Clinical trial NCT03695185
Conditions: Ulcerative Colitis (UC)
Keywords: Ulcerative Colitis (UC) ABBV-323 Ravagalimab
Sponsor: AbbVie
Start date: 2019-03-26; Completion date: 2022-01-10
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study M15-722 is a Phase 2a study to investigate the efficacy and safety of Ravagalimab (ABBV-323) in participants with moderate to severe UC who failed prior therapy.

Detailed description:

Arms: arm 1: Participants received ravagalimab 600 mg intravenous (IV) at Week 0 followed by ravagalimab 300 mg subcutaneously (SC) at Weeks 2, 4, 6, 8, and 10 in a 12-week Induction Period. Participants who achieved clinical response per partial adapted Mayo score at Week 12 of the Induction Period entered the Maintenance Period to receive ravagalimab 300 mg SC every other week (EOW) from Week 12 through Week 102.
Interventions: intervention 1: Ravagalimab 600 mg intervention 2: Ravagalimab 300 mg
Intervention descriptions: intervention 1: Ravagalimab 600 mg was administered intravenously (IV). intervention 2: Ravagalimab 300 mg was administered subcutaneously (SC).

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
STUDY OBJECTIVES AND ENDPOINTS
8
3.1
OBJECTIVES
8
3.2
PRIMARY EFFICACY ENDPOINT
9
3.3
SECONDARY EFFICACY ENDPOINTS
9
3.4
ADDITIONAL EFFICACY ENDPOINTS
10
3.5
SAFETY ENDPOINTS
11
3.6
PHARMACOKINETIC ENDPOINTS
11
3.7
BIOMARKER ENDPOINTS
11
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
15
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
20
5.3
PROHIBITED MEDICATIONS AND THERAPY
21
5.4
PRIOR AND CONCOMITANT THERAPY
22
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY DRUG OR FROM STUDY PARTICIPATION
22
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY PARTICIPATION
23
5.7
STUDY DRUG
24
5.8
RANDOMIZATION/DRUG ASSIGNMENT
25
5.9
PROTOCOL DEVIATIONS
25
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
6.2
TOXICITY MANAGEMENT
29
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6.3
DATA MONITORING COMMITTEE
32
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
32
7.1
STATISTICAL AND ANALYTICAL PLANS
32
7.2
DEFINITION FOR ANALYSIS POPULATIONS
32
7.3
STATISTICAL ANALYSES FOR EFFICACY
32
7.4
STATISTICAL ANALYSES FOR SAFETY
33
8
ETHICS
34
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
34
8.2
ETHICAL CONDUCT OF THE STUDY
34
8.3
SUBJECT CONFIDENTIALITY
34
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
34
10 DATA QUALITY ASSURANCE
34
11 COMPLETION OF THE STUDY
35
12 REFERENCES
35
LIST OF TABLES
TABLE 1.
DESCRIPTION OF STUDY DRUG
24
TABLE 2.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
30
LIST OF FIGURES
FIGURE 1.
INDUCTION AND MAINTENANCE PERIOD SCHEMATIC
14
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
36
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
39
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
40
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APPENDIX D.
ACTIVITY SCHEDULE
41
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
50
APPENDIX F.
OPERATIONS MANUAL
55
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the rectum and/or large intestine 
characterized by inflammation and ulceration of the mucosal and submucosal intestinal layers.  The 
hallmark clinical symptoms include bloody diarrhea associated with rectal urgency and tenesmus.  The 
clinical course is marked by exacerbation and remission.  Extraintestinal complications include arthritis, 
erythema nodosum, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis.  Conventional 
therapies for the induction of remission include 5-aminosalicylic acid (5-ASA) derivatives, corticosteroids 
and the immunomodulatory agent cyclosporine.  5-ASA derivatives as well as thiopurines are used for 
the maintenance of remission.1  The biological agents infliximab, adalimumab, golimumab, vedolizumab, 
and ustekinumab as well as the Janus kinase (JAK) inhibitor tofacitinib are indicated for the induction 
and maintenance of remission in subjects with moderate to severe UC.  Despite increasingly available 
therapies, currently approved UC therapies have limited efficacy2-4 and have a potential for significant 
safety events.5-8  Thus, a large unmet need continues to exist for the treatment of UC.
CD40 is a tumor necrosis factor (TNF) receptor family member that plays an important role in 
lymphocyte activation and antigen presenting cell (APC) function.  CD40 expression on epithelium, 
leukocytes, and vascular endothelium is elevated in systemic inflammatory diseases (e.g., Crohn's 
disease [CD], UC, rheumatoid arthritis [RA], and systemic lupus erythematosus [SLE]).  Ravagalimab is a 
proprietary monoclonal antibody (mAb) that is a potent CD40 antagonist with no evidence of agonist 
activity.
Evidence from in vitro studies, preclinical models, and human disease suggests that CD40 signaling is 
important in the pathogenesis of UC and inhibition of CD40 mediated signaling may be a potential 
treatment for patients with UC.9  For further details, please see ravagalimab Investigator's Brochure.10
Clinical Hypothesis
Ravagalimab is safe and well tolerated in subjects with moderate to severe UC and leads to endoscopic 
improvement at Week 8.
2.2 Benefits and Risks to Subjects
Despite the availability of various UC therapies, including biologic and small molecule therapies, many 
patients still do not respond adequately to these treatments, gradually lose response over time or 
discontinue treatment due to significant adverse events (AEs).  Thus, there remains a large unmet 
medical need for additional therapeutic options in UC for patients with inadequate response or 
intolerance to available therapies.  Based on pre-clinical, clinical, and translational evidence, 
ravagalimab could potentially demonstrate efficacy with a favorable safety profile in the treatment of 
patients with moderately to severely active UC who have failed or have intolerance to approved 
biologics and/or tofacitinib.
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In the Phase 1 studies ravagalimab was safe and well tolerated with no serious or severe AEs observed in 
healthy adult subjects.  The dose regimen in Study M15-722 will not exceed the doses evaluated in the 
Phase 1 studies.
As with any immune modulating agent, ravagalimab has the potential to impair immune function 
resulting in a potential risk of infection, including opportunistic infections.  The role of ravagalimab in 
tumor immunity is not well established at this time, but an increased risk of cancer associated with 
ravagalimab treatment cannot be excluded.  Though the completed Phase 1 studies did not suggest a 
potential for drug-induced liver injury (DILI) with ravagalimab, DILI is under constant surveillance by 
sponsors and regulators and any suspected event of DILI in this study requires timely detection, 
evaluation, and follow-up of laboratory parameters.  Local reactions to intravenous (IV) infusions or 
subcutaneous (SC) administered biologic therapies are uncommon, and are usually limited to redness, 
swelling, or induration at injection site.  In Phase 1 studies, 1 subject on ravagalimab each experienced 
injection site reaction and injection site pain.  The aforementioned safety risks were taken into account 
with the establishment of the safety monitoring measures in the eligibility criteria for this study.  
Furthermore, an internal data monitoring committee (DMC) will monitor safety at regular intervals 
(Section 6.3).
Blood sampling, IV infusions, and subcutaneous SC injections can cause local bruising, inflammation, and 
pain.  The preparation for endoscopy, and the endoscopy and biopsy procedure itself, although 
generally well tolerated, can be associated with diarrhea, abdominal pain, and in more severe cases, 
perforation, bleeding, effects from anesthetic medications, and infection.
In view of the coronavirus disease of 2019 (COVID-19) pandemic, the benefit-risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated.  At this time, the effects of ravagalimab 
on the course of COVID-19 is not known. 
The benefit-risk profile of ravagalimab is considered appropriate for an experimental therapy at this 
stage of clinical development in an especially refractory patient population. 
Taken together, the data support further development of ravagalimab in Phase 2 for subjects with 
moderate to severe UC who have failed prior biologic therapy and/or tofacitinib.  For further details, 
please see findings from completed studies, including safety data in the ravagalimab Investigator's 
Brochure.10
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
To explore the efficacy, safety, and tolerability of ravagalimab as treatment in subjects with moderately 
to severely active UC.
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3.2 Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with endoscopic improvement (Mayo 
endoscopic subscore of 0 or 1) at Week 8.  Note that evidence of friability during endoscopy in subjects 
with a Mayo endoscopic subscore of 0 or 1 will confer an endoscopic subscore of 2.
3.3 Secondary Efficacy Endpoints
Definitions of Efficacy Endpoints:
Clinical Remission per Adapted Mayo Score:  stool frequency subscore (SFS) ≤ 1, and not greater than 
baseline, rectal bleeding subscore (RBS) = 0, and endoscopic subscore ≤ 1
Clinical Response per Adapted Mayo Score:  decrease from Baseline ≥ 2 points and ≥ 30%, PLUS a 
decrease in RBS ≥ 1 or an absolute RBS ≤ 1
Clinical Response per Partial Adapted Mayo Score:  decrease from Baseline ≥ 1 points and ≥ 30%, PLUS 
a decrease in RBS ≥ 1 or an absolute RBS ≤ 1
Clinical Remission per Full Mayo Score:  Full Mayo score ≤ 2 with no subscore > 1
Clinical Response per Full Mayo Score:  decrease from Baseline ≥ 3 points and ≥ 30%, PLUS a decrease 
in RBS ≥ 1 or an absolute RBS ≤ 1
Endoscopic Improvement:  Mayo endoscopic subscore of 0 or 1
Endoscopic Remission:  Mayo endoscopic subscore = 0
Histologic Remission: Geboes score of < 2.0
Mucosal Healing:  endoscopic and histologic remission
Modified Baron Score:  The modified Baron score, which represents an endoscopic classification, ranges 
from 0 to 4, with 0 denoting normal mucosa, 1 granular mucosa with an abnormal vascular pattern, 
2 friable mucosa, 3 microulceration with spontaneous bleeding, and 4 gross ulceration.
Note that evidence of friability during endoscopy in subjects with a Mayo endoscopic subscore of 0 or 1 
will confer an endoscopic subscore of 2.
For this study, Baseline is defined as Week 0.
Key Secondary Efficacy Endpoints for Induction Period (Weeks 0 to 12)

Proportion of subjects with clinical remission per Adapted Mayo score at Week 8

Proportion of subjects with clinical response per Adapted Mayo score at Week 8

Proportion of subjects with clinical response per Partial Adapted Mayo score over time

Proportion of subjects with clinical remission per Full Mayo score at Week 8 in subjects with a 
Full Mayo score of 6 to 12 at Baseline
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
Proportion of subjects with Endoscopic remission at Week 8
3.4 Additional Efficacy Endpoints

Change from Baseline in modified Baron score over time (at visits with endoscopy)

Proportion of subjects with achievement of SFS = 0, RBS = 0, and Mayo endoscopic subscore = 0 
over time (at visits with endoscopy)

Time to clinical response per Partial Adapted Mayo score

Proportion of subjects with endoscopic improvement over time (at visits with endoscopy)

Proportion of subjects with clinical remission per Adapted Mayo score over time (at visits with 
endoscopy)

Proportion of subjects with clinical response per Adapted Mayo score over time (at visits with 
endoscopy)

Proportion of subjects with clinical response per Partial Adapted Mayo score over time

Proportion of subjects with achievement of clinical remission per Adapted Mayo score over time 
among subjects who were taking corticosteroids at Baseline and subsequently discontinued 
corticosteroids for ≥90 days prior to the respective visit.

Proportion of subjects with discontinuation of corticosteroid use for subjects taking 
corticosteroids at Baseline at all visits over time

Proportion of subjects with endoscopic remission over time (at visits with endoscopy)

Proportion of subjects with clinical remission per Full Mayo score over time in subjects with a 
Full Mayo score of 6 to 12 at Baseline (at visits with endoscopy)

Proportion of subjects with clinical response per Full Mayo score over time in subjects with a 
Full Mayo score of 6 to 12 at Baseline (at visits with endoscopy)

Proportion of subjects with SFS ≤ 1 over time

Proportion of subjects with RBS = 0 over time

Change from Baseline in RBS over time 

Change from Baseline in SFS over time 

Change from Baseline in fecal calprotectin (FCP) over time  

Change from Baseline in high sensitivity C-reactive protein (hs-CRP) over time  

Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) over time 

Proportion of subjects with UC-related Hospitalizations (yes/no) over time

Proportion of subjects with UC-related surgery (yes/no) over time

Proportion of subjects reporting no bowel urgency over time

Change from Baseline in weekly abdominal pain score over time 
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
Proportion of subjects with achievement of ≥ 30% reduction from Baseline in weekly abdominal 
pain score over time

Proportion of subjects with weekly abdominal pain score = 0 over time

Change from Baseline in number of extraintestinal manifestations (EIM) over time (as captured 
in the EIM electronic case report form [eCRF])

Proportion of subjects with histologic remission over time (at visits with endoscopy)

Proportion of subjects with mucosal healing (endoscopic and histologic remission) over time (at 
visits with endoscopy)

Change from Baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) over time (at 
visits with endoscopy)

Change from Baseline in UC-100 score over time (at visits with endoscopy)
3.5 Safety Endpoints
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, 
electrocardiogram (ECG) variables (as needed), and clinical laboratory testing (hematology, chemistry, 
and urinalysis) as measures of safety and tolerability.  An internal DMC will monitor safety at regular 
intervals (Section 6.3).
3.6 Pharmacokinetic Endpoints
Serum ravagalimab concentrations will be obtained at the visits indicated in Appendix D and will be 
summarized at each sampling time point using descriptive statistics.  A nonlinear mixed-effects modeling 
approach may be used to estimate the population central value and the empirical Bayesian estimates of 
the individual values for ravagalimab apparent clearance (CL/F) and volume of distribution at 
steady-state (Vss/F).  Ravagalimab anti-drug antibody (ADA) development will also be determined at 
specific visits during the study (Appendix D) and will be summarized using descriptive statistics.  
Additional parameters and relationships (e.g., exposure-receptor occupancy, exposure-efficacy, or 
exposure-safety) may be evaluated if useful for the interpretation of study results.
3.7 Biomarker Endpoints
Biospecimens (blood and tissue biopsy) will be collected at specified time points (Appendix D) 
throughout the study to evaluate known and/or novel disease-related or drug-related biomarkers.  
Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites.  Biopsies for 
biomarker analysis will be done when performing endoscopies.  Up to 4 biopsies will be taken from the 
site of general inflammation at each visit with an endoscopy for biomarker research as outlined in 
Appendix D:  1 biopsy for histologic assessment by central review, 1 biopsy for gene expression analysis 
(including CD40 signature), and 2 biopsies for tissue RO (where applicable).  Biopsies for tissue RO will 
only be collected at sites located in the United States.  Additional biopsies may be collected at the 
Investigator's discretion to confirm disease diagnosis, and/or to rule out dysplasia, colon cancer and 
infection.
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Blood samples will be used to evaluate ravagalimab RO and change in T cells, NK cells, B cells, and 
plasmablast cell numbers.
Blood samples may be used for exploratory research to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  Mandatory intestinal biopsy tissue samples may 
also be used for exploratory research to assess and generate prognostic, predictive, pharmacodynamic, 
or surrogate biomarker signatures.  These assessments may be explored in the context of UC or related 
conditions and/or ravagalimab or drugs of similar classes.
The results from these analyses are exploratory in nature and may not be included with the clinical 
study report.  Biomarker samples will be collected and analyzed from all subjects, unless precluded by 
local regulations or restrictions.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
Study M15-722 is a Phase 2a, multicenter, single arm, open-label (OL) study to investigate the efficacy 
and safety of ravagalimab in subjects with moderate to severe UC who failed prior therapy.  The study 
contains a 35-day screening period, 2 treatment periods, and an 84-day follow up period from the last 
dose of study drug.  The induction period is an open-label 12-week treatment period to evaluate the 
efficacy, safety, tolerability, PK and RO of ravagalimab for inducing endoscopic improvement at Week 8.  
Subjects who achieve clinical response per Partial Adapted Mayo score at Week 12 may continue into 
the maintenance period.  The maintenance period is an OL 92-week treatment period to assess efficacy 
and safety for maintenance of response with ravagalimab.
Prior to protocol version 4.0 the study had a double-blind (DB) placebo-controlled induction period.  
Ongoing subjects enrolled prior to version 4.0 continued their treatment as randomized during the 
induction period and, in case of clinical response at Week 12, their OL treatment during the 
maintenance period.
Induction Period
Up to approximately 40 subjects will be enrolled in the induction period to receive the following 
treatment:

Ravagalimab 600 mg intravenous (IV) Week 0; ravagalimab 300 mg subcutaneous (SC) Weeks 2, 
4, 6, 8, and 10.
Once the 30th subject completes Week 8 assessments an interim analysis will occur.  This interim 
analysis will inform the planning of future Phase 2b and 3 studies.  Enrollment into the induction period 
may continue until approximately 40 subjects have enrolled, or enrollment may be terminated if the 
study objectives are determined to have been met. 
An endoscopy is required at Screening, and evaluation of endoscopic improvement will occur at Week 8.  
In order to explore the time-course of ravagalimab efficacy, subjects will continue through Week 12 and 
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will be assessed for clinical response per Partial Adapted Mayo score at Week 12.  Subjects who 
complete the induction period and achieve clinical response per Partial Adapted Mayo score at Week 12 
will be given the opportunity to continue into the maintenance period.  Subjects not achieving clinical 
response per Partial Adapted Mayo score at Week 12 will be discontinued and have a follow-up visit (or 
call if a visit is not possible) 84 days from the last dose of study drug to obtain information on any new 
or ongoing AEs.
Maintenance Period
Subjects who enter the maintenance period will receive OL ravagalimab 300 mg SC every other week 
(eow) from Week 12 through Week 102.
At Weeks 52 and 104 subjects will undergo endoscopy.  Clinical response and remission, as well as other 
exploratory endpoints will be evaluated throughout the study at specified time points.  Patients who 
complete the maintenance period will have a follow-up visit (or call if a visit is not possible) 84 days from 
the last dose of study drug to obtain information on any new or ongoing AEs.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
See Section 5.1 for information regarding eligibility criteria.
All video endoscopies and mandatory biopsies for histologic assessment will be centrally reviewed.
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Figure 1.
Induction and Maintenance Period Schematic
BL = Baseline; EOW = every other week; IV = intravenous; SC = subcutaneous
Note:
Prior to protocol version 4.0 the study had a double-blind (DB) placebo-controlled induction period.
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4.2 Discussion of Study Design
Choice of Control Group
The efficacy of ravagalimab will be evaluated through comparison with historical control.  The control 
group for this study is placebo data derived from meta-analysis of recent clinical studies that used 
central review of endoscopies and that are aligned in terms of endpoint definition and time point of 
analysis.  The objective nature of the centrally read endpoint, as well as the low placebo rate of 
endoscopic improvement, makes the use of historical placebo control a feasible method to assess the 
effect of ravagalimab.  Subjects will therefore not be enrolled into a concurrent control group within the 
study.
Prior to Version 4.0, a concurrent placebo control arm was used in this study.
Appropriateness of Measurements
Standard data collection, clinical, statistical, endoscopy-related and laboratory procedures will be 
utilized in this study.  All efficacy measurements in this study are standard or are derived from 
commonly used efficacy measurements for assessing disease activity in clinical studies of subjects with 
UC.  All clinical and laboratory procedures in this study are standard and generally accepted. Central 
review of endoscopy will increase study rigor and ensure enrollment of subjects with moderately to 
severely active UC.
Suitability of Subject Population
The specific population chosen was based on the unmet medical need of those subjects who have failed 
prior therapy as defined in Section 5.1.
Selection of Doses in the Study
The dose selection in this study is based on analysis of PK, pharmacodynamics, and safety data from 
Phase 1 studies in healthy volunteers as well as safety data from pre-clinical animal studies.  The Phase 1 
ravagalimab single and multiple ascending dose studies, Study M15-726 and Study M15-730, evaluated 
ravagalimab single doses of 10 - 300 mg SC and 100 - 600 mg IV, and multiple doses of 50 and 150 mg SC 
weekly for 3 weeks following IV loading doses of 50 mg and 300 mg, respectively.  Partial peripheral 
blood B cell CD40 RO was achieved with SC doses of 10 and 30 mg; whereas full peripheral blood B cell 
CD40 RO (i.e., > 90%) was achieved with IV or SC doses ≥ 100 mg.  In Study M15-730, full peripheral 
blood B cell RO was achieved with weekly SC doses of 50 and 150 mg and was maintained for at least 
14 days after the last ravagalimab dose.
In Study M16-641 the impact of ravagalimab on T helper dependent B cell responses following keyhole 
limpet hemocyanin (KLH) administration was evaluated.  Preliminary results from the study showed that 
a single 300 mg SC dose of ravagalimab achieved near full suppression of IgM and IgG response to KLH 
antigen.  On the other hand, a single 100 mg SC dose and multiple 100 mg SC doses given once every 
two weeks (total of three doses) resulted in minimal to no suppression of immune response to KLH, 
despite prolonged maximal peripheral blood B cell CD40 RO.
Given the results from the KLH immunization study and the uncertainty in correlation between 
peripheral blood B cell CD40 RO and efficacy in UC patients and the potential for a tissue sink in UC 
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patients, for this proof-of-concept (POC) study, a 600 mg IV loading dose followed by 300 mg eow SC 
dose was selected for induction to enable rapid achievement of serum steady state ravagalimab 
concentrations as well as presumably high levels of tissue RO.  Such dosing is predicted to provide at 
least a 20-fold safety margin relative to no-observed-adverse-effect-level (NOAEL) exposures observed 
at a dose of 50 mg/kg in the 13-week GLP-compliant toxicology study in cynomolgus monkeys.  Given 
the high inflammatory burden for UC patients, a 300 mg eow SC maintenance dose was selected for 
subjects who demonstrate clinical response after induction.  Furthermore, 300 mg eow SC dosing with 
ravagalimab is predicted to result in serum ravagalimab exposures that are approximately 4-fold lower 
than the NOAEL exposures observed at a dose of 5 mg/kg in 26-week toxicology studies in cynomolgus 
monkeys.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must understand and personally, voluntarily sign and date an informed consent, 
approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to 
the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, between 18 and 75 years of age, inclusive, at time of the Baseline visit.
3. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:  

Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤2 × upper limit of 
normal (ULN);

Total white blood cell (WBC) count ≥3.0 × 109/L;

Absolute neutrophil count (ANC) > 1,200 cells/µL;

Absolute lymphocyte count (ALC) > 750 cells/µL;

Total bilirubin < 2 mg/dL, except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert's syndrome;

Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula ≥40 ml/min/1.73 m2;

Hemoglobin ≥9 g/dL;

Platelet count ≥100,000/µL.
4. Are willing or able to comply with procedures required in this protocol.
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5.Subject must not have an active, chronic, or recurrent infection that based on the 
Investigator's clinical assessment makes the subject an unsuitable candidate for the study, or 
the following:

Subject must not be currently infected with C. difficile toxin as identified during Screening or 
another known intestinal pathogen.

Subject must not be infected with human immunodeficiency virus (HIV)

Subject must not have active hepatitis B or hepatitis C (as defined in Appendix F)

Subject must not have active tuberculosis (TB).  Subjects with a positive QuantiFERON TB / 
or Purified Protein Derivative (PPD) skin test during Screening may participate in the study if 
further workup (including a mandatory chest X-ray [CXR] and other testing according to local 
country guidelines) establishes conclusively that the subject has no evidence of active TB.  If 
latent TB is established, the subject must initiate and complete a minimum of 2 weeks (or 
per local guidelines, whichever is longer) of an ongoing TB prophylaxis/treatment or have 
documented completion of a full course of TB prophylaxis, prior to Baseline.  Subjects with 
active TB or a history of active TB who have documented completion of a full course of anti-
TB therapy may be allowed to enter the study after consultation with the AbbVie 
Therapeutic Area Medical Director (TA MD).

Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of 
signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement in symptoms;

Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known 
exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out 
SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure.
Disease Activity
6. Diagnosis of UC for at least 3 months prior to Baseline.  Appropriate documentation of biopsy 
results consistent with the diagnosis of UC in the assessment of the Investigator, must be 
available.
7. Subject meets the following disease activity criteria:  Active UC with an Adapted Mayo score 
of 5 to 9 points and endoscopic subscore of 2 to 3 (confirmed by central review).
8. No current diagnosis of CD or inflammatory bowel disease-unclassified (IBD-U).
9. No extent of inflammatory disease limited to the rectum as assessed by screening endoscopy.
10. No currently known complications of UC such as:

fulminant colitis,

toxic megacolon,

previous colectomy (total or subtotal),

or any other manifestation that might require surgery while enrolled in the study
11. Subjects must not have an ostomy or ileoanal pouch.
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Subject History
12. History of inadequate response, loss of response, or intolerance to one or more of the 
following:  

Demonstration of intolerance requires no minimum dose or duration of use.

Inadequate response is defined as outlined below:

Signs and symptoms of persistently active disease despite a history of one or more of 
the following:

Infliximab:  At least one 6-week induction regimen of infliximab (≥5 mg/kg 
intravenous [IV] at Weeks 0, 2, and 6),

Adalimumab:  At least one 4-week induction regimen of adalimumab (one 160 mg 
SC dose at Week 0, followed by one 80 mg SC dose at Week 2),

Golimumab:  At least one 4-week induction regimen of golimumab (200 mg SC at 
Week 0 and 100 mg SC at Week 2),

Vedolizumab:  At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6),

Tofacitinib:  At least one 8-week induction regimen of tofacitinib (10 mg PO twice a 
day) or

Ustekinumab:  At least an induction regimen of a single weight-based infusion dose 
of ustekinumab (260 mg IV with body weight [bw] ≤55 kg, 390 mg with bw > 55 kg 
to 85 kg, 520 mg with bw > 85 kg).

Recurrence of symptoms during scheduled maintenance dosing following 
demonstration of clinical benefit of the above biologics or tofacitinib.
13. No history of radiation or ischemic colitis.
14. No history of any malignancy except for successfully treated non metastatic cutaneous 
squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix.
15. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 12 months.
16. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
17. No history of dysplasia of the gastrointestinal tract or evidence of dysplasia in any biopsy 
performed during the Screening endoscopy, other than completely removed low-grade 
dysplastic lesions (historically or during Screening).
18. No history of lymphoproliferative disease, including lymphoma, or signs and symptoms 
suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or 
splenomegaly.
19. No history of an allergic reaction or significant sensitivity to excipients of the study drug or 
the ingredients of Chinese hamster ovary (CHO) cells.
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20. No severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, disorder or 
symptoms thereof.
Contraception
21. For all females of childbearing potential, a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.  
Procedures in the case of a borderline serum pregnancy test are described in Appendix F.
22. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control (Section 5.2), that is effective from Study Day 1 through at least 84 days after 
the last dose of study drug.  Female subjects of non-childbearing potential do not need to use 
birth control.
23. Females must not be pregnant, breastfeeding, or considering becoming pregnant during 
the study or for at least 84 days after the last dose of study drug.
Concomitant Medications
24. Subject must not receive IV anti-infectives within 35 days prior to Baseline visit or 
oral/intramuscular (IM) anti-infectives (non-UC-related) within 14 days prior to the Baseline 
visit.
25. Subject must not receive any parenteral nutrition within 35 days prior to Baseline.
26. Subject must not receive cannabis for either recreational or for medical reasons within 
14 days prior to Baseline.
27. Subject must not receive cyclosporine, tacrolimus, or mycophenolate mofetil (unless for 
ocular application) within 35 days prior to Baseline.
28. Subject must not receive fecal microbial transplantation within 35 days prior to Baseline.
29. Subject must not have been treated with any approved biologic agent (e.g., infliximab, 
adalimumab, golimumab, vedolizumab) within 8 weeks prior to Baseline, or with tofacitinib 
within 14 days prior to Baseline, or any investigational biologic or other agent or procedure 
within 35 days or 5 half-lives prior to Baseline, whichever is longer.  Subject must not have been 
treated with ravagalimab at any time prior to Baseline.
Note:  If there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum 
washout prior to Baseline.
30. Subject must not have received any live vaccine within 35 days prior to Baseline.
31. Subject must not receive oral UC-related antibiotics or oral aminosalicylates within 14 days 
prior to Baseline unless they have been on stable doses for greater than 14 days prior to 
Baseline.
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32. Subjects must not have received oral corticosteroids, unless they have been on that 
corticosteroid for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior 
to Baseline.  Subjects taking oral corticosteroids must not be taking oral corticosteroids at the 
following doses:  budesonide > 9 mg/day, beclomethasone > 5 mg/day, prednisone or 
equivalent > 20 mg/day.
33. Subject must not be on immunomodulators (azathioprine [AZA], mercaptopurine [6-MP], 
methotrexate [MTX]) unless they have been on the course for at least 42 days prior to Baseline 
and have been on a stable dose for at least 35 days prior to Baseline.
34. Subject must not receive the following therapies within 14 days prior to Screening or during 
Screening:  

A combination of 2 or more of the following: oral budesonide, oral beclomethasone, and/or 
oral prednisone (or equivalent) simultaneously, with the exception of inhalers

IV corticosteroids

Therapeutic enema or suppository (i.e., rectal aminosalicylates/corticosteroids), other than 
required for endoscopy
35. Subject must not have received apheresis (e.g., Adacolumn apheresis) within 60 days prior 
to Screening or during Screening.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)

Females, of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug and for at least 
84 days after the last dose of study drug.  Females must commit to one of the following 
methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to study Baseline Day 1.
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
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is/are the sole sexual partner(s) of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when this is 
in line with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable).
If required per local practices, male or female condom with or without spermicide OR cap, diaphragm or 
sponge with spermicide should be used in addition to one of the birth control methods listed above 
(excluding true abstinence).
Contraception recommendations related to the use of concomitant therapies should be based on the 
local label.
5.3 Prohibited Medications and Therapy
Except as listed in the eligibility criteria, the following medications are prohibited throughout the 
duration of the study:

All biologics or small molecule medication (e.g., JAK inhibitors, sphingosine-1-phosphate [S1P] 
receptor modulators) with potential impact on UC

Initiation of oral aminosalicylates, immunomodulators, IV or oral corticosteroids, and/or 
UC-related antibiotics through Week 12

Cyclosporine, tacrolimus, or mycophenolate mofetil (unless for ocular application)

Cannabis

Rectal therapy with any therapeutic enemas or suppositories, with the exception of those 
required for endoscopy

Apheresis 

Any parenteral nutrition

Any investigational agent

Any fecal microbial transplant
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Vaccines
Live or attenuated vaccines are prohibited within 35 days prior to Baseline, during the study, and for 
84 days after the last dose of study drug.  Vaccines recommended by local guidelines should be 
considered.  If the Investigator chooses to administer a vaccine, this should be completed before 
first dose of study drug with appropriate precautions and time interval.  It is recommended that subjects 
be up to date for recommended inactivated, toxoid or biosynthetic vaccines, such as injectable flu 
vaccine, pneumococcal, and pertussis (tetanus, diphtheria, pertussis vaccine [Tdap]).  
5.4 Prior and Concomitant Therapy
Subjects taking oral aminosalicylates, immunomodulators, oral corticosteroids, and/or UC-related 
antibiotics at Baseline must continue their concomitant treatment for the duration of the induction 
period (through Week 12).  Initiating and/or increasing doses of oral aminosalicylates, 
immunomodulators, oral corticosteroids, and/or UC-related antibiotics during the study is prohibited 
through Week 12.  Decreasing doses of oral aminosalicylates, immunomodulators, oral corticosteroids, 
and/or UC-related antibiotics during the induction period is prohibited, except in the event of 
moderate-to-severe treatment related toxicities and after discussion with the AbbVie TA MD.  Starting 
at Week 12 (maintenance period), oral aminosalicylates, immunomodulators, and/or UC-related 
antibiotics may be decreased or discontinued at the discretion of the Investigator.  Starting at Week 12, 
initiating and/or increasing doses of oral aminosalicylates, immunomodulators, oral corticosteroids, 
and/or UC-related antibiotics is permissible after discussion with the AbbVie TA MD.
During the maintenance period, subjects can initiate an optional steroid taper at Week 12.  While 
stopping the taper is permitted, increasing doses above the Baseline dose is permitted only after 
discussion with the AbbVie TA MD.  Below is a suggested tapering schedule.  
Dose
Rate
Prednisone (or equivalent)
> 10 mg/day
5 mg/day per week
≤ 10 mg/day
2.5 mg/day per week
Budesonide
≤ 9 mg/day
3 mg/day per week
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with ravagalimab can be located in the 
ravagalimab Investigator's Brochure.10
5.5 Withdrawal of Subjects and Discontinuation of Study Drug or from 
Study Participation
A subject may voluntarily withdraw or be withdrawn from study participation, or be discontinued from 
study drug, at any time for reasons including, but not limited to, the following:

Disease progression or lack of response to treatment.
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
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD.

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.  This includes if a subject would like to 
discontinue after completion of the Week 52 visit.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Subject has a malignancy, except for localized non-melanoma skin cancer.  Discontinuation for 
carcinoma in situ of the cervix is at the discretion of the Investigator.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
Subjects who complete the induction period and do not achieve clinical response per Partial Adapted 
Mayo score at Week 12 will be discontinued.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
During states of emergency or pandemic situations, it may be necessary to employ mitigation strategies 
to enable the investigator to ensure subject safety and continuity of care.  Acceptable mitigation 
strategies are identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure all acceptable mitigation steps have 
been explored.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study Participation
To minimize missing data for efficacy and safety endpoints, subjects who prematurely discontinue study 
drug treatment should continue to be followed for all regularly scheduled visits, unless subjects have 
decided to discontinue the study participation entirely by withdrawal of informed consent, in which no 
further study procedures or study activities can be performed.  Subjects should be advised on the 
continued scientific importance of their data even if they discontinue treatment with study drug early.
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If a subject prematurely discontinues from the study/study drug, the procedures outlined for the 
Premature Discontinuation visit (PD visit) should be completed as soon as possible, preferably within 2 
weeks.  In addition, if subject is willing, an 84-day follow-up visit after the last dose of study drug may be 
completed to ensure all treatment-emergent AEs/serious adverse events (SAEs) have been resolved.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected for the withdrawn subject or added to the existing data or database(s), and the samples will be 
destroyed.  Data generated for biomarker research before subject withdrawal of consent will remain 
part of the study results.
5.7 Study Drug
Information about the study drug used in this study is presented in Table 1.
Table 1.
Description of Study Drug
Investigational Product
Investigational Product Placebo
Investigational product name
Ravagalimab (ABBV-323)
Placebo
Active ingredient
Ravagalimab (ABBV-323)
N/A
Dosage Form
Lyophilized powder for solution for 
injection/infusion in vials
Lyophilized powder for solution 
for injection/infusion in vials
Strength
100 mg/mL, when reconstituted
N/A, when reconstituted 
Frequency of administration
Induction:  IV × 1 dose then SC eow 
Maintenance:  SC eow
Induction period only:  for IV line 
flush only
IV = intravenous; eow = every other week; N/A = not applicable; SC = subcutaneous
The study drugs will be supplied in cartons containing one vial with quantities sufficient to 
accommodate study design.  Each vial contains 100 mg ravagalimab lyophilized powder for solution for 
injection/infusion, or placebo. Each carton and vial label will contain a unique kit number.  This kit 
number is assigned to a subject via interactive response technology (IRT) and encodes the appropriate 
study drug to be administered at the subject's corresponding study visit.  Each carton and vial will be 
labeled as required per country requirements.  The labels must remain affixed to the cartons and vials.  
All blank spaces should be completed by site staff prior to dispensing to subject.  Study drug will only be 
used for the conduct of this study.
AbbVie will provide instructions for drug preparation.
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5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  No randomization will be used in the single arm, open-label study.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified, including those that may be due to cases of state of emergency or pandemic situations), the 
investigator is responsible for notifying independent ethics committee (IEC)/independent review board 
(IRB), regulatory authorities (as applicable), and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
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of a medicinal (investigational) product, whether or not the event is considered causally related to the 
use of the product.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre planned prior to study entry.  However, if the pre-existing condition 
deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance or CRO (as appropriate) as a serious adverse event 
within 24 hours of the site being made aware of the serious adverse event (refer to Section 4.3 of the 
Operations Manual [Appendix F] for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All adverse events reported from the time of study drug administration until 84 days after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, serious adverse events and protocol-related nonserious adverse 
events will be collected from the time the subject signs the study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
Below is a list of adverse events of special interest.  Related supplemental eCRFs, if applicable, should be 
filled out in response to an event.

Serious infections and opportunistic infections

Active TB (TB screening eCRF in all subjects and supplemental TB eCRF as appropriate)

Malignancies (all types) (Malignancy eCRF);

Hepatic events (Hepatic AE eCRF):

Discontinuation or interruption of study drug due to a hepatic-related AE;

A hepatic-related SAE;

ALT/AST > 8 × ULN or ALT/AST > 3 × ULN with a total bilirubin > 2 × ULN;

Hematologic disorders;

Hypersensitivity reactions (Hypersensitivity Reaction Signs and Symptom eCRF).
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Adverse Event Severity and Relationship to Study Drug
The investigators will rate AEs according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0, which can be accessed at:  
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.11
For AEs not captured by the CTCAE, the following should be used: 
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities (moderate).
Grade 3/4
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life-threatening (severe). 
Grade 5
The adverse event resulted in death of the subject (severe).
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 1 working 
day after the site becomes aware of the pregnancy.  Subjects who become pregnant during the study 
must be discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study 
subject, information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 84 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described in Table 2.
The toxicity management of AEs including AEs of special interest consists of safety monitoring (review of 
AEs on an ongoing basis, and periodical/ad hoc review of safety issues by a DMC), interruption of study 
drug dosing with appropriate clinical management if applicable, and discontinuation of the subjects 
from study drug.  There are no time limits for study drug interruption as long as no permanent study 
discontinuation criteria have been met.  The management of specific AEs and laboratory parameters is 
described below.
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central lab) 
and any intolerability to standard of care therapies should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs and symptoms of 
infection during and after treatment with study drug.  Study drug should be interrupted if a subject 
develops a serious infection or an opportunistic infection.  A subject who develops a new infection 
during treatment with study drug should undergo prompt diagnostic testing appropriate for an 
immunocompromised subject.  As appropriate, antimicrobial therapy should be initiated, and the 
subject should be closely monitored.  Study drug may be restarted once the infection has been 
successfully treated or resolved.  Subjects who develop active TB or experience Hepatitis B reactivation 
must be discontinued from study drug.  For subjects who develop TB during the study, the supplemental 
eCRF should be completed.  
COVID-19:  Interrupt study drug in subjects with a confirmed diagnosis of COVID-19.  Consider 
interrupting study drug in subjects with signs and/or symptoms and suspicion of COVID-19.  The 
COVID-19 eCRF must be completed.  If a subject has a confirmed or suspected SARS-CoV-2 infection and 
study drug was interrupted, the investigator should contact the AbbVie TA MD before reintroducing 
study drug.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ of the cervix must 
be discontinued from study drug.  Information including histopathological results should be queried for 
the confirmation of the diagnosis.  The supplemental eCRF should be completed.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change considered 
clinically significant and with reasonable possibility of relationship to study drug OR a confirmed 
absolute QTcF value > 500 msec.
Surgery:  Subjects who undergo emergency surgery should have study drug interrupted at the time of 
the surgery.  After emergency surgery, reintroduction of study drug is allowed once the physician has 
examined the surgical site and determined that it has healed and there is no sign of infection.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
Investigator should assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal laboratory values 
are described in Table 2 and may require an appropriate supplemental eCRF be completed.  All 
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abnormal laboratory tests that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution.  If a repeat test is required per Table 2, the repeat testing must occur as soon 
as possible.  Subjects who meet any of the criteria for ALT and/or AST listed in Table 2 should be 
evaluated for an alternative etiology and managed as medically appropriate per local guidelines.  The 
investigator should contact the AbbVie TA MD to discuss the management of a subject when an 
alternative etiology has been determined.  The alternative etiology should be documented appropriately 
in the eCRF; study drug should be discontinued if no alternative etiology can be found.
Table 2.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Value
Toxicity Management Guideline
All Subjects
Hemoglobin
< 8 g/dL

If alternative etiology cannot be identified, interrupt study 
drug dosing and redraw lab with a new sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
Decrease 
≥ 3.0 g/dL from 
baseline

If an alternative etiology is known or the hemoglobin value 
remains in the normal reference range, the subject may 
continue study drug dosing at the investigator's discretion.

If alternative etiology cannot be identified, interrupt study 
drug dosing and redraw lab with a new sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
Absolute 
neutrophil 
count (ANC)
< 1000 cells/µL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
< 500 cells/µL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, discontinue study drug.
Absolute 
lymphocyte 
counts 
(ALC)
< 500 cells/µL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
Total white 
blood cell 
count
< 2,500 cells/µL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
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Laboratory 
Parameter
Value
Toxicity Management Guideline
All Subjects 
(continued)
Platelet 
count
< 50,000 
cells/µL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
ALT or AST
ALT or AST
> 8 × ULN

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, discontinue study drug and complete 
supplemental hepatic eCRF.
ALT or AST 
> 5 × ULN

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed for > 2 weeks of duration, discontinue 
study drug and complete supplemental hepatic eCRF.
ALT or AST 
> 3 × ULN

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed and patient has appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%) discontinue study 
drug and complete supplemental hepatic eCRF.

If value is confirmed and total bilirubin > 2 × ULN or 
international normalized ratio (INR) > 1.5, discontinue study 
drug and complete supplemental hepatic eCRF.
Serum 
Creatinine
> 1.5 × the 
baseline value 
and > ULN

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
≥ 2 mg/dL

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, continue to withhold study drug until 
value returns to normal reference range or baseline value.
Subjects who are HBc 
Ab+ and HBV DNA 
negative at Screening
ALT or AST
ALT or AST 
> 5 × ULN

Interrupt study drug dosing and redraw lab with a new 
sample.

If value is confirmed, send HBV DNA by PCR.

If HBV DNA by PCR is positive, discontinue study drug and 
complete supplemental hepatic eCRF.
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6.3 Data Monitoring Committee
An internal DMC will review safety data.  A separate DMC charter will be approved before the first 
subject is enrolled into the study.  The DMC is responsible for monitoring safety data, alerting AbbVie to 
possible safety concerns related to the conduct of the study, and recommending appropriate actions for 
study conduct and management.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the Week 12 database lock for the 
primary analysis.  The statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North 
Carolina, USA).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all enrolled subjects who received at least 1 dose of ravagalimab 
(including subjects randomized to ravagalimab prior to Version 4.0).  The FAS will be used for all efficacy 
and baseline analyses.
Subjects enrolled prior to version 4.0 will be unblinded after they finish Week 8 assessments.  Subjects 
who were randomized to and received ravagalimab will be included in the FAS.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  Subjects 
randomized to the study prior to Version 4.0 will be analyzed along with subjects enrolled after 
Version 4.0 for safety analysis.  Subjects will be grouped based on the treatment received.
Depending on the magnitude of missing data due to COVID-19, additional appropriate analysis may be 
performed with details included in the SAP.
7.3 Statistical Analyses for Efficacy
Primary Analysis
The primary analysis will be performed after all subjects completed the study induction period (i.e., 
completed Week 12 assessments).  The final analysis will be performed after all subjects completed the 
study maintenance period.  Additional analysis may be performed to support program development or 
health authority requests.  There will be no multiplicity test alpha-adjustment for this proof of concept 
study.
The primary efficacy endpoint is the proportion of subjects with endoscopic improvement at Week 8.  
The null hypothesis is that there is no difference in the proportion of subjects with endoscopic 
improvement at Week 8 between ravagalimab treated subjects and historical placebo.
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Analysis of the primary efficacy endpoint will be conducted on the FAS.  Comparison of the primary 
efficacy endpoint will be performed between the ravagalimab group and the historical placebo group 
using Bayesian approach with placebo distribution as 
 from historical data meta-analysis and 
prior for ravagalimab Beta (0.5, 0.5), the Jeffrey's prior for binomial distribution.  The placebo prior is 
determined based on available placebo data from similar trials and may be updated if new placebo data 
from similar trials become available before the primary analysis database lock.
Non-Responder Imputation while incorporating Multiple Imputation to handle missing data due to
COVID-19 (NRI-C) will be applied to the primary endpoint analysis.  
Details on the primary, secondary, and other efficacy analyses are provided in the SAP.
Interim Analysis
An interim efficacy analysis will be performed after approximately 30 subjects complete Week 8 
assessments.  This interim analysis will inform the planning of future Phase 2b and 3 studies.  Enrollment 
into the induction period will continue until approximately 40 subjects have been enrolled.
Sample Size Estimation and Decision Probability
The planned sample size is up to approximately 40 subjects.
Meta-analysis for historical placebo data from tofacitinib (OCTAVE1/2),4 upadacitinib (Phase 2b; data on 
file) and ustekinumab (UNIFI)12 studies gives 
 endoscopic improvement rate at Week 8.  The matched 
prior distribution for placebo is 
 
.  The prior for ravagalimab treatment group will be set to Jeffreys prior Beta (0.5, 0.5) as 
non-informative.  The probability that the posterior probability of rate difference > 0 is larger than 90% 
is more than 90% if the endoscopic improvement rate difference is 25% between ravagalimab and 
historical placebo, given a sample size of 40 subjects for ravagalimab.  If ravagalimab has the same 
endoscopic improvement rate of
 as historical placebo, that probability is approximately 3.1%.
7.4 Statistical Analyses for Safety
Safety analysis will be carried out using the Safety Analysis Set.  Incidence of AEs, changes in vital signs, 
physical examination results, ECGs, and clinical laboratory values will be analyzed.  Treatment-emergent 
AEs will be tabulated by system organ class (SOC) and by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term (PT) for the treatment group.  Mean change from Baseline for laboratory and 
vital signs data will be summarized.  In addition, shift tables and listings will be provided for abnormal 
values, whereby the normal range of the analyzing laboratory will be used.  Vital signs will be analyzed 
similarly.
Missing safety data will not be imputed.  Details for each safety endpoint analysis will be provided in the 
SAP.
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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual (Appendix F), 
International Council for Harmonisation (ICH) guidelines, applicable regulations, and guidelines 
governing clinical study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the investigator are specified in Appendix B.  Investigators should notify 
AbbVie if any urgent safety measures are taken to protect the subjects against any immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  In cases of state of emergency or pandemic situations, remote monitoring of data may 
be employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
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11
COMPLETION OF THE STUDY
The end-of-study is defined as 84 days after the last subject last dose of ravagalimab.
12
REFERENCES
1.
Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of 
Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004;99(7):1371-85.
2.
Cote-Daigneault J, Bouin M, Lahaie R, et al. Biologics in inflammatory bowel disease: what are the 
data? United European Gastroenterol J. 2015;3(5):419-28.
3.
Katsanos KH, Papamichael K, Feuerstein JD, et al. Biological therapies in inflammatory bowel 
disease: Beyond anti-TNF therapies. Clin Immunol. 2019;206:9-14.
4.
Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative 
Colitis. N Engl J Med. 2017;376(18):1723-36.
5.
Bonovas S, Fiorino G, Allocca M, et al. Biologic Therapies and Risk of Infection and Malignancy in 
Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis. Clin 
Gastroenterol Hepatol. 2016;14(10):1385-97.e10.
6.
Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving 
thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 
2009;374(9701):1617-25.
7.
Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of lymphoma in patients with inflammatory bowel 
disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin Gastroenterol 
Hepatol. 2015;13(5):847-58.e4; quiz e48-50.
8.
Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in 
patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 
2011;141(5):1621-28.e1-5.
9.
Arranz A, Reinsch C, Papadakis KA, et al. Treatment of experimental murine colitis with CD40 
antisense oligonucleotides delivered in amphoteric liposomes. J Control Release. 2013;165(3):163-
72.
10. AbbVie. Ravagalimab (ABBV-323) Investigator's Brochure Edition 5. 26 June 2020.
11. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03. 2010.
12. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as Induction and Maintenance Therapy 
for Ulcerative Colitis. N Engl J Med. 2019;381(13):1201-14.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylic acid
6-MP
Mercaptopurine
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine transaminase
APC
Antigen presenting cell
AST
Aspartate transaminase
AZA
Azathioprine
bw
body weight
CD
Crohn's disease
CHO
Chinese hamster ovary
CL/F
Apparent clearance
COVID-19
Coronavirus Disease-2019
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest X-ray
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDP
Extemporaneous Dose Preparation
EIM
Extraintestinal manifestation
eow
Every other week
FAS
Full analysis set
FCP
Fecal calprotectin
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good clinical practice
GFR
Glomerular filtration rate
GLP
Good Laboratory Practice
HIV
Human immunodeficiency virus
hs-CRP
High sensitivity C-reactive protein
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IBDQ
Inflammatory Bowel Disease Questionnaire
IBD-U
Inflammatory Bowel Disease-unclassified
ICH
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent ethics committee
IM
Intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
JAK
Janus kinase
L
Ligand
mAb
Monoclonal antibody
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MTX
Methotrexate
nAb
Neutralizing antibody
NOAEL
No-observed-adverse-effect-level
NRI
Non-Responder Imputation
OL
Open-label
PD
Premature discontinuation
PK
Pharmacokinetic(s)
PO
orally (per os)
POC
Proof of concept
PPD
Purified protein derivative
PT
Preferred term
QTcF
Fridericia-corrected QT interval
RA
Rheumatoid arthritis
RBS
Rectal bleeding subscore
RO
Receptor occupancy
S1P
Sphingosine-1-phosphate
SAE
Serious adverse event
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SAP
Statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
Subcutaneous(ly)
SFS
Stool frequency subscore
SLE
Systemic lupus erythematosus
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
Tdap
Tetanus, diphtheria, pertussis vaccine
TNF
Tumor necrosis factor
UC
Ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
ULN
Upper limit of normal
Vss/F
Volume of distribution at steady-state
WBC
White blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M15-722:  A Multicenter, Single Arm, Open-label Study to Investigate the Efficacy and Safety of 
Ravagalimab (ABBV-323) in Subjects with Moderate to Severe Ulcerative Colitis Who Failed Prior 
Therapy
Protocol Date:  04 December 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Program Lead II
Clinical Program Development
Principal Medical Writer
Medical Writing
Medical Director
Immunology Development
Group Medical Director
Immunology Development
Study Project Manager II
Clinical Program Development
Director
Data and Statistical Sciences
Sr. Director, TA Head
Data and Statistical Sciences
Associate Director
Clinical Pharmacology
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities the subject encounters.  The individual activities are 
described in detail in Appendix F.  Allowed modifications due to states of emergency or pandemic 
situations are detailed within the Operations Manual.
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b.
The 84-day follow up visit (or call if a visit is not possible) will be calculated from the last study drug administration date.
c.
Urine pregnancy test will be performed locally as indicated in the table for all females of childbearing potential.  The urine pregnancy test must be negative to receive study 
drug.  If any urine pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory. 
d.
Urinalysis, chemistry and hematology, hs-CRP, and FCP may be collected at other scheduled and unscheduled visits than indicated in the table if they are warranted by the 
Investigator.
e.
For subjects with a negative TB test, an annual TB test will be required at Weeks 52 and 104.  If the annual TB screen is positive, a CXR will be required for evaluation of active 
TB.  Annual TB screening will not be required for subjects who have been treated for latent, or prior active, TB.
f.
T cells, NK cells and B cells subsets (including plasmablasts) will be analyzed at all indicated study visits.  CD40 RO will only be analyzed at Baseline, Week 8 and Week 52/PD.
g.
Stool sample will be collected at each time point indicated in the table.  For the visit when endoscopy will be conducted, stool sample should be collected prior to bowel prep 
and should be returned to the site within 3 days of collection.  If a sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit.
h.
Mandatory intestinal biopsies will be collected for histopathology, gene expression, and tissue RO (where applicable).  Additional biopsies may also be collected at the 
Investigator's discretion to confirm disease diagnosis and/or to rule out dysplasia, colon cancer and infection.  
i.
Only to be collected at PD visit if subject discontinues prior to Week 52.
j.
Consecutive doses should not be administered less than a week (7 days) apart.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 1.0
07 June 2018
Version 2.0
17 August 2018
Administrative Change 1
23 October 2018
Version 3.0
13 February 2019
Version 4.0
29 May 2019
Version 5.0
06 May 2020
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol, to 
clarify and update statistical methods, and incorporate necessary protocol modifications due to the 
COVID-19 pandemic as follows:

Synopsis – addition of Hungary to study country list
Rationale: to reflect addition of new study country.

Synopsis – addition of ustekinumab to approved therapies list for key eligibility criteria of 
subject having a history of inadequate response, loss of response, or intolerance to one or more 
of the approved therapies
Rationale:  correcting omission of ustekinumab from synopsis in previous version of the protocol.

Synopsis – removal of text from key eligibility criterion requiring OL use of tofacitinib if received 
in a clinical trial
Rationale:  To permit subject enrollment after inadequate response to, or intolerance of, 
tofacitinib received in a clinical trial in all scenarios where treatment allocation is known to have 
been tofacitinib.

Section 2.2 – included a statement on the benefit and risk of ravagalimab for subjects 
participating in the study in light of the SARS-CoV-2 pandemic based on current knowledge 
Rationale:  To update the benefit-risk assessment of ravagalimab with regards to COVID-19 to 
clearly state that risk related to use of this investigational drug on the course of COVID-19 is not 
currently known.

Section 3.3 – clarified endpoint definitions
Rationale:  to provide clear definitions for each endpoint planned for evaluation

Section 3.4 - in the list of additional efficacy endpoints to remove duplicate endpoints, revise 
endpoints for clarity, and remove endpoints which are not expected to be informative
Rationale:  The proportion of subjects with clinical response per Full Mayo score at Week 8 in 
subjects with a Full Mayo score of 6 to 12 at Baseline was removed as duplicative with an 
endpoint listed as a key secondary endpoint in Section 3.3.  The 2 endpoints related to 
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corticosteroid use were revised for clarity. General hospitalizations not informative and already 
captured in SAEs, UC-related hospitalizations will be summarized over time. UC related surgery 
will be summarized over time, not only through Week 12.

Section 4.1 – removed discussion of the data monitoring committee (DMC) from the study 
design 
Rationale:  DMC review of safety data is not a component of the study design.  The use of an 
internal DMC that will review safety at regular intervals is discussed in Section 6.3.

Section 4.1 - revise discussion of changes made in protocol version 4.0
Rationale:  To remove repetitive text to improve clarity and remove the obsolete text which 
stated the maintenance period continued until Week 52 as the study was previously extended to 
include a 92-week OL treatment period

Section 4.1 and Section 7.3 - clarified text regarding primary and interim analysis and the timing 
of termination of study enrollment, and explicitly permit additional statistical analysis if needed
Rationale:  There are 2 separate analyses planned in the induction period.  The primary analysis 
will occur at the end of the induction period after all 40 subjects reach Week 12.  An interim 
analysis will occur after the first 30 subjects reach Week 8 with the purpose to permit early 
decision making for subsequent study planning.  To provide clarity, these 2 previously planned 
analyses have been separated. 
Rationale: Permit additional statistical analysis if needed to support program development or 
health authority request.

Section 4.1 Clarified that an endoscopy is required at Screening
Rationale:  Screening endoscopy has always been required in this protocol and is noted in other 
sections of the protocol and operations manual.  It has been added here for clarity.

Section 4.1 and Section 5.6, Appendix D, and Appendix F, Section 2.1 - Specified that a follow-up 
visit is preferred over a follow-up call and added collection of hematology and clinical chemistry 
at that visit
Rationale: As this is the initial phase 2a study with ravagalimab it is preferred to have a follow-
up visit to ensure comprehensive capture of safety data including new or ongoing AEs and 
collection of hematology and clinical chemistry to ensure resolution/reversibility of any abnormal 
laboratory data.  For subjects in which a visit is not possible, a phone call will be permitted. 

Section 4.1 and Appendix D, footnote b– Remove text pertaining to subjects on protocol version 
5.0
Rationale:  This text is obsolete as all subjects, regardless of protocol amendment enrolled 
under, are to continue the visit schedule in the most current IRB/EC approved protocol, inclusive 
of all activities relative to their Baseline visit, are required to sign the most current IRB/EC 
approved informed consent form, and there is no enrolled subject at risk of experiencing a delay 
in dosing based on different protocol versions.

Section 5.1 – Update eligibility criterion #5, with details regarding subject eligibility with regards 
to COVID-19 (coronavirus SARS-CoV-2) infection, eligibility criterion #12 to remove requirement 
for tofacitinib and ustekinumab to have been given in open label fashion if received in a clinical 
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CONFIDENTIAL INFORMATION
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trial, and corrected language on eligibility criterion #23, prohibiting pregnancy and 
breastfeeding.  
Rationale:  Modified eligibility criteria to exclude subjects with suspected or confirmed active 
COVID-19 infection to maintain subject safety.  To permit subject enrollment after inadequate 
response to, or intolerance of, tofacitinib or ustekinumab received in a clinical trial in all 
scenarios where treatment allocation is known to have been tofacitinib or ustekinumab.  Revised 
language surrounding prohibition of pregnancy and breastfeeding to ensure clarity surrounding 
requirements as ravagalimab has not been studied in human pregnancy or breastfeeding.

Section 5.5 - Appendix D, and Appendix F Section 2, Section 2.1, and Section 4.3 – added 
instructions for necessary changes to activities or procedures in the event of states of 
emergency or pandemic situations 
Rationale:  To provide flexibility during state-of emergency or pandemic situations to ensure the 
safety of subjects, maintain protocol compliance, and minimize risk to the integrity of the study 
while trying to best manage continued care of study subjects. 

Section 5.5 – clarified discontinuation of study drug as well as study participation. 
Rationale: To clarify that PD procedures apply to discontinuation from study and study drug.  To 
clarify handling of subject data accounting for situations when a subject withdraws consent from 
the clinical study or withdraws samples from research. 

Section 5.6 – clarified discontinuation of study drug as well as study participation.  Also added 
text regarding collection of personal data and biomarker research in the event a subject 
withdraws consent.
Rationale: To clarify that PD procedures apply to discontinuation from study and study drug.  To 
clarify handling of subject data accounting for situations when a subject withdraws consent from 
the clinical study or withdraws samples from research.

Section 5.8 – deleted the statement that IRT would assign a randomization number
Rationale: Not applicable to the open-label study.  All subjects are assigned a unique number at 
screening. 

Section 5.9 – clarified that modifications to the protocol, including those due to cases of state of 
emergency or pandemic situations, are considered deviations if not expressly outlined as 
permitted
Rationale: To clarify that unless necessary to eliminate an immediate hazard to study subjects 
that no prospective protocol modifications are permitted, including those which may be related 
to cases of cases of state of emergency or pandemic situations.

Section 6.1, Appendix D - clarified that active TB is an adverse event of special interest
Rationale:  Active TB is a separate category from serious infections and opportunistic infections.

Section 6.2 - clarified that there are no time limits for study drug interruption as long as no 
permanent study discontinuation criteria have been met and added guidance regarding study 
drug interruption in subjects with confirmed diagnosis or suspicion of COVID-19
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STUDY M15-722  |  Version 6.0 | EudraCT 2018-000930-37
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Rationale:  To provide investigators with guidance regarding permissible duration of drug 
interruption and to clarify guidelines for interruption of study drug in the event of confirmed or 
suspected diagnosis of COVID-19 to ensure subject safety.

Section 7.1 – clarified the SAP will be finalized prior to the Week 12 database lock for the 
primary analysis
Rationale:  The primary analysis timepoint is at Week 12.  To maintain statistical rigor the SAP 
will be finalized prior to Week 12.  

Section 7.3 - separated discussion of the interim analysis from the primary analysis 
Rationale:  To clarify that the interim analysis will be performed after approximately 30 subjects 
complete Week 8 assessments is in addition to the primary analysis which is planned after all 
subjects have completed Week 12. 

Section 7.3 - removed POC success criterion
Rationale:  To avoid a purely statistical criterion for POC success claim based on a single 
endpoint and permit more flexibility in the interpretation of the totality of the clinical data which 
is more in line with the exploratory nature and objectives of the POC study.

Section 7.3 – updated external placebo data and related probabilities  
Rationale:  To update the external placebo data and related probabilities based on data which 
have become available from other studies during the conduct of this study and after re-
evaluation of existing data.  In addition, a clarification was made that future updates to the 
historical placebo data to be used in analyses may occur based on emerging clinical data prior to 
database lock.

Section 7.3 – replaced use of NRI with an imputation method for the primary analysis with 
missing data handling due to COVID-19 (NRI-C)
Rationale:  To account for potential missing data due to a contemporary pandemic situation 
(COVID-19).

Section 7.3 – removed sensitivity analysis for the primary efficacy endpoint
Rationale:  Removed sensitivity analysis to avoid possible inconsistent results between Bayesian 
approach and frequentist approach.

Section 8.2 – Specified that investigators must notify AbbVie if any urgent safety measures are 
taken due protect subjects from any immediate hazard 
Rationale:  To ensure subject safety. 

Section 9 – noted that remote monitoring may be employed as needed in cases of state of 
emergency or pandemic situations
Rationale:  To permit an alternative method to monitor study activities during cases of state of 
emergency or pandemic situations if on-site monitoring is not possible.

Section 12 – updated reference 12
Rationale: to remove reference to the abrilumab study and add reference to the ustekinumab
study to align with revisions to Section 7.3.
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STUDY M15-722  |  Version 6.0 | EudraCT 2018-000930-37
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Appendix A – updated definition of ICH to The International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use
Rationale:  To provide official updated definition of the abbreviation

Appendix A – addition of SARS-CoV-2 to abbreviations list
Rationale:  To provide definition of abbreviation

Appendix F, Appendix A - addition of COVID-19 to abbreviations list
Rationale:  To provide definition of abbreviation

Appendix F, Appendix A - addition of TA MD to abbreviations list
Rationale:  To provide definition of abbreviation

Appendix C - Update list of protocol signatories
Rationale:  To reflect changes to personnel at sponsor.

Appendix D and Appendix F, Section 2.1 – added additional timepoints for physical exam and 
hsCRP monitoring; added HBV testing every 12 wks where required locally and add 
administration of the TB risk factor questionnaire at the PD visit
Rationale:  To monitor inflammatory status, support subject safety and monitor extraintestinal 
manifestations of disease, clarify HBV testing requirements where mandated locally, and 
enhance latent TB screening.

Appendix F, Section 1 and Section 4.3 - Update sponsor contact information 
Rationale:  To reflect changes to personnel at sponsor

Appendix F, Section 3.1 – update requirements for informed consent related to cases of state of 
emergency or pandemic situations 
Rationale:  In cases of state of emergency or pandemic situations, it is possible that additional 
protocol modifications not outlined in this protocol may become necessary for which it is 
necessary to obtain verbal consent if it is not possible to travel to the study site and sign a 
written form. 

Appendix F, Section 3.12 – add Hepatitis B screening, Hepatitis C screening, HIV test, and SARS-
CoV-2 molecular test to the list of clinical tests which may be performed during the study
Rationale:  Hepatitis B screening, Hepatitis C screening, HIV test are required for all subjects at 
the screening visit.  The SARS-CoV-2 molecular test was added to align with the update to 
eligibility criterion #5 in which testing for SARS-CoV-2 will be required for selected subjects.

Appendix F, Section 3.12 – update Figure 1 and footnote
Rationale:  To provide interpretation of HBV test results in Scenario A and B, clarify when a 
subject may be enrolled, and clarify when additional screening is required.

Appendix F, Appendix B – addition of UC-100 to endpoint definitions
Rationale:  to provide clear definitions for each endpoint
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/Emergency 
Medical Contact
 MD
Therapeutic Area Medical Director (TA MD)
AbbVie Deutschland GmbH & Co. KG 
(AbbVie)
Knollstrasse
67061 Ludwigshafen
Germany
EMERGENCY 24 hour Number:  
+1 (973) 784-6402
Office:
Mobile
Fax:
Email:
Safety Concerns
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Toll Free: +1 833-942-2226
Email:  
GPRD_SafetyManagement_Immunology@
abbvie.com
SAE Reporting 
outside of RAVE
Email:  
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol Deviations
AbbVie 
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Email:
Certified Clinical Lab
For sites in North America:
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
For sites in Europe:
Covance
7 rue Moise-Marcinhes
1217 Geneva
Meyrin Switzerland
Phone:
+1 (866) 762-6209 (Toll free)
+1 (317) 271-1200 (Local calls)
Fax:
+1 (317) 616-2362
Phone:
+41 (58) 822-7901
+41 (58) 822-7000 (Collect call)
Fax:
+41 (58) 822-7521
For sites in Asia:
Covance (Asia) Pte. Limited
1 International Business Park
#01-01 The Synergy
Singapore 609917
Phone:
+65 6560-8793
Fax:
+65 6565-5901
For country specific toll free numbers 
please refer to the Covance Lab Manual.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Pharmacokinetic 
Lab
AbbVie Deutschland GmbH and Co KG
Bioanalysis Large Molecules
Knollstrasse
Building 11, Room 311
67061 Ludwigshafen, Germany
Phone:
+49 (621) 589-2022
Fax:
+49 (621) 589-3184
Exploratory Sample 
Lab
Refer to the laboratory manuals for lab 
contact details.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
6
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
6
3
STUDY PROCEDURES
24
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
24
3.2
MEDICAL HISTORY AND PRIOR/CONCOMITANT MEDICATIONS
25
3.3
ADVERSE EVENT ASSESSMENT
25
3.4
PATIENT-REPORTED OUTCOMES AND SUBJECT DIARY
25
3.5
PHARMACOKINETIC SAMPLING
27
3.6
BIOMARKER SAMPLING
27
3.7
12-LEAD ELECTROCARDIOGRAM
28
3.8
HEIGHT AND WEIGHT
28
3.9
VITAL SIGNS
29
3.10 PHYSICAL EXAMINATION
29
3.11 ADMINISTER STUDY DRUG
29
3.12 CLINICAL LABORATORY TESTS
29
3.13 SUBJECT WITHDRAWAL FROM STUDY
38
3.14 RESCREENING
38
3.15 ADDITIONAL ASSESSMENTS
39
4
SAFETY MANUAL
41
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
41
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
42
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
42
5
COUNTRY-SPECIFIC REQUIREMENTS
43
5.1
SUSAR REPORTING
43
6
STUDY DRUG
44
6.1
TREATMENTS ADMINISTERED
44
6.2
PACKAGING AND LABELING
44
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
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6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
44
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
45
LIST OF FIGURES
FIGURE 1.
INTERPRETATION AND MANAGEMENT OF HBV SEROLOGIC TEST RESULTS
36
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
46
APPENDIX B.
ADDITIONAL ENDPOINT DEFINITIONS
48
APPENDIX C.
SCREENING/ANNUAL TB RISK ASSESSMENT QUESTIONNAIRE EXAMPLE
49
APPENDIX D.
SCRIPT FOR COLLECTION OF MAYO SCORES FOR USE IN STUDY M15-722
50
APPENDIX E.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS
54
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to cases of state of emergency or pandemic situations.  This may 
include changes such as phone or virtual visits, visits at alternative locations, home visits, or changes in 
the visit frequency and timing of study procedures, among others.  Additional details are provided in the 
subsequent section.  Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.  If visits cannot be conducted onsite due to travel restrictions or 
other state of emergency or pandemic-related reasons, follow the updates below on how to proceed.  
Supplemental study case report forms should be completed in the event of missed/virtual visits, or 
study drug interruptions or discontinuations related to COVID-19.
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Activities are grouped by category (Interview, Exam, etc.).  Further information about each activity is 
provided in Section 2.1, which contains the definitions of superscript text.
Hospitalization and UC-related surgery will be captured as a part of supplemental Health Care Resource 
Utilization (HCRU) form of adverse event (AE) collection in electronic data capture (EDC) for the entire 
study.
Visit windows for the study
The Screening period may be extended as necessary after consultation with the TA MD in case of 
external, but not subject-related (e.g., scheduling conflict), circumstances.
Baseline visit date will serve as the reference for all subsequent visits.  A ± 7 day window is permitted 
around all study visits after Baseline.  All visit windows may be extended as necessary after consultation 
with the TA MD in case of external, but not subject-related (e.g., scheduling conflict), circumstances.  
Consecutive doses should not be administered less than a week (7 days) apart.
If a visit occurs on a day of overlapping visit windows, the subject visit will account for the preceding 
visit, and the subject will attend the next visit as close to the scheduled day based on the Baseline visit.
State of Emergency or Pandemic-Related Acceptable Protocol Modifications
Study Visits and/or activities should be performed as scheduled whenever possible.  Screening and 
Baseline Day 1 visits and all study drug administration must be conducted at the study site.  During a 
state of emergency or pandemic situation, if it is not possible for all study procedures to be performed 
as specified due to travel restrictions or other reasons, the following modifications are allowed:

An endoscopy may be performed at a local center other than the study site if the PI can confirm 
study requirements with the local center.  The local center must be able to provide the PI with a 
recording/video of the required specifications and quality.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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
Laboratory work may be done at a local lab, hospital, or other facility.  Local lab results should 
be obtained along with reference ranges and kept within the subjects' source documentation.  
Local lab results should be reviewed by the investigator as soon as possible.

If laboratory samples cannot be obtained, study drug administration may be continued up to 4 
weeks in the induction period, and up to 12 weeks in the maintenance period, after the last 
laboratory testing provided a post-baseline laboratory analysis is available and the investigator 
has reviewed all prior laboratory results and confirms and discusses with the subject that there 
is no safety concern for the subject to continue use of the study drug in the absence of current 
labs.  The subject should be scheduled for laboratory draws as soon as feasible.

If subjects are not able to enter PRO data, sites will read the PRO questions and response 
options to the subject and record the subject's responses.  The subject's ability to view the PRO 
to understand the questions and response options should be preserved.  Sites may share the 
questionnaire by videoconference or send the questionnaires (email or hard copy) to the 
subjects to allow them to read/understand the questions and responses when the subject is 
providing responses over the phone.  The date and time of PRO data collection should be 
recorded along with who collected the information.

Height, body weight measurements or vital signs may be performed by the subject or caregiver 
as needed, or at home visits.

Physical examination may be performed at a local center, other than the study site, or at home 
visits.

All procedures performed at local facilities outside of the study site must also be performed by 
appropriately qualified personnel. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
k.
Urinalysis, chemistry and hematology, hs-CRP, and FCP may be collected at other scheduled 
and unscheduled visits than indicated in the table if they are warranted by the Investigator.
l.
Mandatory intestinal biopsies will be collected for histopathology, gene expression, and 
tissue RO (sites in the United States).  Four biopsies will be collected in the United States 
and two biopsies will be collected outside of the United States.  Mandatory intestinal 
biopsies may also be used for exploratory biomarker research.  Additional biopsies may also 
be collected at the Investigator's discretion to confirm disease diagnosis and/or to rule out 
dysplasia, colon cancer and infection.
m.
Update eligibility criteria, prior and concomitant therapy, and medical/surgical history 
information at Baseline to assure subject eligibility.
n.
Urine pregnancy test will be performed locally as indicated in the table for all females of 
childbearing potential.  The urine pregnancy test must be negative to receive study drug.  If 
any urine pregnancy test is positive, a serum pregnancy test will be performed by the 
central laboratory.
o.
Lab assessments will only need to be repeated at Baseline if the time between Screening 
and Baseline is greater than 14 days, or if the subject's health status has changed to warrant 
a repeat test.
p.
For the visit when endoscopy will be conducted, stool sample should be collected prior to 
bowel prep and should be returned to the site within 3 days of collection.  If a sample 
cannot be obtained during the site visit, the site will give instructions and a stool sample 
supply kit.
q.
Day 1 serum ravagalimab concentrations will be collected at the end of the ravagalimab IV 
infusion and Day 1 ADA/nAb will be determined from samples collected at any time during
the visit.  All subsequent samples will be collected just prior to dosing on the study visit.  At 
Week 104 or if a patient prematurely discontinues, serum ravagalimab and/or ADA/nAb will 
be collected at any time during the visit.  The date and time of sample collection will be 
captured on the electronic case report form (eCRF).
r.
Administration of drug will be performed after all assessments and examinations scheduled 
for that day have been completed.
s.
CD40 receptor occupancy (RO) and T cells, NK cells and B cell subsets (including 
plasmablasts) should be collected prior to dose at each visit when applicable.
t.
Only to be collected at PD visit if subject discontinues prior to Week 52.
u.
Where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and 
negative HBV DNA at Screening should have HBV DNA PCR testing performed approximately 
every 12 weeks.  HBV DNA PCR testing every 12 weeks is not necessary when the subject 
has a history of HBV vaccination and is HBs Ab+ and HBc Ab-.  If necessary, HBV DNA PCR 
may be tested at unscheduled visits.
3 STUDY PROCEDURES
3.1 Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding this study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject, the person who 
administered the informed consent, and any other signatories according to local requirements.  A copy 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
of the signed informed consent will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that the subject 
received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
In cases of state of emergency or pandemic situations, it is possible that additional protocol 
modifications not outlined in this protocol may become necessary.  If this situation arises, in addition to 
the study informed consent, additional verbal consent may be obtained prior to these adaptations or 
substantial changes in study conduct in accordance with local regulations.
3.2 Medical History and Prior/Concomitant Medications
A complete list of prior/concomitant medications and medical history including demographics, history of 
tobacco, alcohol, and drug use will be taken at screening.  The subject's prior/concomitant medications 
and medical history will be updated at the Study Day 1 visit.  This updated medical history will serve as 
the baseline for clinical assessment.  Concomitant medications will be reviewed at each study visit listed 
in Section 2.1.
3.3 Adverse Event Assessment
Please refer to Section 4.2.
3.4 Patient-Reported Outcomes and Subject Diary
Patient reported data must be completed for each subject screened/enrolled in this study.  Some of 
these data are being collected with an ePRO system called Trialmax, provided by the technology vendor 
CRF Health of Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR Part 11.  
The documentation related to the system validation of the ePRO system is available through the vendor, 
CRF Health, while the user acceptance testing of the study specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded to a server.  
The data on the server will be considered source, and maintained and managed by CRF Health.  
Internet access to the ePRO data will be provided by CRF Health for the duration of the study.  This 
access will be available for the duration of the study to the site Investigator, as well as delegated 
personnel.  Such access will be removed from Investigator sites following the receipt of the study 
archive.  Data from the ePRO system will be archived on appropriate data media (CD-ROM, etc.) and 
provided to the Investigator at that time as a durable record of the site's ePRO data.  It will be possible 
for the Investigator to make paper printouts from that media.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The ePRO data will be collected by diary based and tablet-based methods.  Subject must be able and 
willing to give written informed consent and to comply with the requirements of this study protocol.
Diary Based
The ePRO data (stool information, use of medications used for endoscopy preparation, abdominal pain, 
anti-diarrheal medication, and general well-being) will be collected electronically via a handheld device 
into which the subject will record the required pieces of information on a daily basis.  The electronic 
device will be programmed to allow data entry once per day.  All data entered on the device will be 
immediately stored to the device itself and manually/automatically uploaded to a central server 
administrated by CRF Health.  The investigational site staff will be able to access all uploaded subject 
entered data via a password protected website, up until the generation, receipt and confirmation of the 
study archive.  Completion will be reinforced during study visits as necessary. 
Stool frequency for SFS
The stool frequency is captured by subjects recording the number of stools over the last 
24 hours throughout the trial (range 0 - 99).  The SFS is calculated by comparing the stool 
frequency to a reference number.  The reference number is the number of stools per day 
(24 hours) that is typical for the subject when his/her UC is not active and needs to be 
designated once prior to enrollment.  The reference number should represent a full number of 
at least 1.  A higher score indicates higher stool frequency.
Rectal bleeding for RBS
The RBS is based on diary entries of subjects recording the most severe category that describes 
the amount of blood they had in their stools for a given day (0 = No blood seen, 1 = blood seen 
in fewer than half of the stools, 2 = blood seen in half or more of the stools, 3 = only blood 
without any stool).  A higher score indicates a higher degree of rectal bleeding.
Abdominal Pain
The abdominal pain score is captured from diary entries of subjects recording the level of worst 
abdominal pain experienced over 24 hours using a numeric rating scale (range 0 to 10; 0 = No 
pain and 10 = worst possible abdominal pain).  A higher score indicates a higher level of 
abdominal pain.
Bowel Urgency
Bowel urgency is captured from diary entries of subjects recording the presence (yes/no) of 
bowel urgency over 24 hours.
Tablet Based
The IBDQ will be collected electronically via a Tablet device into which the subject will directly enter the 
required pieces of information while at the site.  The electronic device will be programmed to allow data 
entry for only the visits specified in the protocol and will not allow for subjects to complete more than 
one of the same assessment at any one visit.  All data entered on the device will be immediately stored 
to the device itself and (manually/automatically) uploaded to a central server administrated by CRF 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Health.  The investigational site staff will be able to access all uploaded subject entered data via a 
password protected website, up until the generation, receipt and confirmation of the study archive.
IBDQ
The IBDQ is a widely used questionnaire for health-related quality of life (QoL) assessment in 
patients with inflammatory bowel diseases (IBD).  It consists of 32 items categories into 
4 dimensions:  "bowel symptoms," "systemic symptoms," "social function," and "emotional 
function."  Item responses are graded on a 7-point Likert scale, with 1 being most severe and 
7 being no problem at all.  A higher score indicates a better health status.
3.5 Pharmacokinetic Sampling
On the day of the study visit, subjects will be administered the ravagalimab intravenous (IV) or 
subcutaneous (SC) dose and blood samples for pharmacokinetic (PK) and ADA assessments should be 
collected at the specified time points at each visit as follows:
For PK samples:

At Baseline (Week 0) at the end of the ravagalimab IV infusion

At Weeks 2, 4, 8, 12, and 52 prior to administration of ravagalimab SC dose

At Week 104 or in the event of PD at any time during the visit.
For ADA and nAb samples:

At Baseline (Week 0) at any time during the visit 

At Weeks 4, 12, and 52 prior to administration of ravagalimab SC dose

At Week 104 or in the event of PD at any time during the visit.
The date and time of sample collection will be captured on the electronic case report form (eCRF).
3.6 Biomarker Sampling
Blood samples will be collected for biomarker research at the designated study visits as specified in 
Section 2.1.  Biopsies for biomarker analysis will be done when performing endoscopies.  Up to 
4 biopsies will be taken at each visit with endoscopy for biomarker research; 1 biopsy for histologic 
assessment by central review, 1 biopsy for gene expression analysis (including CD40 signature), 
2 biopsies for tissue RO (where applicable).  Collection of biomarker samples should occur prior to 
administration of drug on treatment days when applicable.  Whole blood for CD40 RO and/or analysis of 
T cells, NK cells and B cell subsets (including plasmablasts) will be collected prior to drug administration 
at Baseline, Week 4, Week 8, and Week 12; and at any time during the visit at Week 52 or in the event 
of PD prior to Week 52.  All biomarker samples should be collected, labeled, and shipped as outlined in 
the study-specific laboratory manual.  AbbVie (or people or companies working with AbbVie) will store 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
the samples and data in a secure storage space with adequate measures to protect confidentiality.  The 
samples may be retained while research on ravagalimab (or drugs of this class) or UC and related 
conditions continues, but for no longer than 20 years after study completion, or per local requirement.
3.7 12-Lead Electrocardiogram
A 12-lead ECG will be performed at the designated study visits as specified in Section 2.1.  For subjects 
with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required, 
provided source documentation is available.  Subjects can have a repeat ECG at any time during the 
study as warranted based on the opinion of the Investigator.  The ECG should be performed prior to 
blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
ECGs with QT interval corrected for heart rate using Fridericia's correction formula (QTcF) should be 
reported (or calculated) and documented in the source documents and later transcribed on to the 
appropriate eCRF if QTcF prolongation is observed.
A valid QTcF cannot be calculated in subjects who have a pacemaker or supraventricular or ventricular 
conduction abnormalities.  In cases of QTcF prolongation, the baseline QTcF will need to be entered into 
the appropriate eCRF for comparison as well.  In addition, any clinically significant findings will be 
documented in the source documents and later transcribed on to the appropriate eCRF.  Each signed 
original ECG will be monitored by the responsible site monitor and kept with subject's source 
documents onsite.
3.8 Height and Weight
Height will be measured at screening only.  Body weight will be measured at scheduled visits as specified 
in Section 2.1 and before blood draws are performed.  The subject will wear lightweight clothing and no 
shoes during weighing.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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3.9 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits as specified in Section 2.1.  Blood pressure and pulse rate should be measured after 
the subject has been sitting for at least 3 minutes.  Blood pressure, pulse rate, temperature, and 
respiratory rate should be performed before blood draws are performed.
3.10 Physical Examination
A complete physical examination, including an assessment of EIMs, will be performed at the designated 
study visits as specified in Section 2.1.  The physical examination performed on Study Day 1 will serve as 
the baseline physical examination for the entire study.  Any significant physical examination findings 
after the first dose will be recorded as adverse events.  All findings, whether related to an AE or part of 
each subject's medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
3.11 Administer Study Drug
Intravenous study drug will be administered to all subjects on-site.  For female subjects of childbearing 
potential, the urine pregnancy test needs to be negative prior to receiving study drug.  The site will be 
provided administration instructions.  Study drug will be administered to subjects beginning at baseline 
(Day 1) and as specified in Section 2.1.  Administration of drug will be performed after all assessments 
and examinations scheduled for that day have been completed.  At the visits specified in Section 2.1, the 
site personnel will review and retain a copy of the subject diary, review returned study drug kits, and 
empty study drug packaging to verify compliance.  A separate study drug administration guideline will 
be provided as well.
3.12 Clinical Laboratory Tests
The baseline laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory and sent to the following certified laboratory addresses:
For sites in North America:
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Covance
8211 SciCor Drive
Indianapolis, IN 46214 USA
For sites in Europe:
Covance
7 rue Moise-Marcinhes
1217 Geneva
Meyrin Switzerland
Blood samples will be obtained for the laboratory tests listed in the Clinical Laboratory Tests table 
below.  Blood draws should be performed, as much as possible, after efficacy assessments and 
questionnaires (IBDQ, etc.) and vital sign determinations are obtained during a visit.  Blood draws should 
be performed before study drug administration. 
All abnormal laboratory tests that are considered clinically significant by the Investigator will:  1) be 
followed to a satisfactory resolution, 2) follow the toxicity management instructions for Select 
Laboratory Abnormalities as applicable (see Section 6.2 of the protocol).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count 
Platelet count
Diff. Automatic (absolute 
count):
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Manual Differential (ONLY IF 
Automated Differential is 
abnormal):
Neutrophils, bands (Stabs)
Neutrophils, 
polymorphonuclear
Eosinophils
Basophils
Monocytes
Lymphocytes
Enzymes
Aspartate transaminase (AST, GOT) 
Alanine transaminase (ALT, GPT)
Alkaline Phosphatase
Creatine Kinase
Electrolytes
Calcium
Sodium 
Potassium
Chloride
Bicarbonate
Substrates
Blood urea nitrogen 
Creatinine 
Bilirubin Total
Bilirubin Direct (if total is elevated) 
Bilirubin Indirect (if total is elevated) 
Albumin
Cholesterol, total
Low-density lipoprotein
(LDL)-Cholesterol
High-density lipoprotein
(HDL)-Cholesterol
Triglycerides 
Glucose
Dipstick Urinalysis (local)
Urine Nitrite 
Urine Protein 
Urine Glucose
Urine Ketone 
Urobilinogen 
Urine Bilirubin
Urine RBC/Erythrocytes 
Urine WBC/Leukocytes 
Urine pH
Urine creatinine
Urine-Sediment (microscopic 
examination, only if urine 
analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells 
Urine Sediment Crystals, 
Unspecified 
Urine Sediment 
RBC/Erythrocytes Urine 
Sediment WBC/Leucocytes
Urine
Urine Albumin-to-Creatinine 
Ratio
Stool Samples
Coagulation
Other Tests
C. difficile toxin
Fecal calprotectin (FCP)
INRa
Urine Pregnancy testb (local)
Serum Pregnancy testb
Tryptasec
Histaminec
Hepatitis B screening
Hepatitis C screening 
HIV test
SARS-CoV-2 molecular test, if 
applicable
PK/Immunogenicity
Biomarkers
Biopsy
Serum ravagalimab 
concentrationc
Serum ADAc and nAbc
high-sensitivity C-reactive protein (hs-CRP)
CD40 receptor occupancy (RO)
Plamablast frequency
Exploratory biomarker research
Histopathology scoring
Tissue RO (If applicable)
Gene expression
a.
INR test only drawn if ALT or AST > 3 × ULN (upper limit of normal) and Total Bilirubin < 2 × ULN.  Refer to Section 6.2 in the 
protocol for more information.
b.
Pregnancy testing is not required for women of nonchildbearing potential.
c.
To be done with the occurrence of a suspected anaphylaxis.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Pregnancy Tests (Serum and Urine)
A serum pregnancy test will be performed for all female subjects of childbearing potential during 
Screening.  Pregnancy testing should not be performed for postmenopausal women. Determination of 
postmenopausal status will be made during the Screening period based on the subject's history or FSH 
testing.
A quantitative serum pregnancy test will be performed at Screening and a urine pregnancy test will be 
performed at baseline for all female subjects of childbearing potential.  The serum pregnancy test will be 
sent to and performed by the central laboratory.  If the serum pregnancy test is positive the subject is 
considered a screen failure.  If the serum pregnancy test is borderline, it should be repeated ≥3 days 
later to determine eligibility.
If the repeat serum pregnancy test is:

Positive, the subject is considered a screen failure;

Negative, the subject can be enrolled into the trial;

Still borderline ≥ 3 days later (considered documentation of continued lack of a positive result), 
the subject can be enrolled into the study (unless prohibited per local requirements) in the 
absence of clinical suspicion of pregnancy and other pathological causes of borderline results.
Additional urine pregnancy tests will be performed at visits indicated in Section 2.1.
More frequent pregnancy tests can be performed throughout the study at the investigator's discretion 
or if required per local/country requirements.  

If the baseline urine pregnancy test is negative, then dosing with study drug may begin.  

If the baseline or post-baseline urine pregnancy test is positive, dosing with study drug must be 
withheld and a serum pregnancy test is required (as stated above).
Clinical Chemistry
For serum chemistry tests, it is preferred that the subject has fasted (8 hours, except for water) prior to 
sample collection, however it is not required.  It must be recorded whether the subject has fasted or not 
at the time of collection in the laboratory request, source document, and eCRF.
Urinalysis
Dipstick urinalysis will be provided by the central laboratory and completed locally at the site at all 
required visits.  If the dipstick urinalysis is abnormal, then a microscopic analysis will be sent to the 
central laboratory in the event the dipstick results show protein, ketones or blood other than negative 
or glucose greater than normal.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Tuberculosis (TB) Testing/TB Prophylaxis
All subjects must be evaluated for TB at Screening and annually.  The TB screening tests provide 
diagnostic test results to be interpreted in the context of the subject's epidemiology, history, exam 
findings, etc., and it is the responsibility of the Investigator to determine if a subject has previous, active, 
or latent TB.  Expert consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion.
At screening, all subjects will be assessed for evidence of increased risk for TB by a risk assessment form 
(Appendix C) and tested for TB infection by QuantiFERON-TB Gold test or purified protein derivative 
(PPD) test.  The site staff will complete the TB risk assessment form and enter the data into the 
appropriate eCRF.  The TB risk assessment questionnaire will be completed annually (Part I only) for all 
subjects, regardless of TB test results.
If a subject had a negative purified protein derivative (PPD) test within 90 days prior to Screening and a 
QuantiFERON-TB Gold test cannot be performed by Central Lab at Screening and source documentation 
is available, TB testing by PPD Skin Test does not need to be repeated, provided nothing has changed in 
the subject's medical history to warrant a repeat test.  These cases may be discussed with the AbbVie TA 
MD.  The results of the TB test(s) will be retained at the site as the original source documentation. 
Subjects with a negative TB test may be enrolled.  Subjects with a positive TB test must be assessed for 
evidence of active TB versus latent TB, including signs and symptoms and CXR.  Subjects with no signs or 
symptoms and a CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis.  
Subjects with evidence of active TB must not be enrolled.
Any positive TB test after a subject with a negative test at Baseline has started the study should be 
reported as an AE of latent TB or active TB (as applicable). 
If the subject is experiencing signs or symptoms suspicious for TB or something has changed in the 
subject's medical history to warrant a repeat test, the case (including the TB test results) must be 
discussed with the AbbVie TA MD.
TB Test

Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) and/or PPD test are not required to repeat either test at Screening or during the 
study and should be considered positive. 

For regions that require both PPD and QuantiFERON-TB Gold testing, both will be performed.  If 
either PPD or QuantiFERON-TB Gold are positive, the TB test is considered positive.

The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be utilized only when a 
QuantiFERON-TB Gold Test is not possible for any reason (unless both tests are required per 
local guidelines).  

If subjects require repeat TB testing during the trial, the TB test used for repeat testing should 
be the same as the test used during Screening.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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
Subjects without a history of active or latent TB and who have a negative TB test result at 
Screening or the most recent evaluation will undergo annual TB testing by QuantiFERON-TBGold 
Test and/or PPD skin test.

If a subject enters the study with a QuantiFERON-TB Gold test alone, then the subject should 
have their annual TB test performed with a QuantiFERON-TB Gold test.  Similarly, if only a PPD is 
placed at Screening, then the TB test to be used for the remainder of the study for that subject 
is the PPD.

If the QuantiFERON-TB Gold Test is NOT possible (or if both the QuantiFERON-TB Gold Test and 
the PPD are required per local guidelines) the PPD will be performed.  The PPD should be read 
by a licensed healthcare professional between 48 and 72 hours after administration.  A subject 
who does not return within 72 hours will need to be rescheduled for another skin test.  The 
reaction will be measured in millimeters (mm) of induration and induration ≥ 5 mm is 
considered a positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."  Subjects who have an ulcerating reaction to the PPD in the past should not be re-
exposed and the PPD should be considered positive.

If the QuantiFERON-TB Gold test is indeterminate, then the investigator should perform a local 
QuantiFERON-TB Gold test (or through the central laboratory if not locally available) to rule out 
a positive test result.  If testing remains indeterminate or is positive, then the subject is 
considered to be positive for the purpose of this study.  If the testing result is negative, then the 
subject is considered to be negative.

If the subject is experiencing signs or symptoms suspicious for TB or something has changed in 
the subject's medical history to warrant investigation and a repeat test before the next 
scheduled annual TB retest, the case (including the TB test results) should be discussed with the 
AbbVie TA MD.

If TB testing is done for subjects with a prior positive TB test at the annual evaluation, repeated 
TB prophylaxis is not required for a positive result unless indicated by the subject's medical 
history.
TB Prophylaxis
At screening, if the subject has evidence of latent TB infection, prophylactic treatment must be initiated 
at least 2 weeks prior to administration of study drug (or per local guidelines, whichever is longer).  At 
least 6 months of prophylaxis need to be completed.  However, the full course of prophylaxis does not 
need to be completed prior to the first dose of study drug.  
Of note, Rifampicin or Rifapentine is not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full course of anti-TB 
therapy will be allowed to enter the study provided nothing has changed in the subject's medical history 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
to warrant repeat treatment.  For subjects with completion of a full course of anti-TB therapy, but 
insufficient documentation, the investigator should consult with the AbbVie TA MD. 
During the study, subjects with new evidence of latent TB should initiate prophylactic treatment 
immediately per local guidelines and complete at least 6 months of prophylaxis.  TB prophylaxis should 
be initiated and study drug(s) should not be withheld.  The subject should be re-evaluated (unscheduled 
visit) for signs and symptoms as well as laboratory assessment of toxicity to TB prophylaxis 2 to 4 weeks 
later.  Newly initiated prophylactic treatment and prior therapy should be captured in the eCRF.
Chest X-Ray
Chest X-ray (posterior-anterior and lateral views) is required for all subjects at Screening who have a 
positive QuantiFERON-Gold TB and/or PPD test.  Subjects can have a CXR at any time during the study as 
warranted based on the opinion of the Investigator.  A radiologist or pulmonologist must perform and 
document an assessment of the CXR.  The Investigator will indicate the clinical significance of any 
findings and will sign and date the report. 
A CXR is required annually for subjects with a newly positive PPD and/or QuantiFERON-TB Gold test after 
Baseline or a positive response to the TB risk questionnaire Part I questions.
In the assessment of the CXR, if possible per local / site guidelines, the Investigator or their delegate 
must indicate the presence or absence of calcified granulomas, pleural scarring/thickening, and signs of 
active TB.  If the CXR demonstrates changes suggestive of previous TB (e.g., calcified nodule, fibrotic 
scar, apical or basilar pleural thickening) or other findings that are clinically significant, the Investigator 
should contact the AbbVie TA MD before enrolling the subject.
Hepatitis B Testing
All subjects will be tested for the presence of HBV at screening using the following tests:

HBs Ag (Hepatitis B surface antigen)

HBc Ab/anti-HBc (Hepatitis B core antibody)

HBs Ab/anti-HBs (Hepatitis B surface antibody)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger automatic reflex testing for core antibodies (HBc Ab) and surface 
antibodies (HBs Ab).

A negative test result for HBc Ab does not require HBV DNA PCR qualitative testing and the 
subject may be enrolled (Figure 1, Scenarios A and B).  

For a subject who has had a HBV vaccination (should document in the medical history), a 
positive test result for HBs Ab is expected, the HBV DNA PCR qualitative testing is not required 
and the subject may be enrolled (Figure 1, Scenario B*).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex testing) 
(Figure 1, Scenarios C and D).

A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.

A subject with a negative result for HBV DNA may be enrolled.

Where mandated by local requirements:  A positive result for HBs Ab requires HBV DNA PCR 
testing.

A result that exceeds detection sensitivity by central laboratory will be considered a positive 
result for HBV DNA and will be exclusionary.

A subject with a negative result for HBV DNA may be enrolled.

For subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA 
PCR test should be performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+, HBc Ab-.

At any time during the study for subjects with HBc Ab+ (irrespective of HBs Ab status) and 
negative HBV DNA at screening, a positive result for HBV DNA PCR testing accompanied by the 
following will require immediate interruption of study drug:

an ALT > 5 × ULN OR 

ALT/AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR

ALT/AST > 3 × ULN along with clinical signs of possible hepatitis.
Figure 1.
Interpretation and Management of HBV Serologic Test Results
*
Subjects who have had a HBV vaccination are expected to have a positive test result for HBs Ab and do not require HBV 
DNA PCR testing. For subjects without a history of HBV vaccination (and where mandated by local requirements) a 
positive result for HBs Ab requires HBV DNA PCR testing.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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**
Where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening 
should have HBV DNA PCR testing performed approximately every 12 weeks. HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccination and is HBs Ab+ and HBc Ab-.  If necessary, HBV DNA PCR may 
be tested at unscheduled visits.
Hepatitis C Testing
All subjects will be tested for the presence of the hepatitis C Virus (HCV) antibody at Screening.  Subjects 
with positive HCV antibody will have a HCV RNA test.  If the HCV RNA is positive, then the subject will be 
excluded.
HIV Testing
Subjects with a known history of HIV infection are excluded from study participation.  HIV testing will be 
conducted as part of the infection screening at the Screening visit.  The Investigator must discuss any 
local reporting requirements to local health agencies with the subject.  The site will report these results 
to their health agency per local regulations, if necessary.  If a subject has a confirmed positive result, the 
Investigator must discuss with the subject the potential implications to the subject's health and subjects 
should be referred for clinical care promptly.  A subject will not be eligible for study participation if test 
results indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be 
made aware of any positive result.  This testing is to be done at the central lab.
Stool Sample Testing
If the investigator has a reasonable suspicion of a gastrointestinal infection they should ensure this has 
been excluded prior to screening the subject. 
FCP
Fecal calprotectin will be performed at the study visits indicated in Section 2.1.  If subjects are unable to 
provide a sample at the site visit, subjects will be sent home with a stool sample supply kit and the site 
will give instructions to assist with collection procedures.  If the FCP sample is collected during the 
Screening period, it may be used as the Baseline.  All stool samples should be collected before any bowel 
preparation for endoscopy is started and returned to the site within 3 days of collection.
C. Difficile Stool Testing
During the Screening period a stool sample will be collected and sent to the central laboratory for 
testing.  The sample will be assessed for the presence of C. difficile toxin.  Subjects who are positive for 
C. difficile toxin may be treated appropriately and re-screened.
The sample must be shipped to the central laboratory using dry ice.
High-Sensitivity C-Reactive Protein (hs-CRP)
Blood samples for hs-CRP will be obtained at the study visits indicated in Section 2.1.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Anaphylaxis Testing
In the event of a suspected anaphylaxis, a PK, ADA, and nAb sample should be collected once within 
24 hours of the reaction.  In addition to PK, ADA, and nAb assays, blood tests to be conducted in the 
event of a suspected anaphylaxis are: 

Serum tryptase:  Optimally, measurement needs to be obtained from 15 minutes to 3 hours of 
symptom onset, and no later than 6 hours (as tryptase may remain elevated for 6 or more hours 
after the onset and therefore may still be informative if obtained after 3 hours); it is also 
recommended requested to collect a follow-up tryptase level that can be collected a minimum 
of 2 weeks after the recorded event or at the next study visit, and within 2 months of the 
reaction.

Plasma histamine:  Optimally, within 5 to 15 minutes of the onset of symptoms, and no later 
than 1 hour.
Refer to Appendix E (Clinical Criteria for Diagnosing Anaphylaxis) for more information.
3.13 Subject Withdrawal from Study
All attempts must be made to determine the primary reason for discontinuation of study drug or study 
participation.  The information along with the date of the last study drug dose will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
If a subject withdraws from the main study, biomarker research samples will continue to be stored and 
analyzed.  A subject must contact the Investigator if they no longer want their samples to be stored and 
analyzed.  Once AbbVie is notified, no new information will be collected, no new analysis will be started, 
and the samples will be destroyed unless a regulatory authority requires AbbVie to keep them.  
However, if AbbVie (or people or companies working with AbbVie) collected any information or did any 
testing before withdrawal, AbbVie (or people or companies working with AbbVie) will still use and 
disclose such information, use the test results, and keep the data generated from the samples.
3.14 Rescreening
Subjects who initially screen fail for the study or who received placebo only in the study prior to 
version 4.0 may be permitted to re-screen following re-consent.  The subject must meet all the eligibility 
criteria as assessable at the time of re-screening in order to qualify for the study.  There is no minimum 
period of time a subject must wait to re-screen for the study.  
If the subject had a complete initial screening evaluation including the TB test, Hepatitis B virus (HBV), 
Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and electrocardiogram (ECG), these tests 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
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will not be required to be repeated for re-screening provided the conditions noted in Section 3 are met 
and no more than 90 days have passed.
If a subject is being rescreened ≤ 14 days from the date of the previous screening testing, it is not 
required to repeat testing for chemistry/hematology, urinalysis, serum pregnancy, and C. difficile
provided that the subject's health status has not changed to warrant a repeat test.  However, if 
> 14 days have passed from the date of testing and Baseline, then Baseline samples should be collected 
(with the exception of C. difficile).
All subjects who rescreen need to have their RBS, SFS, and Adapted Mayo score calculated and meet the 
eligibility criteria before enrollment at Baseline.
An endoscopy with biopsy will not be required to be repeated for re-screening provided the conditions 
noted in Section 3.15 are met and the endoscopy is within 45 days of the Baseline visit.  All other 
screening procedures will be repeated (with the possible exceptions noted above).  Sites may contact 
the AbbVie TA MD if there are questions on if subjects should or should not be re-screened.
3.15 Additional Assessments
Endoscopy
Endoscopy at/during Screening or within 45 days of the Baseline visit will be required to calculate the 
Mayo endoscopy subscore (confirmed by a central reader) at Baseline.  Endoscopic evaluations using 
Mayo endoscopic score confirmed by central reader will be done at Screening, Week 8, Week 52, and 
Week 104/PD.
The same endoscopist, where possible, should perform all endoscopies.  In addition, where possible, the 
Investigator or sub-Investigator should be the endoscopist for the study.  It is expected that all subjects 
who remain in the study through at least Week 6 will have a Week 8/PD endoscopy. 
An endoscopy performed before the Screening visit, independently of the study, may be used as the 
Screening endoscopy, with the approval of the AbbVie TA MD, if the following conditions are met:

Biopsy confirmation of the diagnosis is available according to section "Intestinal Biopsy" below, 
as applicable.

The endoscopy took place within 45 days prior to Baseline visit.

The endoscopy was recorded in a video format as the endoscopic eligibility will be determined 
by the central reviewers.  
A full colonoscopy will be performed at Screening unless the subject underwent a full colonoscopy 
within 24 months prior to Screening.  There must be appropriate documentation available to confirm 
the diagnosis, extent of disease, and to exclude dysplasia and colon cancer.  If this is available, the 
screening endoscopy may be either a full colonoscopy or a flexible sigmoidoscopy.  All other 
endoscopies may be flexible sigmoidoscopies or colonoscopies at the discretion of the Investigator.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
All endoscopies will be performed and recorded at the site in a video format.  Videos from subjects with 
eligible Mayo endoscopic sub-scores during Screening and all videos from subjects at Week 8, Week 52, 
and Week 104/PD will be sent to a central review vendor and scored as described in the central review 
charter.  Endoscopies will be evaluated using the Mayo endoscopic subscore.  The Mayo endoscopic 
subscore, including the presence or absence of friability will be documented by the endoscopist at the 
site and maintained in the subject's source documents.  If, in the assessment of the site endoscopist, the 
Screening endoscopy does not indicate an endoscopy subscore of 2 or 3 or the extent of inflammation is 
limited to the rectum, per eligibility requirements, the subject should be screen-failed and the video 
should not be sent for central reading.  In addition to the Mayo endoscopy subscore, the central reader 
will assess the endoscopy findings using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and 
UC-100 scoring system for additional exploratory analyses.  
There will be a window of ± 7 days to conduct the endoscopy.  This window may be extended as
necessary after consultation with the AbbVie TA MD in case of external, not subject-related 
circumstances (e.g., scheduling conflict).  
Intestinal Biopsy
Mandatory biopsies will be collected from the site of general inflammation during endoscopies occurring 
during Screening, Week 8, Week 52, Week 104, and/or PD visits as described below:

US sites:  collect 4 biopsies at each time point for histology (centrally read), tissue RO (if 
applicable), and gene expression analysis

Ex-US sites:  collect 2 biopsies at each time point for histology (centrally read) and gene 
expression analysis
The biopsies for histopathological and gene expression analysis collected for the main study may 
also be used for exploratory research to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  

Additional biopsies as indicated:

Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the 
assessment of the Investigator, must be available in order to confirm the subject's eligibility 
for the study.  If this documentation is not available a diagnostic biopsy from the most 
affected observed area of the colon must be performed during the Screening endoscopy and 
read by a qualified local pathologist and the results reviewed by the Investigator.  

Biopsies to rule out dysplasia, colon cancer and infection may be taken per the Investigator's 
discretion during any endoscopy performed during this study and evaluated by the local 
pathologist.  The signed pathology report will be monitored by the responsible Clinical 
Research Associate (CRA) and kept with the subject's source documents onsite.  

Biopsy sampling should be recorded on the endoscopy video. 

Unless indicated otherwise, biopsies will be taken from the rectosigmoid segment of the colon 
at each visit with endoscopy from an area which represents the general degree of mucosal 
inflammation of the segment.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6 STUDY DRUG
6.1 Treatments Administered
The study drug (ravagalimab) will be administered in the form of IV infusions or SC injections at the visits 
listed in Section 2.1.
Ravagalimab and placebo will be provided by AbbVie as lyophilized powder for solution for 
injection/infusion in vials to be reconstituted by a pharmacist or qualified designee.
Ravagalimab will be administered IV once (induction) then SC every other week (eow).
Study drug must not be administered without contacting the interactive response technology (IRT) 
system.  Study drug may only be administered to subjects enrolled in the study through the IRT system.  
At the end of the Treatment Period or at the PD visit, the site will contact the IRT system to provide visit 
date information and study drug return information for each kit.
6.2 Packaging and Labeling
All study drugs will be supplied in cartons containing one vial with quantities sufficient to accommodate 
study design.  Each vial will contain 100 mg ravagalimab lyophilized powder for solution for 
injection/infusion or placebo.  Each carton and vial label will contain a unique kit number.  This kit 
number is assigned to a subject via IRT and encodes the appropriate study drug to be administered at 
the subject's corresponding study visit.  Each carton and vial will be labeled as required per country 
requirements.  The labels must remain affixed to the cartons and vials.  All blank spaces should be 
completed by site staff prior to dispensing to subject.
Storage and Disposition of Study Drug
Ravagalimab and placebo must be refrigerated (2° to 8°C/36° to 46°F), protected from light, and must 
not be frozen.  The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be maintained under 
adequate security and stored under the conditions specified on the label until administered for subject 
use or destroyed on site as appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a Phase 2a, multicenter, single arm, open-label study.  All eligible subjects will receive 
ravagalimab 600 mg IV at Baseline (Week 0), and ravagalimab 300 mg SC eow from Week 2 during the 
induction period.  Subjects who enter the maintenance period will receive open-label ravagalimab 
300 mg SC eow.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
The dose selection in this study is based on analysis of PK, pharmacodynamics, and safety data from 
Phase 1 studies in healthy volunteers as well as safety data from preclinical animal studies.  Ravagalimab 
dose of 600 mg IV at Week 0, 300 mg SC for Weeks 2, 4, 6, 8, and 10, and 300 mg SC eow from Week 12 
to Week 102 is selected for this study.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine transaminase
AST
Aspartate transaminase
CXR
Chest X-ray
COVID
Coronavirus Disease-2019
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eow
Every other week
FCP
Fecal calprotectin
FSH
Follicle-stimulating hormone
HBc Ab
Hepatitis B core antibodies
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCRU
Health Care Resource Utilization
HCV
Hepatitis C Virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
hs-CRP
High sensitivity C-reactive protein
IBDQ
Inflammatory Bowel Disease Questionnaire
IMP
Investigational Medicinal Product
IRT
Interactive response technology
IV
Intravenous(ly)
LDL
Low-density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
nAb
Neutralizing anti-drug antibody
PK
Pharmacokinetic(s)
PPD
Purified protein derivative
PRO
Patient-reported outcome
PT
Preferred term
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
QoL
Quality of life
RBC
Red blood cell
RBS
Rectal bleeding subscore
RO
Receptor occupancy
SAE
Serious adverse event
SC
Subcutaneous(ly)
SFS
Stool frequency subscore
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
WBC
White blood cell
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. ADDITIONAL ENDPOINT DEFINITIONS
UCEIS
The UCEIS is a tool for the overall assessment of endoscopic severity of UC.  It is calculated based on the 
following 3 descriptors:  vascular pattern (scored 0-2), bleeding (scored 0-3), and erosions and ulcers 
(scored 0-3).  The final score is a sum of these 3 items and ranges from 0 (remission) to 8 (severe).
UC-100
A composite index of disease activity in UC that combines clinical, endoscopic, and histological data that 
ranges from 1 to 100, with higher values indicating more severe disease activity.
Reference:
Travis SP, Schnell D, Feagan BG, et al.  The Impact of Clinical Information on the Assessment of 
Endoscopic Activity: Characteristics of the Ulcerative Colitis Endoscopic Index Of Severity [UCEIS].  
J Crohns Colitis.  2015;9(8):607-16.
Jairath V, Jeyarajah J, Guangyong Z, 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 Jan;4(1):63-70.  doi: 10.1016/S2468-1253(18)30306-6.  Epub 2018 Oct 18.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. SCREENING/ANNUAL TB RISK ASSESSMENT 
QUESTIONNAIRE EXAMPLE
For Screening TB risk assessment, ask Part I and Part II questions.
Part I
1.
Has an immediate family member or other close contact been newly diagnosed with or treated 
for active or latent tuberculosis during the last 3 months?
2.
Within the past year, have you, or an immediate family member, had any of the following 
problems lasting for 3 weeks or longer which remained unexplained:

Chronic Cough

Production of Sputum

Blood-Streaked Sputum

Weight Loss

Fever

Fatigue/Tiredness

Night Sweats

Shortness of Breath
(reference:  https://www.cdc.gov/tb/topic/testing/diagnosingltbi.htm)
Part II
3.
Have you ever been diagnosed or treated for active or latent tuberculosis?
4.
Have you lived in or had prolonged travels to a TB endemic region?
(reference:  http://gamapserver.who.int/gho/interactive_charts/tb/cases/atlas.html)
5.
Have you lived or worked in a prison, refugee camp, homeless shelter, immigration center, or 
nursing home?
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. SCRIPT FOR COLLECTION OF MAYO SCORES FOR
USE IN STUDY M15-722
Mayo Score
Three different Mayo Score are evaluated in this protocol:

Full Mayo Score

Adapted Mayo Score

Partial Adapted Mayo Score
The Full Mayo Score is a composite of the following subscores:  SFS, RBS, Endoscopy subscore, and PGA 
subscore. 
The adapted Mayo Score is a composite of the following subscores:  SFS, RBS and Endoscopy subscore.  
The Partial Adapted Mayo Score is a composite of the following subscores:  SFS and RBS.
Subscores
Stool frequency Subscore* 
0 = Normal number of stools for this subject 
1 = 1 – 2 stools more than normal 
2 = 3 – 4 stools more than normal 
3 = 5 or more stools more than normal 
*
Each patient serves as his or her own control to establish normal stool frequency and the degree 
of abnormal stool frequency.  
Rectal bleeding Subscore**
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passed 
** The daily bleeding score represents the most severe bleeding of the day.  
Endoscopy Subscore:  Findings of flexible sigmoidoscopy
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern, mild friability) 
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration)
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Physician's Global Assessment Subscore*** 
0 = Normal (Subscores are 0) 
1 = Mild disease (Subscores are mostly 1's) 
2 = Moderate disease (Subscores are 1 to 2) 
3 = Severe disease (Subscores are 2 to 3) 
***The physician's global assessment acknowledges the three other subscores, the subject's daily 
record of abdominal discomfort and functional assessment, and other observations such as 
physical findings, and the subject's performance status.  
References:
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-ASA therapy for mildly to moderately active ulcerative colitis.  
N Engl J Med.  1987;317(26):1625-9. 
Lewis JD, Chuai S, Nessel L, et al.  Use of the noninvasive components of the Mayo Score to assess clinical response in 
ulcerative colitis.  Inflamm Bowel Dis.  2008;14(12):1660-6. 
Stool Frequency Subscore

The stool frequency subscore is calculated by comparing the stool frequency to a reference 
number.  The reference number is the number of stools per day (24 hours) that is typical for the 
subject when having active UC but not experiencing a flare and needs to be designated once 
prior to enrollment.  The reference number should represent a full number of at least 1.

Subjects will record the daily number of stools throughout the trial.  Using these numbers, the 
Stool Frequency subscore will be assessed for each study day as follows: 

A number of bowel movements lower than or equal to the reference number of bowel 
movements should be scored as 0 = Normal.

One or 2 bowel movements more than the reference number of bowel movements should 
be scored as 1.

Three or 4 bowel movements more than the reference number of bowel movements should 
be scored as 2.

Five or more bowel movements more than the reference number of bowel movements 
should be scored as 3.

The Stool Frequency subscores based on 3 days prior to each study visit will be averaged and 
used for the Stool Frequency subscore for each study visit.  

The Stool Frequency subscore during days which the subject received anti-diarrheal medication 
will be scored as a 3.

Diary entries for stool frequency should not be included in the 3 days prior to the visit that are 
evaluated for the Stool Frequency subscore for the following days:  (1) the day the subject 
received medication for bowel preparation prior to endoscopy, (2) the day the subject 
underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier diary entries will be 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
used accordingly in order to provide the most recent data for 3 days prior to the respective 
study visit.
Rectal Bleeding Subscore

Subjects will be assigned a daily rectal bleeding subscore value as follows:

No visible blood with stool during the respective day should be scored as 0.

Visible blood with stool less than half the time during the respective day should be scored as 
1.

Visible blood with stool at least half the time during the respective day should be scored as 
2.

A score of 3 for bleeding requires subjects to have at least 50% of bowel movements 
accompanied by visible blood and at least one bowel movement with blood alone.

The score entries into subject's diary based on 3 days prior to each study visit will be averaged 
and used for the Rectal Bleeding subscore for each study visit.  

Diary entries for rectal bleeding should not be included in the 3 days prior to the visit that are 
evaluated for the Rectal Bleeding subscore for the following days:  (1) the day the subject 
received medication for bowel preparation prior to endoscopy, (2) the day the subject 
underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier diary entries will be 
used accordingly in order to provide the most recent data for 3 days prior to the respective 
study visit.
Physician's Global Assessment Subscore
The physician's global assessment acknowledges the 2 subject-reported subscores, the endoscopy 
subscore as applicable, the subject's daily record of abdominal discomfort and general well-being during 
based on the 3 days prior to the visit, and other observations such as physical findings, and the subject's 
performance status in order to assess disease activity as follows:

0 = Normal

1 = Mild disease

2 = Moderate disease

3 = Severe disease
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Endoscopy Subscore

The endoscopist should evaluate each observed segment of the colon (rectum, sigmoid, 
descending colon, transverse colon, ascending colon/cecum) by using the classification as 
follows:

0 = Normal or inactive disease

1 = Mild disease (erythema, decreased vascular pattern)

2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)

3 = Severe disease (spontaneous bleeding, ulceration)

The endoscopic subscore for the subject will be the worst score of the observed segments.

The local endoscopist should also separately assess presence or absence of friability (yes/no).

The endoscopy will be recorded (not a still image) and sent to a central review vendor for 
scoring as described in the central review charter.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M15-722 Version 6.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (e.g., generalized hives, pruritus or flushing, swollen lips tongue-uvula) AND AT LEAST 
ONE OF THE FOLLOWING
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b.
Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips 
tongue-uvula)
b.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)
c.
Reduced blood pressure (BP) or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d.
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children:  low systolic BP (age specific) or greater than 30% decrease in systolic 
BP*
b.
Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's 
baseline
*
low systolic BP for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 × age]) from 
1 to 10 years, and less than 90 mgHg from 11 to 17 years.
References:
Sampson HA, Muñoz-Furlong A, Campbell RL, 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.
Page 109 of 111
 

SAP_001.pdf: 
Ravagalimab
M15-722 – Statistical Analysis Plan
Version 3.0 – 10 February 2021
1
Statistical Analysis Plan for Study M15-722
A Multicenter, Single Arm, Open-label Study to 
Investigate the Efficacy and Safety of Ravagalimab 
(ABBV-323) in Subjects with Moderate to Severe 
Ulcerative Colitis Who Failed Prior Therapy
Date:  10 February 2021
Version 3.0
 
NCT03695185


Ravagalimab
M15-722 – Statistical Analysis Plan
Version 3.0 – 10 February 2021
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination........................................................................8
3.0
Endpoints..................................................................................8
3.1
Primary Endpoint.......................................................................................8
3.2
Secondary Endpoints .................................................................................8
3.3
Additional Efficacy Endpoints...................................................................9
3.4
Safety Endpoint(s) ...................................................................................10
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................12
7.1
Demographics and Baseline Characteristics............................................12
7.2
Medical History .......................................................................................14
7.3
Prior and Concomitant Medications ........................................................14
8.0
Efficacy Analyses...................................................................15
8.1
General Considerations............................................................................15
8.2
Handling of Missing Data........................................................................15
8.3
Primary Efficacy Endpoint and Analyses ................................................17
8.3.1
Primary Efficacy Endpoint ......................................................................17
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ................17
8.3.3
Primary Analysis of the Primary Efficacy Endpoint ...............................17
8.3.4
Sensitivity and Supplementary Analysis of the Primary Efficacy 
Endpoint...................................................................................................17
8.3.5
Additional Analyses of the Primary Efficacy Endpoint...........................18
8.4
Secondary Efficacy Endpoint and Analyses............................................19
8.5
Additional Efficacy Analyses ..................................................................19
 


Ravagalimab
M15-722 – Statistical Analysis Plan
Version 3.0 – 10 February 2021
3
9.0
Safety Analyses ......................................................................21
9.1
General Considerations............................................................................21
9.2
Adverse Events ........................................................................................22
9.2.1
Treatment-Emergent Adverse Events ......................................................22
9.2.2
Adverse Event Overview .........................................................................23
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................23
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................24
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................24
9.2.6
Adverse Events of Special Interest ..........................................................24
9.3
Analysis of Laboratory Data....................................................................27
9.4
Analysis of Vital Signs ............................................................................28
10.0
Other Analyses.......................................................................29
11.0
Interim Analyses....................................................................29
11.1
Data Monitoring Committee....................................................................29
12.0
Overall Type-I Error Control ..............................................30
13.0
Version History......................................................................30
14.0
References...............................................................................30
List of Tables
Table 1.
SAP Version History Summary...............................................................30
Table 2.
Criteria for Potentially Clinically Significant Hematology Values .........34
Table 3.
Criteria for Potentially Clinically Significant Chemistry Values ............35
Table 4.
Criteria for Potentially Clinically Significant Vital Sign Values.............35
Table 5.
Major Inclusion/Exclusion Criteria..........................................................37
Table 6.
Historical Placebo Data for Secondary Endpoints...................................40
Table 7.
Operating Characteristics of Using 
 
Prior for Placebo Group and Beta(0.5, 0.5) for ravagalimab (N = 
40) ............................................................................................................41
 


Ravagalimab
M15-722 – Statistical Analysis Plan
Version 3.0 – 10 February 2021
4
List of Figures
Figure 1.
Induction and Maintenance Period Schematic...........................................7
Figure 2.
Meta-analysis of Historical Placebo Rate ................................................38
Figure 3.
Meta-analysis of Updated Historical Placebo Rate (including 
Upadacitinub UC Phase 3).......................................................................39
Figure 4.
Flowchart of Implementation...................................................................46
List of Appendices
Appendix A.
Protocol Deviations..................................................................................31
Appendix B.
Common Toxicity Criteria (CTC) Grade for Laboratory Data................32
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............34
Appendix D.
Details for Historical Data Borrowing.....................................................36
Appendix E.
Details for Analysis with a Synthetic Placebo Arm.................................43
 


Ravagalimab
M15-722 – Statistical Analysis Plan
Version 3.0 – 10 February 2021
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ravagalimab 
(ABBV-323) Study M15-722 Ulcerative Colitis (UC):  Ravagalimab in Subjects with 
Moderately to Severely Active UC Who Failed Prior Therapy.
Study M15-722 examines the efficacy and safety of ravagalimab in subjects with 
moderately to severely active UC who failed prior therapy.
The analyses of pharmacokinetic and biomarker analyses will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
To explore the efficacy, safety, and tolerability of ABBV-323 as treatment in subjects 
with moderately to severely active UC.
2.2
Study Design Overview
This is a Phase 2a, multicenter, single arm, open-label (OL) study to investigate the 
efficacy and safety of ABBV-323 in subjects with moderate to severe UC who failed prior 
therapy.  The study contains a 35-day screening period, 2 treatment periods, and an 84-
day follow up period from the last dose of study drug.  The induction period is an open-
label 12-week treatment period to evaluate the efficacy, safety, tolerability, PK and RO of 
ABBV-323 for inducing endoscopic improvement at Week 8. Subjects who achieve 
 


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clinical response per Partial Adapted Mayo score at Week 12 may continue into the 
maintenance period.  The maintenance period is an OL 92-week treatment period to assess 
efficacy and safety for maintenance of response with ABBV-323. An internal data 
monitoring committee (DMC) will review safety at regular intervals.
Induction Period
Up to approximately 40 subjects will be enrolled in the induction period to receive the 
following treatment:
●
ravagalimab 600 mg intravenous (IV) Week 0; ravagalimab 300mg 
subcutaneous (SC) Weeks 2, 4, 6, 8, 10.
Prior to protocol Version 4.0 subjects were to be randomized in a 2:1 ratio to the 
following treatment groups:
●
Group 1:  ravagalimab 600mg intravenous (IV) Week 0; ravagalimab 300 mg 
subcutaneous (SC) Weeks 2, 4, 6, 8, 10
●
Group 2:  Placebo IV Week 0; Placebo SC Weeks 2, 4, 6, 8, 10
Maintenance Period
Subjects who enter the maintenance period will receive OL ravagalimab 300mg SC every 
other week (eow) from Week 12 through Week 102.
The schematic of the study is shown in Figure 1.
 


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Figure 1.
Induction and Maintenance Period Schematic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The primary analysis will be performed after all subjects completed the study induction 
period (i.e., completed Week 12 assessments). The final analysis will be performed after 
all subjects completed the study maintenance period.  There will be no multiplicity control 
for this proof of concept study.
2.3
Treatment Assignment and Blinding
This is a single arm, open-label (OL) study. 
2.4
Sample Size Determination
The planned sample size is up to approximately 40 subjects.
Meta-analysis for historical placebo data from tofacitinib (OCTAVE1/2)1, upadacitinib 
(Phase 2b; data on file) and ustekinumab (Stelara Phase 3 UNIFI) 2 studies gives 
 
endoscopic improvement rate at Week 8.  The matched prior distribution for placebo is 
  The 
prior for ravagalimab treatment group will be set to Jeffreys prior Beta (0.5, 0.5) as non-
informative.  The probability that the posterior probability of rate difference > 0 is larger 
than 90% is more than 90% if the endoscopic improvement rate difference is 25% 
between ravagalimab and historical placebo, given a sample size of 40 subjects for 
ravagalimab.  If ravagalimab has the same endoscopic improvement rate of 
 as 
historical placebo, that probability is approximately 
3.0
Endpoints
3.1
Primary Endpoint
The primary efficacy endpoint is endoscopic improvement (Mayo endoscopic subscore of 
0 or 1) at Week 8.  Note that evidence of friability during endoscopy in subjects with a 
Mayo endoscopic subscore of 0 or 1 will confer an endoscopic subscore of 2.
3.2
Secondary Endpoints
●
Clinical remission per Adapted Mayo score at Week 8
 


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●
Clinical response per Adapted Mayo score at Week 8
●
Clinical response per Partial Adapted Mayo score over time (Week 0 to 12)
●
Clinical remission per Full Mayo score at Week 8 in subjects with a Full Mayo 
score of 6 to 12 at Baseline
●
Endoscopic remission at Week 8
3.3
Additional Efficacy Endpoints
Additional efficacy endpoints are:  
●
Change from Baseline in modified Baron score over time (at visits with 
endoscopy)
●
Achievement with stool frequency subscore (SFS) = 0, rectal bleeding subscore 
(RBS) = 0, and Mayo endoscopic subscore = 0 over time (at visits with 
endoscopy)
●
Time to clinical response per Partial Adapted Mayo score
●
Endoscopic improvement over time (at visits with endoscopy)
●
Clinical remission per Adapted Mayo score over time (at visits with endoscopy)
●
Clinical response per Adapted Mayo score at over time (at visits with 
endoscopy)
●
Clinical remission per Partial Adapted Mayo score over time
●
Clinical response per Partial Adapted Mayo score over time
●
Clinical remission per Adapted Mayo score over time among subjects who 
were taking corticosteroids at Baseline and subsequently discontinued 
corticosteroids for ≥ 90 days prior to the respective visit
●
Discontinuation of corticosteroid use for subjects taking corticosteroids at 
Baseline at all visits over time
●
Endoscopic remission over time (at visits with endoscopy)
●
Clinical remission per Full Mayo score over time in subjects with a Full Mayo 
score of 6 to 12 at Baseline (at visits with endoscopy)
●
Clinical response per Full Mayo score over time in subjects with a Full Mayo 
score of 6 to 12 at Baseline (at visits with endoscopy)
 


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●
Achievement of SFS ≤ 1 over time
●
Achievement of RBS = 0 over time
●
Change from Baseline in RBS over time 
●
Change from Baseline in SFS over time 
●
Change from Baseline in fecal calprotectin (FCP) over time  
●
Change from Baseline in high sensitivity C-reactive protein (hs-CRP) over time  
●
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) 
over time 
●
UC-related Hospitalizations (yes/no) over time
●
UC-related surgeries (yes/no) over time
●
No bowel urgency over time
●
Change from Baseline in weekly abdominal pain score over time 
●
Achievement of ≥ 30% reduction from Baseline in weekly abdominal pain 
score over time
●
Achievement of Weekly abdominal pain score = 0 over time
●
Change from Baseline in number of extraintestinal manifestations (EIM) over 
time (as captured in the EIM electronic case report form [eCRF])
●
Histologic remission over time (at visits with endoscopy)
●
Mucosal healing (endoscopic and histologic remission) over time (at visits with 
endoscopy)
●
Change from Baseline in Ulcerative Colitis Endoscopic Index of Severity 
(UCEIS) over time (at visits with endoscopy)
●
Change from Baseline in UC-100 score over time (at visits with endoscopy)
3.4
Safety Endpoint(s)
Safety evaluations include AE monitoring, physical examinations, vital sign 
measurements, and clinical laboratory testing (hematology, chemistry, and urinalysis) as 
measures of safety and tolerability.  An internal DMC is monitoring safety at regular 
intervals.
 


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4.0
Analysis Populations
The following population sets will be used for the analyses.
The Full Analysis Set (FAS) includes all enrolled subjects who received at least 1 dose of 
ravagalimab (including subjects randomized to ravagalimab prior to protocol 
Version 4.0).  The FAS will be used for all efficacy and baseline analyses.
Subjects enrolled prior to protocol version 4.0 will be unblinded after they finish Week 8 
assessments.  Subjects who were randomized to and received ravagalimab will be 
included in the FAS.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  
Subjects randomized to the study prior to Version 4.0 will be analyzed along with subjects 
enrolled after protocol Version 4.0 for safety analysis.  
5.0
Subject Disposition
The total number of subjects who were enrolled (randomized), and treated will be 
summarized.  
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized:
●
Subjects enrolled (randomized) in the study;
●
Subjects included in key analysis populations (FAS, Safety Analysis Set);
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
 


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For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be 
summarized.
6.0
Study Drug Duration and Compliance
For the FAS, duration of treatment will be summarized.  Duration of treatment is defined 
for each subject as last dose date minus first dose date + 14 days.  Duration of treatment 
will be summarized using the number of subjects treated, mean, standard deviation, 
median, minimum and maximum.  In addition, the number and percentage of subjects in 
each treatment duration interval (1 to 14, 15 to 28, 29 to 42, 43 to 56, 57 to 84, and > 84 
days) will be summarized.
Treatment compliance will be summarized for the entire treatment period for the FAS.  
Treatment compliance is defined as the number of injection actually taken divided by the 
number of injection that should have been taken.  Percent compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS.  Categorical variables will be 
summarized with the number and percentage of subjects; percentages will be calculated 
based on the number of non-missing observations.  Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean and 
standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include 
●
Age (years), 
●
weight (kg), 
●
body weight – female (kg)
 


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●
body weight – male (kg)
●
height (cm), 
●
height – female (cm)
●
height – male (cm)
●
body mass index (bmi) (kg/ m2).  
Categorical demographic variables include 
●
sex (male, female),
●
age (< 40, 40 -  < 65, ≥65 years), 
●
ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
race (white, non-white), 
●
region (Europe, North America, or rest of world), 
●
tobacco user (current, former, never, unknown), 
●
alcohol user (current, former, never, unknown).
Continuous disease characteristics at baseline include 
●
full mayo score and its components (stool frequency, rectal bleeding, PGA and 
endoscopy subscores), 
●
partial mayo score, 
●
adapted mayo score, 
●
hs-CRP (mg/L), 
●
fecal calprotectin (mg/kg), 
●
albumin (g/L),
●
UC disease duration in years,
●
modified Baron score,
●
UCEIS,
●
Geboes score,
●
number of extraintestinal manifestations.
 


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Categorical disease characteristics include 
●
baseline steroid use (yes, no), 
●
baseline immunosuppressant use (yes, no), 
●
baseline aminosalicylates use (yes, no), 
●
prior exposure to biologic/JAK therapy for UC (1, >1)
●
prior inadequate response/intolerance to biologic/JAK therapy for UC (1, > 1)
●
prior exposure to biologic therapy for UC (1, >1), 
●
prior exposure to anti-TNF use for UC (yes, no), 
●
baseline hs-CRP (<=5mg/L, > 5mg/L), 
●
mayo endoscopic subscore (2, 3), 
●
adapted mayo score (<= 7, > 7), 
●
full mayo score (<= 9, > 9),
●
disease duration (≤ 3 years, > 3 years),
●
disease extent (left-sided, extensive/pancolitis, limited to rectum)
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
 


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of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug plus 84 days.  The number and percentage of 
subjects taking medications will be summarized by generic drug name based on the World 
Health Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
UC-Related corticosteroids intercurrent events are defined as follows:
●
subjects not on UC-related corticosteroids (systemic or locally acting
corticosteroids for UC) at Baseline who initiated UC-related corticosteroids
during the Induction Period;
●
subjects on UC-related systemic corticosteroids at Baseline who had dosages
increased to greater than the prednisone equivalent dose of corticosteroid at
Baseline, or initiation of any rectal corticosteroids during the Induction
Period regardless of rectal corticosteroid dose.
The time point of the UC-related corticosteroids intercurrent event is defined as the date 
when one of the scenarios above occurs for a subject.  As such, subjects will be 
considered as "non-responder" for binary endpoints at or after the occurrence of the UC-
related corticosteroids intercurrent event through the end of the Induction Period.  For 
continuous endpoints, all measurements at or after the occurrence of the UC-related 
corticosteroids intercurrent event through the end of the Induction Period will not be used 
in the analysis.
8.2
Handling of Missing Data
Missing data imputation will be done only for efficacy variables (categorical and 
continuous variables).  For the analysis other than efficacy, no imputation will be done for 
missing values.
 


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Censoring  
For the time-to-event endpoint, i.e., time to clinical response per Partial Adapted Mayo 
score, missing data will be considered as censored at the last available time for the 
information.
Non-Responder Imputation incorporating Multiple Imputation to handle missing 
data due to COVID-19 (NRI-C)
The NRI-C will categorize any subject who does not have an evaluation during a pre-
specified visit window (either due to missing assessment or due to early withdrawal from 
the study) as a non-responder for the visit.  In addition, at or after the UC-related 
corticosteroids intercurrent event (see Section 8.1), subjects will be counted as non-
responders. The only exception is that missing data due to COVID-19 infection or 
logistical restrictions related to the COVID-19 pandemic will be handled by Multiple
Imputation (MI).  At each visit, subjects will be characterized as responders or non-
responders based on MI imputed values if missing due to COVID-19; otherwise, subjects 
will be considered as non-responders for missing due to other reasons in the NRI-C 
approach. 
Mixed-Effect Model Repeated Measurements (MMRM)
MMRM analysis will be conducted using mixed-effect model including observed 
measurements at all visits. For the MMRM analysis, data collected at or after UC-Related 
corticosteroids intercurrent event will be excluded.  The mixed model includes the 
categorical fixed effects of visit, baseline corticosteroid use (yes vs no), baseline Mayo 
endoscopic sub-score (2 vs 3), the continuous fixed covariate of baseline measurement 
and treatment and treatment-by-visit interaction, if applicable.  An unstructured variance 
covariance matrix will be used.  If there is a convergence issue, a compound symmetry 
structure and a variance components structure will be considered in sequence. The 
parameter estimations are based on the assumption of data being missing at random and 
using the method of restricted maximum likelihood (REML). 
 


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As Observed (AO)
The AO analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the AO analysis 
for that visit.  All observed data will be used in the analysis.  
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is endoscopic improvement (Mayo endoscopic subscore of 
0 or 1) at Week 8.  Note that evidence of friability during endoscopy in subjects with a 
Mayo endoscopic subscore of 0 or 1 will confer an endoscopic subscore of 2.
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint
For the primary analysis, NRI-C will be used for missing data imputation.
8.3.3
Primary Analysis of the Primary Efficacy Endpoint
Analysis of the primary efficacy endpoint will be conducted on the FAS.  Comparison of 
the primary efficacy endpoint will be performed between the ravagalimab group and the 
historical placebo group using Bayesian approach with placebo distribution 
 
from historical data meta-analysis and prior for ravagalimab Beta (0.5, 0.5), the Jeffrey's 
prior for binomial distribution. The posterior probability of rate difference > 0 given data, 
i.e., (	
 − > 0|) will be calculated. In addition, the mean 
difference and 95% credible interval for the mean difference will be provided. 
8.3.4
Sensitivity and Supplementary Analysis of the Primary 
Efficacy Endpoint
The same Bayesian approach will be also conducted based on the FAS using AO data as a 
sensitivity analysis. 
As a supplementary analysis for the primary efficacy endpoint, the following approach 
will be used. For more details, see Appendix D.
 


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1.
Bayesian approach using 
 prior for placebo group and Beta(0.5, 0.5) 
prior for treatment group. Note 
 
 
In addition, point estimate and 95% CI using normal approximation will be provided for 
the response rate for the ravagalimab group using NRI-C and AO data.
8.3.5
Additional Analyses of the Primary Efficacy Endpoint
In addition, a set of synthetic placebo subjects will be created from Bio-IR placebo 
subjects of Upadacitinib UC Study M14-234 (Substudy 1, ph2b and Substudy 2, ph3) 
based on the similarity of inclusion/exclusion criteria and definitions of efficacy endpoints 
of the studies. 
A logistic regression with potential firth adjustment model with being treated as the 
outcome will be performed using treatment subjects in Study M15-722 and placebo 
subjects from the two historical Study M14-234 Substudy 1 and Study M14-234 
Substudy 2. Selected common baseline demographics and disease characteristics 
variables among all the three studies will be included as predictive covariates in the 
model. See Appendix E for the full list. Propensity score for each subject will be the 
estimated probability of being treated conditional on the covariates.
A 1:1 matched placebo group will be generated from the above set of synthetic placebo 
subjects using "greedy matching" i.e., nearest neighbor matching without replacement 
within a pre-specified caliper distance 0.2 of the standard deviation of the logit of the 
propensity scores, to match the treatment subjects in Study M15-722. Other matching 
ratios or calipers may also be considered to preserve matched number of patients and 
considering the similarity with historical data.  If multiple placebo subjects have 
propensity scores that are equally close to that of the treated subject, one of these placebo 
subjects will be selected at random. Subjects who are not selected in the matching 
process will be excluded from data analysis. Pairwise comparison between the matched 
treatment and placebo groups will be performed for primary endpoints using the Cochran-
 


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Mantel-Haenszel (CMH) test stratified by baseline corticosteroid use (yes, no) and Mayo 
endoscopic subscore (2 vs 3). NRI-C will be used to handle missing data. 
As a sensitivity analysis, 1:1 matched placebo group will be generated from the above set 
of synthetic placebo subjects using optimal matching to match the treated subjects in 
Study M15-722. 
Additional analysis based on stratification on the propensity score may also be performed. 
All the subjects including synthetic placebo subjects in the logistic regression model will 
be ranked according to their estimated propensity score. Subjects are then stratified into 
five equal-size groups based on the treatment arm using the quintiles of the estimated 
propensity score. Pairwise comparison between the treatment and synthetic placebo 
groups will then be performed using the Cochran- Mantel-Haenszel (CMH) test stratified 
by the quintiles of the estimated propensity score, baseline corticosteroid use (yes, no) and 
Mayo endoscopic subscore (2 vs 3). NRI-C will be used to handle missing data.
8.4
Secondary Efficacy Endpoint and Analyses
For binary endpoints, point estimate and 95% CI using normal approximation will be 
provided for the response rate for the ravagalimab using NRI-C and AO data.  The same 
Bayesian approach specified in Section 8.3.3 will be also conducted based on the FAS 
using NRI-C and AO data, if applicable. 
The same additional analyses specified in Section 8.3.5 will be also conducted for 
secondary endpoints.  Point estimate, 95% CI and p-value will be provided for the 
treatment comparison between ravagalimab and the placebo group based on the CMH test 
adjusting for baseline corticosteroid use (yes vs no) and Mayo endoscopic sub-score (2 vs 
3).
8.5
Additional Efficacy Analyses
Additional endpoints defined in Section 3.3 will be summarized at scheduled time points. 
 


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Additional Efficacy Analyses for Induction Period
For additional binary endpoints, point estimate and 95% CI using normal approximation 
will be provided for the response rate of the ravagalimab group using NRI-C and AO data.  
For additional continuous endpoints, the LS-mean and 95% CI will be reported for the 
ravagalimab group using MMRM model and ANCOVA model baed on AO data with 
baseline corticosteroid use (yes vs no) and baseline Mayo endoscopic sub-score (2 vs 3) 
as the fixed factors and the corresponding baseline value as the covariates. 
For selected additional binary endpoints, point estimate and 95% CI using normal 
approximation will be provided for the response rate of ravagalimab and matched placebo 
group.  Point estimate, 95% CI and p-value will be provided for the treatment comparison 
between ravagalimab and the matched placebo group based on the CMH test adjusting for 
baseline corticosteroid use (yes vs no) and Mayo endoscopic sub-score (2 vs 3).  
For selected additional continuous endpoints, the LS mean and 95% CI will be reported 
for ravagalimab and matched placebo group.  The LS mean treatment difference and 
associated 95% CI and p-values between ravagalimab and matched placebo group will be 
provided using MMRM model. For the MMRM analysis, data collected at or after UC-
Related corticosteroids intercurrent event will be excluded. Supplementary analysis will 
be conducted based on ANCOVA model using AO data, with treatment, baseline 
corticosteroid use (yes vs no) and baseline Mayo endoscopic sub-score (2 vs 3) as the 
fixed factors and the corresponding baseline value as the covariates.  
Additional Efficacy Analyses for Maintenance Period
Descriptive statistics will be provided for the ravagalimab group.  These include the 
number of observations, mean, standard deviation, 95% CI, median, minimum, and 
maximum for continuous endpoints using AO data; and frequencies and percentages with 
95% CI using normal approximation for binary endpoints using AO data.
 


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9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  Safety summaries will be 
presented.  
There are two sets of planned safety analysis:  safety analysis for the Induction Period, 
and long-term safety analysis.  
Safety Analysis for the Induction Period 
Safety analysis for the Induction Period will include reporting of adverse events (AEs), 
laboratory, and vital signs measurements.  Frequency tables of subjects with treatment-
emergent adverse events (TEAEs) by system organ class (SOC) and by preferred term 
(PT) as in the Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be 
provided.  All continuous laboratory parameters and vital signs variables at each visit will 
also be summarized.  Frequency tables of subjects meeting criteria for potentially 
clinically significant vital sign values and for potentially clinically significant laboratory 
values will be provided.
Long-Term Safety Analysis
Long-term safety analysis will be performed on all cumulative safety data in Induction 
Period and Maintenance Period up to data cutoff date for any interim lock as deemed 
appropriate and final lock.
Long-term safety analyses include reporting of AE rate adjusted by cumulative exposure, 
descriptive summary in laboratory parameters and vital sign variables, and rate of 
potentially clinically significant laboratory and vital signs values.
Exposure-adjusted event rate (EAER) will be provided for long term safety analysis.  For 
EAER calculation, the numerator will be the total number of AEs reported for the event 
(i.e., a subject can contribute more than one event to the numerator) and the denominator 
 


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will be the total exposure time among subjects under the treatment.  The number of AEs 
reported (numerator), the total number of years of study drug exposure (denominator 
calculated as total number of days exposed to study drug (i.e., last dose date – first dose 
date + 84 days) for all treated subjects divided by 365.25), and the exposure-adjusted AE 
event rate per 100 patient-years calculated as ([numerator (number of AEs)/denominator]) 
• 100 will be presented.
All continuous laboratory parameters and vital signs variables at each visit will be 
summarized. 
Frequency tables and listings of subjects meeting criteria for potentially clinically 
significant vital sign values and for potentially clinically significant laboratory values will 
be provided.  Missing safety data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset that is on or after the 
first dose of study drug to the last dose date prior to cut-off date + 84 days or the cut-off 
date for database lock, whichever occurs first.  Events where the onset date is the same as 
the study drug start date are assumed to be treatment emergent.  All treatment-emergent 
AEs will be summarized overall, as well as by primary MedDRA SOC and Preferred 
 


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Term.  The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any COVID-19 related treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
AEs of Special Interest
●
All deaths
○
COVID-19 related deaths
○
Deaths occurring ≤ 84 days after last dose of study drug
○
Deaths occurring > 84 days after last dose of study drug.
COVID-19 cases will be identified using relevant terms for COVID-19 search available in 
MedDRA version 23.1 or higher.  All COVID-19 related AEs and COVID-19 related 
deaths will be summarized in the TEAE Overview table.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
 


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subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the active group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years.
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Special Interest
Adverse events of special interest (AESI) will be summarized by SOC and PT and will be 
based on standardized or company MedDRA queries (SMQs or CMQs) or based on 
adjudication results.  Adverse events of special interest are categorized as follows:  
 


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AESI Grouping
Categories (AESI)
Search Criteria
Terms to 
Display
Include 
in AE 
Overview 
(Y/N)
Serious Infections and 
Opportunistic 
Infections (excluding 
Tuberculosis and
Herpes Zoster)
Serious Infections
Serious PTs of the 
SOC Infections 
and Infestations 
PTs
Y
Opportunistic Infections 
excluding Tuberculosis 
and Herpes Zoster
Opportunistic 
infections CMQ 
excluding 
Tuberculosis and 
Herpes Zoster 
(code 800000189)
PTs
Y
Active Tuberculosis
Active Tuberculosis
Active 
Tuberculosis CMQ 
(code 80000188)
PTs
Y
Malignancies
All Possible Malignancies
Narrow 
Malignancies 
(SMQ 20000090)
All Possible 
Malignancies
N
Malignant Tumours
Narrow Malignant 
tumours 
(SMQ 20000194)
Malignant 
Tumours
Y
Non-Melanoma Skin 
Cancer (NMSC)
Broad Skin 
malignant tumours 
(SMQ 20000204) 
excluding terms 
identified by the 
Melanoma CMQ 
(code 80000119)
Non-Melanoma 
Skin Cancer 
(NMSC)
Y
Malignancies excluding 
NMSC
'Malignancies 
excluding NMSC' 
is identified by the 
'Malignant 
Tumours' search 
excluding terms 
identified by the 
'Non-melanoma 
skin cancer' 
(NMSC) search.
PTs
Y
 


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AESI Grouping
Categories (AESI)
Search Criteria
Terms to 
Display
Include 
in AE 
Overview 
(Y/N)
Hypersensitivity 
Reaction 
Hypersensitivity
Narrow 
Hypersensitivity 
(SMQ 20000214)
PTs
Y
Anaphylactic 
Reaction
Anaphylactic Reaction
Narrow 
Anaphylactic 
reaction 
(SMQ 20000021)
PTs
Y
Hepatic Events
Hepatic Events
Broad
Hepatic failure, 
fibrosis and 
cirrhosis and other 
liver damage-
related conditions 
(SMQ 20000013) 
Broad Hepatitis, 
non-infectious 
(SMQ 20000010) 
Broad Cholestasis 
and jaundice of 
hepatic origin 
(SMQ 20000009) 
Broad
Liver related 
investigations, 
signs and 
symptoms 
(SMQ 20000008) 
Narrow Liver-
related coagulation 
and bleeding 
disturbances 
(SMQ 20000015)
PTs
Y
Hematologic disorder
Hematologic Events
Broad 
"Haematopoietic 
Cytopenias" (SMQ 
20000027)
PTs
Y
 


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9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  
The baseline and post-baseline laboratory observations will be categorized as Grade 0, 
Grade 1, Grade 2, Grade 3, and Grade 4 and shifts from baseline grade to worst on-
therapy grade will be summarized.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.  Toxicity grading scale is based on 
CTCAE version 4.03 (Appendix B).  
Laboratory abnormalities will be evaluated based on Potentially Clinically Significant 
(PCS) criteria (Appendix B).  For each laboratory PCS criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCS criteria.
In addition, ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin will be 
categorized as follows:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
 


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●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
(ALT and/or AST ≥ 3 × ULN) and (TBL ≥ 1.5 × ULN)
●
(ALT and/or AST ≥ 3 × ULN) and (TBL ≥ 2 × ULN)
where ULN is the upper limit of normal.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 3 × ULN, or
●
AST ≥ 3 × ULN, or
●
Alkaline phosphatase ≥ 1.5 × ULN, or
●
Total bilirubin ≥ 1.5 × ULN.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions at any post-baseline visit will be provided:
●
ALT of > 3 × ULN or AST of > 3 × ULN, 
●
Total bilirubin ≥ 2 × ULN.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and body 
temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
 


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minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  
Vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix B).  For each vital sign PCS criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCS 
criteria.
10.0
Other Analyses
Not applicable.
11.0
Interim Analyses
After 30 ongoing subjects complete Week 8 assessments, an interim analysis will be 
performed in order to explore if proof of concept has already been demonstrated. This 
interim analysis will inform the planning of future Phase 2b and 3 studies.  Enrollment 
into the induction period will continue until approximately 40 subjects have been enrolled. 
For this proof of concept study, no alpha adjustment will be conducted for this interim 
analysis. 
11.1
Data Monitoring Committee  
An internal data monitoring committee (DMC) will review unblinded safety data from the 
study.  The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study.
A DMC charter describes the roles and responsibilities of the DMC members, frequency 
of data reviews, relevant data to be assessed, and general operations.
 


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12.0
Overall Type-I Error Control
No multiplicity adjustment will be performed for this single-arm open-label proof of 
concept study.
13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
11 June 2018
Original version
2.0
15 Aug 2018
Section 6.0 Secondary Endpoints:  Highlighted key secondary 
endpoints and moved the rest to exploratory endpoints.
Rationale:  to align with protocol amendment per regulatory
feedback.
Section 7.0 Statistical Analyses for Efficacy:  Updated sample 
size estimation language.
Rationale:  To align with protocol amendment per regulatory 
feedback.
Section 11.0 Efficacy Analyses:  Added priors for sensitivity 
analysis.
Rationale:  To align with regulatory feedback.
3.0
10 Feb 2021
Section 7.0 Demographics, baseline characteristics added
Section 8.0 Analysis method updated per Protocol updates 
Appendix C: PCS criteria updated
Section 8.3.3, Section 8.3.4 and Appendix D: updated 
historical rate 
 as primary analysis due to new UPA UC 
phase 3 data available after protocol finalization and included 
historical rate
 which was specified in protocol as 
sensitivity analysis.
14.0
References
1.
Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance 
Therapy for Ulcerative Colitis. N Engl J Med. 2017;376(18):1723-36.
2.
Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as Induction and 
Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2019;381(13):1201-
14.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
Common Toxicity Criteria (CTC) Grade for Laboratory Data
Test
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry Variables
SGPT/ALT 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
SGOT/AST 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
GGT increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
ALP increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
TBL increased
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 10.0 × ULN
> 10.0 × ULN
Creatinine 
increased
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 6.0 × ULN
> 6.0 × ULN
CPK increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
Total Cholesterol 
increased
> ULN - 7.75
> 7.75 - 10.34
> 10.34 - 12.92
> 12.92
Albumin decreased
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
-
Triglycerides 
increased
1.71 - 3.42 mmol/L
> 3.42 - 5.7 mmol/L
> 5.7 - 11.4 mmol/L
> 11.4 mmol/L
Glucose
< LLN - 3.0 mmol/L 
or
> ULN - 8.9 mmol/L
< 3.0 - 2.2 mmol/L or
> 8.9 - 13.9 mmol/L
< 2.2 - 1.7 mmol/L or
> 13.9 - 27.8 mmol/L
< 1.7 mmol/L or 
> 27.8 mmol/L
Sodium 
< LLN – 130 mmol/L 
or
> ULN – 150 mmol/L
> 150 – 155 mmol/L
< 130 – 120 mmol/L 
or
> 155 – 160 mmol/L
< 120 mmol/L or 
> 160 mmol/L
Potassium
< LLN - 3.0 mmol/L 
or
> ULN - 5.5 mmol/L
< LLN - 3.0 mmol/L 
or
> 5.5 - 6.0 mmol/L
< 3.0 - 2.5 mmol/L or
> 6.0 - 7.0 mmol/L
< 2.5 mmol/L or 
> 7.0 mmol/L
Calcium
< LLN - 2.0 mmol/L 
or
> ULN - 2.9 mmol/L
< 2.0 - 1.75 mmol/L 
or
> 2.9 - 3.1 mmol/L
< 1.75 - 1.5 mmol/L 
or
> 3.1 - 3.4 mmol/L
< 1.5 mmol/L or
> 3.4 mmol/L
 


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Test
Grade 1
Grade 2
Grade 3
Grade 4
Hematology Variables
Hemoglobin 
decreased
< LLN – 100.0 g/L
< 100.0 – 80.0 g/L
< 80.0 g/L
-
Neutrophil count 
decreased
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
WBC decreased
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Lymphocyte count 
decreased
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
Lymphocyte count 
increased
-
> 4.0 – 20.0 × 109/L
20.0 × 109/L
-
Platelets count 
decreased
< LLN - 75.0 × 109/L
< 75.0 - 50.0 × 109/L
< 50.0 - 25.0 × 109/L
< 25.0 × 109/L
 


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Significant (PCS) laboratory findings are described 
in Table 2 and Table 3, and the PCS criteria for vital sign findings are described in 
Table 4.
Table 2.
Criteria for Potentially Clinically Significant Hematology Values
Hematology 
Variables
Units
Definition of Potentially Clinically Significant
NCI CTCAE Grade 3 or Greater
Very Low
Very High
Hemoglobin
g/dL
< 8.0
Neutrophil
109/L
< 1.0
Lymphocytes
109/L
< 0.5
> 20.0
WBC count
109/L
< 2.0
Platelets count
109/L
< 50.0
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
significant finding.
 


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Table 3.
Criteria for Potentially Clinically Significant Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Significant
NCI CTCAE Grade 3 or Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × ULN
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
significant finding.
Table 4.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure 
(mmHg)
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure 
(mmHg)
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
 


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Appendix D.
Details for Historical Data Borrowing
D1. Historical Placebo Rate
The historical placebo rate 
 (Figure 2) is based on a robust meta-analysis of four 
historical trials evaluating centrally-assessed endoscopic improvement rate at Week 8 in a 
total of 325 placebo subjects with moderate to severe UC who failed prior anti-TNF or 
biologic therapy. These studies have similar population, inclusion and exclusion criteria 
as shown in Table 5.
 


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Table 5.
Major Inclusion/Exclusion Criteria
Criteria
Historical Studies
Current Study
OCTAVE-1
OCTAVE-2
Stelara Ph3
Upadacitinib 
M14-234
M15-722
Target 
Population
Sub population: 
Anti-TNF 
Failure
Sub population: 
Anti-TNF 
Failure
Sub population: 
Anti-TNF Failure
Subpopulation: 
Inadequate 
Response to 
Biologic 
Therapy
Prior Therapy (bio 
or tofa) Failure
Disease 
Activity
Baseline Mayo 
Score 6-12, 
Endoscopy 
subscore >= 2
Baseline Mayo 
Score 6-12, 
Endoscopy 
subscore >= 2
Baseline Mayo 
Score 6-12, 
Endoscopy 
subscore >= 2
Baseline 
Adapted Mayo 
Score 5-9, 
Endoscopy 
subscore >= 2
Baseline Adapted 
Mayo Score 5-9, 
Endoscopy 
subscore >= 2
Age
>= 18 years
>= 18 years
>= 18 years
18-75 years
18-75 years 
Prior 
Medication
Treatment 
experienced
Treatment 
experienced
Previously not 
treated with 
interleukin-12 or 
interleukin-23 
antagonists
Previously not 
treated with JAK 
inhibitor (e.g.,
tofacitinib, 
baricitinib, 
filgotinib)
Previously treated 
with biologic 
therapy or tofa
Prohibited 
Medication
TNF antagonists
TNF antagonists
TNF antagonists
All biologic 
therapy or other 
JAK inhibitor
All biologic 
therapy or small 
molecule 
medication with 
potential impact 
on UC
Concomitant 
medication
Oral 
Aminosalicylates, 
oral 
glucocorticoids 
Oral 
Aminosalicylates, 
oral 
glucocorticoids
Oral 
Corticosteroids, 
Aminosalicylates, 
immunomodulators
Oral 
Corticosteroids, 
Antibiotics, 
Aminosalicylates, 
and/or MTX
Oral 
Corticosteroids, 
Antibiotics, 
Aminosalicylates, 
or 
immunomodulators
In all the four trials, evidence of friability during endoscopy in subjects with a Mayo 
endoscopic subscore of 0 or 1 are conferred an endoscopic subscore of 2.
●
Tofacitinib Phase 3 
○
OCTAVE – Induction 1 (4/65)
○
OCTAVE – Induction 2 (4/65)
●
Stelara Phase 3 UNIFI – Induction (11/161). 
 


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●
Figure 2.
Meta-analysis of Historical Placebo Rate
Prior to the database lock for the interim analysis, Upadacitinib UC Phase 3 study data 
became available.  This Phase 3 study has the same population, inclusion and exclusion 
criteria with Upadacitinib UC Phase 2b study as shown in Table 5.
●
Tofacitinib Phase 3 
○
OCTAVE – Induction 1 (4/65)
○
OCTAVE – Induction 2 (4/65)
●
Stelara Phase 3 UNIFI – Induction (11/161). 
●
●
A historical rate of 
 is obtained based on the meta-analysis, see Figure 3 as below.  The 
prior distribution was updated to 
  Primary analysis will be conducted using 
this prior distribution for placebo.
 


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Figure 3.
Meta-analysis of Updated Historical Placebo Rate (including 
Upadacitinub UC Phase 3)
Historical rates for secondary endpoints at Week 8 are summarized in Table 6 below. 
 




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difference > 0 is larger than 90% assuming there is a 25% treatment difference between 
ravagalimab and placebo. 
 prior corresponds to borrowing 
 subjects with a historical placebo 
rate of 
 and 
 prior corresponds to borrowing 
 subjects with a 
historical placebo rate of 
. Operating characteristics of using 
 prior are the 
similar as using 
 prior based on the calculation. 
Based on Table 7, within 90% confidence interval of placebo rate 
 20 historical 
subjects or less could be borrowed while controlling false positive rates < 10% and not 
exceeding in study sample size.
D3.  Comparison between ravagalimab and Placebo. 
Posterior probability of rate difference 
 given the endoscopic improvement at Week 8 
results, i.e.,
will be calculated as 
follows. 
 
 
are the response rates of ravagalimab and placebo, 
respectively.
Let n and N be the number of responders and number of subjects at Week 8. The 
conjugate priors used for 
 
are 
 
respectively. Therefore the posterior distributions for  !"#$ and  will be 
 respectively. Note that in primary analysis, the 
 


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response rate is estimated using NRI-C which incorporates MI to handle missing data due 
to Covid-19; then the number of responders (n) is calculated based on the total number of 
subjects and estimated response rate, without rounding to an integer, to calculate the 
posterior probability.
Then the posterior probability is given by
where B(p, q) is the Beta function with parameters p and q, 1 is corresponding to the pre-
specified treatment difference under the proposed alternative hypothesis.
The posterior mean difference will be determined as 
 .
In addition, 
 credible interval for  !"#$ − will be calculated from
and
where @AB and @AF are 
 credible interval upper limit and lower limit.
Similar comparison will be performed using 
 prior for placebo group. Note 
that if observed response rates in ravagalimab group and historical placebo group are both 
zero, no comparison will be performed using Bayesian approach.
 


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Appendix E.
Details for Analysis with a Synthetic Placebo Arm
E1.  Historical Data Selection
The historical data are carefully selected based on the similarity in target population, entry 
criteria, prior and concomitant medications, central review of endoscopies and years 
conducted between historical trials and Study M15-722. Subject-level historical placebo 
data consists of subjects from two recent AbbVie clinical trials with similar populations 
(Bio-IR), entry criteria and study designs:  upadacitinib phase 2b/3 Study M14-234 
Substudy 1 and Substudy 2. All bio-IR placebo subjects from M14-234 Substudy 1 and 
Substudy 2 will be identified.
E2.  Propensity Score Estimation
Propensity score method will be used to balance the population-level baseline 
characteristics between in trial data and historical placebo group.  In order to calculate 
propensity scores, selected common baseline demographics and characteristics variables 
among Study M15-722 and the two historical Studies M14-234 Substudy 1 and 
Substudy 2 bio-IR will be used as covariates in propensity score estimation. 
Main baseline demographic characteristics can include:
●
age (years)*, 
●
weight (kg)*, 
●
body mass index (BMI) (kg/ m2).  
●
sex (male, female)*,
●
ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
race (white, non-white), 
●
region (Europe, North America, or rest of world), 
●
tobacco user (current, former, never, unknown), 
●
alcohol user (current, former, never, unknown).
 


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*
indicating those demographic characteristics must be included.
Main baseline disease characteristics can include 
●
adapted Mayo score*, 
●
hs-CRP (mg/L), 
●
fecal calprotectin (mg/kg), 
●
albumin (g/L),
●
UC disease duration in years,
●
UCEIS,
●
Geboes score,
●
baseline steroid use (yes, no)*, 
●
baseline immunosuppressant use (yes, no)*, 
●
baseline aminosalicylates use (yes, no), 
●
prior exposure to biologic/JAK therapy for UC (1, >1)
●
prior exposure to anti-TNF use for UC (yes, no), 
●
mayo endoscopic subscore (2, 3)*, 
●
disease extent (left-sided, extensive/pancolitis, limited to rectum)*
*
indicating those baseline disease characteristics must be included due to their clinical 
relevance. Other baseline characteristics (and their specific levels of categorical 
variables) will be assessed in model diagnostics if data does not allow large number of 
covariates when estimating propensity score.
Propensity score is the probability of a patient being assigned to a treatment instead of the 
other one conditional on a given set of baseline characteristics.  It is determined by a 
logistic regression with selected above common baseline covariates.  Overlap and balance 
of propensity score between the in-trial data and synthetic placebo control will be assessed 
using histogram and descriptive statistics. 
 


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Specifically, covariate balance will be checked between all subjects enrolled in Study 
M15-722 and historical placebo subjects from the two historical trials using standardized 
mean difference (SMDs) and a threshold of 0.1 for each of the baseline characteristics. 
To assess overall performance of different synthetic control algorithms, the mean of 
absolute SMDs across all baseline characteristics that are included in estimating 
propensity score is the main measure with smaller values indicating better balance. 
Considering the modest sample size in the current trial, sample size preservation in the 
matched patients is another key consideration in determining the final recommendation. 
E3.  Analysis using placebo synthetic control with propensity score matching
Propensity score matching method (Rosenbaum and Rubin, 1985) matches treatment 
patients with synthetic placebo subjects based on propensity scores such that matched 
treatment subjects and placebo subjects are comparable in terms of covariates used in 
propensity score determination.  This process mimics randomization to create two 
comparable groups with a caution of limitation that the matching is conditional on 
included covariates.  
A 1:1 matched placebo group will be generated from the above set of synthetic placebo 
subjects using greedy matching to match the treatment subjects in Study M15-722. We 
will start the matching with the optimal caliper 0.2, which was recommended by Austin 
(2011), with the intention to match 40 placebo subjects.  Other caliper values or matching 
ratios may also be considered to improve balance and preserve sample size in matched 
patients.  If multiple placebo subjects have propensity scores that are equally close to that 
of the treated subject, one of these untreated subjects will be selected at random. Subjects 
who are not selected in the matching process will be excluded from further analysis. 
Following matching, baseline covariates will be summarized for subjects in Study 
M15-722 and matched historical placebo subjects to ensure balance is generally achieved.
The optimal matching will also be performed based on a distance measure, caliper, 
calculated from the propensity scores estimates.  
 


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E4.  Implementation
To reduce operational bias and maintain study validity, the propensity score calculation 
and matching described in Appendix E will be conducted by an independent statistician 
who is removed from Study M15-722.  Prior to the first dose of the 40th subject, the study 
team and the independent statistician will meet as needed and agree on the statistical 
details of each step above, with any question (must be unrelated to treatment assignment 
information and in trial and historical subjects outcome) from the independent statistician 
resolved during the meeting(s). 
The process to implement the propensity score analysis is summarized in Figure 4.  Each 
step is described in detail below. These steps should happen after 40 subjects enrolled 
into Study M15-722 and prior to the primary database lock.
Figure 4.
Flowchart of Implementation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Input baseline datasets of Study M15-722
A dataset of Study M15-722 containing study ID, de-identified subject IDs, and baseline 
characteristics will be delivered to the independent statistician by the study team.  No 
post-baseline data should be contained in this dataset.  
2. Input integrated baseline dataset of historical placebo subjects
A dataset integrating the baseline characteristics from the two studies with historical 
placebo subjects will be delivered to the independent statistician by the study team.  No 
post-baseline data should be contained.  In addition, study IDs and subject IDs in this 
dataset will be de-identified by the study programing team before delivering to the 
independent statistician. 
3. Post-baseline dataset of historical placebo subjects
A dataset of historical placebo subjects integrating endoscopic improvement at Week 8 
from Study M14-234 Substudy 1 and Substudy 2 will be generated.  Subject ID will be 
included.  This dataset is to be kept by study team for the final analysis and should not be 
accessible to the independent statistician.  
4. Propensity score analysis and communication with study team
Prior to enrollment completion, the study team and the independent statistician will meet 
as needed and agree on the final propensity score analysis rules (for example, matching 
ratio, matching caliper) of each step.  Any question (must be unrelated to treatment 
assignment information) from the independent statistician will also be addressed during 
these meeting(s).
After Study M15-722 enrolled 40 subjects, the input datasets will be delivered to the 
independent statistician for propensity score estimation and matching, without accessing 
the subject-level post-baseline data (including primary endpoint data) of selected 
historical placebo subjects and Study M15-722 subjects.  The independent statistician will 
 


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check the covariate balance before and after matching is performed to make sure the 
balance is improved following the matching.
5. Final covariate datasets
The resultant datasets (matched) containing subject-level covariate data will be delivered 
by the independent statistician to the study team prior to the primary database lock for 
analysis.  Matched datasets should discard those unmatched subjects.  The analysis-ready 
datasets should include variables such as re-identified subject ID, baseline characteristics, 
propensity score. 
There is no plan to share interim data with external experts or with Regulatory Agencies 
(prior to study completion and availability of final study results).  
6. Final data analysis
After database lock, the study programming team will merge the final output datasets with 
datasets containing post-baseline data of ravagalimab and historical placebo subjects and 
perform the pre-specified analyses.