 
study. 
Clarification of data collection 
procedures for patients rolling into 
the long-term extension study. 
Section 3.1 General Study Design and Study Schematic Diagram, Figure 2 
Note: After the end of the 14-week treatment period, patients may 
be offered the option to enter a long-term extension study (to be 
described in a separate protocol). If they choose to enter (sign the 
extension study ICF) and will subsequently be randomized into 
the long-term extension study, they will not need to complete the 
follow-up visit in this study. All other patients will return to the 
site for a follow-up visit (day 127 [±14 days]). 
Note: After the end of the 14-week treatment period, patients 
may be offered the option to enter a long-term extension 
study (to be described in a separate protocol). If they choose 
to enter (sign the extension study ICF) and will subsequently 
be randomized into the long-term extension study, they will 
not need to complete the follow-up visit in this study. All 
other patients will return to the site for a follow-up visit 
(day 127 [±14 days]). 
Clarification of data collection 
procedures for patients rolling into 
the long-term extension study. 
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Section 3.5, Schedule of Study Procedures and Assessments, Table 1 
Footnote a: 
After the end of the 14-week treatment period, patients may be 
offered the option to enter a long-term extension study (to be 
described in a separate protocol). If they choose to enter (sign the 
extension study ICF) and will subsequently be randomized into 
the long-term extension study, they will not need to complete the 
follow-up visit in this study. All other patients will return to the 
site for a follow-up visit (day 127 [±14 days]). 
Footnote a: 
After the end of the 14-week treatment period, patients may 
be offered the option to enter a long-term extension study (to 
be described in a separate protocol). If they choose to enter 
(sign the extension study ICF) and will subsequently be 
randomized into the long-term extension study, they will not 
need to complete the follow-up visit in this study. All other 
patients will return to the site for a follow-up visit (day 127 
[±14 days]). 
Clarification of data collection 
procedures for patients rolling into 
the long-term extension study. 
Footnote t:  
For each patient, adverse events will be captured from signature of 
the ICF to the end of study (ie, patient’s last visit). For those 
patients who enter the long-term extension study, adverse events 
will be recorded in the dose-ranging study CRF up until the date 
of extension study randomization (defined as the study 
completion date for the dose-ranging study). For those patients 
who screen fail the long-term extension study, adverse events 
will be recorded in the dose-ranging study up until the follow-up 
visit (day 127 [±14 days]) CRF. 
Footnote t:  
For each patient, adverse events will be captured from 
signature of the ICF to the end of study (ie, patient’s last 
visit). For those patients who enter the long-term extension 
study, adverse events will be recorded in the dose-ranging 
study CRF up until the date of extension study 
randomization (defined as the study completion date for the 
dose-ranging study). For those patients who screen fail the 
long-term extension study, adverse events will be recorded 
in the dose-ranging study up until the follow-up visit (day 
127 [±14 days]) CRF. 
Clarification of adverse event 
collection procedures for patients 
rolling into the long-term extension 
study. 
See new wording column 
Footnote u was added as described below: 
u For each patient, concomitant medication data will be 
captured from signature of the ICF to the end of study (ie, 
patient’s last visit). For those patients who enter the 
long-term extension study, concomitant medication data will 
be recorded in the dose-ranging study CRF up until the date 
of extension study randomization (defined as the study 
completion date for the dose-ranging study). For those 
patients who screen fail the long-term extension study, 
concomitant medication data will be recorded in the dose-
ranging study up until the follow-up visit (day 
127 [±14 days]) CRF. 
Subsequent footnotes were re-lettered. 
Added footnote to clarify 
concomitant medication collection 
procedures for patients rolling into 
the long-term extension study. 
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Section 7.1.10.1 Protocol-Defined Adverse Events of Special Interest that Require Reporting to Sponsor’s Global Patient Safety and Pharmacovigilance 
… 
• 
opportunistic or severe and/or serious infections 
 
… 
Opportunistic or severe and/or serious infections 
… 
• 
opportunistic or severe and/or serious infections 
 
… 
• 
Opportunistic or severe and/or serious infections 
Health authority (FDA) advice and 
information request dated 
29Nov2022 – include serious 
infections as protocol-defined 
adverse events of special interest.  
Section 9.1 Sample Size and Power Considerations 
A total study sample size of 280 patients is planned, with 140 
patients (35 patients per dose arm) each for the 2 indications 
disease groups of UC and CD. 
A total study sample size of 280 patients is planned, with 
140 patients (35 patients per dose arm) each for the 2 disease 
groups of UC and CD. 
Correction. 
Simulation-based operating characteristics for the analysis of the 
primary efficacy variable using a Bayesian hierarchical 
3-parameter Emax model for the interim and final analysis, with a 
posterior probability futility cutoff of 0.55 for each disease group 
and final success posterior probability cutoff of 0.86, are 
presented in Table 10. The indicate a family-wise false-positive 
rate (ie, probability of at least 1 false-positive conclusion under 
the global null assumption) of is no more than 15% 12%, and the 
probability of declaring success for both UC and CD groups at 
about 99% is 94%, under the assumptions stated above. 
Simulation-based operating characteristics for the analysis of 
the primary efficacy variable using a Bayesian hierarchical 
3-parameter Emax model for the interim and final analysis, 
with a posterior probability futility cutoff of 0.55 for each 
disease group and final success posterior probability cutoff 
of 0.86, are presented in Table 10. The family-wise 
false-positive rate (ie, probability of at least 1 false-positive 
conclusion under the global null assumption) is no more 
than 12%, and the probability of declaring success for both 
UC and CD groups is 94%, under the assumptions stated 
above. 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
revised to allow the Sponsor to 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
See new wording column. 
Table 10 (Operating Characteristics of Interim and Final 
Analysis) was added to Section 9.1 to provide additional 
details on the operating characteristics of the interim and 
final analyses (ie, the probability to stop for futility or be 
successful at final). 
 
Subsequent in-text tables were renumbered. 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
revised to allow the Sponsor to 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
Under a less optimistic scenario for mid- and high-dose groups, 
when the clinical remission rate in the UC group is reduced to 
20% (from 30%) and endoscopic response rate in the CD group is 
Under a less optimistic scenario for mid- and high-dose 
groups, when the clinical remission rate in the UC group is 
reduced to 20% (from 30%) and endoscopic response rate in 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
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reduced to 25% (from 34%), while maintaining the identical 
response rates for placebo and low-dose (in both UC and CD 
groups), the probability of declaring success in both UC and CD 
groups is about 83%69%. 
Note that in the computation of operating characteristics 
summarized above, study success is defined as a posterior 
probability threshold of 0.86 for the population level summary 
(defined in the primary estimand).  
Details regarding the statistical decision criteria and Bayesian 
hierarchical model, including priors and hyper-priors used in the 
computation of the operating characteristics, are provided in 
Appendix N. The operating characteristics under additional 
scenarios, including discordant scenarios where the treatment is 
effective only in one disease group, are presented in Appendix N. 
the CD group is reduced to 25% (from 34%), while 
maintaining the identical response rates for placebo and 
low-dose (in both UC and CD groups), the probability of 
declaring success in both UC and CD groups is about 69%. 
Details regarding the statistical decision criteria and 
Bayesian hierarchical model, including priors and hyper-
priors used in the computation of the operating 
characteristics, are provided in Appendix N. The operating 
characteristics under additional scenarios, including 
discordant scenarios where the treatment is effective only in 
one disease group, are presented in Appendix N. 
revised to allow the Sponsor to 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
Section 9.13 Planned Interim Analysis 
Interim analyses for safety and efficacy are planned for this study. 
An interim efficacy analysis for futility is planned in each disease 
group (UC and CD) when at least 50% of 44 patients 
(approximately 30%) in that group has have completed the 14-
week primary efficacy readout or had the opportunity to do so.  
Interim analysis futility criterion is defined by  
𝑃𝑜𝑠𝑡𝑒𝑟𝑖𝑜𝑟 𝑃𝑟𝑜𝑏𝑎𝑏𝑖𝑙𝑖𝑡𝑦 (𝑝𝑑,𝑖> 𝑝0,𝑖 | 𝐼𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎) <
0.45 𝑓𝑜𝑟 𝑖= 1 𝑎𝑛𝑑 2 (𝑝𝑑,𝑖  denotes the probability of response for 
dose d = 0, 1, 2, 3 for placebo, low, mid, and high doses).  
Simulation-based operating characteristics indicate the probability 
of incorrectly stopping the study for futility is about 0.1%, 
whereas the probability of correctly stopping the study at the 
interim analysis is about 13.8%. Further details regarding the 
assumptions and futility decision criteria are provided in Appendix 
N.  
In the interim analysis, the same Bayesian hierarchical Emax 
dose-response model used as the primary analysis model will be 
used to analyze the primary efficacy variable (clinical remission 
for UC and endoscopic response for CD, hereafter denoted as 
Interim analyses for safety and efficacy are planned for this 
study. An interim efficacy analysis for futility is planned in 
each disease group (UC and CD) when at least 44 patients 
(approximately 30%) in that group have completed the 
14-week primary efficacy readout or had the opportunity to 
do so.  
In the interim analysis, the same Bayesian hierarchical Emax 
dose-response model used as the primary analysis model 
will be used to analyze the primary efficacy variable 
(clinical remission for UC and endoscopic response for CD, 
hereafter denoted as “response”) for each disease group. The 
futility criterion for each disease group is: 
• 
If the posterior probability 
𝑃(𝐸𝑚𝑎𝑥,𝑖> 0|𝑖𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎) for disease group i is 
<0.55, then the corresponding disease group is 
futile. 
An analysis of each disease group independently will be 
performed at the interim analysis for the disease group as a 
supporting analysis, as follows: 
The interim analysis timing, 
method, and cutoff were updated to 
allow the Sponsor to offset any 
potential adverse impacts of 
uncertainty associated with patient 
accrual on a timely assessment of 
futility. 
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“response”) for each disease group. The futility criterion for 
each disease group is: 
• 
If the posterior probability 
𝑷(𝑬𝒎𝒂𝒙,𝒊> 𝟎|𝒊𝒏𝒕𝒆𝒓𝒊𝒎 𝒅𝒂𝒕𝒂) for disease group i is 
<0.55, then the corresponding disease group is futile. 
An analysis of each disease group independently will be 
performed at the interim analysis for the disease group as a 
supporting analysis, as follows: 
• 
A Beta-Binomial model with a non-informative prior 
Beta(1,1) will be fitted to the response rate π in each 
treatment group d in the disease group i, and the 
posterior probability that the response rate in each 
active group is higher than the response rate in the 
placebo group, 𝑷( 𝝅𝒅,𝒊> 𝝅𝟎,𝒊), will be calculated. 
Refer to Table 12 and Appendix N for operating characteristics 
of the interim and final analysis. 
• 
A Beta-Binomial model with a non-informative 
prior Beta(1,1) will be fitted to the response rate π 
in each treatment group d in the disease group i, 
and the posterior probability that the response rate 
in each active group is higher than the response rate 
in the placebo group, 𝑃( 𝜋𝑑,𝑖> 𝜋0,𝑖), will be 
calculated. 
Refer to Table 12 and Appendix N for operating 
characteristics of the interim and final analysis. 
Additionally periodic analysis of safety data will also be done 
during the study. Analyses will focus on the following events: 
• 
Incidence of serious adverse events 
• 
Incidence of CTCAE grade 3 or grade 4 events 
• 
Incidence of opportunistic infections and severe and/or 
serious infections 
• 
Incidence of anaphylaxis 
… 
The results will be reviewed by an IDMC comprised of external 
medical and statistical experts. The IDMC will make a 
recommendation after evaluation of the totality of available 
safety data. The details regarding the statistical analysis methods 
will be provided in the Statistical Analysis Plan. The IDMC 
charter will provide details regarding procedures to protect the 
scientific integrity of the study, conduct of the interim analysis, 
dissemination of results, and decision criteria based on the futility 
analysis. 
Additionally periodic analysis of safety data will also be 
done during the study. Analyses will focus on the following 
events: 
• 
Incidence of serious adverse events 
• 
Incidence of CTCAE grade 3 or grade 4 events 
• 
Incidence of opportunistic infections and severe 
and/or serious infections 
• 
Incidence of anaphylaxis 
... 
The results will be reviewed by an IDMC comprised of 
external medical and statistical experts. The IDMC will 
make a recommendation after evaluation of the totality of 
available safety data. The details regarding the statistical 
analysis methods will be provided in the Statistical Analysis 
Plan. The IDMC charter will provide details regarding 
procedures to protect the scientific integrity of the study, 
conduct of the interim analysis, dissemination of results, and 
decision criteria based on the futility analysis. 
CTCAE: Correction. 
 
And/or serious infections: Health 
authority (FDA) advice and 
information request dated 
29Nov2022 – include serious 
infections as protocol-defined 
adverse events of special interest. 
Additional Analyses: 
Additional Analyses: 
Clarification. 
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As part of the interim analysis for futility, the primary efficacy 
endpoints may be analyzed by the presence of TEV-48574 ligand 
or other relevant biomarkers. 
Additional endpoints, including PK and PD analysis, may also be 
provided to the IDMC as part of the interim analyses for futility or 
as requested by the IDMC. 
Pharmacokinetic (PK) and PD analysis may be provided to the 
IDMC upon request. Population PK and PD analysis will be 
performed by an external analysis group independent of the study 
team. The process to ensure the study integrity, the maintenance of 
the double blind, and the responsibilities of the external members, 
and relevant study personnel will be described in the IDMC 
charter. The details regarding the population PK or PD analysis 
will be described in the pharmacometric analysis plan. 
As part of the interim analysis for futility, the primary 
efficacy endpoints may be analyzed by the presence of TEV-
48574 ligand or other relevant biomarkers.  
Additional endpoints may also be provided to the IDMC as 
part of the interim analyses for futility. 
Pharmacokinetic (PK) and PD analysis may be provided to 
the IDMC upon request. Population PK and PD analysis will 
be performed by an external analysis group independent of 
the study team. The process to ensure the study integrity, the 
maintenance of the double blind, and the responsibilities of 
the external members and relevant study personnel will be 
described in the IDMC charter. The details regarding the 
population PK or PD analysis will be described in the 
pharmacometric analysis plan. 
Appendix N. Operating Characteristics and Assumptions for Final and Interim Analysis 
Final Analysis and Interim Futility Analysis 
Final Analysis and Interim Futility Analysis 
Clarification of subheading title. 
See new wording column. 
A new row was added to Table 11 as described below: 
• 
Added the scenario Null-UC, Efficacy CD 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
revised to allow the Sponsor to 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
See new wording column. 
A new section of Appendix N was added as described 
below: 
Number of Patients at the Interim Analysis: 
The interim analysis for each indication is planned when at 
least 44 patients (approximately 30%) in that group have 
completed the 14-week primary efficacy readout or had the 
opportunity to do so. Operating characteristics were obtained 
from simulations assuming that exactly 11 patients per arm 
in the corresponding disease group will be included in the 
interim analysis. Due to the expected difference in 
The interim analysis timing, 
method, and cutoff were updated to 
allow the Sponsor to offset any 
potential adverse impacts of 
uncertainty associated with patient 
accrual on a timely assessment of 
futility. 
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recruitment rate between UC and CD, it is assumed that at 
the time of the interim analysis for UC, data from ~20 
patients (5 patients per arm) in CD will be available; at the 
time of the interim analysis for CD, data from ~96 patients 
(24 patients per arm) in UC will be available if UC was not 
stopped for futility at the UC interim analysis. 
Statistical Decision Criteria – Final Analysis 
… 
Thus, if the Posterior Probability P (𝐸𝑚𝑎𝑥,𝑖>
0 | 𝑓𝑢𝑙𝑙 𝑑𝑎𝑡𝑎) exceeds a the pre-specified threshold of 0.86, the 
study will have met the criterion for success. The threshold is was 
selected to achieve optimal operating characteristics for the 
assumed scenarios. 
Statistical Decision Criteria – Final Analysis 
… 
Thus, if the Posterior Probability P (𝐸𝑚𝑎𝑥,𝑖>
0 | 𝑓𝑢𝑙𝑙 𝑑𝑎𝑡𝑎) exceeds the pre-specified threshold of 0.86, 
the study will have met the criterion for success. The 
threshold was selected to achieve optimal operating 
characteristics for the assumed scenarios. 
Clarification. 
See new wording column. 
A new section of Appendix N was added as described 
below: 
Statistical Futility Cutoff – Interim Analysis: 
The Bayesian hierarchical Emax model will be used in the 
futility analysis of each disease group (UC and CD). For 
each interim analysis, the available data from the patients 
that completed 14 weeks or early terminated, in both 
treatment groups, will be used. However, the futility 
decision will be for the disease group under investigation, ie, 
at the UC interim analysis only futility of UC will be tested, 
and vice versa. 
The futility decision rule is:  
If the posterior probability 𝑃(𝐸𝑚𝑎𝑥,𝑖> 0|𝑖𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎) for 
disease group i is <0.55, then the corresponding disease 
group is futile. The threshold was selected to achieve 
optimal operating characteristics for the null and efficacy 
scenarios. 
The interim analysis timing, 
method, and cutoff were updated to 
allow the Sponsor to offset any 
potential adverse impacts of 
uncertainty associated with patient 
accrual on a timely assessment of 
futility. 
See new wording column. 
New text was added to the Operating Characteristics of 
Appendix N as described below: 
Clinical trial simulations were performed under assumptions 
for the interim and primary analysis to generate the 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
revised to allow the Sponsor to 
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Reason/Justification for change 
operating characteristics (presented in Table 12), for a target 
sample size of 35 patients per arm in each indication, and an 
interim analysis for futility for each indication at 11 patients 
per group in the indication. The posterior probability futility 
cutoff is 0.55 for each disease group and final success 
posterior probability cutoff is 0.86. 
For all scenarios presented in Table 12, it is assumed that the 
Emax model is used for decision making in the interim 
analysis. 
These simulations demonstrate that the probability of a false 
positive is no more than 12% for the trial, with the 
probability of declaring success for both UC and CD disease 
groups under the high efficacy assumption at 94%. The 
discordant scenarios of Efficacy-UC, Null-CD and Null-UC, 
Efficacy-CD result in a higher rate of positive trials for the 
null indication as compared to the other relevant concordant 
scenarios. 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
See new wording column. 
Table 12 (Simulation-based Operating Characteristics for 
Interim and Final Analysis – All Scenarios) was added to the 
Operating Characteristics section of Appendix N as 
described below: 
• 
Simulations performed to generate the operating 
characteristics for a sample size of 35 patients per arm 
in the final analysis and 11 patients per group in each 
indication for the interim analysis 
• 
Probability to stop at interim analysis or to be successful 
at final analysis is presented 
Subsequent in-text tables were renumbered. 
The futility analysis and futility 
rules with a corresponding update to 
the operating characteristics were 
revised to allow the Sponsor to 
offset any potential adverse impacts 
of uncertainty associated with 
patient accrual on a timely 
assessment of futility. 
Operating Characteristics: 
… 
Clinical trial simulations were also performed under these 
assumptions for the primary analysis only (without interim 
analysis) to generate the operating characteristics (shown in Table 
11 13) with a posterior probability threshold of 0.86 and 35 
Operating Characteristics: 
… 
Clinical trial simulations were also performed under these 
assumptions for the primary analysis only (without interim 
analysis) to generate the operating characteristics (shown in 
Table 13) with a posterior probability threshold of 0.86 and 
35 patients per (dose) arm for each of UC, CD disease 
Clarification. 
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patients per (dose) arm for each of UC, CD disease groups. 
groups. 
Operating Characteristics: 
Further simulations to assess the impact of varying degrees of 
borrowing (shrinkage) on the same dose response scenarios are 
tabulated below in Table 14. These simulations are for the final 
analysis only, without an interim analysis. 
Operating Characteristics: 
Further simulations to assess the impact of varying degrees 
of borrowing (shrinkage) on the same dose response 
scenarios are tabulated below in Table 14. These simulations 
are for the final analysis only, without an interim analysis. 
Clarification. 
Operating Characteristics: 
Further simulations provided below involve independent (ie., by 
UC, CD) analyses using: 
… 
These simulations are for the final analysis only, without an 
interim analysis (Table 15). 
Operating Characteristics: 
Further simulations provided below involve independent (ie, 
by UC, CD) analyses using: 
… 
These simulations are for the final analysis only, without an 
interim analysis (Table 15). 
Clarification. 
Interim Futility Analysis 
An interim efficacy analysis for futility is planned for each 
indication (UC and CD) when at least 50% of patients (in each 
indication) complete the 14 week primary efficacy readout or 
withdrawn from the study. The futility analysis may result in 
either: 
• 
stopping the study or 
• 
stopping enrolment within a dose or an indication  
Notation and Assumptions:  
The following notations and distributional assumptions are used in 
evaluating the operating characteristics of the interim futility 
analysis: 
Let 
• 
𝑝𝑑,𝑖  denote the probability of response for dose d, where 
d = 0, 1, 2, 3 for placebo, low, mid, and high doses, and i 
= 1, 2 for UC, CD.  
• 
𝑛𝑑,𝑖 and 𝑥𝑑,𝑖 denote the sample size and number of 
responses at interim analysis 
Assuming a 𝐵𝑒𝑟𝑛𝑜𝑢𝑙𝑙𝑖(𝑝𝑑,𝑖) distribution for response (= Yes, No), 
and a 𝐵𝑒𝑡𝑎(1, 1) prior, the posterior distribution for 𝑝𝑑,𝑖 is given 
Not applicable; this section (Interim Futility Analysis) and 
its corresponding table were deleted. 
 
Subsequent in-text tables were renumbered. 
The interim analysis timing, 
method, and cutoff were updated to 
allow the Sponsor to offset any 
potential adverse impacts of 
uncertainty associated with patient 
accrual on a timely assessment of 
futility; therefore, this section was 
deleted and applicable text was 
added throughout Appendix N. 
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Reason/Justification for change 
by 𝐵𝑒𝑡𝑎(1 + 𝑥𝑑,𝑖, 1 + 𝑛𝑑,𝑖
𝑥𝑑,𝑖). 
Statistical Decision Criteria:  
• 
The trial will be deemed futile if interim results indicate: 
𝑃𝑜𝑠𝑡𝑒𝑟𝑖𝑜𝑟 𝑃𝑟𝑜𝑏𝑎𝑏𝑖𝑙𝑖𝑡𝑦 (𝑝3,𝑖> 𝑝0,𝑖 | 𝐼𝑛𝑡𝑒𝑟𝑖𝑚 𝑑𝑎𝑡𝑎) <
𝑡ℎ𝑟𝑒𝑠ℎ𝑜𝑙𝑑 𝑓𝑜𝑟 𝑖= 1 𝑎𝑛𝑑 2. 
• 
Individual indications may be deemed futile if this 
criterion is achieved for either 𝑖= 1 𝑜𝑟 2. 
The threshold is selected to achieve optimal operating 
characteristics for the assumed scenarios.  
Operating Characteristics: 
With a posterior probability threshold of 0.45 and 18 patients per 
(dose) arm for each of UC, CD indications, the simulation-based 
operating characteristics for high dose are provided in the Table 14 
below. 
See new wording column. 
Table 16 (Posterior Probability of Adverse Events) of 
Appendix N was renumbered based on table 
additions/deletions explained above and revised as described 
below: 
• 
Classified grade 3 and 4 adverse events as CTCAE 
• 
Added serious infections to AE type 
Clarification. 
Safety Stopping Rules 
… 
• 
The DMC will review in detail any safety signal that meets 
the safety stopping rule, taking and take into account the 
totality of safety and efficacy data. Additional analyses, eg, 
SAEs in the same HLT, may be performed. 
• 
The DMC will make a recommendation if the safety signal 
and the totality of the safety data warrants stopping the 
dose/indication/study. 
Safety Stopping Rules 
… 
• 
The DMC will review in detail any safety signal that 
meets the safety stopping rule, and take into account the 
totality of safety data. Additional analyses, eg, SAEs in 
the same HLT, may be performed. 
• 
The DMC will make a recommendation if the safety 
signal and the totality of the safety data warrants 
stopping the dose/indication/study. 
Health authority (FDA) advice and 
information request dated 
29Nov2022 – stopping the study for 
safety should be based on totality of 
safety data. 
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17.7. 
Amendment 01 Dated 13 June 2022  
The protocol was amended for the following reasons:  
• Clarification of the objectives and endpoints  
• Inclusion of additional efficacy assessments using non-invasive measures  
• Change in the grading method for AE severity  
• Inclusion of subject (individual) and study stopping rules 
• Inclusion of severe infections to the list of adverse events of special interest  
• Additional scenarios for operating characteristics and revisions to the description of the 
interim analyses including establishing an IDMC for unblinded data monitoring 
• Updates to the inclusion and exclusion criteria  
• Updates for the estimand  
• Inclusion of information on the SC infusion method/device, infusion duration, and 
infusion rate  
• Addition of a description of the proposed time and storage conditions between study drug 
dilution and administration 
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc) have been made to the 
protocol (and protocol synopsis, as appropriate). Table 1 (Study Procedures and Assessments) 
has been revised to reflect changes described below. 
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Reason/Justification for change 
Section 2.1. Primary and Secondary Study Objectives and Endpoints 
The primary objective of the study is to evaluate characterize 
the efficacy and dose response of 3 different dose regimens of 
TEV-48574 sc administered every 2 weeks (Q2W) and to 
evaluate the efficacy in adult patients with inflammatory bowel 
disease (IBD; (IBD with moderate to severe ulcerative colitis 
[UC] or Crohn’s disease [CD])), as assessed by induction of 
clinical remission (UC) and endoscopic response (CD) at week 
14. 
The primary objective of the study is to 
characterize the dose response of TEV-48574 sc 
administered Q2W and to evaluate the efficacy in 
adult patients with IBD (IBD with moderate to 
severe UC or CD), as assessed by induction of 
clinical remission (UC) and endoscopic response 
(CD) at week 14. 
Clarification. Objective updated to 
remove dose response of 3 different 
doses. 
Endoscopic response at week 14 in patients with moderate to 
severe CD, defined as a reduction from baseline in Simple 
Endoscopic Score for Crohn’s Disease (SES-CD) of > at least 
50% 
Endoscopic response at week 14 in patients with 
moderate to severe CD, defined as a reduction 
from baseline in Simple Endoscopic Score for 
Crohn’s Disease (SES-CD) of at least 50% 
Clarification. Reduction from baseline in 
Simple Endoscopic Score for Crohn’s 
Disease (SES-CD) updated. 
The secondary efficacy endpoints to be measured in patients 
with moderate to severe UC are as follows: 
• 
Clinical response defined as decrease from baseline of 
at least 50% in 2-item patient-reported outcome 
(PRO2; rectal bleeding and stool frequency) at weeks 
2, 4, 6, 8, 10, 12 and 14  
• 
Clinical remission defined as score of rectal bleeding 
= 0 and stool frequency = 0 on the PRO2 scale at 
weeks 2, 4, 6, 8, 10, 12 and 14  
The secondary efficacy endpoints to be measured in patients 
with moderate to severe CD are as follows: 
• 
Clinical response defined as a ≥100-point decrease in 
Crohn’s Disease Activity Index (CDAI) score from 
baseline at week 14 weeks 2, 4, 6, 8, 10, 12 and 14   
• 
Clinical remission defined as a CDAI score ≤<150 at 
week 14  
• 
Endoscopic remission defined as SES- CD: <3 points 
or the absence score of ulcerations (0-2, or SES- CD 
ulceration subscore = 0) score of 0-4, with no 
individual sub score >1 at week 14 
• 
Clinical response defined as a decrease from baseline 
The secondary efficacy endpoints to be measured 
in patients with moderate to severe UC are as 
follows: 
• 
Clinical response defined as decrease 
from baseline of at least 50% in 2-item 
patient-reported outcome (PRO2; rectal 
bleeding and stool frequency) at weeks 2, 
4, 6, 8, 10, 12 and 14  
• 
Clinical remission defined as score of 
rectal bleeding = 0 and stool frequency = 
0 on the PRO2 scale at weeks 2, 4, 6, 8, 
10, 12 and 14  
The secondary efficacy endpoints to be measured 
in patients with moderate to severe CD are as 
follows: 
• 
Clinical response defined as a ≥100-point 
decrease in Crohn’s Disease Activity 
Index (CDAI) score from baseline at 
weeks 2, 4, 6, 8, 10, 12 and 14   
• 
Clinical remission defined as a CDAI 
score <150 at week 14  
• 
Endoscopic remission defined as SES CD 
Update. The secondary efficacy 
endpoints updated to include more 
assessment times.  
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Reason/Justification for change 
of at least 50% in PRO2 (PRO2 is defined as having 2 
components, abdominal pain and stool frequency) at 
weeks 2, 4, 6, 8, 10, 12 and 14  
• 
Clinical remission defined as abdominal pain ≤1 and 
stool frequency ≤3 on the PRO2 scale at weeks 2, 4, 
6, 8, 10, 12 and 14  
• 
Endoscopic response defined as a decrease in 
modified multiplier (MM)-SES-CD of  >50% from 
baseline at week 14  
• 
Histologic response defined as a ≥50% decrease in 
Global Histologic Activity Score from baseline at 
week 14 
score of 0-2, or SES CD score of 0-4, 
with no individual sub score >1 at 
week 14  
• 
Clinical response defined as a decrease 
from baseline of at least 50% in PRO2 
(PRO2 is defined as having 2 
components, abdominal pain and stool 
frequency) at weeks 2, 4, 6, 8, 10, 12 and 
14  
• 
Clinical remission defined as abdominal 
pain ≤1 and stool frequency ≤3 on the 
PRO2 scale at weeks 2, 4, 6, 8, 10, 12 and 
14  
• 
Endoscopic response defined as a 
decrease in modified multiplier (MM)-
SES-CD of  >50% from baseline at 
week 14  
• 
Histologic response defined as a ≥50% 
decrease in Global Histologic Activity 
Score from baseline at week 14 
Section 2.1.1.Justification of Primary Endpoints 
The selected primary endpoint for patients with moderate to 
severe CD is endoscopic response, defined as a reduction from 
baseline in Simple Endoscopic Score for Crohn’s Disease (SES 
CD) of > at least 50%. 
The selected primary endpoint for patients with 
moderate to severe CD is endoscopic response, 
defined as a reduction from baseline in Simple 
Endoscopic Score for Crohn’s Disease (SES CD) 
of at least 50%. 
Update. Text updated to include revised 
primary endpoint. 
Section 2.2. Primary Estimand 
Variable: Response for the primary efficacy analysis is 
defined as clinical remission status at week 14 for UC patients 
or endoscopic response status at week 14 for CD patients, 
when not receiving rescue medications prior to the week 14 
assessment. 
Variable: Response for the primary efficacy 
analysis is defined as clinical remission status at 
week 14 for UC patients or endoscopic response 
status at week 14 for CD patients. 
Clarification. Response variable updated. 
• Handling of intercurrent events: Intercurrent events addressed 
here are (a) use of rescue medication and (b) other important 
Handling of intercurrent events: Intercurrent 
events addressed here are (a) use of rescue 
Update. Primary estimand updated to 
reflect the latest guidance documents for 
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Reason/Justification for change 
protocol deviations (c) UC only: UC related surgery (d) 
discontinuation due to lack of efficacy or adverse events. These 
intercurrent events will be addressed as follows: (a) Patients 
who used rescue medications prior to their week 14 evaluation 
of response (clinical remission in the UC group and prior to the 
week 14 evaluation of endoscopic response in the CD group) 
will be reported as non responders, ie, the composite variable 
strategy; and (b) Patients experiencing any other important 
protocol deviations, including namely, use or changes in other 
medications, will be analyzed as if the deviation had not 
occurred, ie, treatment policy strategy. (c) UC only: Patients 
undergoing UC related surgery will be treated as non-
responders, ie, the composite strategy (d) Patients 
discontinuing treatment due to lack of efficacy or adverse 
events will be treated as non-responders, ie, the composite 
strategy 
medication and (b) important protocol deviations 
(c) UC only: UC related surgery (d) 
discontinuation due to lack of efficacy or adverse 
events. These intercurrent events will be addressed 
as follows: (a) Patients who used rescue 
medications prior to their week 14 evaluation of 
response (clinical remission in the UC group and 
prior to the week 14 evaluation of endoscopic 
response in the CD group) will be reported as 
non-responders, ie, the composite variable 
strategy; and (b) Patients experiencing any 
important protocol deviations, namely, use or 
changes in other medications, will be analyzed as 
if the deviation had not occurred, ie, treatment 
policy strategy (c) UC only: Patients undergoing 
UC related surgery will be treated as non-
responders, ie, the composite strategy (d) Patients 
discontinuing treatment due to lack of efficacy or 
adverse events will be treated as non-responders, 
ie, the composite strategy 
developing treatments for UC and CD. 
The population-level summary of interest is the quantity 
Posterior Probability (𝑝𝑑,𝑖−𝑝0,𝑖> 0) (𝐸𝑚𝑎𝑥,𝑖, > 0) estimated 
from a Bayesian hierarchical 3-parameter Emax model (with 
𝐸0,𝑖, 𝐸𝐷50,𝑖 and 𝐸𝑚𝑎𝑥,𝑖, 𝑖= 1,2 𝑓𝑜𝑟 𝑈𝐶, 𝐶𝐷) for the logit of 
response rate. 𝑝𝑑,𝑖 denotes either the clinical remission (for 
UC) or endoscopic response rate (for CD) and doses d =0,1,2,3 
represent placebo, low, mid, and high doses of TEV-48574. 
The population-level summary of interest is the 
quantity Posterior Probability (𝑝𝑑,𝑖−𝑝0,𝑖> 0) 
estimated from a Bayesian hierarchical 
3-parameter Emax model (with 𝐸0,𝑖, 𝐸𝐷50,𝑖 and 
𝐸𝑚𝑎𝑥,𝑖, 𝑖= 1,2 𝑓𝑜𝑟 𝑈𝐶, 𝐶𝐷) for the logit of 
response rate. 𝑝𝑑,𝑖 denotes either the clinical 
remission (for UC) or endoscopic response rate 
(for CD) and doses d =0,1,2,3 represent placebo, 
low, mid, and high doses of TEV-48574. 
Update. Population level summary 
updated. 
Section 2.3.Exploratory Objectives and Endpoints 
An exploratory objective of the study is to obtain trough serum 
TEV 48574 concentrations, to evaluate population 
pharmacokinetics compare major pharmacokinetic (PK) 
characteristics between UC and CD patients with healthy 
volunteers and asthma patients, and, if data allows, to evaluate 
An exploratory objective of the study is to obtain 
trough serum TEV-48574 concentrations, to 
compare major PK characteristics between UC and 
CD patients with healthy volunteers and asthma 
patients, and, if data allows, to evaluate the 
pharmacokinetics/pharmacodynamics and/or 
Update. Exploratory objective revised. 
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Reason/Justification for change 
the pharmacokinetics/pharmacodynamics and/or exposure-
response relationship of 3 different dose regimens of TEV-
48574 sc. 
exposure-response relationship of 3 different dose 
regimens of TEV-48574 sc. 
• Population pharmacokinetic-pharmacodynamic parameters 
• Exposure-response parameters 
• Population pharmacokinetic-pharmacodynamic 
parameters 
• Exposure-response parameters 
Update.  Exploratory endpoint added. 
Section 3.3 Justification for Study Design and Selection of Population 
In this study, an An overall primary efficacy analysis 
incorporating all data from both indications will be performed 
using a Bayesian hierarchical model. The estimated treatment 
effects and corresponding estimated standard errors for UC and 
for CD derived from separate per-indication analyses will be 
input to a hierarchical model to re-estimate the treatment 
effects using empirical Bayes shrinkage estimators, as 
described in Section 9.5.4.1. 
In this Phase 2 dose-range study, a functional relationship 
(namely Emax model) between the doses is assumed. While 
there are many options for specifying these relationships (i.e., 
Emax, logistic, exponential etc.), the Emax model (with Hill 
parameter close to 1) has been shown to provide a good fit 
across a range of pharmaceutical studies (Thomas et al 2014). 
Additionally, as demonstrated in Gajewski et al (2019), the 
Emax model performs adequately when non-monotonicity is not 
expected, thereby resulting in a higher likelihood of identifying 
the correct dose. Further, previously conducted phase 2 trial for 
Tofacitinib (Sandborn et al 2013) has implemented such an 
approach to characterize the dose response and to identify 
efficacious doses via Emax models. 
An overall primary efficacy analysis incorporating 
all data from both indications will be performed 
using a Bayesian hierarchical model. 
 
In this Phase 2 dose-range study, a functional 
relationship (namely Emax model) between the 
doses is assumed. While there are many options 
for specifying these relationships (i.e., Emax, 
logistic, exponential etc.), the Emax model (with 
Hill parameter close to 1) has been shown to 
provide a good fit across a range of pharmaceutical 
studies (Thomas et al 2014). Additionally, as 
demonstrated in Gajewski et al (2019), the Emax 
model performs adequately when non-
monotonicity is not expected, thereby resulting in 
a higher likelihood of identifying the correct dose. 
Further, previously conducted phase 2 trial for 
Tofacitinib (Sandborn et al 2013) has implemented 
such an approach to characterize the dose response 
and to identify efficacious doses via Emax models.   
Addition. Text added to justify study 
design. 
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New wording 
Reason/Justification for change 
Section 3.4. Stopping Rules for the Study 
3.4.1. 
Individual Stopping Criteria 
3.4.1. 
Individual Stopping Criteria 
Addition. Section describing the 
stopping criteria for individual patients 
added.  
3.4.2. 
Study Stopping Criteria 
3.4.2. 
Study Stopping Criteria 
Addition. Section describing stopping 
criteria for the study added. 
Table 1 
±3 days based on day 1 previous visit 
Table 1 
±3 days based on previous visit 
Update. Timing for visits during the 
induction period updated. 
Table 1 
±14 days based on day 1 previous visit 
Table 1 
±14 days based on previous visit 
Update. Timing of the follow-up visit 
updated. 
Table 1 
Row: Stool frequency and Rectal bleeding Mayo sub-scores 
(PRO2 UC) i 
Assessments added at Visits 2 to 8 
Table 1 
Row: Stool frequency and Rectal bleeding Mayo 
sub-scores (PRO2 UC) i 
Assessments added at Visits 2 to 8 
Addition. PRO2 split across two rows 
and additional assessments included. 
Table 1 
Row: CDAI score (CD only) 
Assessments added at Visits 2 to 7 
Table 1 
Row: CDAI score (CD only) 
Assessments at Visits 2 to 7 
Addition. Additional assessments added. 
Table 1 
Row: Stool frequency and Abdominal pain  
(PRO2 CD) i 
Assessments added at Visits 2 to 8 
Table 1 
Stool frequency and Abdominal pain  
(PRO2 CD) i 
Assessments added at Visits 2 to 8 
Addition. PRO2 split across two rows 
and additional assessments included. 
Table 1 
Row: PRO2 (UC and CD)d  
Table 1 
Row removed 
Update. PRO2 split across two rows. 
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Reason/Justification for change 
mClinical laboratory tests include serum chemistry and 
hematology. Patients should be fasting for at least 8 hours prior 
to safety laboratory assessments only at the screening, week 
14, and early termination visits (ie, visits at which low density 
lipoprotein, high density lipoprotein, and triglycerides will be 
measured). Coagulation tests (PT/PTT/INR) will be performed 
at screening only. or in case of suspected liver injury (see 
Appendix M). 
mClinical laboratory tests include serum chemistry 
and hematology. Patients should be fasting for at 
least 8 hours prior to safety laboratory assessments 
only at the screening, week 14, and early 
termination visits (ie, visits at which low density 
lipoprotein, high density lipoprotein, and 
triglycerides will be measured). Coagulation tests 
(PT/PTT/INR) will be performed at screening only 
or in case of suspected liver injury (see Appendix 
M). 
Update. Footnote updated to state when 
coagulation tests will be performed. 
Section 4.1. Patient Inclusion Criteria 
c. UC patients only: Patient with moderate to severe active UC 
as defined by the 3 component modified Mayo score of 5 to 9, 
inclusive, with an endoscopic subscore of ≥2 (from central 
reading), and a rectal bleeding subscore of ≥1.) 
c. UC patients only: Patient with moderate to 
severe active UC as defined by the 3 component 
modified Mayo score of 5 to 9, inclusive, with an 
endoscopic subscore of ≥2 (from central reading) 
Update. Rectal bleeding subscore 
removed. 
e. CD patients only: SES-CD score of > ≥6 or > (≥4 for 
isolated ileal disease). 
e. CD patients only: SES-CD score of ≥6   
(≥4 for isolated ileal disease). 
Update. Inclusion criteria revised. 
• 
Inadequate response to, loss of response to, or intolerance 
to prior biologics or small molecules defined as 1 or more 
of the following: 
• 
Loss of response: Persistent signs and symptoms of 
active disease despite at least one 8-week induction 
and one maintenance regimen of the locally approved 
highest dosing regimen of anti-TNF inhibitors, anti-
integrins, anti-IL-12/23 mAbs monoclonal antibodies, 
JAK inhibitors, or S1P receptor S1Preceptor 
modulators. 
• 
Discontinuation Inadequate response (primary non-
response): Persistent signs and symptoms of active 
disease despite at least one induction regimen of the 
locally approved highest dosing regimen of anti-TNF 
inhibitors, anti-integrins, anti-IL-12/23 mAbs, JAK 
inhibitors, or S1P receptor modulators  due to an 
adverse drug reaction as determined by the 
• 
Inadequate response to, loss of response to, or 
intolerance to prior biologics or small 
molecules defined as 1 or more of the 
following: 
• 
Loss of response: Persistent signs and 
symptoms of active disease despite at 
least one induction and one maintenance 
regimen of the locally approved regimen 
of anti-TNF inhibitors, anti-integrins, 
anti-IL-12/23 monoclonal antibodies, 
JAK inhibitors, or S1Preceptor 
modulators. 
• 
Inadequate response (primary non-
response): Persistent signs and symptoms 
of active disease despite at least one 
induction regimen of the locally approved 
highest dosing regimen of anti-TNF 
inhibitors, anti-integrins, anti-IL-12/23 
Update. Text updated to describe 
inadequate response to biologics and 
small molecules. 
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investigator. 
• 
Intolerance: Discontinuation of anti-TNF inhibitors, 
anti-integrins, anti-IL-12/23 monoclonal antibodies, 
JAK inhibitors, or S1P receptor modulators due to an 
adverse drug reaction as determined by treating 
physician. Such adverse drug reactions include, but 
are not limited to, nausea/vomiting, abdominal pain, 
pancreatitis, liver function testing abnormalities, 
lymphopenia, and infections. 
mAbs, JAK inhibitors, or S1P receptor 
modulators   
• 
Intolerance: Discontinuation of anti-TNF 
inhibitors, anti-integrins, anti-IL-12/23 
monoclonal antibodies, JAK inhibitors, or 
S1P receptor modulators due to an 
adverse drug reaction as determined by 
treating physician. Such adverse drug 
reactions include, but are not limited to, 
nausea/vomiting, abdominal pain, 
pancreatitis, liver function testing 
abnormalities, lymphopenia, and 
infections. 
Section 4.2. Patient Exclusion Criteria 
k. Current or history of chronic liver or biliary disease (with 
the exception of Gilbert’s syndrome, asymptomatic gallstones 
or uncomplicated fatty liver disease) or ALT >2x ULN and 
bilirubin >1.5x ULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin 
<35%) at screening. 
l. 
Absolute neutrophil count <1.5x109/L or Hemoglobin <8 
g/dL or lymphocyte count <0.8x109/L or platelet count 
<100,000/mL 
k. Current or history of chronic liver or biliary 
disease (with the exception of Gilbert’s syndrome, 
asymptomatic gallstones or uncomplicated fatty 
liver disease) or ALT >2x ULN and bilirubin 
>1.5x ULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35%) at screening. 
l. 
Absolute neutrophil count <1.5x109/L or 
Hemoglobin <8 g/dL or lymphocyte count 
<0.8x109/L or platelet count <100,000/mL 
Addition. Text added to include liver and 
biliary disease as exclusion criteria. 
Absolute neutrophil count, hemoglobin, 
lymphocyte count and platelet count 
added to exclusion criteria. 
m. The patient has QTc>480 ms 
m. The patient has QTc>480 ms 
Addition. QTC exclusion criteria added. 
p. s. Patient is receiving any of the following therapies within 
the designated time period: 
− 
The patient is currently using any systemic 
immunosuppressant or immunomodulatory biologic or 
nonbiologic (other than those listed in inclusion 
criterion “h” and those that are used for IBD) within 
30 days or 5 half-lives (whichever is longer) prior to 
p. s. Patient is receiving any of the following 
therapies within the designated time period: 
− 
The patient is currently using any systemic 
immunosuppressant or immunomodulatory 
biologic or nonbiologic (other than those 
listed in inclusion criterion “h” and those 
that are used for IBD) within 30 days or 5 
Update. Text updated to include the 
number of half-lives needed to wash out 
certain small molecules and biologics.  
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the endoscopy. 
− 
>9 mg/day of oral budesonide or >20 mg/day 
prednisone or equivalent within 2 weeks prior to the 
endoscopy. 
− 
Topical (rectal) treatment of 5-ASA or intravenous, 
intramuscular (parenteral), or enema/suppository 
administration of corticosteroids within 2 weeks prior 
to the endoscopy. 
− 
Biologics or small molecules, including anti-TNF 
inhibitors, anti-integrin inhibitors, anti-IL-12/23 
inhibitors, JAK inhibitors, or S1P receptor modulators, 
within 4 weeks 3 half-lives prior to the endoscopy 
randomization. 
− 
Small molecules including JAK inhibitors, or S1P 
receptor modulators, within 5 half-lives or shorter 
washout duration if undetectable drug levels can be 
demonstrated prior to the endoscopy randomization 
− 
Other investigational procedures or products, within 
30 days or 5 half-lives of investigational product prior 
to the endoscopy, whichever is longer 
− 
Live vaccine within 14 days prior to the first screening 
visit. Inactivated vaccines (including approved 
inactivated COVID-19 vaccines) should preferably be 
completed 14 days before first IMP dosing. If 
administered during the study, it is recommended to 
be at least 3 days before and after IMP administration, 
or as required by local country regulations. 
half-lives (whichever is longer) prior to the 
endoscopy. 
− 
>9 mg/day of oral budesonide or >20 
mg/day prednisone or equivalent within 
2 weeks prior to the endoscopy. 
− 
Topical (rectal) treatment of 5-ASA or 
intravenous, intramuscular (parenteral), or 
enema/suppository administration of 
corticosteroids within 2 weeks prior to the 
endoscopy. 
− 
Biologics including anti-TNF inhibitors, 
anti-integrin inhibitors, anti-IL-12/23 
inhibitors within 3 half-lives prior to 
randomization. 
− 
Small molecules including JAK inhibitors, 
or S1P receptor modulators, within 5 half-
lives or shorter washout duration if 
undetectable drug levels can be 
demonstrated prior to randomization 
− 
Other investigational procedures or 
products, within 30 days or 5 half-lives of 
investigational product prior to the 
endoscopy, whichever is longer. 
− 
Live vaccine within 14 days prior to the first 
screening visit. Inactivated vaccines 
(including approved inactivated COVID-19 
vaccines) should preferably be completed 14 
days before first IMP dosing. If 
administered during the study, it is 
recommended to be at least 3 days before 
and after IMP administration, or as required 
by local country regulations. 
Section 4.3.Withdrawal Criteria and Assessments/Procedures for the Patient 
• 
in the event of intercurrent illness, adverse events, 
pregnancy, or any other reason concerning the health or well-
• 
in the event of intercurrent illness, adverse 
events, pregnancy, or any other reason concerning 
Update. Cross reference added for 
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being of the patient that indicates to the investigator that 
continued participation is not in the best interest of the patient 
(see also Individual Stopping Rules can be found in Section 
3.4.1); 
the health or well-being of the patient that 
indicates to the investigator that continued 
participation is not in the best interest of the 
patient (see also Individual Stopping Rules can be 
found in Section 3.4.1); 
Stopping Rules. 
Section 5.1.Investigational Medicinal Products Used in the Study 
The volume of the solution of each IMP (TEV-48574 and 
placebo) will be constant (15 mL loading dose volume and 12 
mL induction dose volume).) and will be administered as 
single sc administrations. 
Active IMP will be diluted with placebo to achieve the final 
delivered concentrations. Patients will receive the following 
regimens as a single sc Q2W using a commercial sc infusion 
system: the 
, 
 
 
 
• TEV-48574 2250 mg (single loading dose)/1800 mg (6 
induction doses) 
• TEV-48574 2250 mg (single loading dose)/900 mg (6 
induction doses) 
• TEV-48574 2250 mg (single loading dose)/450 mg (6 
induction doses) 
• Placebo to match TEV-48574 (single loading 
dose)/(Induction doses) 
The volume of the solution of each IMP (TEV-
48574 and placebo) will be constant (15 mL 
loading dose volume and 12 mL induction dose 
volume) and will be administered as single sc 
administrations. 
Active IMP will be diluted with placebo to achieve 
the final delivered concentrations. Patients will 
receive the following regimens as a single sc Q2W 
using the 
 
, 
 
 
• TEV-48574 2250 mg (single loading dose)/1800 
mg (6 induction doses) 
• TEV-48574 2250 mg (single loading dose)/900 
mg (6 induction doses) 
• TEV-48574 2250 mg (single loading dose)/450 
mg (6 induction doses) 
• Placebo to match TEV-48574 (single loading 
dose)/(Induction doses) 
Update. IMP dilution information 
included. 
Section 5.1.3.Test and Placebo Investigational Medicinal Product Administration 
TEV-48574 or placebo IMP will be administered using a 
commercial sc infusion system. The  For this study, the  
 will be utilized. This 
syringe infusion system will be CE marked and is cleared for 
use in the US under a current 510(k).) K092313 and CE 
marked for use in the EU. This infusion system will be is 
indicated for the iv or sc infusion of medications and fluids in 
TEV-48574 or placebo IMP will be administered 
using a commercial sc infusion system.  For this 
study, the 
 
will be utilized. This syringe infusion system is 
cleared for use in the US under a 510(k) K092313 
and CE marked for use in the EU. This infusion 
system is indicated for the iv or sc infusion of 
Update. Dosing details included. 
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the hospital and clinics where the use of the pump can be 
supervised by a clinician. 
medications and fluids in the hospital and clinics 
where the use of the pump can be supervised by a 
clinician. 
This system safely enables single-site sc administration of 
large volumes to avoid the need for multiple injections from 
individual syringes. The commercial syringe infusion systems 
are and is capable of sc drug administration of up to 60 mL 
syringe using a sc safety needle set. The system controls the 
rate of drug entry into the tissues surrounding the sc infusion 
site as well as the duration of infusion. The syringe infusion 
system is a mechanical or electromechanical syringe pump that 
pushes the syringe plunger at a constant rate throughout the 
infusion to infuse drug. The sponsor has evaluated the 
suitability of these types of syringe infusion system 
This system safely enables single-site sc 
administration of large volumes to avoid the need 
for multiple injections from individual syringes 
and is capable of administration of up to 60 mL 
syringe using a sc safety needle set. The system 
controls the rate of drug entry into the tissues 
surrounding the sc infusion site as well as the 
duration of infusion. The syringe infusion system 
is a mechanical or electromechanical syringe pump 
that pushes the syringe plunger at a constant rate 
throughout the infusion to infuse drug.  
Update. 
 details included 
A sterile disposable 20 mL syringe is utilized with the infusion 
systems and is connected to a subcutaneous needle set, via a 
luer lock connector, which has a 6mm needle length and 
delivers the IMP to the subcutaneous tissue. The subcutaneous 
needle set, which is used in conjunction with the pump and 20 
mL syringe, is the KORU (RMS 12606) 26G 6mm single 
needle infusion set that is cleared under 510k (K102512) and is 
also CE marked.   
 
The infusion rate is fixed at 30 mL/hr for all sc infusions. The 
expected infusion durations will therefore be 30 minutes for 
the 15 mL loading dose and 24 minutes for the 12 mL 
induction doses. 
A sterile disposable 20 mL syringe is utilized with 
the infusion systems and is connected to a 
subcutaneous needle set, via a luer lock connector, 
which has a 6mm needle length and delivers the 
IMP to the subcutaneous tissue. The subcutaneous 
needle set, which is used in conjunction with the 
pump and 20 mL syringe, is the KORU (RMS 
12606) 26G 6mm single needle infusion set that is 
cleared under 510k (K102512) and is also CE 
marked.   
 
The infusion rate is fixed at 30 mL/hr for all sc 
infusions. The expected infusion durations will 
therefore be 30 minutes for the 15 mL loading 
dose and 24 minutes for the 12 mL induction 
doses. 
Update. Syringe and infusion rate details 
included. 
The sponsor has evaluated the suitability of these types of 
syringe infusion systems to deliver TEV-48574 and the 
compatibility of TEV-48574 with the appropriate syringe and 
tubing sets (drug fluid path) that would will be used for sc 
delivery of TEV-48574. 
The sponsor has evaluated the suitability of these 
types of syringe infusion systems to deliver TEV-
48574 and the compatibility of TEV-48574 with 
the appropriate syringe and tubing sets (drug fluid 
path) that will be used for sc delivery of TEV-
48574. 
Update. Infusion system suitability 
statement added. 
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Section 5.2.1. Preparation, Storage and Security 
Prepared doses of TEV-48574 and placebo IMP will be kept 
for no more than 4 hours at 25ºC from time of opening the first 
vial, to completion of dose administration. Additional 
preparation details may be found in the Pharmacy Manual. 
Prepared doses of TEV-48574 and placebo IMP 
will be kept for no more than 4 hours at 25ºC from 
time of opening the first vial, to completion of 
dose administration. Additional preparation details 
may be found in the Pharmacy Manual. 
Update. Addition of a description of the 
proposed time and storage conditions 
between study drug dilution and 
administration 
Section 5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
In line with this concept, a single loading dose of 2250 mg is 
used in this study. This dose level is within the range of doses 
safely administered to patients with asthma in the MAD 
portion of Study TV48574-SAD-10126 and in Study 
TV48574-AS-20031. The loading dose as part of the induction 
dose regimen has been selected to rapidly achieve steady-state 
concentration and address the significant over-production of 
TL1A in the colon (Jia Wenxiu et al 2021) within the first 
weeks of induction.  
 
 The TEV-48574 dosing regimen is designed to achieve steady 
state-concentration fast, whereas PF-06480605 achieves steady 
state at approximately 8 weeks (Danese et al 2021).  TEV-
48574 has linear PK for the dose range of 200 to 2300 mg, as 
described in FIH TV48574-SAD-10126 study, with 
elimination half-life of 7-9 days. In MAD portion of TV48574-
SAD-10126 trial, a 2300 mg loading dose followed by 1600 
mg doses reached steady-state after 2 weeks and no 
accumulation was observed. Using population PK approaches, 
we described TEV-48574 PK characteristics and used the 
model subsequently to simulate the proposed loading and 
induction doses in study TV48574-IMM-20036 and therefore 
predict resulting exposures. 
In line with this concept, a single loading dose of 
2250 mg is used in this study.  This dose level is 
within the range of doses safely administered to 
patients with asthma in the MAD portion of Study 
TV48574-SAD-10126 and in Study TV48574-AS-
20031. The loading dose as part of the induction 
dose regimen has been selected to rapidly achieve 
steady-state concentration and address the 
significant over-production of TL1A in the colon 
(Jia Wenxiu et al 2021) within the first weeks of 
induction.  
 
 The TEV-48574 dosing regimen is designed to 
achieve steady state-concentration fast, whereas 
PF-06480605 achieves steady state at 
approximately 8 weeks (Danese et al 2021).  TEV-
48574 has linear PK for the dose range of 200 to 
2300 mg, as described in FIH TV48574-SAD-
10126 study, with elimination half-life of 7-9 days. 
In MAD portion of TV48574-SAD-10126 trial, a 
2300 mg loading dose followed by 1600 mg doses 
reached steady-state after 2 weeks and no 
accumulation was observed. Using population PK 
approaches, we described TEV-48574 PK 
characteristics and used the model subsequently to 
simulate the proposed loading and induction doses 
in study TV48574-IMM-20036 and therefore 
Clarification. Addition text included to 
justify dose.  
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predict resulting exposures. 
Section 5.6.4. 
Prohibited Medications and Therapies 
• 
Any investigational drug or biologic or small molecule 
The patient is currently using any systemic 
immunosuppressant or immunomodulatory treatments 
biologic or nonbiologic (other than those listed in 
inclusion criterion “h”)” and those that are used for IBD) 
within 30 days or 5 half-lives of the drug (whichever is 
greater), longer) prior to the endoscopy and/ . 
• 
Biologics including anti-TNF inhibitors, anti-integrin 
inhibitors, and anti-IL-12/23 inhibitors within 3 half-
lives prior to randomization. 
• 
Small molecules including JAK inhibitors, or S1P 
receptor modulators, within 5 half-lives or during study 
participation shorter washout duration if undetectable 
drug levels can be demonstrated prior to randomization. 
• 
Oral budesonide of >9 mg/day or equivalent from 2 
weeks prior to endoscopy through week 14. 
• 
Patients requiring a surgical intervention for UC or CD 
will be discontinued from the study 
• 
The patient is currently using any systemic 
immunosuppressant or immunomodulatory 
biologic or nonbiologic (other than those 
listed in inclusion criterion “h” and those 
that are used for IBD) within 30 days or 5 
half-lives (whichever is longer) prior to the 
endoscopy. 
• 
Biologics including anti-TNF inhibitors, 
anti-integrin inhibitors, and anti-IL-12/23 
inhibitors within 3 half-lives prior to 
randomization. 
• 
Small molecules including JAK inhibitors, 
or S1P receptor modulators, within 5 half-
lives or shorter washout duration if 
undetectable drug levels can be 
demonstrated prior to randomization. 
• Oral budesonide of >9 mg/day or equivalent 
from 2 weeks prior to endoscopy through 
week 14. 
• Patients requiring a surgical intervention for 
UC or CD will be discontinued from the 
study 
Update. Section updated to state that 
surgical interventions for UC and CD are 
prohibited during the study. 
Section 5.8. Randomization and Blinding 
Patients Approximately 140 UC patients and 140 CD patients 
Approximately 140 UC patients and 140 CD 
Clarification. Additional details 
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will be randomly assigned to the treatment groups by means of 
a computer-generated randomization list using interactive-
response technology. The specifications for randomization will 
be under the responsibility and oversight of Teva Global 
Statistics. 
 
The study patients, sponsor, and the clinical team at the site 
will be blinded to treatment assignment until the database is 
locked for analysis. Individuals who may not be blinded 
include (but are not limited to) the bioanalytical scientists, 
pharmacokineticists, and biostatisticians who are not directly 
involved in study conduct. 
patients will be randomly assigned to the treatment 
groups by means of a computer-generated 
randomization list using interactive-response 
technology. The specifications for randomization 
will be under the responsibility and oversight of 
Teva Global Statistics. 
 
The study patients, sponsor, and the clinical team 
at the site will be blinded to treatment assignment 
until the database is locked for analysis. 
describing the randomization process 
added. 
Section 5.9.2. 
Blinding and Unblinding 
Blinded pharmacokinetic Pharmacokinetic, pharmacodynamics 
and immunogenicity data may samples will be assessed 
collected for bioanalysis during the study. For patients who 
have pharmacokinetic or immunogenicity sample bioanalysis 
or data analysis conducted, the individuals Individuals 
responsible for sample bioanalysis and other responsible 
personnel will may know who received test IMP and who 
received placebo IMP during the study (of those patients 
only).. Personnel responsible for bioanalysis will be provided 
with the randomization code to facilitate the analysis. 
However, the personnel responsible for bioanalysis and 
pharmacokinetic data analysis will not have access to clinical 
safety and efficacy data and will provide concentration data to 
other personnel in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to the 
concentration data of an individual patient). The process to 
ensure study integrity, maintenance of the double blind, and 
Pharmacokinetic, pharmacodynamics and 
immunogenicity samples will be collected for 
bioanalysis during the study.  Individuals 
responsible for sample bioanalysis and other 
responsible personnel may know who received test 
IMP and who received placebo IMP during the 
study. Personnel responsible for bioanalysis will 
be provided with the randomization code to 
facilitate the analysis. However, the personnel 
responsible for bioanalysis will not have access to 
clinical safety and efficacy data and will provide 
concentration data to other personnel in a manner 
that will not identify individual patients (ie, a 
dummy patient identifier will be linked to the 
concentration data of an individual patient). 
Clarification. Blinding procedure 
updated. 
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the responsibilities of the relevant study personnel will be 
described in a pharmacokinetic analysis plan that will be 
approved prior to any data transfer, per the sponsor’s relevant 
SOPs (Section  .)9.13 
An interim efficacy analysis for futility will be performed 
separately in each indication (UC and CD) by an independent, 
unblinded statistician. An Internal Review Committee Charter 
defining the procedures for the unblinding and decision making 
will be finalized prior to interim unblinding. The charter will 
specify the sponsor personnel who are to be unblinded. Interim 
analyses as described in Section 9.13 will be performed 
throughout the study by unblinded analysis groups external to 
Teva and will be reviewed by an independent data monitoring 
committee. 
Interim analyses as described in Section 9.13 will 
be performed throughout the study by unblinded 
analysis groups external to Teva and will be 
reviewed by an independent data monitoring 
committee. 
Update. Additional text added to 
describe interim analysis.  
Section 5.9.3. 
Independent Data Monitoring Committee 
Text describing the Internal Review Committee removed and 
text added to describe the Independent Data Monitoring 
Committee. 
Description of the Independent Data Monitoring 
Committee. 
Update. Description of the Internal 
Review Committee removed. 
Section 6.1.2.1.  Biopsy Collection 
Biopsies will be used for measures of histologic disease, 
pharmacokinetic assessments, and exploratory biomarker 
assays.  
Biopsies will be used for measures of histologic 
disease and exploratory biomarker assays. 
Update. Text revised to state that biopsy 
drug concentrations will not be 
collected. 
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Section 7. Assessment of Safety 
There will be an ISRDMC to monitor safety in this study 
(Section 5.9.3
 .)
 
There will be an IDMC to monitor safety in this 
study (Section 5.9.3
 .)
 
Update. The ISRC committee updated 
with IDMC. 
Section 7.1.5. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the 
following: 
Mild: 
No limitation of usual activities 
Moderate: 
Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
The severity of each adverse event must be recorded. The 
adverse event severity grading scale for the current version of 
the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE; version 5) will be used for 
assessing adverse event severity. Table 6 will be used for 
assessing severity for adverse events that are not specifically 
listed in the NCI CTCAE. 
The severity of each adverse event must be 
recorded. The adverse event severity grading scale 
for the current version of the National Cancer 
Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE; version 5) will be 
used for assessing adverse event severity. Table 6 
will be used for assessing severity for adverse 
events that are not specifically listed in the NCI 
CTCAE. 
Update. Change in the grading method 
for AE severity presented in section. 
Table 6: Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 
Table 6: Adverse Event Severity Grading Scale for 
Events Not Specifically Listed in NCI CTCAE 
Addition. Adverse Event Severity 
Grading Scale table added. 
Section 7.1.10. 
Protocol-Defined Adverse Events of Special Interest 
Adverse events of special interest (AESIs)—which are not 
necessarily adverse drug reactions (ADRs) but are of special 
interest based on standard drug registration topics, safety 
findings from previous studies, potential risks associated with 
biologic immunomodulators, are listed below. 
Adverse events of special interest (AESIs)—which 
are not necessarily adverse drug reactions (ADRs) 
but are of special interest based on standard drug 
registration topics, safety findings from previous 
studies, potential risks associated with biologic 
immunomodulators, are listed below. 
Addition. Text describing adverse events 
of special interest included. 
Section 7.1.10.1. Protocol-Defined Adverse Events of Special Interest that Require Reporting to Sponsor’s Global Patient Safety and Pharmacovigilance 
For purposes of this protocol, the following are considered 
protocol-defined adverse events of special interest to be sent to 
For purposes of this protocol, the following are 
considered protocol-defined adverse events of 
Update. Text updated to include severe 
infections, liver injury and severe 
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the sponsor’s GPSP for evaluation: 
• systemic severe reactions (including anaphylaxis) 
• opportunistic or severe infections 
• malignancies (including non-melanoma skin cancer) 
• liver injury 
• severe hematology abnormalities 
special interest to be sent to the sponsor’s GPSP 
for evaluation: 
• systemic severe reactions (including 
anaphylaxis) 
• opportunistic or severe infections 
• malignancies (including non-melanoma skin 
cancer) 
• liver injury 
• severe hematology abnormalities 
hematology abnormalities as 
protocol-defined adverse events of 
special interest to be sent to the 
sponsor’s GPSP for evaluation. 
As a precaution, each site should have a resuscitation 
medication/equipment nearby. If a patient has symptoms of 
anaphylaxis or severe hypersensitivity, the administration of 
study drug must be discontinued permanently. In addition, 
information about all suspected anaphylaxis and 
hypersensitivity events will be recorded on the Suspected 
Anaphylaxis CRF, which is based on the 2006 Joint National 
Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network Second Symposium on Anaphylaxis 
(Sampson et al 2006). Investigators should report these events 
immediately to the Sponsor as adverse events of special 
interest and as serious adverse events, if appropriate. 
 
A list of opportunistic infections is included in  .Appendix L 
As a precaution, each site should have a 
resuscitation medication/equipment nearby. If a 
patient has symptoms of anaphylaxis or severe 
hypersensitivity, the administration of study drug 
must be discontinued permanently. In addition, 
information about all suspected anaphylaxis and 
hypersensitivity events will be recorded on the 
Suspected Anaphylaxis CRF, which is based on 
the 2006 Joint National Institute of Allergy and 
Infectious Diseases/Food Allergy and Anaphylaxis 
Network Second Symposium on Anaphylaxis 
(Sampson et al 2006). Investigators should report 
these events immediately to the Sponsor as adverse 
events of special interest and as serious adverse 
events, if appropriate. 
Update. Text updated to describe steps to 
be taken if a patient experiences 
anaphylaxis or severe hypersensitivity. 
Opportunistic or severe infections 
In the event of opportunistic or severe infections (CTCAE 
grade 3 to 4), the patient should not receive further study drug 
until the event has completely resolved. Study drug will be 
permanently stopped in case of infections following stopping 
criteria (see section 3.4.1). Study drug may be restarted 
following consultation with the Medical Monitor. Treatment of 
infections should be initiated promptly according to standard of 
care and all efforts should be made to identify the infectious 
agent. Events should be reported to the Sponsor immediately 
(ie, no more than 24 hours after learning of the event), either as 
Opportunistic or severe infections 
In the event of opportunistic or severe infections 
(CTCAE grade 3 to 4), the patient should not 
receive further study drug until the event has 
completely resolved. Study drug will be 
permanently stopped in case of infections 
following stopping criteria (see section 3.4.1). 
Study drug may be restarted following 
consultation with the Medical Monitor. Treatment 
of infections should be initiated promptly 
according to standard of care and all efforts should 
Update. Text updated to describe steps to 
be taken if a patient experiences 
opportunistic or severe infections. 
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a serious adverse event or an adverse event of special interest. 
Examples for opportunistic infections are included in 
Appendix L. 
be made to identify the infectious agent. Events 
should be reported to the Sponsor immediately (ie, 
no more than 24 hours after learning of the event), 
either as a serious adverse event or an adverse 
event of special interest. Examples for 
opportunistic infections are included in Appendix 
L. 
Malignancies 
Any signs or symptoms that could be suggestive of malignancy 
should be promptly and aggressively evaluated. Patients who 
develop a malignancy (with the exception of an appropriately 
treated basal cell carcinoma or squamous cell carcinoma of the 
skin or in situ carcinoma of uterine cervix) should be 
withdrawn from study drug and must not receive additional 
doses of study drug. Malignancies should be reported to the 
Sponsor immediately (ie, no more than 24 hours after learning 
of the event). 
Malignancies 
Any signs or symptoms that could be suggestive of 
malignancy should be promptly and aggressively 
evaluated. Patients who develop a malignancy 
(with the exception of an appropriately treated 
basal cell carcinoma or squamous cell carcinoma 
of the skin or in situ carcinoma of uterine cervix) 
should be withdrawn from study drug and must not 
receive additional doses of study drug. 
Malignancies should be reported to the Sponsor 
immediately (ie, no more than 24 hours after 
learning of the event).  
Update. Text updated to describe steps to 
be taken if a patient experiences 
malignancies. 
Liver injury 
If any of the following criteria occur, study drug should be 
withheld and additional monitoring and follow-up assessment 
will be required (as detailed in the Liver Safety Required 
Actions and Follow-up Assessments section in Appendix M): 
• 
Alanine transaminase (ALT) or aspartate 
aminotransferase (AST) ≥5x upper limit of normal 
(ULN) 
• 
ALT or AST ≥3x ULN with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
AST and/or ALT ≥3 fold ULN combined with an 
elevation of total bilirubin ≥2 fold ULN measured in 
the same blood draw sample or in combination with 
clinical jaundice or INR>1.5 (not applicable for 
patients on anticoagulants) 
The additional information will be recorded on the Liver Event 
Liver injury 
If any of the following criteria occur, study drug 
should be withheld and additional monitoring and 
follow-up assessment will be required (as detailed 
in the Liver Safety Required Actions and Follow-
up Assessments section in Appendix M): 
• 
Alanine transaminase (ALT) or aspartate 
aminotransferase (AST) ≥5x upper limit 
of normal (ULN) 
• 
ALT or AST ≥3x ULN with the 
appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
• 
AST and/or ALT ≥3 fold ULN combined 
with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw 
sample or in combination with clinical 
Update. Text updated to describe steps to 
be taken if a patient experiences liver 
injury. 
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CRF. 
The most appropriate diagnosis or (if a diagnosis cannot be 
established) the abnormal laboratory values should be recorded 
on the Adverse Event eCRF (see Section 7.1.3) and reported to 
the Sponsor immediately (ie, no more than 24 hours after 
learning of the event), either as a serious adverse event (ie, a 
possible Hy’s Law case: ALT≥3xULN and Bilirubin≥2xULN 
or INR>1.5) or an adverse event of special interest. 
jaundice or INR>1.5 (not applicable for 
patients on anticoagulants) 
The additional information will be recorded on the 
Liver Event CRF. 
The most appropriate diagnosis or (if a diagnosis 
cannot be established) the abnormal laboratory 
values should be recorded on the Adverse Event 
eCRF (see Section 7.1.3) and reported to the 
Sponsor immediately (ie, no more than 24 hours 
after learning of the event), either as a serious 
adverse event (ie, a possible Hy’s Law case: 
ALT≥3xULN and Bilirubin≥2xULN or INR>1.5) 
or an adverse event of special interest. 
Severe hematology abnormalities 
Predefined confirmed hematology stopping criteria (see section 
3.4.1) should be re-tested every 3 to 5 days until values have 
returned to above the hematological exclusion criteria 
threshold, at which point dosing can be resumed (however, two 
consecutive doses of IMP, should never be given less than 7 
days apart).  
Severe hematology abnormalities 
Predefined confirmed hematology stopping criteria 
(see section 3.4.1) should be re-tested every 3 to 5 
days until values have returned to above the 
hematological exclusion criteria threshold, at 
which point dosing can be resumed (however, two 
consecutive doses of IMP, should never be given 
less than 7 days apart).  
Update. Text updated to describe steps to 
be taken if a patient experiences severe 
hematology abnormalities. 
 
Section 7.1.10.2. Protocol-Defined Adverse Events of Special Interest that Do Not Require Reporting to Sponsor’s Global Patient Safety and 
Pharmacovigilance 
The following are considered protocol-defined adverse events 
of special interest that do not need to be sent to the sponsor’s 
GPSP department (unless assessed as serious) and will be 
recorded only in the clinical database as described in 
Section 7.2:: 
• 
administration site reactions (as described in 
Section 7.2) 
The following are considered protocol-defined 
adverse events of special interest that do not need 
to be sent to the sponsor’s GPSP department 
(unless assessed as serious) and will be recorded 
only in the clinical database: 
• 
administration site reactions (as described 
in Section 7.2) 
Updated. Text updated to state that 
hematology abnormalities do not need to 
be sent to the sponsor’s GPSP 
department. 
Section 7.5.2. Other Clinical Laboratory Tests 
In case of a suspected liver injury, additional laboratory tests 
In case of a suspected liver injury, additional 
Addition. Text added to state that 
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will be required  (see Appendix M). 
laboratory tests will be required  (see Appendix 
M). 
additional clinical laboratory 
assessments should be performed if a 
patient experiences liver injury.  
Section 9.5.4.1. Primary Efficacy Analysis 
Inference will be based on posterior distribution of these 
parameters, along with summaries presented as posterior 
means and/or medians and the corresponding 95% credible 
intervals for UC and CD disease groups.  
Inference will be based on posterior distribution of these 
parameters and summarized as follows for each indication 
(UC, CD):  
•Posterior means and/or medians of the response rates for 
TEV-48574 doses, placebo  
•95% credible intervals for difference in response rates (TEV-
48574 doses – placebo)   
•For each TEV-48574 dose, Posterior Probability (TEV-48574 
dose – placebo response rate > 0)  
•Posterior Probability (Emax > 0) 
Inference will be based on posterior distribution of 
these parameters and summarized as follows for 
each indication (UC, CD):  
•Posterior means and/or medians of the response 
rates for TEV-48574 doses, placebo  
•95% credible intervals for difference in response 
rates (TEV-48574 doses – placebo)   
•For each TEV-48574 dose, Posterior Probability 
(TEV-48574 dose – placebo response rate > 0)  
•Posterior Probability (Emax > 0) 
Update. Primary efficacy analysis 
methods updated. 
Section 9.5.4.3. Supplementary Analysis 
The following additional analyses will be undertaken to 
examine the robustness of the primary efficacy analysis results: 
• 
Cochran-Mantel-Haenszel (CMH) test for pairwise 
comparisons between the active dose groups and placebo 
separately for UC and CD. Nominal p-values will be presented 
for each of the comparisons. 
• 
Bayesian Emax dose-response model fit separately (i.e., no 
borrowing) for UC and CD. Inferences presented for the 
primary efficacy analysis will be re-produced for this 
approach. 
• 
Frequentist Emax dose-response model fit separately for 
UC and CD. Response rates of TEV-48574 doses, placebo and 
95% confidence intervals for difference in response rates 
(TEV-48574 doses – placebo), along with summaries of model 
The following additional analyses will be 
undertaken to examine the robustness of the 
primary efficacy analysis results: 
• 
Cochran-Mantel-Haenszel (CMH) test for 
pairwise comparisons between the active dose 
groups and placebo separately for UC and CD. 
Nominal p-values will be presented for each of the 
comparisons. 
• 
Bayesian Emax dose-response model fit 
separately (i.e., no borrowing) for UC and CD. 
Inferences presented for the primary efficacy 
analysis will be re-produced for this approach. 
• 
Frequentist Emax dose-response model fit 
separately for UC and CD. Response rates of TEV-
Update. Supplementary analysis 
described. 
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parameters will be presented 
• 
Logistic regression model with fixed effects for dose, 
randomization stratification factors and baseline response fit 
separately for UC and CD. 
48574 doses, placebo and 95% confidence 
intervals for difference in response rates (TEV-
48574 doses – placebo), along with summaries of 
model parameters will be presented 
• 
Logistic regression model with fixed effects 
for dose, randomization stratification factors and 
baseline response fit separately for UC and CD. 
Section 9.13.  Planned Interim Analysis 
Section revised to describe interim analysis and who will be 
blinded to the analysis. 
Section updated to describe  interim analysis. 
Update. Section updated to detail  
interim analysis. 
APPENDIX A. Departments And Institutions 
  
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
  
  
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
 
Update. Staff change. 
APPENDIX B. Study Procedures And Assessments By Visit 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 ([±3 
days based on day 1 previous visit]) 
•CDAI score (CD only) 
•Stool frequency and Abdominal pain (PRO2 CD) 
•Stool frequency and Rectal bleeding Mayo sub-scores (PRO2 
UC) 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 
43, 71 ([±3 days based on previous visit]) 
•CDAI score (CD only) 
•Stool frequency and Abdominal pain (PRO2 CD) 
•Stool frequency and Rectal bleeding Mayo sub-
scores (PRO2 UC) 
Update. Additional assessments added to 
visits and timing of visits updated. 
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c. 
Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 ([±3 
days based on day 1 previous visit]) 
•CDAI score (CD only) 
•Stool frequency and Abdominal pain (PRO2 CD) 
•Stool frequency and Rectal bleeding Mayo sub-scores (PRO2 
UC) 
c. 
Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 
57, 85 ([±3 days based on  previous visit]) 
•CDAI score (CD only) 
•Stool frequency and Abdominal pain (PRO2 CD) 
•Stool frequency and Rectal bleeding Mayo sub-
scores (PRO2 UC) 
Update. Additional assessments added to 
visits and timing of visits updated. 
d. Visit 8 (week 14, day 99 [±3 days based on day 1 previous 
visit]) 
d. Visit 8 (week 14, day 99 [±3 days based on 
previous visit]) 
Update. Timing of visit updated. 
3. Follow-up (visit 9, week 18, day 127 [±14 days based on 
day 1 previous visit]) 
3. Follow-up (visit 9, week 18, day 127 [±14 
days based on previous visit]) 
Update. Timing of follow-up visit 
updated. 
Appendix K. 
Management Of Study Activities During Covid-19 Outbreaks 
Section 4.4. Replacement of Patients 
In the event of an emergency situation (eg, COVID-19 
outbreaks), the number of patients to be randomized may be 
increased to ensure the targeted number of completers per arm. 
Section 5.9. Maintenance of Randomization and Blinding 
Unblinded data review of COVID-19 patients by member(s) 
not part of the blinded study team may be conducted upon 
Internal Safety Review Committee recommendations and 
Teva’s discretion. 
Active COVID-19 cases will be monitored throughout the 
study. If a total of number COVID-19 infections are confirmed 
and related to a serious adverse event to reach a minimum 
threshold (based on total randomized patients, detailed in the 
medical monitoring plan) the pharmacovigilance physician in 
consultation with the clinical study physician will determine if 
an unblinded review of the cases is warranted to ensure patient 
safety. Any unblinded review will be conducted by appropriate 
personnel that are not connected with the study. 
Section 4.4. Replacement of Patients 
In the event of an emergency situation (eg, 
COVID-19 outbreaks), the number of patients to 
be randomized may be increased to ensure the 
targeted number of completers per arm. 
Update. Description of the maintenance 
of the randomization and blinding of 
COVID-19 patients removed from 
appendix. 
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APPENDIX M. Liver Safety: Required Actions And Follow-Up Assessments Guidelines 
Appendix M added. 
Appendix M. 
Addition. Appendix added to detail the 
liver stopping and increased monitoring 
criteria. 
Appendix N. Operating Characteristics And Assumptions For Final And Interim Analysis 
Appendix updated to include additional simulations and Safety 
Stopping Rules.  
Appendix updated. 
Update. Appendix updated. 
 
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APPENDIX A. STUDY PROCEDURES AND ASSESSMENTS BY VISIT  
1. Procedures for Screening (week -6 to week -1, days -42 to -1) 
The screening visit will take place not more than 6 weeks before the baseline visit (visit 1). 
The following procedures will be performed at the screening visit: 
• obtain written informed consent before any study-related procedures are performed (a 
separate informed consent form will be provided for pharmacogenetics samples) 
• review inclusion and exclusion criteria 
• review demographics and medical history 
• vital signs measurements 
• weight and height measurements 
• full physical examination 
• electrocardiography 
• endoscopy 
• Modified Mayo score (ulcerative colitis [UC] only) 
• Robarts Histopathology Index (UC only) 
• Crohn’s Disease Activity Index (CDAI) score (Crohn’s disease [CD] only) 
• Simple Endoscopic Score for Crohn’s Disease (SES-CD) (CD only) 
• modified multiplier (MM)-SES-CD (CD only) 
• 2-item patient-reported outcome (PRO2) 
• stool sample tests for enteric pathogens (including stool culture and Clostridium difficile 
toxin assay) 
• infectious serologies 
• tuberculosis (TB) screening (QuantiFERON® TB Gold Test) 
• follicle-stimulating hormone testing (to confirm postmenopausal status) 
• pregnancy test (serum) in women of childbearing potential 
• clinical laboratory tests 
• urinalysis 
• biopsy towards tissue transcriptomics 
• adverse event monitoring 
• review prior and concomitant medication and treatments 
2. Procedures During Administration of Investigational Medicinal Product (Double-Blind 
Treatment Period) 
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a. Visit 1 (week 0, day 1) 
The following procedures and assessments will be performed at visit 1: 
• review inclusion and exclusion criteria 
• vital signs measurements 
• weight measurement 
• pregnancy test (urine) in women of childbearing potential 
• clinical laboratory tests 
• urinalysis 
• retained pharmacogenetic sample 
• biomarker high sensitivity C-reactive protein (hsCRP) 
• serum free and total tumor necrosis factor (ligand) 1A (TL1A) 
• stool sample for fecal calprotectin (FeCal) or other stool-derived markers 
• serum measure of PD 
• biomarker 
 
• serum measures of tissue condition 
• serum TEV-48574 concentration 
• anti-drug antibody (ADA) and neutralizing ADA 
• randomization (after all screening procedures complete and eligibility confirmed) 
• investigational medicinal product (IMP) administration 
• adverse event monitoring 
• review prior and concomitant medication and treatments 
• local tolerability assessment 
b. Visits 2, 4, and 6 (weeks 2, 6, and 10, days 15, 43, 71 ([±3 days based on previous visit]) 
The following procedures and assessments will be performed at visits 2, 4, and 6: 
• vital signs measurements 
• Stool frequency and Abdominal pain (PRO2 CD) 
• Stool frequency and Rectal bleeding Mayo sub-scores (PRO2 UC) 
• pregnancy test (urine) in women of childbearing potential) 
• biomarker hsCRP (visit 2 only) 
• serum free and total TL1A (visit 2 only) 
• stool sample for fecal calprotectin (FeCal) or other stool-derived markers (visit 2 only) 
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• serum measure of PD (visit 2 only) 
• biomarker 
 (visit 2 only) 
• serum measures of tissue condition (visit 2 only) 
• serum TEV-48574 concentration (visit 2 only) 
• ADA and neutralizing ADA (visit 2 only) 
• IMP administration 
• adverse event monitoring 
• review prior and concomitant medication and treatments 
• local tolerability assessment 
c. Visits 3, 5, and 7 (weeks 4, 8, and 12, days 29, 57, 85 ([±3 days based on previous visit]) 
The following procedures and assessments will be performed at visits 3, 5, and 7: 
• vital signs measurements 
• weight measurement 
• brief physical exam 
• electrocardiography (visits 3 and 5 only) 
• CDAI score (CD only) 
• Stool frequency and Abdominal pain (PRO2 CD) 
• Stool frequency and Rectal bleeding Mayo sub-scores (PRO2 UC) 
• pregnancy test (urine) in women of childbearing potential) 
• clinical laboratory tests  
• urinalysis (visits 3 and 5 only) 
• biomarker hsCRP (visits 3 and 5 only) 
• serum free and total TL1A (visits 3 and 5 only) 
• stool sample for fecal calprotectin (FeCal) or other stool-derived markers (visits 3 and 
5 only) 
• serum measure of PD (visits 3 and 5 only) 
• biomarker
 (visit 5 only) 
• serum measures of tissue condition (visits 3 and 5 only) 
• serum TEV-48574 concentration (visits 3 and 5 only) 
• ADA and neutralizing ADA (visits 3 and 5 only) 
• IMP administration 
• adverse event monitoring 
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• review prior and concomitant medication and treatments 
• local tolerability assessment 
d. Visit 8 (week 14, day 99 [±3 days based on previous visit]) 
The following procedures and assessments will be performed at visit 8: 
• vital signs measurements 
• weight measurement 
• full physical exam 
• electrocardiography 
• endoscopy 
• Modified Mayo score (UC only) 
• Robarts Histopathology Index (UC only) 
• CDAI score (CD only) 
• Stool frequency and Abdominal pain (PRO2 CD) 
• Stool frequency and Rectal bleeding Mayo sub-scores (PRO2 UC) 
• SES-CD (CD only) 
• MM-SES-CD (CD only) 
• pregnancy test (urine) in women of childbearing potential) 
• clinical laboratory tests 
• urinalysis 
• biomarker hsCRP 
• serum free and total TL1A 
• stool sample for fecal calprotectin (FeCal) or other stool-derived markers 
• biopsy towards tissue transcriptomics 
• serum measure of PD 
• biomarker
 
• serum measures of tissue condition 
• serum TEV-48574 concentration 
• ADA and neutralizing ADA 
• adverse event monitoring 
• review prior and concomitant medication and treatments 
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3. Follow-up (visit 9, week 18, day 127 [±3 days based on previous visit]) 
The following procedures and assessments will be performed at the follow-up visit: 
• vital signs measurements 
• weight measurement 
• full physical exam 
• pregnancy test (urine) in women of childbearing potential 
• clinical laboratory tests 
• urinalysis 
• biomarker hsCRP 
• serum free and total TL1A 
• stool sample for fecal calprotectin (FeCal) or other stool-derived markers 
• serum measure of PD 
• serum measures of tissue condition 
• serum TEV-48574 concentration 
• ADA and neutralizing ADA 
• adverse event monitoring 
• review prior and concomitant medication and treatments 
4. Early Termination 
The procedures and assessments performed at the early termination visit are identical to those 
performed at the visit 8 (week 14 visit; see item “d” above), except that weight is measured 
as well. If a patient develops COVID-19 during the course of the trial this is not an indication 
for early termination. 
5. Unscheduled Visits 
The investigator may schedule unplanned visits in addition to those listed in the Schedule of 
Study Procedures and Assessments, in order to conduct evaluations or assessments required 
to protect the well-being of the patient. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained from procedures and assessments. 
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APPENDIX B. QUALITY CONTROL AND QUALITY ASSURANCE  
Protocol Amendments and Protocol Deviations 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and national and local competent authorities, as 
applicable, except when necessary to address immediate safety concerns to the patients or when 
the change involves only nonsubstantial logistics or administration. The principal investigator at 
each investigational center, the coordinating investigator (if applicable), and the sponsor will 
sign the protocol amendment. 
Important Protocol Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include 
non-adherence on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or Good Clinical Practice 
(GCP) guidelines; noncompliance to investigational medicinal product administration; use of 
prohibited medications. Important protocol deviations will be documented by investigational 
center personnel. All important protocol deviations will be reported to the responsible IEC/IRB, 
as required. 
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation. If such patient has already completed the study or 
has withdrawn early, no action will be taken but the deviation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 
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Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable Standard Operating Procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
In case of an emergency situation (eg, the COVID-19 pandemic), where trial monitors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
monitored remotely, where allowed, and in accordance with global and/or local regulations. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 
In case of an emergency situation (eg, the COVID-19 pandemic), where auditors may not be able 
to access the investigational centers for on-site visits, investigational centers will be audited 
remotely, where allowed, and in accordance with global and/or local regulations. 
 
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APPENDIX C. ETHICS  
Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the patient. The patient should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents. 
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form (ICF), which will be signed and personally dated by 
the patient and by the person who conducted the informed consent discussion. The investigator 
will keep the original ICFs, and copies will be given to the patients. It will also be explained to 
the patients that the patient is free to refuse participation in the study and free to withdraw from 
the study at any time without prejudice to future treatment. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start before the IEC/IRB and 
competent authority (as applicable) for the investigational center give written approval or a 
favorable opinion. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance, or competent authorities. 
Personal medical information will always be treated as confidential. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on clinical trial registries if applicable. 
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APPENDIX D. BIRTH CONTROL METHODS  
Only highly effective birth control methods (methods that can achieve a failure rate of less 
than 1% per year when used consistently and correctly) may be used. Such methods include the 
following: 
• Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
14 days before the first dose of investigational medicinal product (IMP) 
• Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation; these should be initiated at least 14 days before the first dose of 
IMP 
• Intrauterine device and intrauterine hormone-releasing system need to be in place at least 
2 months before screening 
• Bilateral tubal occlusion, except for hysteroscopic bi-tubal ligation (Essure®), for which a 
hysterosalpingogram is required 3 months post procedure to assess surgical success 
• Vasectomized partner, provided he is the sole sexual partner and has received medical 
assessment of the surgical process 
• Heterosexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. Minimum time adherence prior to first dosing 
is 6 months. 
Male patients (including vasectomized) with women of childbearing potential partners (whether 
pregnant or not) must use condoms after the first IMP administration and throughout the study or 
until 50 days after the last IMP dose, whichever is longer. 
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APPENDIX E. LOST TO FOLLOW-UP  
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center must attempt to contact the patient and reschedule the missed 
visit as soon as possible and counsel the patient on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the patient wishes to and/or should 
continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls [preferably on different days] and, if necessary, a certified letter to the patient’s last 
known mailing address or local equivalent methods). These contact attempts should be 
documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of “lost to follow-up.” 
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APPENDIX F. PHARMACOGENETIC ASSESSMENTS  
Blood samples (2.5 mL) for pharmacogenetic assessments will be collected from all patients in 
the study who signed the informed consent form (ICF) for the pharmacogenetic assessments at 
the time point detailed in Table 1. Genetic assessments will be conducted only as part of an 
ancillary study. Each patient will sign a separate ICF for genetic assessment. Patients who do not 
wish to participate in the genetic research may still participate in the study. 
Pharmacogenetic assessment potentially includes the association of DNA variations with clinical 
responses (eg, efficacy, pharmacokinetics, tolerability, and safety features or disease 
susceptibility and severity features). The final list of genes that might be investigated will be 
selected at a later stage before the analysis to allow updating with new scientific information. 
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APPENDIX G. PRODUCT COMPLAINTS  
I. 
Clinical Product Complaints/Device Deficiency 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include but are not limited to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center with 
more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue. 
For complaints involving a device/combination product or other retrievable item, it is required 
that the device/combination product (or item) be sent back to the sponsor for investigative testing 
whenever possible. For complaints involving an IMP, all relevant samples (eg, the remainder of 
the patient’s IMP supply) should be sent back to the sponsor for investigative testing whenever 
possible. 
1. Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if applicable 
• product name and strength for open-label studies 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
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• description or nature of complaint 
• device deficiency associated with adverse event Yes/No  
• device deficiency associated with serious adverse event Yes/No 
• device deficiency that could lead to a serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
2. Handling of Investigational Medicinal Product(s)/Devices at the Investigational 
Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP or device. 
If it is determined that the investigational center must return all IMP or devices, the sponsor will 
provide the information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient, if applicable. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 8.1.3 and Section 8.1.8, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
the initial determination whether the deficiency could have led to a serious adverse event 
(Section II), and any actions taken to resolve the complaint and to preserve the safety of the 
patient. Once the complaint has been investigated by the sponsor and the investigator, if 
necessary, an event closure letter may be sent to the investigational center where the complaint 
originated or to all investigational centers using the product. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 
II. 
Assessment of Device Performance 
Device performance will be assessed by device deficiencies and product complaints.  
A device deficiency is defined as any inadequacy of an investigational medical device or 
combination product with respect to its identity, quality, durability, reliability, usability, safety, 
or performance (Figure 4). This definition includes malfunctions, use errors, inadequate labeling 
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(eg, unintelligible label, incorrect expiry date), and product complaints that are related to the 
device. 
The investigator should make an initial determination whether the device deficiency could have 
led to a serious adverse event and notify the sponsor by completing the product complaint form 
provided by Teva and emailing it to clinical.productcomplaints@tevapharm.com. 
Device deficiencies with potential serious adverse device effect are defined as deficiencies that 
might have led to a serious adverse device effect if (Figure 4): 
• suitable action had not been taken (or) 
• intervention had not been made (or) 
• if circumstances had been less fortunate 
These device deficiencies shall be reported to the sponsor and the Independent Ethics 
Committee/Institutional Review Board by the investigator, and to the regulatory authorities by 
the sponsor according to the national and local regulations. Device complaints related to 
potential device malfunctions will be initially assessed by the sponsor to determine the root cause 
of the complaint. Device complaints that are assessed to be caused specifically by device 
deficiencies will be reported to the device manufacturer for evaluation and further reporting 
according to national and local regulations. 
Figure 4: 
Decision Tree for Device Deficiencies 
 
IEC=Independent Ethics Committee; IRB=Institutional Review Board; SAE=serious adverse event. 
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Appendix H. 
DATA MANAGEMENT AND RECORD KEEPING  
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management). 
The medical experts, study monitors, auditors, Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), and inspectors from competent authority (or their agents) will be given 
direct access to source data and documents (eg, medical charts/records, laboratory test results, 
printouts, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in Title 21 Code of Federal Regulation Part 11 (United States 
of America) and documents of other concerned competent authorities. Before using the CDMS, 
it will be fully validated and all users will receive training on the system and study-specific 
training. After they are trained, users will be provided with individual system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, or electronic patient-reported outcome tablet), these data will 
be sent to the investigational center, where they will be retained but not transcribed to the CRF, 
unless otherwise noted in the protocol. These data may also be sent electronically to the sponsor 
(or organization performing data management). All patient data must have supportive original 
source documentation in the medical records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and considered as source data unless the 
sponsor provides written instructions specifying which data are permitted to be recorded directly 
to the CRF. 
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For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF. 
Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s Standard Operating Procedures (SOPs) for clinical studies. Day-to-day data 
management tasks for this study are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities. 
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS, and any discrepancies will be queried. 
Applicable terms will be coded according to the coding conventions for this study. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate. 
Archiving of Case Report Forms and Source Documents 
Sponsor Responsibilities 
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms 
• patient identification lists 
• CRFs for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary) 
• safety reports 
• financial disclosure reports/forms 
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• reports of receipt, use, and disposition of the IMPs 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization or sponsor notifies the institution in writing that records may be destroyed. 
If, after 25 years from study completion, or earlier in the case of the investigational center 
closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to sponsor at least 60 days before 
any planned disposition of study records. After receipt of such request, the sponsor may make 
arrangements for appropriate archival or disposition, including requiring that the investigator 
deliver such records to the sponsor. The investigator shall notify the sponsor of any accidental 
loss or destruction of study records. 
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APPENDIX I. PUBLICATION POLICY  
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with the following International 
Committee of Medical Journal Editors authorship requirements: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 
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Appendix J. 
LIST OF EXAMPLES OF OPPORTUNISTIC 
INFECTIONS  
• Bacterial enteric infections 
• Bartonellosis 
• Candidiasis (excluding vulvovaginal candidiasis) 
• Chagas disease 
• Coccidioidomycosis 
• Community-acquired pneumonia 
• Cryptococcosis 
• Cryptosporidiosis 
• Cystoisosporiasis (Formerly Isosporiasis) 
• Cytomegalovirus Disease 
• Hepatitis B Virus Infection 
• Hepatitis C Virus Infection 
• Herpes Simplex Virus 
• Histoplasmosis 
• Human Herpesvirus-8 
• Human Papillomavirus 
• Leishmaniasis 
• Malaria 
• Microsporidiosis 
• Mycobacterium avium  
• Mycobacterium tuberculosis 
• Pneumocystis Pneumonia 
• Progressive Multifocal Leukoencephalopathy/JC Virus Infection 
• Syphilis 
• Talaromycosis (Formerly Penicilliosis) 
• Toxoplasma gondii 
• Varicella-Zoster Virus 
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Any suspected opportunistic infections (ie, infections that are not listed above [eg, Clostridium 
difficile, aspergillosis, etc] and/or infections that occur more frequently and are more severe than 
expected) are to be reported. 
Further details are available in “Guidelines for Prevention and Treatment of Opportunistic 
Infections in HIV-Infected Adults and Adolescents.” Available at: 
https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/0). 
Accessed 18 August 2021. Vulvovaginal candidiasis was removed from the list above as it may 
be expected in the study patient population. 
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APPENDIX K. LIVER SAFETY: REQUIRED ACTIONS AND FOLLOW-
UP ASSESSMENTS GUIDELINES  
The liver chemistry stopping and increased monitoring criteria (see Section 4.4.1) have been 
designed to assure patient safety and evaluate liver event etiology and require follow up 
assessments as detailed below: 
Required Actions and Follow up Assessments 
Actions 
Follow up Assessment 
o 
Withhold study drug. 
o 
Report the event to Sponsor within 
24 hours  
o 
Complete the liver event CRF and 
complete an SAE/PDAESI form. 
o 
Perform liver chemistry event 
follow-up assessments. 
o 
Monitor the patient and repeat liver 
chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and 
INR) weekly (if bilirubin >2x ULN 
or INR>1.5, twice weekly) until 
liver chemistries resolve, stabilize 
or return to within baseline  
o 
Do not restart/patient with study 
drug unless allowed per protocol 
and Sponsor approval is granted.  
o 
If restart is not allowed per protocol 
or not granted, permanently 
discontinue study treatment and 
complete the assessments for the 
early termination visit and the 
follow-up period in the study. 
o 
Viral hepatitis serology1 
o 
Obtain INR. 
o 
Obtain blood sample for pharmacokinetic 
analysis, as soon as possible, and at least within 7 
days. 
o 
Obtain complete blood count with differential to 
assess eosinophilia. 
o 
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form. 
o 
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications. 
o 
Record alcohol use on the liver event CRF 
o 
If bilirubin and/or INR are elevated: 
▪ Test Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-live kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma globulins. 
▪ Check serum acetaminophen levels if definite 
or likely acetaminophen use in the preceding 
week:  
▪ Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy. 
▪ Consider a specialist or hepatology 
consultation. 
1Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody. 
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APPENDIX L. OPERATING CHARACTERISTICS AND ASSUMPTIONS 
FOR FINAL AND INTERIM ANALYSIS  
Final Analysis and Interim Futility Analysis 
A Beta-binomial model with a non-informative Beta (1,1) prior will be used to analyze the 
primary response endpoint, clinical remission (for UC) or endoscopic response (for CD), 
hereafter denoted as “response”. The model will be fit separately for each dose within each 
indication. 
Assumptions: 
Various scenarios for remission (UC), response rates (CD) are assumed as outlined in Table 9 to 
investigate the operating characteristics. 
Table 9: 
Remission (UC), Response (CD) Rates Scenarios for Clinical Trial 
Simulations 
Scenario 
Indication 
Placebo 
(%) 
Low Dose  
450 mg Q2W  
(%) 
High Dose  
900 mg Q2W  
(%) 
Null 
UC 
8 
8 
8 
CD 
12 
12 
12 
Intermediate Efficacy 
UC 
8 
20 
20 
CD 
12 
25 
25 
Efficacy 
UC 
8 
30 
30 
CD 
12 
34 
34 
Efficacy-high  dose 
only 
UC 
8 
8 
30 
CD 
12 
12 
34 
CD=Crohn’s disease; Q2W=every 2 weeks; UC=ulcerative colitis. 
 
Number of Patients at the Interim Analysis: 
The interim analysis for each indication is planned when approximately 50% of patients in the 
indication have completed the 14-week primary efficacy readout or had the opportunity to do so. 
Operating characteristics were obtained from simulations assuming that exactly 20 patients per 
arm in the corresponding indication will be included in the interim analysis. Since the analysis is 
separate for each indication, no assumptions on the expected difference in recruitment rate 
between UC and CD are required. 
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Statistical Decision Criteria – Final Analysis: 
A TEV-48574 dose will be declared successful at the final analysis if the posterior probability 
that the response rate in the TEV-48574 dose is higher than the response rate in the placebo arm 
is ≥0.90, ie, the success criterion for each dose within indication is: 
• Posterior Probability (TEV-48574 response rate – placebo response rate >0) ≥0.90 
Statistical Futility Cutoff – Interim Analysis: 
The same Bayesian Beta-Binomial model described in the primary analysis model will be used 
for the interim futility analysis for each dose within each indication. A TEV-48574 dose will be 
declared futile at the interim analysis if the posterior probability that the response rate in the 
TEV-48574 dose is higher than the response rate in the placebo arm is <0.30, ie, the futility 
criterion for each dose within indication is: 
• Posterior Probability (TEV-48574 response rate – placebo response rate >0) <0.30 
Operating Characteristics: 
Clinical trial simulations were performed under the assumptions for the interim and primary 
analysis to generate the operating characteristics (presented in Table 10), for a target sample size 
of 40 patients per arm in each indication, and an interim analysis for futility for each indication at 
21 patients per arm in the indication. The posterior probability futility cutoff is <0.30 for each 
indication and final success posterior probability cutoff is ≥0.90. 
Table 10: 
Operating Characteristics for Interim and Final Analysis – All Scenarios 
 
UC 
CD 
% Futile at interim 
analysis 
% Successful at end of 
trial 
% Futile at interim 
analysis  
% Successful at end of 
trial 
TEV-48574 doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both  
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
450 
mg 
Q2W 
900 
mg 
Q2W 
Both 
Doses 
450 
mg 
Q2W 
900 
mg 
Q2W 
At 
least 
1 dose 
Null 
25% 
24% 
11% 
8% 
8% 
13% 
24% 
24% 
12% 
9% 
10% 
16% 
Intermediate 
efficacy 
both doses 
4% 
4% 
1% 
61% 
61% 
77% 
4% 
4% 
1% 
59% 
59% 
76% 
Efficacy  
both doses 
1% 
1% 
<1% 
91% 
91% 
98% 
1% 
1% 
<1% 
87% 
87% 
95% 
Efficacy  
high dose 
only 
24% 
1% 
<1% 
8% 
91% 
91% 
25% 
1% 
1% 
10% 
87% 
87% 
CD=Crohn’s disease; Q2W=every 2 weeks; UC=ulcerative colitis. 
Note: Beta-Binomial model with non-informative prior; posterior probability futility cutoff: <0.30; final analysis 
posterior probability cutoff of ≥0.90.  
Note: Operating characteristics based on 500,000 simulations. 
 
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These simulations demonstrate that the probability of a false positive result is ≤16% for each 
indication, while the probability of declaring success for at least 1 dose within each indication 
under the efficacy assumption for both doses is ≥95%.  
The futility threshold was selected to control the probability to declare an effective dose to be 
futile at a maximum of 1%, while making the correct decision in the null with a probability of 
approximately 25%. 
Since the analysis is done separately for each dose and each indication, the probability to 
demonstrate efficacy in one dose is not affected by the other dose. Moreover, no inflation of the 
Type 1 error rate is expected in hypothetical discordant scenarios where TEV-48574 is effective 
in 1 indication but not in the other.  
Safety Stopping Rules 
• For each of the 4 types of AEs listed below (Table 11), a Bayesian analysis using the 
Beta-binomial model with a non-informative Beta(1,1) prior will be conducted. The 
posterior probability of each type of AE will be compared for each dose and the 3 dose 
levels combined versus placebo. If the posterior probability that the AE rate in the active 
group is larger than the AE rate in the placebo group with a posterior probability cutoff 
defined below, the stopping rule will be triggered. The analyses and evaluation will be 
conducted for UC and CD separately and across the entire study population.  
Table 11: 
Posterior Probability of Adverse Events 
AE type 
Posterior probability cutoff 
Serious adverse events (aggregated) 
90% 
CTCAE grade 3/4 adverse events (aggregated) 
90% 
Opportunistic and severe and/or serious infections 
85% 
Anaphylaxis 
85% 
AE=adverse event; CTCAE= Common Terminology Criteria for Adverse Events. 
• The DMC will review in detail any safety signal that meets the safety stopping rule, and 
take into account the totality of safety data. Additional analyses, eg, SAEs in the same 
HLT, may be performed. 
• The DMC will make a recommendation if the safety signal and the totality of the safety 
data warrants stopping the dose/indication/study. 
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APPENDIX M. COUNTRY-SPECIFIC REQUIREMENTS  
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Country-Specific Requirements: France  
The following country specific requirements are applicable to all subjects enrolled at study 
centers in France. 
 
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Amendment 04 (JP 05) (ES 01) (FR 01): Local Administrative Letter 01 
Dated 11 March 2024 
 
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Country-Specific Requirements: Japan  
The following country-specific requirements are applicable to all subjects enrolled at study 
centers in Japan. 
Revised Text is captured in the format strikethrough=deleted text; underline=new text.  
 
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Amendment 04 (JP 05) (ES 01) (FR 01): Local Administrative Letter 01 
Dated 12 March 2024 
 
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Study TV48574-IMM-20036 
267 
Amendment 03 (JP 04): Dated 21 September 2023 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Section 6.1.2.1 Biopsy Collection 
For patients with CD, an ileo-colonoscopy will be performed 
at screening and week 14. During each endoscopy, a total of 
16 to 18 8 mucosal biopsies will be obtained from the area 
with the greatest inflammation in each segment at screening 
and at the same location at week 14 or early termination. If 
ulceration is present, biopsies should be taken from the edge 
of the largest ulcer. If no ulceration is present, then biopsies 
should be taken from the most affected area of the segment. If 
the mucosa appears normal (eg, at follow-up), then random 
biopsies of the segment should be obtained.  
For patients with UC, a flexible sigmoidoscopy will be 
performed at screening and week 14 (colonoscopy may be 
performed instead for baseline endoscopy if not done in the 
prior 12 months). During each endoscopy, a total of 8 to 12 7 
biopsies will be obtained from the area with the worst disease 
15 to 25 cm from the anal verge. 
For patients with CD, an ileo-colonoscopy will be 
performed at screening and week 14. During each 
endoscopy, a total of 8 mucosal biopsies will be obtained 
from the area with the greatest inflammation in each 
segment at screening and at the same location at week 14 
or early termination. If ulceration is present, biopsies 
should be taken from the edge of the largest ulcer. If no 
ulceration is present, then biopsies should be taken from 
the most affected area of the segment. If the mucosa 
appears normal (eg, at follow-up), then random biopsies 
of the segment should be obtained.  
For patients with UC, a flexible sigmoidoscopy will be 
performed at screening and week 14 (colonoscopy may 
be performed instead for baseline endoscopy if not done 
in the prior 12 months). During each endoscopy, a total of 
7 biopsies will be obtained from the area with the worst 
disease 15 to 25 cm from the anal verge. 
To specify the number of total 
biopsies 
for 
each 
endoscopy 
procedure in Japan as follows: 
• 
For CD: 8 mucosal 
biopsies 
• 
For UC: 7 mucosal 
biopsies 
 
Amendment 03 (JP 03): Dated 28 June 2023 
Original text with changes shown 
New wording 
Reason/justification for change 
Section 4.1 Patient Inclusion Criteria 
 
Concomitant use of Chinese herbal medicines/Chinese 
herbal supplements (except Seitai and other indigo 
supplements) is allowed for patients who have been 
taking Chinese herbal medicines/Chinese herbal 
supplements prior to the start of the study, except that the 
dosage of Chinese herbal medicines/Chinese herbal 
Adding inclusion criteria as 
standard Japanese medical 
practice in IBD. 
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Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
268 
Original text with changes shown 
New wording 
Reason/justification for change 
supplements will not be changed during the study period. 
 
 
As for Seitai (Indigo naturalis)1) , the Ministry of 
Health, Labour and Welfare (MHLW) issued an alert to 
the relevant academic societies on 27 December 2016 to 
use Sentai for IBD treatment. Because it was found that 
there were several cases of pulmonary arterial 
hypertension (PAH) in patients with ulcerative colitis 
who took Seitai)(Indigo naturalis) or health foods 
containing Seitai (Indigo naturalis), PAH causality 
could not be denied. With that, concomitant use of Seitai 
(Indigo naturalis) is not allowed. 
 
1): Seitai (Indigo naturalis [IN]): IN is a herbal 
medicine extracted from leaves and stems of plants such 
as Indigofera tinctoria, Strobilanthes cusia O Kuntze, 
and Polygonum tinctorium Lour. In China, IN is quality 
controlled as an herbal medicine containing more than 
2.0% indigo and more than 0.13% indirubin. IN made 
from Fujian is regarded as being of the highest quality. 
IN is usually used as a raw material in Japan, and is 
classified as a dye, rather than a medicine. IN is 
considered an anti-inflammatory agent in Chinese 
textbooks from the tenth century 
 
Reference: Naganuma M. Treatment with indigo naturalis 
for inflammatory bowel disease and other immune 
diseases. Immunol Med 2019;42(1):16-21 
Section 5.6.4 Prohibited Medications and Therapies 
See new wording column 
Any Chinese herbal medicine/Chinese herbal supplement 
is prohibited during the study unless taken prior to the 
start of the study and the dosage will remain unchanged 
during the study period. 
Adding these prohibited 
medications as standard Japanese 
medical practice in IBD 
 
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Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
269 
Amendment 01 (JP 02): Dated 03 October 2022 
Original text with changes shown 
New wording 
Reason/justification 
for change 
TEV-48574 and Inflammatory Bowel Disease (Section 1.1.3) 
TEV-48574 is a highly potent, fully human immunoglobulin G 
(IgG) subclass 1 (lambda) monoclonal antibody (mAb) with a 
molecular weight of 146 kDA that targets TL1A, encoded by the 
TNF superfamily member 15 (TNFSF15) gene. TEV-48574 is a 
recombinant drug product that is manufactured using a cell line 
derived from Chinese hamster ovaries. 
TEV-48574 is a highly potent, fully human immunoglobulin G 
(IgG) subclass 1 (lambda) monoclonal antibody (mAb) with a 
molecular weight of 146 kDA that targets TL1A, encoded by the 
TNF superfamily member 15 (TNFSF15) gene. TEV-48574 is a 
recombinant drug product that is manufactured using a cell line 
derived from Chinese hamster ovaries. 
Clarification of cell 
line used to 
manufacture IMP. 
 
Amendment 01 (JP 01): Dated 15 August 2022 
Original text with changes shown 
New wording 
Reason/justification 
for change 
Patient Inclusion Criteria: item ‘g’ (Section 4.1 and in Synopsis) 
Patient must have inadequate response to, loss of response to, or 
intolerance of at least 1 of the following agents and no more than 
2 classes of biologics: corticosteroids, immunosuppressant drugs, 
and/or TNF-α antagonist therapy, anti-integrins, anti-IL-12/23, 
JAK inhibitors, and/or S1P receptor modulators.  
• 
Inadequate response to, loss of response to, or intolerance 
to corticosteroid treatment is defined as 1 or more of the 
following: 
− 
Steroid refractory: persistent symptoms of active 
disease despite treatment with at least one 4-week 
induction regimen that included a dose of ≥30 mg 
prednisone* (oral) daily for at least 2 weeks or 
intravenous (iv) for at least 1 week within the 
Patient must have inadequate response to, loss of response to, or 
intolerance of at least 1 of the following agents and no more than 
2 classes of biologics: corticosteroids, immunosuppressant drugs, 
and/or TNF-α antagonist therapy, anti-integrins, anti-IL-12/23, 
JAK inhibitors, and/or S1P receptor modulators.  
• 
Inadequate response to, loss of response to, or intolerance 
to corticosteroid treatment is defined as 1 or more of the 
following: 
− 
Steroid refractory: persistent symptoms of active 
disease despite treatment with at least one 4-week 
induction regimen that included a dose of ≥30 mg 
prednisone* (oral) daily for at least 2 weeks or 
intravenous (iv) for at least 1 week within the 
Adding a note to 
indicate prednisone is 
not licensed in Japan 
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Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
270 
Original text with changes shown 
New wording 
Reason/justification 
for change 
previous 5 years; 
− 
Steroid dependent: 2 failed attempts to taper steroids 
below a dose equivalent to 10 mg prednisone* (oral) 
daily within the previous year; 
* Prednisone is not licensed in Japan. 
previous 5 years; 
− 
Steroid dependent: 2 failed attempts to taper steroids 
below a dose equivalent to 10 mg prednisone* (oral) 
daily within the previous year; 
* Prednisone is not licensed in Japan. 
Patient Exclusion Criteria: item ‘f’ (Section 4.2 and Synopsis) 
A patient is Hepatitis B core antibody (HBcAb), or surface 
antigen (HBsAg), surface antibody (HBsAb; in line with the 
HBV testing flow chart in Figure 5), and/or Hepatitis C antibody 
positive with detectable ribonucleic acids, or positive human 
immunodeficiency virus types 1 or 2 at screening. 
A patient is Hepatitis B core antibody (HBcAb), surface antigen 
(HBsAg), surface antibody (HBsAb; in line with the HBV testing 
flow chart in Figure 5), and/or Hepatitis C antibody positive with 
detectable ribonucleic acids, or positive human 
immunodeficiency virus types 1 or 2 at screening. 
Adding HBsAb to 
serology test (in line 
with the HBV testing 
flow chart) as standard 
Japanese medical 
practice 
Patient Exclusion Criteria: item ‘s’ (Section 4.2 and Synopsis) 
Patient is receiving any of the following therapies within the 
designated time period: 
− >9 mg/day of oral budesonide or >20 mg/day prednisone* 
or equivalent within 2 weeks prior to the endoscopy. 
* Prednisone is not licensed in Japan. 
Patient is receiving any of the following therapies within the 
designated time period: 
− >9 mg/day of oral budesonide or >20 mg/day prednisone* 
or equivalent within 2 weeks prior to the endoscopy. 
* Prednisone is not licensed in Japan. 
Adding a note to 
indicate prednisone is 
not licensed in Japan. 
Patient Exclusion Criteria: item w (Section 4.2 and Synopsis) 
See new wording column 
Patient is receiving any of the following therapies within the 
designated time period: 
• 
The patient (UC or CD) had received cytapheresis therapy 
within 27 days before the first dose of IMP administration. 
• 
For CD patients only 
- The patient had received central intravenous nutrition 
therapy or complete enteral nutrition therapy, or had fasted 
Adding these 
exclusion criteria as 
standard Japanese 
medical practice in 
IBD 
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Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
271 
Original text with changes shown 
New wording 
Reason/justification 
for change 
within 20 days before the first dose of IMP administration. 
- The patient had received over 900 kcal/day of enteral 
nutrition therapy, or had started enteral nutrition at 900 
kcal/day or less within 20 days before the first dose of IMP 
administration. 
- The patient had started enteral nutritional supplements of 
900 kcal/day or less 21 days or more before the start of 
administration of the investigational drug, and those who 
had changed or discontinued the dose within 20 days 
before the first dose of IMP administration. 
Investigational Medicinal Products Used in the Study (Section 5.1) 
See new wording column 
ʻDrug Used in Clinical Trialʼ is defined as approved or 
non-approved drugs (including test drugs that are used for 
efficacy and safety evaluation of test drugs in clinical trial. ʻDrug 
Used in Clinical Trialʼ includes test drugs, comparators, 
concomitant drugs, rescue drugs, pre-medication drugs, and the 
like. Drugs that are not specified in protocol or are not used for 
efficacy and safety evaluation of test drugs are excluded from 
ʻDrug Used in Clinical Trialʼ. The regulation/guidance stipulated 
in Japan GCP is also applied for medical devices (ʻDevice Used 
in Clinical Trialʼ) and regenerative products (ʻRegenerative 
Medical Product Used in Clinical Trialʼ) used for efficacy and 
safety evaluation of test drugs. 
In this study, ʻDrug Used in Clinical Trialʼ is defined as below: 
• 
TEV-48574 and placebo 
In this study, ʻDevice Used in Clinical Trialʼ is defined as below: 
• 
 and accessories 
By JGCP guidelines, 
identifying and 
describing drug and 
device to be used in 
the current study in 
Japan 
Permitted Inflammatory Bowel Disease Medications and Rescue Medications (bullet 2 in Section 5.6.3) 
• 
A stable dose of oral corticosteroids (prednisone* equivalent 
of up to 20 mg/day; budesonide of up to 9 mg/day) for at 
• 
A stable dose of oral corticosteroids (prednisone* equivalent 
of up to 20 mg/day; budesonide of up to 9 mg/day) for at 
Adding a note to 
indicate prednisone is 
not licensed in Japan. 
VV-00492862 v6.0

Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
272 
Original text with changes shown 
New wording 
Reason/justification 
for change 
least 2 weeks prior to endoscopy and through week 14. If 
oral corticosteroids have been recently discontinued, they 
must have been stopped at least 2 weeks prior to endoscopy. 
Decreases in steroid use due to adverse events are allowed. 
* Prednisone is not licensed in Japan. 
least 2 weeks prior to endoscopy and through week 14. If 
oral corticosteroids have been recently discontinued, they 
must have been stopped at least 2 weeks prior to endoscopy. 
Decreases in steroid use due to adverse events are allowed. 
* Prednisone is not licensed in Japan. 
Prohibited Medications and Therapies (bullet 3 in Section 5.6.4) 
• Prednisone* dose of >20 mg/day or equivalent oral systemic 
corticosteroid from 2 weeks prior to endoscopy through week 
14. 
* Prednisone is not licensed in Japan. 
• Prednisone* dose of >20 mg/day or equivalent oral systemic 
corticosteroid from 2 weeks prior to endoscopy through week 
14. 
* Prednisone is not licensed in Japan. 
Adding a note to 
indicate prednisone is 
not licensed in Japan. 
Prohibited Medications and Therapies (Section 5.6.4) 
See new wording column 
• 
Cytapheresis therapy within 27 days before the first dose of 
IMP administration. 
• 
For CD patients only: 
- 
Central intravenous nutrition therapy or complete enteral 
nutrition therapy, or had fasted within 20 days before the 
first dose of IMP administration. 
- 
Over 900 kcal/day of enteral nutrition therapy, or had 
started enteral nutrition at 900 kcal/day or less within 20 
days before the first dose of IMP administration. 
- 
Enteral nutritional supplements of 900 kcal/day or less 21 
days or more before the start of administration of the 
investigational drug, and those who had changed or 
discontinued the dose within 20 days before the first dose 
of IMP administration. 
Meeting JGCP 
requirement 
Appendix E (item 1 & item2): Birth Control Methods 
• 
Combined estrogen and progestogen hormonal 
• 
Combined 
estrogen 
and 
progestogen 
hormonal 
contraception (oral, intravaginal*, transdermal*) associated 
Adding a note to 
indicate these methods 
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Placebo-Controlled Study–IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
273 
Original text with changes shown 
New wording 
Reason/justification 
for change 
contraception (oral, intravaginal*, transdermal*) associated 
with inhibition of ovulation*; these should be initiated at least 
14 days before the first dose of investigational medicinal 
product (IMP) 
• 
Progestogen-only hormonal contraception* (oral, 
injectable, implantable) associated with inhibition of 
ovulation*; these should be initiated at least 14 days before 
the first dose of IMP 
*Not approved in Japan 
with inhibition of ovulation*; these should be initiated at 
least 14 days before the first dose of IMP 
• 
Progestogen-only hormonal contraception* (oral, injectable, 
implantable) associated with inhibition of ovulation*; these 
should be initiated at least 14 days before the first dose of 
IMP 
*Not approved in Japan. 
 
are not approved in 
Japan 
Appendix I:  Data Management and Record Keeping 
Archiving of Case Report Forms and Source Documents  
See new wording column 
The institution, IRB, and sponsor are required by the JGCP 
ordinance, etc. to preserve the records. 
In accordance with the JGCP ordinance, etc., a person 
responsible for the preservation of various records (including 
data) related to this clinical trial must be designated for each, and 
these records must be preserved under appropriate conditions. 
The storage period must comply with Appendix I. 
Adding the statements 
of responsibilities for 
various perspectives  
Appendix M (footnote): Liver Safety: Required Actions and Follow-Up Assessments Guidelines 
Includes: Hepatitis A immunoglobulin M (IgM) antibody; 
HBsAg, HBcAb, and HBsAb; Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); Hepatitis E IgM antibody. 
Includes: Hepatitis A immunoglobulin M (IgM) antibody; 
HBsAg, HBcAb, and HBsAb; Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); Hepatitis E IgM antibody. 
Adding HBsAb to 
serology test (in line 
with the HBV testing 
flow chart, Figure 5) 
as standard Japanese 
medical practice 
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Placebo-Controlled Study-IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
274 
Figure 5: 
Hepatitis B Testing Flow Chart  
 
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Placebo-Controlled Study-IBD 
Clinical Study Protocol Amendment 04 (JP 05) (ES 01) (FR 01) 
Study TV48574-IMM-20036 
275 
Country-Specific Requirements: Spain  
The following country-specific requirements are applicable to all subjects enrolled at study 
centers in Spain. 
Revised text is captured in the format strikethrough=deleted text; underline=new text.  
Amendment 02 (JP 02) (ES 01): Dated 27 March 2023 
Original text with changes shown 
New wording 
Reason/justification 
for change 
Patient Inclusion Criteria: item ‘g’ (Section 4.1 and in Synopsis) 
Patient must have inadequate response to, 
loss of response to, or intolerance of at least 
1 of the following agents and no more than 
2 classes of biologics: corticosteroids, 
immunosuppressant drugs, and/or to anti-
TNF-α antagonist therapy inhibitors., anti-
integrins, anti-IL-12/23, JAK inhibitors, 
and/or S1P receptor modulators  
Patient must have inadequate response to, 
loss of response to, or intolerance to anti-
TNF inhibitors. 
The local Spanish 
Health Authority and 
Ethics Committee 
requested 
modifications. 
 
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