Clinical trial NCT03001219
Conditions: Rheumatoid Arthritis
Sponsor: Hoffmann-La Roche
Start date: 2016-12-22; Completion date: 2018-11-06
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IIa/b double-blind, placebo-controlled, randomized, parallel group, multicenter study to evaluate the safety and efficacy of RO7123520 as adjunctive therapy in participants with RA who are inadequately responding to standard-of-care (methotrexate and anti-TNF-alpha therapy). Part 1 of the study will evaluate safety. Part 2 will evaluate efficacy and safety. Part 3 will evaluate dose-ranging efficacy. Participants will have the option of continuing to the extension period of the study.

Detailed description:

Arms: arm 1: Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. arm 2: Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. arm 3: Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. arm 4: Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. arm 5: Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

NOTE: Part 3 was not conducted. arm 6: Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate.

NOTE: Part 3 was not conducted.
Interventions: intervention 1: Anti-TNF-alpha intervention 2: Methotrexate intervention 3: Placebo intervention 4: RO7123520
Intervention descriptions: intervention 1: Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose. intervention 2: Participants will continue their pre-trial methotrexate therapy at a stable dose. intervention 3: Participants will receive intravenous infusion of placebo. intervention 4: Participants will receive intravenous infusion of RO7123520.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, 
MULTI-CENTER PHASE II STUDY TO EVALUATE THE SAFETY 
AND EFFICACY OF RO7123520 AS ADJUNCT TREATMENT IN 
PATIENTS WITH MODERATELY TO SEVERELY ACTIVE 
RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO 
TNF-α INHIBITORS 
NCT Number: 
NCT03001219 
Document Date:  Protocol Version 4: 28-March-2018 
 
 
 


CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7123520 —F. Hoffmann-La Roche Ltd
Protocol BP39261, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTI-CENTER PHASE II STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
RO7123520 AS ADJUNCT TREATMENT IN PATIENTS 
WITH MODERATELY TO SEVERELY ACTIVE 
RHEUMATOID ARTHRITIS AND AN INADEQUATE 
RESPONSE TO TNF-INHIBITORS
PROTOCOL NUMBER:
BP39261
VERSION:
4
EUDRACT NUMBER:
2016-002126-36
IND NUMBER:
112,481
TEST PRODUCT:
RO7123520
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 3 September 2016
DATE AMENDED:
Version 2: 14 December 2016
Version 3: 09 May 2017
Version 4: See electronic date stamp below
FINAL PROTOCOL APPROVAL
 
28-Mar-2018 13:49:02
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTI-CENTER PHASE II STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
RO7123520 AS ADJUNCT TREATMENT IN PATIENTS 
WITH MODERATELY TO SEVERELY ACTIVE 
RHEUMATOID ARTHRITIS AND AN INADEQUATE 
RESPONSE TO TNF-INHIBITORS
PROTOCOL NUMBER:
BP39261
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-002126-36
IND NUMBER:
112,481
TEST PRODUCT:
RO7123520
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
Study Monitor.


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PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE
Protocol BP39261 version 3 has been amended to incorporate the following changes:
Patients receiving intravenous administration with infliximab (or biosimilars) were 
previously excluded due to the potential risk of developing anti-drug antibodies (ADA). 
However, as the patients in this study are receiving methotrexate and possibly other 
non-biological DMARDs in line with the primary objective, this should prevent the 
formation of ADA (based on multiple studies, as summarized by Jani et al 2014).
Inclusion criteria are therefore modified to permit patients receiving infliximab (or 
biosimilar) to be enrolled.
In Part 2, the patient’s dominant hand/ wrist is assessed with magnetic resonance 
imaging (MRI) to ensure that only patients with active rheumatoid arthritis (RA) will be 
enrolled. This criterion has been modified so the non-dominant hand can also be 
assessed, as disease activity might otherwise be missed.
Concomitant treatment with non-biological agents such as sulfasalazine, leflunomide 
and gold salts were prohibited in the study. However, as it is permitted to treat patients 
with the non-biological Disease Modifying Anti-Rheumatic Drug (DMARD) methotrexate 
(MTX), other non-biological agents will be allowed in addition to MTX. No safety 
concerns are expected due to the non-overlapping mode-of-actions and toxicities 
between RO7123520 and tumor necrosis factor (TNF) inhibitors, MTX and combination 
with other non-biologic DMARDs.
The dose range of MTX has been modified to include a lower dose, i.e., 5.0 mg/week 
(instead of 7.5 mg/week) to allow for country-specific differences in dosing.
The age of the study population has been expanded to include patients older than 80 
years of age. This allows patients with elderly-onset RA to be captured. Although this
group of patients may have many concomitant medications, there are no concerns about 
including very elderly patients as differences in pharmacokinetics and drug-drug 
interactions are not anticipated.
The wording of inclusion criterion 6 has been adjusted to recommended and stable dose
instead of approved and stable dose, as it is not intended to limit the investigators’
country-specific approvals.
Sections on overdose and reporting have been updated in line with new requirements 
from the Sponsor’s GCP council, with impact on company protocol templates and 
electronic case report forms (eCRFs). The protocol templates have been updated with 


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language to account for special situations (overdose, medication error, drug abuse, and 
drug misuse).
Other:
- Exclusion criterion for requiring major surgery updated to planned surgery.
- The joint chosen for synovial fluid aspiration will be at the Investigator’s discretion. The 
time points of synovial fluid aspiration versus synovial biopsy samples have been 
clarified (inconsistency with the Schedule of Assessment tables).
- Complete versus symptom-directed physical examination clarified.
- As testing for drugs of abuse are not actively requested at screening, the text on drug 
panel was removed from the laboratory assessments.
- Adjustments for local laboratory test reporting: only if required for AE/SAE or for 
erythrocyte sedimentation rate (optional).
- The analysis method enzyme-linked immunosorbent assay (ELISA) for measuring 
soluble cadherin-11 has been replaced by immunoassay.
- The Brief Fatigue Inventory (BFI) from 1997 has been replaced by the BFI of 1999, 
which was the version used for the ePRO programming.
- The Schedule of Assessment tables have been updated as applicable. Additionally, 
minor consistency errors have been corrected.
References:
Jani M, Barton A, Warren RB, et al. The role of DMARDs in reducing the immunogenicity 
of TNF inhibitors in chronic inflammatory diseases. Rheumatology; 2014; 53:213-222.


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PROTOCOL AMENDMENT, VERSION 4:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
3.1.1.2. Part 2: Phase IIa Proof-of-Concept Study
…
In Part 2 only, patients will undergo contrast-enhanced MRI imaging of the dominant 
hand/wrist , the site to be determined by the Investigator, to confirm disease activity at 
baseline and examine joint changes in patients with active RA on MTX and inadequate 
response to anti-TNF-therapy.
…
The study will proceed to Part 3 if there are no more than one-third of the patients who 
received RO7123520 reporting serious study drug-related adverse events of a similar 
nature (e.g., laboratory abnormalities, vital sign changes, ECG changes, etc.) orand if 
there are no other reasons to stop the study (see Section 4.7.2).
3.2.5. Rationale for Biomarker Assessments
Cadherin-11 expression in synovium and synovial fluid might differ from patient to 
patient which might impact the response to the treatment. The expression of Cad-11 in 
the synovium will might be measured by tissue staining while the soluble form of Cad-11 
will be measured by ELISA (shed Cad-11) in the synovial fluid of patients who 
consented to the sampling. Blood soluble Cad-11 concentrations which might vary upon 
treatment may be measured by immunoassayELISA.
MRI scans will be performed to assess disease severity for patients in Study Part 2. 
Inflammatory lesions in the joints and the bone erosion will be evaluated, and soft tissue 
and bone marrow involvement will be assessed. The readings will be done centrally, by 
a blinded reader. 
As active synovitis of the dominant hand/wrist as determined by MRI is an inclusion 
criterion for active disease in Part 2 (Section 4.2.2), the central reader will also give the 
confirmation that this criterion is met.
3.3.4. Exploratory Outcome Measures
Change from baseline in Cad-11 synovium level and in synovial fluid and blood soluble 
Cad-11 concentration at Weeks 12 and 24


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4.2.2. Inclusion Criteria
2. Adult men and women, of more than 18 to 80 years of age (inclusive).
5. For Part 2 only: Active synovitis and/or osteitis of the dominant hand/wrist as 
determined by contrast-enhanced MRI.
6. Patients must be taking one of the following anti-TNF-therapies: certolizumab, 
golimumab, etanercept, adalimumab, infliximab or approved biosimilars of these, 
given at a recommended approved and stable dose for at least 12 weeks before 
randomization, and have experienced in the opinion of the Investigator an inadequate 
response to anti-TNF-therapy with a DAS28 3.2.
Note: prior use of other anti-TNF-therapies is allowed.
7. Patients must be taking MTX (PO, SC, or IM) for at least 12 weeks before 
randomization and must be on a stable dose for at least 4 weeks before 
randomization (5.07.5 to 25 mg/week).
…
8. Patients on glucocorticoids (10 mg/day PO prednisone or equivalent) are permitted if 
doses are stable within 6 weeks of planned randomization. 
Note: Patients should remain on stable doses of glucocorticoids throughout the 
duration of study unless for medical reasons (e.g., safety, or intolerability, RA flare, 
etc) reasons.
4.2.3. Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1. Currently receiving concomitant treatment with sulfasalazine or leflunomide.
2. Note: Enrollment is allowed after an appropriate wash out period (i.e., 5 half lives).
3. Patients currently on IV infliximab or an approved IV biosimilar of it are excluded. 
4.
1. Parenteral glucocorticoids administration (IM, IV) of 50 mg within 6 weeks or ≤50 mg 
within 4 weeks prior to planned randomization, or scheduled parenteral 
administrations during the study.
...
14. Major surgery within 28 days prior to randomization, or requiring planned major 
surgery (e.g., elective joint replacement surgery) during the trial.
4.5 Concomitant Treatment
Patients must be receiving stable regimens of MTX (i.e., 7.55.0 to 25 mg/week, per oral, 
subcutaneous, or intra-muscular application) and at least one anti-TNF-therapy (from 


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the following certolizumab, golimumab, etanercept, adalimumab, infliximab or approved 
biosimilars of these) in order to be eligible for the study. The recommended dose of anti-
TNF-therapy should be stable for at least 12 weeks, and the dose of MTX should be 
stable for at least 4 weeks before randomization. The doses should not be adjusted 
during the study except for safety or intolerability reasons.
Local standard-of-care should be followed for concomitant administration of folic acid.
Where possible all other concomitant medications (e.g., glucocorticoids, NSAIDs) should 
be kept stable during the study and only adjusted where clinically indicated, e.g., as in 
RA flare..
4.5.1. Prohibited Therapy
The following medications are prohibited after randomization:

Live vaccines, including herpes zoster vaccination. Non-live seasonal vaccinations 
and/or emergency vaccination, such as rabies or tetanus vaccinations, are allowed.

Any biologic therapy such as anti-IL-1, anti-IL-6, or T-cell or B-cell targeted 
therapies for any indication.

Any interferon therapy for any indication.

Any parenteral corticosteroid administered by IV injection.

Concomitant RA treatment with sulfasalazine, leflunomide, or gold salts.
4.6.1.2. Physical Examination
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, and neurological systems and should be done as indicated 
in Appendix 1.
Any abnormality identified at baseline should be recorded on the appropriate eCRF.
Height (screening only) and weight will be recorded.
Additionally, or as clinically indicated, limited, symptom-directed physical examinations 
should be performed. Changes from baseline abnormalities should be recorded in 
patient’s notes. New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF.


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4.6.1.6. Laboratory Assessments
…
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for an
positiveabnormal urine or blood test for drugs of abuse, e.g., previous occasional intake 
of a medication or food containing for example codeine, benzodiazepines or opiates, the 
test could be repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory. Local 
laboratory analysis should only be used for study parameters related to AE/SAE. 
Erythrocyte sedimentation rate (ESR) may be performed locally.
Samples for the following blood and urine laboratory tests will be collected and sent to 
the appropriate laboratory for analysis according to the lab manual:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count ([neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells])
erythrocyte sedimentation rate [ESR], HsCRP
…
4.6.1.10 Biomarker Assessments
Blood, Urine, Plasma and Serum Samples
Whole Blood, urine, plasma and serum samples will be collected for the following 
assessments:

Multi-biomarker disease activity (MBDA) test

Bone remodeling and cartilage markers (e.g., CTX-I, PINP and osteocalcin)

Safety biomarkers which will include T cells, B cells, NK cells, granulocyte and 
monocyte markers.
Plasma/serum samples may also be used for analysis of inflammatory, synovial and 
angiogenesis markers.
Urine samples will be collected to measure CTX-II.


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Synovial Fluid Samples
Synovial fluid aspiration, which will be done at  two timepoints (or three in case of 
optional extension; see Appendix 1 and Appendix 2)), can be performed from the same 
joint being biopsied but should precede the biopsy. Samples will be processed for 
routine histology, immunohistochemistry and RNA expressionseveral protein biomarkers 
assessments and may be used for measuring RNA expression.. The joint used for fluid 
aspiration is at the Investigator’s discretion. If possible, the same joint should be 
aspirated during the study.
Synovial Biopsy Samples
Synovial biopsy samples will be taken by arthroscopy under local anesthesia at four 
timepoints at two timepoints (or three in case of optional extension; Appendix 1 and 
Appendix 2). Samples will be processed for routine histology, immunohistochemistry 
and potentially to assess RNA expression. The joint used for synovial biopsy is at the 
Investigator’s discretion. If possible, the same joint should be assessed during the study.
Immunohistochemistry of Synovial Tissue
The immunohistochemical analyses may include the following markers: Cad 11CD106, 
CD68CD55, CD68, IL 8.
4.6.1.11 Disease-Specific Assessments
MRI
For Part 2 only: Fat-suppressed, T1-weighted 3D gradient-echo and short tau inversion 
recovery (STIR) images of the dominant hands/wrists will be obtained with and without 
gadolinium contrast using 1.5T MRI and a hand frame to ensure reproducible positioning.
5.3.5.11.    Overdoses
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).


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5.4  Immediate Reporting Requirements from Investigator to Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies

Accidental overdoses or medication errors (see Section 5.4.4. for details on 
reporting requirements).
5.4.4. Reporting Requirements for Cases of Accidental Overdose or Medication 
Error
Accidental overdose and medication error  (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Medication error: accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with RO7123520, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.


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
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For RO7123520, each adverse event associated with a special situation should be
recorded separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4).  For 
RO7123520, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.
6.8 Exploratory Analyses
Potentially Prognostic and Disease Severity Biomarkers 
The potentially prognostic and disease severity biomarkers (MBDA and CTX-II, 
Section 3.2.5) will be summarized descriptively at Baseline by treatment/dose arm. In 
addition, the synovium cadherin-11 measuredata and, synovial fluid and blood soluble 
cadherin-11 data will be summarized descriptively by visit and treatment/dose arm. 
Those biomarkers will be summarized using the efficacy analysis population.
Appendix 1 and 2, Schedule of Assessment tables
The Schedule of Assessment tables have been revised to reflect the changes in the 
protocol (in Appendix 1 [Main table for Parts 1, 2 and 3] and Appendix 2 [Main table, 
Optional Extension for Parts 1, 2 and 3]).
Appendices 8 and 10
The BFI from 1997 has been replaced by the BFI of 1999 (Appendix 8). The text for the 
morning stiffness assessment (Appendix 10) has been updated with the text used in the 
ePRO.


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL SYNOPSIS .................................................................................... 19
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................. 33
1.
BACKGROUND AND RATIONALE ............................................................ 36
1.1
Background on Disease......................................................... 36
1.2
Background on RO7123520 .................................................. 37
1.2.1
Previous Non-Clinical Studies ............................................... 37
1.2.2
Previous Clinical Studies ....................................................... 38
1.3
Study Rationale and Benefit–Risk Assessment..................... 39
1.3.1
Study Rationale ..................................................................... 39
1.3.2
Benefit-Risk Assessment....................................................... 40
2.
OBJECTIVES.............................................................................................. 42
2.1
Primary Objectives ................................................................ 42
2.2
Secondary Objectives............................................................ 42
2.3
Exploratory Objectives........................................................... 42
3.
STUDY DESIGN......................................................................................... 42
3.1
Description of Study .............................................................. 42
3.1.1
Overview of Study Design ..................................................... 42
3.1.1.1
Part 1: Safety Cohort ............................................................. 43
3.1.1.2
Part 2: Phase IIa Proof-of-Concept Study.............................. 43
3.1.1.3
Part 3: Phase IIb Dose-Ranging Study.................................. 44
3.1.1.4
Extension Period ................................................................... 44
3.1.1.5
Study Duration....................................................................... 47
3.1.2
Internal Monitoring Committee and Scientific 
Oversight Committee............................................................. 47
3.1.3
End of Study.......................................................................... 48
3.2
Rationale for Study Design.................................................... 48
3.2.1
Rationale for Design .............................................................. 48
3.2.2
Rationale for Dosage Selection ............................................. 49
3.2.2.1
Dosing Algorithm Selection.................................................... 49


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3.2.2.2
Dosing Regimen Selection .................................................... 50
3.2.2.3
Dose-Selection ...................................................................... 51
3.2.3
Rationale for Study Population .............................................. 52
3.2.4
Rationale for Control Group................................................... 53
3.2.5
Rationale for Biomarker Assessments................................... 54
3.2.6
Rationale for Pharmacokinetic Assessments......................... 55
3.3
Outcome Measures ............................................................... 55
3.3.1
Safety Outcome Measures .................................................... 55
3.3.2
Pharmacokinetic Outcome Measures.................................... 56
3.3.3
Efficacy Outcome Measures.................................................. 56
3.3.4
Exploratory Outcome Measures ............................................ 57
4.
MATERIALS AND METHODS .................................................................... 57
4.1
Center.................................................................................... 57
4.2
Study Population ................................................................... 58
4.2.1
Recruitment Procedures........................................................ 58
4.2.2
Inclusion Criteria.................................................................... 58
4.2.3
Exclusion Criteria................................................................... 59
4.3
Method of Treatment Assignment and Blinding..................... 61
4.4
Study Treatment.................................................................... 62
4.4.1
Formulation, Packaging, and Handling.................................. 62
4.4.2
Dosage, Administration and Compliance............................... 62
4.4.3
Investigational Medicinal Product Accountability ................... 63
4.4.4
Post-Trial Access to RO7123520 .......................................... 64
4.5
Concomitant Therapy ............................................................ 64
4.5.1
Prohibited Therapy ................................................................ 65
4.5.2
Vaccination............................................................................ 65
4.6
Study Assessments ............................................................... 65
4.6.1
Description of Study Assessments ........................................ 65
4.6.1.1
Medical History and Demographic Data ................................ 65
4.6.1.2
Physical Examinations........................................................... 65
4.6.1.3
Skin Examination................................................................... 66
4.6.1.4
Vital Signs.............................................................................. 66
4.6.1.5
Electrocardiograms................................................................ 66


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4.6.1.6
Laboratory Assessments ....................................................... 67
4.6.1.7
Additional Samples................................................................ 68
4.6.1.8
Immunogenicity Assessments ............................................... 69
4.6.1.9
PK Assessments ................................................................... 69
4.6.1.10
Biomarker Assessments........................................................ 70
4.6.1.11
Disease-Specific Assessments.............................................. 71
4.6.1.12
Patient-Reported Outcomes and 
Clinician-Reported Outcomes................................................ 71
4.6.1.13
Samples for Research Biosample Repository ....................... 73
4.6.2
Timing of Study Assessments ............................................... 76
4.6.2.1
Screening and Pre-Treatment Assessments ......................... 76
4.6.2.2
Assessments during Treatment............................................. 76
4.6.2.3
Safety Follow-Up Phone Call................................................. 77
4.6.2.4
Assessments at Study Completion/Early 
Termination Visit.................................................................... 77
4.6.2.5
Follow-Up Assessments ........................................................ 77
4.6.2.6
Assessments at Unscheduled Visits...................................... 77
4.7
Patient, Study, and Site Discontinuation................................ 77
4.7.1
Patient Discontinuation.......................................................... 77
4.7.1.1
Discontinuation from Study Drug........................................... 78
4.7.1.2
Withdrawal from Study........................................................... 78
4.7.2
Study and Site Discontinuation.............................................. 78
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Parameters and Definitions ........................................ 79
5.1.1
Adverse Events ..................................................................... 79
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 80
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 80
5.2
Safety Plan ............................................................................ 81
5.2.1
Management of Specific Adverse Events .............................. 81
5.2.1.1
Contact Dermatitis ................................................................. 81
5.2.1.2
Headache .............................................................................. 81
5.2.1.3
Hypersensitivity ..................................................................... 81


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5.2.1.4
Reduced Bone Density.......................................................... 81
5.2.1.5
Impaired Wound Healing ....................................................... 81
5.2.1.6
Decreased Fertility................................................................. 82
5.2.1.7
Teratogenicity........................................................................ 82
5.2.1.8
Serious Infection.................................................................... 82
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 82
5.3.1
Adverse Event Reporting Period ........................................... 82
5.3.2
Eliciting Adverse Event Information....................................... 83
5.3.3
Assessment of Severity of Adverse Events ........................... 83
5.3.4
Assessment of Causality of Adverse Events ......................... 83
5.3.5
Procedures for Recording Adverse Events............................ 83
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 84
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 84
5.3.5.3
Persistent or Recurrent Adverse Events................................ 85
5.3.5.4
Abnormal Laboratory Values ................................................. 85
5.3.5.5
Abnormal Vital Sign Values ................................................... 86
5.3.5.6
Abnormal Liver Function Tests.............................................. 86
5.3.5.7
Deaths ................................................................................... 86
5.3.5.8
Preexisting Medical Conditions.............................................. 87
5.3.5.9
Lack of Efficacy or Worsening of Rheumatoid 
Arthritis .................................................................................. 87
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 87
5.3.5.11
Patient-Reported Outcome Data ........................................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 88
5.4.1
Emergency Medical Contacts................................................ 89
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 89
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 89
5.4.2.2
Events That Occur after Study Drug Initiation........................ 89
5.4.3
Reporting Requirements for Pregnancies.............................. 89
5.4.3.1
Pregnancies in Female Patients............................................ 89


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5.4.3.2
Pregnancies in Female Partners of Male Patient................... 90
5.4.3.3
Abortions ............................................................................... 90
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 90
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 91
5.5
Follow-Up of Patients after Adverse Events .......................... 92
5.5.1
Investigator Follow-Up........................................................... 92
5.5.2
Sponsor Follow-Up ................................................................ 92
5.6
Post-Study Adverse Events................................................... 92
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 93
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93
6.1
Determination of Sample Size ............................................... 93
6.2
Summaries of Conduct of Study............................................ 94
6.3
Analysis Populations ............................................................. 94
6.3.1
Safety Analysis Population .................................................... 94
6.3.2
Efficacy Analysis Population.................................................. 94
6.3.3
Immunogenicity Analysis Population ..................................... 94
6.4
Summaries of Treatment Group Comparability ..................... 95
6.5
Safety Analyses..................................................................... 95
6.5.1
Adverse Events ..................................................................... 95
6.5.2
Clinical Laboratory Test Results............................................ 95
6.5.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 96
6.5.2.2
Definition of Laboratory Abnormalities................................... 96
6.5.3
Vital Signs.............................................................................. 96
6.5.4
ECG Data Analysis................................................................ 96
6.5.5
Concomitant Medications ...................................................... 97
6.6
Efficacy Analyses .................................................................. 97
6.6.1
Primary Efficacy Endpoint...................................................... 97
6.6.2
Secondary Efficacy Endpoints............................................... 97
6.7
Pharmacokinetic Analyses................................................... 100
6.8
Exploratory Analyses........................................................... 100


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6.9
Interim Analyses .................................................................. 102
6.9.1
Planned Interim Analyses.................................................... 102
6.9.2
Optional Interim Analyses.................................................... 102
7.
DATA COLLECTION AND MANAGEMENT ............................................. 102
7.1
Data Quality Assurance....................................................... 102
7.2
Electronic Case Report Forms............................................. 103
7.3
Electronic Patient-Reported Outcome Data......................... 103
7.4
Source Data Documentation................................................ 104
7.5
Use of Computerized Systems ............................................ 104
7.6
Retention of Records........................................................... 104
8.
ETHICAL CONSIDERATIONS.................................................................. 105
8.1
Compliance with Laws and Regulations .............................. 105
8.2
Informed Consent................................................................ 105
8.3
Institutional Review Board or Ethics Committee.................. 106
8.4
Confidentiality...................................................................... 106
8.5
Financial Disclosure ............................................................ 107
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 107
9.1
Study Documentation .......................................................... 107
9.2
Site Inspections ................................................................... 107
9.3
Administrative Structure....................................................... 108
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 108
9.5
Protocol Amendments ......................................................... 108
10. REFERENCES ......................................................................................... 109
LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale ....................................... 83


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LIST OF FIGURES
Figure 1
Study Design............................................................................... 45
Figure 2
Simulated Plasma Concentration versus Time Profiles from 
10 mg/kg and 800 mg Dosing Algorithms ................................... 50
Figure 3
Simulations of Predicted Steady-State RO7123520 
Exposures for Different Doses Using the Proposed Dosing 
Regimen...................................................................................... 51
LIST OF APPENDICES
Appendix 1
Schedule of Assessments for Parts 1, 2 and 3 (without 
Extension)................................................................................. 111
Appendix 2
Schedule of Assessments for Optional Extension for Parts 1, 
2 and 3...................................................................................... 114
Appendix 3
Visual Analogue Scale  Patient Global Assessment of 
Disease Activity (PtGA)............................................................. 117
Appendix 4
Visual Analogue Scale Physician Global Assessment of 
Disease Activity (PGA).............................................................. 118
Appendix 5
Visual Analogue Scale Patient’s Global Assessment of Pain 
(PtPA) ....................................................................................... 119
Appendix 6
Health Assessment Questionnaire (HAQ-DI)............................ 120
Appendix 7
Short-form Health Survey (SF-36v2)......................................... 123
Appendix 8
Brief Fatigue Inventory (BFI)..................................................... 129
Appendix 9
Swollen/Tender Joint Count (SJC/TJC) .................................... 130
Appendix 10
Assessment of Morning Stiffness.............................................. 131


RO7123520 —F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTI-CENTER PHASE II STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF RO7123520 
AS ADJUNCT TREATMENT IN PATIENTS WITH 
MODERATELY TO SEVERELY ACTIVE RHEUMATOID 
ARTHRITIS AND AN INADEQUATE RESPONSE TO TNF-
INHIBITORS
PROTOCOL NUMBER:
BP39261
VERSION:
3
EUDRACT NUMBER:
2016-002126-36
IND NUMBER:
112,481 
TEST PRODUCT:
RO7123520
PHASE:
II
INDICATION:
Rheumatoid Arthritis
SPONSOR:
F. Hoffmann-La Roche Ltd


RO7123520 —F. Hoffmann-La Roche Ltd
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OBJECTIVES 
Primary Objectives
The primary objective of this study is:

To assess the safety, tolerability and efficacy of RO7123520 as adjunctive treatment with
methotrexate (MTX), and anti-TNF-therapy in patients with moderately to severely active 
rheumatoid arthritis (RA) with an anti-TNF-inadequate response (Study Parts 1,2,3).
Secondary Objectives
The secondary objectives for this study are as follows:

To assess the dose-ranging efficacy of RO7123520 (Study Part 3).

To assess the exposure versus response relationship and immunogenicity of RO7123520 
(Study Parts 1,2,3).
Exploratory Objectives
The exploratory objectives for this study are as follows:

To explore biomarker changes in serum, plasma, urine, synovial fluid and synovial tissue 
(Study Parts 1,2,3).

To explore biomarker changes and their relationship with clinical efficacy endpoints (Study 
Parts 1,2,3).

To explore joint changes by magnetic resonance imaging (MRI; Study Part 2).
STUDY DESIGN
Description of Study
This is a Phase IIa/b double-blind, placebo-controlled, randomized, parallel group, global 
multicenter study to evaluate the safety and efficacy of RO7123520 as adjunctive therapy in 
patients with RA who are inadequately responding to standard-of-care (MTX and anti-TNF-
therapy).
Patients with moderately to severely active RA will be recruited if they experience an 
inadequate response to disease-modifying anti-rheumatic drug (DMARD) therapy with MTX 
plus anti-TNF-therapy for at least 3 months before randomization. This first- and second-line 
therapy will be continued throughout the study. The MTX and anti-TNF-dose and product 
should not be changed during the study, unless for safety or intolerability reasons, until the 
primary endpoint assessment. All patients will receive concomitant folic acid supplementation 
as per local standard-of-care. The randomization will be stratified by the patient’s duration of 
prior anti-TNF-therapy (3-12 months vs 12 months) for Study Parts 2 and 3.
The study will be conducted in three parts. A final safety visit will occur 8 weeks (German sites: 
16 weeks) after the patient’s final study dose, regardless of the study part of the last received 
dose.
Part 1: Safety Cohort
A safety cohort of patients with moderately to severely active RA will be treated with 
RO7123520 as adjunctive therapy with MTX and anti-TNF-therapy. Nine patients will be 


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randomized in a 1:2 ratio and will receive placebo (N 3), or RO7123520 360 mg/dose as 
adjunct treatment (N 6). In Part 1 dosing will be staggered and no more than two patients will 
be dosed on any given day. Four doses of RO7123520/placebo will be given as intravenous 
(IV) infusions on Days 1, 14, 28 and 56. A double-blind design will be used with placebo-
administered patients receiving IV infusions of saline only. When all of the nine patients in Part 
1 have reached the Day 42 (Week 6) visit, i.e., two weeks after the 3rd dose administration, an 
Internal Monitoring Committee (IMC) along with an external Scientific Oversight Committee 
(SOC) will perform a safety review on unblinded data. The SOC and the IMC will advise the 
clinical trial team of their opinion on the study conduct.
The study will proceed to Part 2 if there are no more than one-third of the patients who 
received RO7123520 reporting serious study drug-related adverse events of a similar nature 
(e.g., laboratory abnormalities, vital sign changes, ECG changes, etc.) or if there are no other 
reasons to stop the study.
All patients in Part 1 will have the option of continuing to the Extension Period of the study.
Part 2: Phase IIa Proof-of-Concept Study
In Part 2, a Phase IIa proof-of-concept study will be conducted in patients with moderately to 
severely active RA experiencing an inadequate response to DMARD baseline therapy with 
MTX plus anti-TNF-therapy.
Ninety patients will be randomized in a 1:2 ratio and will receive MTX plus anti-TNF-therapy 
plus placebo (N 30), or MTX plus anti-TNF-therapy plus RO7123520 810 mg/dose as 
adjunct therapy (N 60). As in Part 1, RO7123520 will be given as IV infusions on Days 1, 14, 
28, and 56 (with patients randomized to placebo receiving IV saline), followed by the primary 
endpoint assessment at Week 12.
In Part 2 only, patients will undergo contrast-enhanced MRI imaging of hand/wrist, the site to 
be determined by the Investigator, to confirm disease activity at baseline and examine joint 
changes in patients with active RA on MTX and inadequate response to anti-TNF-therapy. 
As Part 2 is the pivotal proof-of-concept part of the trial, only patients with active disease on an 
MRI will be enrolled. 
Once the first 45 patients in Part 2 have completed the Week 12 visit, an interim analysis will 
be conducted with the opportunity to stop the study for futility, initiate Part 3 of the study or 
continue Part 2 until all 90 patients have completed the Week 12 visit.
The study will proceed to Part 3 if there are no more than one-third of the patients who received 
RO7123520 reporting serious study drug-related adverse events of a similar nature 
(e.g., laboratory abnormalities, vital sign changes, ECG changes, etc.) and if there are no other 
reasons to stop the study.
All patients in Part 2 will have the option of continuing to the Extension Period of the study.
Part 3: Phase IIb Dose-Ranging Study
Based on the results of an interim analysis planned during Part 2 of the study, the Phase IIb 
dose-ranging part of the study will begin. Applying the same criteria as in Part 2 (i.e., patients 
with moderately to severely active RA experiencing an inadequate response to DMARD 
baseline therapy with MTX plus anti-TNF-therapy), 105 patients will be randomized 2:2:2:1 to 


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one of three selected RO7123520 doses, and placebo (or 5:5:5:5:1 if four RO7123520 doses 
and placebo are selected) in the range of 90 mg/dose to 720 mg/dose (e.g., 90, 180, 450 
mg/dose). Final doses and the number of dose arms (3 or 4) for Part 3, along with the 
clarification of the sample size will be decided after analysis of safety and efficacy in the Part 2 
interim analysis. Patients will receive study treatment on Days 1, 14, 28, and 56, followed by 
the primary endpoint assessment at Week 12. 
All patients in Part 3 will have the option of continuing to the Extension Period of the study.
Extension Period
In Parts 1, 2 and 3, following the blinded, placebo-controlled 12-week study and Week 12 visit 
assessments an optional extension period will be conducted to collect additional safety and 
efficacy data up to Week 24, with the last dose being administered at Week 20. A final safety 
visit will occur at Week 28 (German sites: Week 36).
Patients who received active treatments in Study Parts 1, 2 or 3 will continue on the same dose 
of RO7123520 as they previously received in Parts 1, 2 or 3. It is planned that patients who
received placebo treatment in Part 1 will receive a 360 mg dose, while patients on placebo in 
Parts 2 or 3 will receive an 810 mg dose of RO7123520, although a lower dose may be 
employed at the recommendation of the IMC/SOC.
NUMBER OF PATIENTS
A total of approximately 204 patients will take part in the study, with 9 patients in Part 1, 90 
patients in Part 2 and 105 patients in Part 3.
TARGET POPULATION
Male and female patients with moderately to severely active RA who experience an inadequate 
response to disease-modifying anti-rheumatic drug (DMARD) therapy with MTX plus anti-TNF-
therapy for at least 3 months before randomization. This first- and second-line therapy will be 
continued throughout the study.
INCLUSION/EXCLUSION CRITERIA
Inclusion criteria:
Patients must meet the following criteria for study entry:
1.
Able and willing to provide written consent by signing the Informed Consent Form (ICF),
and to comply with the study protocol according to ICH and local regulations.
2.
Adult men and women, of more than 18 years of age (inclusive).
3.
Diagnosis of adult-onset RA as defined by the American College of Rheumatology (ACR) 
2010 criteria, for at least 6 months before screening.
4.
Moderately to severely active RA as defined by at least 4/28 tender joints and at least 4/28 
swollen joints (Note: surgically treated joints cannot be counted in TJC/SJC for enrollment 
purposes).
5.
For Part 2 only: Active synovitis and/or osteitis of the hand/wrist as determined by contrast-
enhanced MRI.
6.
Patients must be taking one of the following anti-TNF-therapies: certolizumab, 
golimumab, etanercept, adalimumab, infliximab or approved biosimilars of these, given at 
a recommended and stable dose for at least 12 weeks before randomization and have 


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experienced in the opinion of the Investigator an inadequate response to anti-TNF-
therapy with a DAS28 3.2. Note: prior use of other anti-TNF-therapies is allowed.
7.
Patients must be taking MTX (PO, SC, or IM) for at least 12 weeks before randomization 
and must be on a stable dose for at least 4 weeks before randomization (5.0 to 25 
mg/week). Note: The dose of MTX is expected to remain stable throughout the study and 
may be adjusted only for safety or intolerability reasons. Local standard-of-care should be 
followed for concomitant administration of folic acid.
8.
Patients on glucocorticoids (10 mg/day PO prednisone or equivalent) are permitted if 
doses are stable within 6 weeks of planned randomization. Note: Patients should remain on 
stable doses of glucocorticoids throughout the duration of study unless for medical reasons 
(e.g., safety, intolerability, RA flare, etc.).
9.
Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) intermittently (e.g., up to 2-3 
times weekly) for short-term relief of pain are allowed, and patients on regular NSAID use 
(i.e., on stable dose for 4 weeks) are allowed.
Note: NSAIDs must not be taken for at least 2 days before clinical assessments in the study 
for patients with intermittent use of NSAIDs. If needed for symptomatic relief, paracetamol 
(up to 3 g/day) is permitted.
10. Negative pregnancy test at screening and baseline (women only), and agreement to comply 
with measures to prevent pregnancy and restrictions on sperm donation as follows:

Male or female patients: The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.

For males: men with female partners of childbearing potential or pregnant female 
partners, must remain abstinent or use a condom during the treatment period and up 
to the post-treatment follow-up visit to avoid exposing the embryo. Men must refrain 
from donating sperm during this same period.

For females: Females are eligible to participate if not pregnant and not breastfeeding. 
A woman of childbearing potential and female partners with childbearing potential of 
male patients must agree to remain abstinent (refrain from heterosexual intercourse) 
or use one highly effective form of contraception that results in a failure rate of 1% 
per year during the treatment period and up to the post-treatment follow-up visit. A 
woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a post-menopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.

Male and female patients should continue to use contraception after the last study 
drug administration until the end of relevant systemic exposure (i.e., ~115 days).


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Exclusion criteria:
Patients who meet any of the following criteria will be excluded from study entry:
1.
Parenteral glucocorticoids administration (IM, IV) of ≥50 mg within 6 weeks or ≤50 mg within 
4 weeks prior to planned randomization, or scheduled parenteral administrations during the 
study.
2.
Joint(s) injected with intra-articular glucocorticoids within 6 weeks prior to planned 
randomization.
3.
Active inflammatory diseases of the joints not related to RA: Gout, reactive arthritis, 
psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease.
4.
Systemic autoimmune disease other than RA: Systemic lupus erythematosus, Crohn's 
disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed forms of 
connective tissue inflammatory diseases.
5.
Juvenile idiopathic arthritis or juvenile RA and/or RA developed before the age of 16.
6.
Active fibromyalgia that makes appropriate RA disease activity challenging for the 
Investigator.
7.
RA patients functional status class IV according to the ACR 1991 criteria (i.e., largely or 
wholly incapacitated permitting little or no self-care, such as being bedridden or confined to 
wheelchair).
8.
Patients with severe chronic or recurrent viral, bacterial, parasitic or fungal infections.
9.
History of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV) infection.
10. Any identified confirmed congenital or acquired immunodeficiency.
11. Abnormal laboratory values:

Hemoglobin level is less than 80 g/L.

Leucocyte level is less than 2.5 109/L.

Absolute neutrophil count is less than 1.0 109/L.

Thrombocyte level is less than 75 109/L.
12. Laboratory test results for liver function meeting criteria for marked abnormality (ULN: upper 
limit of normal): Alkaline phosphatase: 3 ULN; aspartate aminotransferase: 3 ULN; 
alanine aminotransferase: 3 ULN; -glutamyl transferase: 3 ULN.
13. Other unstable somatic diseases apart from RA that can increase the probability of adverse 
events during the study, mask, enhance or alter the symptoms of RA or cause clinical or 
laboratory symptoms similar to that of RA.
14. Major surgery within 28 days prior to randomization, or planned major surgery (e.g., elective 
joint replacement surgery) during the trial.
15. Any mental disorder, including major depressive disorder and/or suicidal thoughts in 
anamnesis that can, in the Investigator's opinion, create a risk for the patient or influence 
the patient's ability to follow the study protocol.
16. Myocardial infarction within less than 6 months prior to participation in the study.
17. Severe central or peripheral nervous system diseases.
18. Chronic drug or alcohol abuse.
19. Known hypersensitivity to any components of the medications used in the study. 
20. Acute forms of any infectious diseases or history of chronic infections with severe clinical 
manifestations that would increase risk in participation of trial in the opinion of the 
Investigator.


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21. Presence of malignant neoplasm, with the exception of adequately treated basal cell 
carcinoma and cervical carcinoma in situ and any malignancy with complete remission of 
more than 5 years.
22. Simultaneous participation in any other clinical trial, as well as former participation in other 
clinical trials within 3 months before this study initiation; and previous study drug 
administration in this study.
23. German sites: Patients who are institutionalized due to regulatory or juridical order.
24. German sites: Patients who are occupationally or medically dependent on the Sponsor, the 
Investigator, or the medical site.
LENGTH OF STUDY
The total duration of the study for each patient will be up to 32 weeks (German sites: 40 weeks)
divided as follows:

Screening: Up to 4 weeks

Study treatment duration: Days 1 up to 84 (Baseline to Week 12)

Study treatment duration including Extension Period: Days 1 up to 168 (Baseline to 
Week 24)

Safety Follow-up: Day 112 (Week 16). German sites: Day 112 (Week 16) and Day 168 
(Week 24).

Safety Follow-up including Extension Period: Day 196 (Week 28). German sites: Day 196 
(Week 28) and Day 252 (Week 36).
Only Patients in Study Part 1 will be required to stay overnight at the Study Center after each 
dose of study treatment up to and including the Week 8 administration. The first 15 patients in 
Part 2 will be required to stay overnight at the Study Center after the first dose of study 
treatment, or alternatively, two visits within 24 hours post-dose can be made by an ambulatory 
at-home visiting nurse to perform assessments as described in the SoA.
END OF STUDY
The end of the study is defined as the date when the last patient last observation (LPLO) 
occurs. LPLO is expected to occur 28 weeks (German sites: 36 weeks) after the last patient is 
enrolled.


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OUTCOME MEASURES
SAFETY OUTCOME MEASURES
The safety outcome measures for this study are as follows:

Incidence, nature and severity of adverse events, including targeted adverse events, 
number of participants with SAEs, treatment-related SAEs, SAEs leading to 
discontinuation, treatment-related AEs, or AEs leading to discontinuation

Incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results

ECGs

Vital signs

Assessment of bone remodeling and cartilage markers (e.g., CTX-I, PINP and osteocalcin)

Assessment of blood cell markers (including, but not limited to, CD4, CD8, CD19,
CD16/56, CD3, CD45, CD14)

Anti-drug antibodies (ADA)

Bone mineral density lumbar spine L1-L4 by dual energy X-ray absorptiometry (DEXA) 
scans, which involves the exposure of a very small amount of X-ray radiation around one 
to six microSievert (μSv).
PHARMACOKINETIC OUTCOME MEASURES
RO7123520 serum and synovial fluid concentration data will be pooled with corresponding 
data from other studies (e.g., SDP051-001) for population PK and PK/PD modelling of the 
exposure versus response relationship.
EFFICACY OUTCOME MEASURES
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure:

Proportion of patients achieving an ACR50 response at Week 12
Secondary Outcome Measures:

Change from baseline in CDAI Score at Week 12

Change from baseline in DAS28 at Week 12

Proportion of patients achieving DAS28 remission at Week 12

Proportion of patients achieving CDAI remission at Week 12

Proportion of patients achieving an ACR20 response at Week 12

Proportion of patients achieving an ACR70 response at Week 12

Simple Disease Activity Index (SDAI) Score at Week 12

Change from baseline in the Stanford Health Assessment Questionnaire Disability Index 
(HAQ-DI) at Week 12


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EXPLORATORY OUTCOME MEASURES
The exploratory outcome measures for this study include but are not limited to the following:

Proportion of patients achieving an ACR50 response at Week 24

CDAI Score at Week 24

DAS28 at Week 24

Proportion of patients achieving DAS28 remission at Week 24

Proportion of patients achieving CDAI remission at Week 24

Proportion of patients achieving an ACR20 response at Week 24

Proportion of patients achieving an ACR70 response at Week 24

Proportion of patients achieving a mACR50 response at Weeks 12 and 24

Proportion of patients achieving a mACR20 response at Weeks 12 and 24

Proportion of patients achieving a mACR70 response at Weeks 12 and 24

SDAI Score at Week 24

Change from baseline in the Stanford HAQ-DI at Week 24

Change from baseline in Short-form 36 health questionnaire Physical and Mental Health 
component scores (SF36V2 standard recall) at Weeks 12 and 24

Change from baseline in Brief Fatigue Inventory (BFI) total and item scores at Weeks 12 
and 24

Change from baseline in patient global assessment of disease activity at Weeks 12 and 24

Change from baseline in patient global assessment of pain at Weeks 12 and 24

Change from baseline in Cad-11 synovium level and in synovial fluid and blood soluble
Cad-11 concentration at Weeks 12 and 24

Change from baseline of the PD biomarkers (e.g., bone remodeling and cartilage markers) 
at Weeks 12 and 24

Change from baseline in synovitis, osteitis, joint erosions, cartilage loss, bone marrow 
edema, total damage and total inflammation at Weeks 12 and 24 evaluated by rheumatoid 
arthritis MRI score (RAMRIS) of the hand/wrist.
Biomarkers (non-DNA)
Roche Research Biosample Repository (RBR) non-DNA specimen (s) will be taken from 
consenting subjects at the timepoints specified in the Schedule of Assessments (SoA). 

Residual synovial tissue and fluid from any patient who consents to their collection and to 
store in RBR post-study

Plasma, serum, to assess for biomarkers

Blood for DNA and RNA extraction to assess for biomarkers
These specimen(s) may be stored for up to 15 years after the end of study.  
Biomarkers (DNA)
All subjects who have been enrolled in the study will be asked to donate an optional DNA 
specimen for pharmacogenetic and genetic research. RBR DNA sampling will involve taking a 
blood sample at at the timepoints specified in the SoA. These specimen(s) may be stored for 
up to 15 years after the end of study.  


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INVESTIGATIONAL MEDICINAL PRODUCT(S)
Test Product
RO7123520 drug product (30 mg/mL) will be provided in single-use, 6 mL vials.
For IV infusion, RO7123520 concentrate for solution for infusion should be diluted in 0.9% 
(w/v) sodium chloride solution prior to administration.
Placebo 
Patients randomized to placebo will receive IV infusions of saline alone, therefore no actual 
matching placebo will be provided. It is not possible to differentiate between the IV bags which 
contain only saline and those which have RO7123520 added.
PROCEDURES
Informed consent will be obtained prior to any study-specific procedures. Following eligibility at 
screening and the confirmation at baseline, patients will be enrolled into the study. The 
assessments will be conducted at times as indicated in the SoA. 
Assessments scheduled on the day of study treatment administration should be performed 
prior to administration of study treatment, unless otherwise noted in the SoA. 
The exact assessments may vary by specific visit date and the sequence will be standardized 
as follows (at visits as specified in the SOA):
1.
Patients will complete health outcomes assessments using an electronic ePRO device, 
specific to each study visit day/week. 

SF36v2

HAQ-DI

BFI

PtPA (pain VAS)

PtGA (Global Assessment of disease activity VAS)
2.
Laboratory samples for safety, efficacy, PD and PK; must be drawn after patient 
self-assessments are completed, at least 30 min before Investigator assessments or at any 
time after nurse/Investigator assessments but prior to study drug infusion.
Note: providing all listed restrictions are met, the lab samples can be collected before or 
after the joint count is performed.
3.
Investigator assessments:

Joint counts

Physician’s global assessment of disease activity VAS, safety assessments (adverse 
events, vital signs, concomitant medications, review of laboratory data)
4.
RO7123520/placebo infusion
5.
Post-dose vital signs, post-dose PK (at the visits scheduled), adverse events.
Patients who complete the study or discontinue from the study early will be asked to return to 
the clinic 8 weeks (German sites: 8 and 16 weeks) after the last dose of study drug for a 
follow-up visit.


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STATISTICAL METHODS
PRIMARY ANALYSIS
The primary analysis will include all patients in the efficacy analysis population, with patients 
grouped according to the treatment and dose assigned at randomization.
The primary efficacy endpoint to demonstrate the proof of concept of RO7123520 is the 
proportion of patients achieving an ACR50 response at Week 12 using RO7123520 as adjunct 
therapy to MTX+anti-TNF-compared to MTX+anti-TNF-plus placebo.
An ACR50 response is defined by achieving an improvement of 50% compared to baseline in 
the American College of Rheumatology (ACR) core set of outcome measures in both SJC and 
TJC as well as in 3 out of 5 additional parameters: physician’s global assessment of disease 
activity, patient’s global assessment of disease activity, patient’s assessment of pain (PtPA), 
HAQ-DI, and acute phase reactant (CRP will be used as the ACR APR in this study).
Patients who withdraw from the study prior to the Week 12 ACR assessment, and all patients 
in whom the Week 12 ACR50 response cannot be determined for any reason, will be 
considered non-responders for the summaries of ACR50.
The proportion of patients achieving an ACR50 response at Week 12 will be summarized 
descriptively by treatment/dose arm.
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population and reported by the 
treatment group and dose actually received.

Adverse events will be summarized by mapped term and appropriate thesaurus level.
Incidence, nature and severity of adverse events, including targeted adverse events, 
number of participants with serious adverse events (SAEs), treatment-related SAEs, SAEs 
leading to discontinuation, treatment-related AEs, or AEs leading to discontinuation will be 
tabulated by treatment group and dose.

Clinical Laboratory Test Results will be presented by individual listings with flagging of 
values outside the normal ranges.

Vital signs and weight data will be presented by individual listings with flagging of values 
outside the normal ranges and flagging of marked abnormalities. In addition, tabular 
summaries will be used, as appropriate.

ECG data will be presented by individual listings with flagging of values outside the normal 
ranges and flagging of marked abnormalities. In addition, tabular summaries will be used, 
as appropriate.

Concomitant medications will be presented in summary tables and listings.
PHARMACOKINETIC ANALYSES
RO7123520 concentration data will be pooled with data from other studies (e.g., SDP051-001) 
for population PK and PK/PD modelling. The methods and results of that population modelling 
will be reported separately.


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EXPLORATORY ANALYSES

The proportion of mACR20/mACR50/mACR70 responders at Week 12 and Week 24 will 
be summarized descriptively using the efficacy analysis population.

The change from Baseline in SF-36v2 mental component score (MCS) and physical 
component score (PCS) at Week 12 and Week 24 will be summarized descriptively by 
treatment/dose arm using the efficacy analysis population.

The change from Baseline in BFI items 2, 3 and 4, as well as total score will be
summarized descriptively at Week 12 and Week 24 by treatment/dose arm using the 
efficacy analysis population.

The PtGA VAS and PGA VAS will be presented individually to describe, respectively, the 
patient and physician global assessment of disease activity changes from baseline at 
Week 12 and Week 24 using the efficacy analysis population.
The PtPA VAS change from baseline at Week 12 and Week 24 will also be presented 
using the efficacy analysis population.
PtGA, PGA and PtPA VAS changes from baseline will be summarized descriptively.

The potentially prognostic and disease severity biomarkers (MBDA and CTX-II) will be 
summarized descriptively at Baseline by treatment/dose arm. In addition, the synovium 
cadherin-11 data, synovial fluid and blood soluble cadherin-11 data will be summarized 
descriptively by visit and treatment/dose arm. Those biomarkers will be summarized using 
the efficacy analysis population.
The relationship between the potentially prognostic and disease severity biomarkers and 
efficacy endpoints will also be analyzed and reported descriptively.

Bone remodeling and cartilage markers (including but not limited to CTX-1, PINP and 
osteocalcin) will be summarized descriptively by visit and treatment/dose arm. Those 
biomarkers will be summarized using the efficacy analysis population.
The relationship between the markers mentioned above and efficacy endpoints will also be 
analyzed and reported descriptively.

Safety biomarkers (T cells, B cells, NK cells, granulocyte and monocyte markers) will be 
summarized descriptively by visit and treatment/dose arm using the safety analysis 
population.

Disease activity as assessed by MRI (Part 2 only):
The OMERACT RA MRI scoring system (RAMRIS) will be used for the evaluation of 
inflammatory and destructive changes in RA hands and wrists at baseline, Week 12 and 
Week 24. The change from baseline in synovitis, osteitis, bone erosions, cartilage loss,
bone marrow edema, total damage and total inflammation will be summarized descriptively 
by visit and treatment arm using the efficacy analysis population.
SAMPLE SIZE JUSTIFICATION
Part 1:
No formal sample size estimation was performed for Part 1 of the study. A total of 9 patients (6 
on the RO7123520 arm and 3 on the placebo arm) is deemed sufficient to provide initial safety 
information on RO7123520 in RA patients.


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Part 2:
A total of 90 patients will be randomized 2:1 to either the RO7123520 or placebo arm. The 
probability of observing a difference of at least 15% between the RO7123520 and placebo 
Week 12 ACR50 response rates is approximately 0.73, assuming that the true ACR50 
response rate on placebo is 15% and 35% on RO7123520. With 60 patients receiving 
RO7123520 810 mg, there is at least a 95% chance of observing an AE with true incidence of 
5%. This number of Ninety patients will therefore give a reasonable assessment of the safety 
and efficacy of RO7123520 before progressing to Part 3.
Part 3:
Following the decision to initiate Part 3 at the interim analysis of Part 2 of the study or after the 
end of Part 2 (when all 90 patients have reached the Week 12 visit) (Section 6.9), 105 patients 
will be randomized 2:2:2:1 to one of 3 selected RO7123520 doses, and placebo (or 5:5:5:5:1 if 
four RO7123520 doses and placebo are selected). 
The total sample size for the combined Study Parts 1, 2 and 3 will be 204 patients (either 60, 
30, 30, 30 receiving different doses of RO7123520, plus 6 RO7123520 patients from Study 
Part 1, and 48 receiving placebo, or 60, 25, 25, 25, 25 receiving different doses of RO7123520, 
plus 6 RO7123520 patients from Study Part 1, and 38 receiving placebo). This provides 
approximately 80% power of observing a positive dose response curve with a maximum effect 
of RO7123520 compared to placebo of -8.0 in change from baseline in CDAI score at Week 12 
(placebo change from baseline in CDAI is assumed to be -10.0, with a common standard 
deviation of 15.0), allowing for a 10% drop-out rate and using a two-sided alpha level of 0.1.
If conflicting results are observed from Study Part 2 of the study between the change from 
baseline in CDAI at Week 12 endpoint and ACR50 response at Week 12 endpoint, then the 
following sample size for Part 3 will be undertaken and the dose-response analysis will be 
based on ACR50 at Week 12:
A total sample size of 150 patients will be recruited into part 3 of the study. Therefore the total 
sample size for the combined Study Parts 1, 2 and 3 will be 249 patients (either 60, 45, 45, 45 
receiving different doses of RO7123520, plus 6 RO7123520 patients from Study Part 1, and 48 
receiving placebo, or 60, 36, 36, 36, 36 receiving different doses of RO7123520, plus 6 
RO7123520 patients from Study Part 1, and 39 receiving placebo), which provides 
approximately 80% power of observing a positive dose response curve using a two-sided alpha 
level of 0.1, and assuming a placebo ACR50 response of 15% and active RO7123520 
response of 35%, i.e., a delta effect size of 20%.
Interim Analyses
An interim analysis of the primary efficacy outcome measure (ACR50 at Week 12) will be 
carried out after the first 50% of the patients within Part 2 of the study have completed their 
Week 12 assessment visit. The data will be reviewed by the IMC and SOC.
The difference in ACR50 response rate at Week 12 between the RO7123520 810 mg dose 
group and the placebo group will be compared descriptively. If no difference between the 
treatment arms is observed for ACR50 (i.e., the difference is 0%) then, the study may be 
stopped for futility. If a positive difference is observed then, the Sponsor will determine whether 
to start Part 3 of the study at this point (also continuing Part 2 recruitment until completion) or 
wait until all of the Part 2 patients have been recruited and have completed the Week 12 visit, 


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where the decision will be revisited.
Once all of the patients in Study Part 3 have completed their Week 12 visit, a data snapshot 
will be taken for the purpose of the dose-response analysis. The study will not be modified at 
this point and will continue until all patients have completed the final follow-up visit.
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up 
to two additional interim efficacy analyses. The decision to conduct an optional interim analysis 
and the timing of the analysis will be documented in the Sponsor’s trial master file prior to the 
conduct of the interim analysis. The interim analysis will be performed and interpreted by 
members of the Sponsor study team and appropriate senior management personnel, who will 
be unblinded at the treatment group level.  Access to treatment assignment information will 
follow the Sponsor’s standard procedures.
LIST OF PROHIBITED MEDICATIONS
The following medications are prohibited after randomization:

Live vaccines, including herpes zoster vaccination. Non-live seasonal vaccinations and/or 
emergency vaccination, such as rabies or tetanus vaccinations, are allowed.

Any biologic therapy such as anti-IL-1, anti-IL-6, or T-cell or B-cell targeted therapies for 
any indication.

Any interferon therapy for any indication.

Any parenteral corticosteroid administered by IV injection.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACR
American College of Rheumatology
ADA
Anti-drug antibody
AE
Adverse events
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BFI
Brief Fatigue Inventory
BP
Blood pressure
CDAI
Clinical Disease Activity Index
CL
Clearance
CL/F
Apparent clearance
CRO
Contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CTX-II
Collagen type II C-telopeptide
DAS28
Disease Activity Score
DMARD
Disease-modifying anti-rheumatic drug 
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
ePRO
Electronic patient-reported outcome
ESF
Eligibility Screening Form
EU
European Commission
FDA
Food and Drug Administration
HAQ-DI
Stanford Health Assessment Questionnaire Disability 
Index 
HBsAG
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C
HDL
High-density lipoproteins
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure


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Abbreviation
Definition
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
IMC
Internal Monitoring Committee
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IUD
Intrauterine Device
IV
Intravenous
IxRS
Interactive (voice/web) response system
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LPLV
Last patient, last visit
MBDA
Multi-biomarker disease activity
MRI
Magnetic resonance imaging
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug
NGS
Next Generation Sequencing
NOAEL
No-observed-adverse-effect level
OTC
Over-the-counter
PD
Pharmacodynamic
PGA
Physician Global Assessment of Disease Activity
PINP
Aminoterminal propeptide of type I collagen
PK
Pharmacokinetic
PRO
Patient-reported outcome
PT
Prothrombin time
PtGA
Patient Global Assessment of Disease Activity
PtPA
Patient Assessment of Pain
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate


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Abbreviation
Definition
QTcF
QT corrected for heart rate using the Fridericia 
correction factor
RA
Rheumatoid arthritis
RBC
Red blood cell
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RR
RR interval
SAD
Single-Ascending Dose
SAE
Serious Adverse Event
SD
Single dose
SDAI
Simple Disease Activity Index
SoA
Schedule of Assessments
SOC
Scientific Oversight Committee
SF-36v2
Short-form Health Survey Version 2
SUSAR
Suspected unexpected serious adverse reactions
TNF-
Tumor necrosis factor-
TQT
Thorough QT
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
Vz
Volume of distribution
VAS
Visual analogue scale
WBC
White blood cell
WGS
Whole genome sequencing


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1.
BACKGROUND AND RATIONALE
1.1
BACKGROUND ON DISEASE
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect 
many tissues and organs, but principally attacks synovial joints, resulting in joint damage 
with loss of function and mobility. Current first-line treatment regimens include the use of 
corticosteroids alone or in combination with conventional disease-modifying 
anti-rheumatic drugs (cDMARDs), most commonly methotrexate. However, only 
approximately 50% of RA patients experience a 50% improvement in clinical signs and 
symptoms, with the majority of patients demonstrating only a partial response to 
treatment (Voll and Kalden 2005). As second-line treatments, biologic agents (including
monoclonal antibodies, mostly directed against TNF-and its receptorsso-called 
biological DMARDs, bDMARDS) are added in order to control the disease with the target 
to achieve low disease activity (LDA) or even remission.
Synovial fibroblasts are the major non-immune cell population of the inflamed RA joint 
and are thought to play a significant role in cartilage destruction and in tissue 
inflammation. Therefore, targeting synovial fibroblasts comprises an attractive and novel 
non-immunosuppressive approach for interrupting pathophysiology of the RA joint, 
particularly if combined with existing DMARDs and biologics as an adjunctive approach 
to increase efficacy without increasing immunosuppressive side-effects.
Cadherin-11 (Cad-11) is a classical cadherin adhesion molecule that mediates 
homophilic cell-to-cell adhesion. Cad-11 is selectively expressed in synovial fibroblasts, 
and plays an important role in the pathogenesis of inflammatory arthritis (Lee et al 2007).
There is mounting evidence from preclinical in vitro and in vivo studies which suggest 
that Cad-11–mediated activation of synovial fibroblasts results in their production of pro-
inflammatory factors. This suggests that Cad-11 may be an important modulator of 
inflammation and cytokine release by synovial fibroblasts. In fact, Cad-11 engagement 
was shown to synergize with TNF-to markedly increase cytokine (i.e., IL-6) production, 
which in contrast was decreased in ankle joints from Cad-11-deficient mice compared 
with wild-type mice with inflammatory arthritis (Chang et al 2011). These and additional 
published findings suggest that Cad-11 plays a critical role in evoking synovial fibroblast 
inflammatory factors that contribute to RA (Chang et al 2011).
Further supportive evidence for Cad-11 as a potential therapeutic target in RA is that 
expression of Cad-11 in fibroblasts is restricted to the site of active inflammation. There 
is little to no general, systemic fibroblast protein expression of Cad-11 (Valencia et al 
2004); therefore, blocking Cad-11 has the potential to be a targeted and local approach 
with limited side-effects expected due to very limited Cad-11 interference outside of
inflamed joints in RA. 
Selectively blocking upregulated Cad-11 function in inflamed tissues using a 
non-immunosuppressive strategy might represent a potentially effective and novel 


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therapy for the treatment of patients with moderately to severely active RA and an 
inadequate response to anti-TNF-therapy. 
RO7123520 is a novel, humanized IgG4 monoclonal antibody that specifically binds to
the first extracellular (EC1) domain of Cad-11. It is being investigated for the treatment of 
moderate to severe RA as an adjunctive treatment to biologic and non-biologic DMARDs.
1.2
BACKGROUND ON RO7123520
See the RO7123520 Investigator’s Brochure for details on non-clinical and clinical
studies.
1.2.1
Previous Non-Clinical Studies
In vitro studies to evaluate the potential beneficial effects of RO7123520 in RA were 
conducted in human synovial fibroblasts. Exposure to RO7123520 in vitro significantly 
reduced both matrix metalloproteinase-3 (MMP-3) levels and invasion into a 
Matrigel-coated membrane at drug concentrations as low as 0.3 g/mL. 
In vivo studies in a relevant murine model of RA involving synovitis, the KBN model, 
showed that RO7123520 reduced swelling of joints and joint destruction at 10 mg/kg and 
resulted in a trend towards reduced joint swelling at 3 mg/kg. The reduction of joint 
swelling by RO7123520 was correlated with a reduction in the levels of some cytokines 
implicated in RA pathogenesis in humans.
Among cadherins, RO7123520 binds preferentially to Cad-11, with an EC50 that is at 
least 500-fold lower than for other closely-related cadherins.
RO7123520 is considered unlikely to produce adverse effects on nervous system, 
cardiovascular system, or respiratory system function in humans, based on results of 
safety pharmacology evaluations. RO7123520 did not adversely affect respiratory 
system function or functional observational battery (FOB) test results in rats given single 
intravenous (IV) doses at up to 200 mg/kg, and did not affect electrocardiograms (ECGs) 
in cynomolgus monkeys given weekly IV doses for 4 weeks at up to 200 mg/kg. 
Single- and repeat-dose IV toxicity studies in mice, rats, and cynomolgus monkeys 
included evaluation of systemic exposure (toxicokinetics), immunogenicity (anti-drug 
antibodies [ADA]), and reversibility of effects (recovery). No adverse effects were 
observed at any dose level in the rat and cynomolgus monkey single-dose and 4- or 
26-week toxicity studies following single or once weekly IV administration of RO7123520 
up to the maximum feasible dose of 200 mg/kg. The no-observed-adverse-effect level 
(NOAEL) for these studies in each species was considered to be 200 mg/kg. In the 2-
week single and 4-week IV toxicity studies in mice, death was reported in three mice. It 
occurred shortly after administration of the third or fourth weekly dose at 30 mg/kg, and 
was considered to be immune-mediated anaphylaxis triggered by a response against the 


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humanized RO7123520. Based on these findings, the NOAEL was considered to be 10 
mg/kg in mice.
The pharmacokinetics and toxicokinetics of RO7123520 were studied after single IV 
bolus doses in Sprague-Dawley rats and cynomolgus monkeys and after repeated 
weekly IV bolus doses in CD-1 mice, Sprague-Dawley rats, and cynomolgus monkeys. 
Weekly IV administration of RO7123520 produced substantial, long-lasting serum 
concentrations in all species. In each species, the volume of distribution (Vz), clearance 
(CL), and half-life (t1/2) generally were similar in both sexes. Vz approximated or was 
slightly larger than the serum volume (40-60 mL/kg), which is typical for monoclonal 
antibodies. RO7123520 was cleared slowly from the serum with t1/2 ranging from ~2 to 
16 days across species. Clearance did not change substantially with dose level in rats 
and cynomolgus monkeys, but increased with dose level in mice, likely a result of a 
robust anti-drug antibody (ADA) response at the higher dose levels.
For more details on nonclinical studies see the RO7123520 Investigator’s Brochure.
1.2.2
Previous Clinical Studies
RO7123520 has been administered to healthy subjects in one clinical Phase 1 study 
(SDP051-001). Study SDP051-001 was a randomized, double-blind, placebo-controlled,
single-ascending dose (SAD) design in which healthy male and female subjects received 
single IV doses of either RO7123520 or placebo. The primary objectives were to 
establish the pharmacokinetics (PK), safety and tolerability of single IV doses of 
RO7123520. Subjects underwent PK, pharmacodynamics (PD) and safety assessments 
at regular intervals up to 84 days after dosing. A total of 35 eligible subjects were 
enrolled into the study in five cohorts. Within each cohort, 5 subjects received 
RO7123520 and 2 subjects received placebo. Study drug was administered as a 1-hour 
IV infusion and the five RO7123520 doses tested were 0.1, 0.3, 1, 3, and 10 mg/kg of 
body weight (i.e., average actual doses 8, 22, 79, 243 and 847 mg, respectively).
RO7123520 pharmacokinetics after administration of a single IV dose were linear across 
the dose range tested. RO7123520 peak and total exposure increased in a 
dose-proportional manner. Volume of distribution was approximately 6.5 L, while 
clearance was approximately 0.008 L/h. The apparent terminal half-life was 
approximately 23 days on average.
Single IV doses of RO7123520 up to 10 mg/kg (average actual dose 847 mg) were 
tolerated similarly to placebo by healthy subjects. There were no deaths, serious 
adverse events (SAEs), or discontinuations from the study because of adverse events 
(AEs). No dose-limiting AEs were identified. 
There were a total of 45 treatment-emergent AEs reported for 19 of 25 (76.0%) 
RO7123520-administered and 6 of 10 (60.0%) placebo-administered subjects. The most 
frequently reported treatment-emergent AEs during the study were contact dermatitis 


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and headache. Contact dermatitis was reported in 6 of 25 (24.0%) RO7123520
administered subjects and in no placebo-administered subjects. Contact dermatitis was 
attributed to ECG patches in four subjects and poison ivy in one subject. One additional 
case of application site erythema due to foam antiseptic was reported by a subject who 
received 0.1 mg/kg RO7123520. Headache was reported in 4 of 25 (16.0%) 
RO7123520-administered subjects and in no placebo-administered subjects. All 4
reported episodes of headache were mild and resolved without treatment. All other 
treatment-emergent AEs were reported in two or fewer individuals, and showed no 
apparent relationship to treatment.
The immunogenic potential of RO7123520 was assessed by measurement of 
anti-RO7123520 drug antibodies (ADA) before, and 2, 4, 8, and 12 weeks after study 
drug dosing. One of 25 subjects who received RO7123520 developed ADAs. This 
subject was negative prior to receiving a 0.1 mg/kg dose of RO7123520 but was positive 
for ADA at all post-dose assessments.
Four additional subjects (one placebo subject, one subject at 0.1 mg/kg, and two
subjects at 0.3 mg/kg dose) tested positive for ADAs at baseline (pre-dose) as well as at 
all post-dose visits.
For more details on the previous clinical study, see the RO7123520 Investigator’s 
Brochure.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
1.3.1
Study Rationale
RO7123520 is a novel anti-cadherin-11 monoclonal antibody. Cadherin-11 (Cad-11) is a 
classical cadherin adhesion molecule that mediates homophilic cell-to-cell adhesion. 
Recent studies have demonstrated that Cad-11 is selectively expressed in synovial 
fibroblasts and plays an important role in the pathogenesis of inflammatory arthritis (Lee 
et al 2007). Selectively blocking upregulated Cad-11 function in inflamed tissues might
represent a potentially effective and novel therapy for the treatment of patients with 
moderately to severely active RA and an inadequate response to anti-TNF-therapy.
The principal aim of the study is to establish the safety, tolerability and efficacy profile of 
RO7123520 when administered to patients with RA who have had an inadequate 
response (IR) to at least one biologic anti-TNF-therapy (RA TNF-IR patients) and who 
are also taking background cDMARDs (i.e., with methotrexate [MTX]). However, 
because this is an early study in the clinical development of a compound with a novel 
mechanism of action, there is a need to profile the pharmacological effects of 
RO7123520 treatment. The study is, therefore, also intended to characterize the effects 
of RO7123520 through appraisal of a variety of relevant pharmacodynamic measures 
and biomarkers, and to establish the relationship between drug exposure and any 
treatment response. Data from this study are intended to inform the future development 
potential for RO7123520 in RA TNF-IR patients.


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1.3.2
Benefit-Risk Assessment
Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by 
progressive damage to synovial joints. Although there are a number of approved, 
effective treatments for RA available, many patients nevertheless experience significant 
ongoing disease activity. This study will recruit patients with RA who have had an 
inadequate response to current first- and second-line standard-of-care treatments, a 
group for whom switching to another immunosuppressive/immunomodulatory biologic 
therapy with a different mode of action is recommended in order to achieve better 
treatment response (e.g., American College of Rheumatology [ACR] guidelines, Singh et 
al. 2016; European League Against Rheumatism [EULAR] guidelines, Smolen et al 
2014). The available data on Cad-11 and preclinical data on RO7123520 provide a
reasonable expectation that RO7123520 treatment might provide benefit on the signs 
and symptoms of RA and ameliorate joint destruction. However, this is the first study to 
test the effects of a therapy targeting Cad-11; there are no clinical data to prove that 
individuals will derive any benefit from RO7123520 treatment. Furthermore, as this is a 
placebo-controlled study, patients who are randomized to placebo will not derive direct 
benefit from participation in the blinded parts of the study.
The risks of study participation are primarily those associated with adverse reactions to 
the study drug, although there may also be some discomfort from collection of blood and 
synovial fluid samples and other study procedures. Participants in the optional synovial 
biopsy sub-study will also have additional discomfort and risk of sequelae from the 
biopsy procedure.
Study BP39261 is the second study involving dosing of RO7123520 to humans but the 
first involving dosing in patients with RA. Data from a previously completed clinical study
performed in healthy subjects (SDP051-001) show an acceptable tolerability profile over 
the dose range tested. There were no notable safety findings from single doses up to 
10 mg/kg (average actual dose 847 mg), indicating there are no acute safety risks 
associated with RO7123520 dosing or the mechanism of action. Similarly, mice lacking 
Cad-11 (“knockout” mice) have a largely normal phenotype, suggesting that there are no 
serious safety concerns associated with depletion of Cad-11. Therefore, repeat-dose 
non-clinical toxicology studies are the principal guide to potential adverse drug reactions 
from long-term dosing with RO7123520. Those studies did not reveal any findings of 
particular concern for dosing patients at the proposed doses of up to 810 mg for up to 
24 weeks. The preclinical safety profile in repeat-dose GLP toxicology studies in rats and 
cynomolgus monkeys, and the associated margins versus NOAEL exposures, support 
the initiation of long-term clinical studies. Using model-predicted human exposure from 
810 mg dosing, the exposure margins based on NOAEL exposures in the 26-week rat 
and monkey studies, were 7-fold in rat and 9-fold in monkey with AUC-based safety 
margins, and 28-fold in rat and 54-fold in monkey with Cmax-based safety margins.


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The potential for clinically relevant drug-drug interactions between RO7123520 and 
other concomitant medications is believed to be minimal. There are no data available on 
the use of RO7123520 with MTX or biologic anti-TNF-therapies, but clinically important 
drug-drug interactions are not anticipated. There is limited potential for pharmacokinetic 
drug-drug interactions between monoclonal antibodies and other therapies, and because 
the mode of action of RO7123520 is distinct from those of MTX and anti-TNF-
therapies, clinically important pharmacodynamic drug-drug interactions are also not 
anticipated. In particular, because RO7123520 does not appear to have direct effects on 
the immune system, there is believed to be limited risk of clinically important 
immunosuppression from RO7123520 treatment, even when used in conjunction with 
immunosuppressive biological anti-TNF-therapies.
All study participants will undergo safety assessments at intervals throughout the study, 
including measurements of bone density and careful assessments of the skin 
(Section 5.1.2). No test article-related effects were observed in GLP toxicology studies in 
rats and monkeys, and hence do not indicate a requirement for specific safety 
monitoring measures. Non-clinical studies and available clinical data reveal no evidence 
suggesting a risk of clinically important immunosuppression and special measures to 
monitor immune function are not considered to be necessary.
Synovial fluid sampling, also termed arthrocentesis or joint aspiration, is a standard, 
minimally invasive technique that can be performed by rheumatologists in a clinic setting 
with minimal risk of complications or sequelae. While not routinely performed for 
management of patients in clinical practice, sampling in the context of a clinical study 
can be justified as an investigational tool in order to allow assessment of target 
engagement and local pharmacodynamic effects.
Patients who choose to participate in the optional synovial biopsy will have biopsies 
performed at the beginning and end of the study. Synovial biopsies are minimally 
invasive and are commonly used in clinical practice for diagnostic purposes. Closed-
needle processes are safely performed in a clinic setting, however they may be 
uncomfortable, require use of anesthetic and may result in post-procedural soreness.
There is also a risk of sequelae from the biopsy procedure such as pain, bleeding,
infection or damage to the joint, or surrounding nerves or blood vessels. Therefore, 
biopsies will only be performed on consenting individuals at selected study centers with 
experience of performing biopsies, i.e., centers where biopsies are routinely performed 
by experienced practitioners.
In summary, non-clinical data provide the necessary rationale that RO7123520 may 
provide a treatment benefit for patients with RA. The safety findings from the Phase 1 
study (Study SDP051-001) support the use of RO7123520 in patients with RA. Where 
theoretical risks from RA treatment have been identified, appropriate clinical safety 
monitoring measures are implemented. Hence, the risks to participants in this study are 
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2.
OBJECTIVES
2.1
PRIMARY OBJECTIVES
The primary objective of this study is:

To assess the safety, tolerability and efficacy of RO7123520 as adjunctive treatment 
with MTX and anti-TNF-therapy in patients with moderately to severely active RA 
with an anti-TNF-inadequate response (Study Parts 1,2,3).
2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:

To assess the dose-ranging efficacy of RO7123520 (Study Part 3).

To assess the exposure versus response relationship and immunogenicity of 
RO7123520 (Study Parts 1,2,3).
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To explore biomarker changes in serum, plasma, urine, synovial fluid and synovial 
tissue (Study Parts 1,2,3).

To explore biomarker changes and their relationship with clinical efficacy endpoints 
(Study Parts 1,2,3).

To explore joint changes by magnetic resonance imaging (MRI; Study Part 2).
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a Phase IIa/b double-blind, placebo-controlled, randomized, parallel group, global 
multicenter study to evaluate the safety and efficacy of RO7123520 as adjunctive 
therapy in patients with RA who are inadequately responding to standard-of-care (MTX 
and anti-TNF-therapy).
Patients with moderately to severely active RA will be recruited if they experience an
inadequate response to DMARD therapy with MTX plus anti-TNF-therapy for at least 
3 months before randomization. This first- and second-line therapy will be continued 
throughout the study. The MTX and anti-TNF-dose and product should not be changed 
during the study, unless for safety or intolerability reasons, until the primary endpoint 
assessment. All patients will receive concomitant folic acid supplementation as per local 
standard-of-care. The randomization will be stratified by the patient’s duration of prior 
anti-TNF-therapy (3-12 months vs 12 months) for Study Parts 2 and 3.


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The study will be conducted in three parts. A final safety visit will occur 8 weeks 
(German sites: 16 weeks) after the patient’s final study dose, regardless of the study part 
of the last received dose. See Figure 1 for an overview of the study design.
3.1.1.1
Part 1: Safety Cohort
A safety cohort of patients with moderately to severely active RA will be treated with 
RO7123520 as adjunctive therapy with MTX and anti-TNF-therapy. Nine patients will 
be randomized in a 1:2 ratio and will receive placebo (N3), or RO7123520 
360 mg/dose as adjunct treatment (N6). In Part 1 dosing will be staggered and no 
more than two patients will be dosed on any given day. Four doses of 
RO7123520/placebo will be given as IV infusions on Days 1, 14, 28 and 56 (see 
Section 3.2.2 for the rationale for dosage selection). A double-blind design will be used 
with placebo-administered patients receiving IV infusions of saline only. When all of the 
nine patients in Part 1 have reached the Day 42 (Week 6) visit, i.e., two weeks after the 
3rd dose administration, an Internal Monitoring Committee (IMC) along with an external 
Scientific Oversight Committee (SOC) will perform a safety review of unblinded data
(Section 3.1.2). The SOC and the IMC will advise the clinical trial team of their opinion 
on the study conduct.
The study will proceed to Part 2 if there are no more than one-third of the patients who 
received RO7123520 reporting serious study drug-related adverse events of a similar 
nature (e.g., laboratory abnormalities, vital sign changes, ECG changes, etc.) or if there 
are no other reasons to stop the study (see Section 4.7.2).
All patients in Part 1 will have the option of continuing to the Extension Period of the 
study (Section 3.1.1.4).
3.1.1.2
Part 2: Phase IIa Proof-of-Concept Study
In Part 2, a Phase IIa proof-of-concept study will be conducted in patients with 
moderately to severely active RA experiencing an inadequate response to DMARD 
baseline therapy with MTX plus anti-TNF-therapy
Ninety patients will be randomized in a 1:2 ratio and will receive MTX plus anti-TNF-
therapy plus placebo (N30), or MTX plus anti-TNF-plus RO7123520 810 mg/dose as 
adjunct therapy (N60) (see Section 3.2.2). As in Part 1, RO7123520 will be given as IV 
infusions on Days 1, 14, 28, and 56 (with patients randomized to placebo receiving IV 
saline), followed by the primary endpoint assessment at Week 12.
In Part 2 only, patients will undergo contrast-enhanced MRI imaging of the hand/wrist , 
the site to be determined by the Investigator, to confirm disease activity at baseline and 
examine joint changes in patients with active RA on MTX and inadequate response to 
anti-TNF-therapy. As Part 2 is the pivotal proof-of-concept part of the trial, only 
patients with active RA disease on an MRI will be enrolled. The MRI readings will be 


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conducted centrally by a blinded reader, and the Imaging CRO will confirm and 
communicate patient eligibility in Study Part 2 to the Investigator(s).
Once the first 45 patients in Part 2 have completed the Week 12 visit, an interim analysis 
will be conducted (Section 6.9) with the opportunity to stop the study for futility, initiate 
Part 3 of the study (Section 3.1.1.3) or continue Part 2 until all 90 patients have 
completed the Week 12 visit.
The study will proceed to Part 3 if there are no more than one-third of the patients who 
received RO7123520 reporting serious study drug-related adverse events of a similar 
nature (e.g., laboratory abnormalities, vital sign changes, ECG changes, etc.) and if 
there are no other reasons to stop the study (see Section 4.7.2).
All patients in Part 2 will have the option of continuing to the Extension Period of the 
study (Section 3.1.1.4).
3.1.1.3
Part 3: Phase IIb Dose-Ranging Study
Based on the results of an interim analysis planned during Part 2 of the study 
(Section 6.9), the Phase IIb dose-ranging part of the study will begin. Applying the same 
criteria as in Part 2 (i.e., patients with moderately to severely active RA experiencing an 
inadequate response to DMARD baseline therapy with MTX plus anti-TNF-therapy), 
105 patients will be randomized 2:2:2:1 to one of three selected RO7123520 doses, and 
placebo (or 5:5:5:5:1 if four RO7123520 doses and placebo are selected) in the range of 
90 mg/dose to 720 mg/dose (e.g., 90, 180, 450 mg/dose). Final doses and the number 
of dose arms (3 or 4) for Part 3, along with the clarification of the sample size 
(Section 6.1) will be decided after analysis of safety and efficacy in the Part 2 interim 
analysis (Section 6.9). Patients will receive study treatment on Days 1, 14, 28, and 56, 
followed by the primary endpoint assessment at Week 12. 
All patients in Part 3 will also have the option of continuing to the Extension Period of the 
study (Section 3.1.1.4).
3.1.1.4
Extension Period
In Parts 1, 2 and 3, following the blinded, placebo-controlled 12-week study and 
Week 12 visit assessments, an optional extension period will be conducted to collect 
additional safety and efficacy data up to Week 24, with the last dose being administered 
at Week 20 (Appendix 2). A final safety visit will occur at Week 28 (German sites: 
Week 36).
Patients who received active treatments in Study Parts 1, 2 or 3 will continue on the 
same dose of RO7123520 as they previously received in Parts 1, 2 or 3. It is planned 
that patients who received placebo treatment in Part 1 will receive a 360 mg dose, while 
patients on placebo in Parts 2 or 3 will receive an 810 mg dose of RO7123520, although 
a lower dose may be employed at the recommendation of the IMC/SOC.


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Figure 1
Study Design
Note: This figure displays the follow-up period for non-German sites; for German sites, the follow-up period is from Day 85 to 
Day 168.




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3.1.1.5
Study Duration
The total duration of the study for each patient will be up to 32 weeks (German sites: 
40 weeks) divided as follows:

Screening: Up to 4 weeks

Study treatment duration: Days 1 up to 84 (Baseline to Week 12)

Study treatment duration including Extension Period: Days 1 up to 168 (Baseline to 
Week 24)

Safety Follow-up: Day 112 (Week 16). German sites: Day 112 (Week 16) and 
Day 168 (Week 24)

Safety Follow-up including Extension Period: Day 196 (Week 28). German sites: 
Day 196 (Week 28) and Day 252 (Week 36)
Patients in Study Part 1 will be required to stay overnight at the Study Center after each 
dose of study treatment up to and including the Week 8 administration. The first 
15 patients in Part 2 will be required to stay overnight at the Study Center after the first 
dose of study treatment, or alternatively, two visits within 24 hours post-dose can be 
made by an ambulatory at-home visiting nurse to perform assessments as described in 
the SoA.
3.1.2
Internal Monitoring Committee and Scientific Oversight 
Committee
To carefully review the accumulating safety data for RO7123520, and to decide upon the 
doses selected for inclusion into Part 3 of the study, an Internal Monitoring Committee 
(IMC) and Scientific Oversight Committee (SOC) will be established.
The IMC will include Sponsor representatives from Translational Medicine, Drug Safety, 
Clinical Pharmacology and Biostatistics. The SOC members will be external experts in 
the field of RA. The SOC will function as a consultative body to the Sponsor, providing 
individual expert opinions. The Sponsor retains all decision-making authority for this 
study.
The first safety review meeting will be held once the 9th patient from Part 1 has 
completed the Week 6 visit (i.e., two weeks after their 3rd dose of RO7123520/placebo). 
The IMC and SOC will then meet approximately every month until the Part 2 interim 
analysis (Section 6.9) to review unblinded summaries of overall rates of death, SAEs, all 
AEs, and AEs leading to treatment discontinuation. In addition, the IMC and SOC will 
meet once the first 15 patients in Study Part 2 have completed their overnight stay after 
their first infusion of RO7123520/placebo, to determine whether the overnight stay will 
be a requirement for subsequent patients entering into Part 2 of the study. After the Part 
2 Interim Analysis, the IMC and SOC will meet approximately every 3-6 months. All 
enrolled patients will be included in the safety summaries. 


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At the time of each review, the IMC and SOC will make one of the following 
recommendations: the trial continues as planned, a study arm stops, the protocol be 
amended, additional analyses be performed, or enrollment be held pending further 
safety evaluations. At the time of the interim analysis within Part 2 (Section 6.9), the IMC 
and SOC can also recommend the study stop for futility, or select the doses to be used 
in Part 3 and select the sample size for Part 3.
To maintain adequate patient safety oversight throughout the conduct of the study, all 
SAEs will be reviewed by the IMC Chair or delegate within 24–48 hours after being 
reported, and serious, unexpected, related AEs will be reviewed for regulatory reporting 
purposes per Roche standard operating procedures and will be submitted to the 
appropriate regulatory agencies, Institutional Review Boards (IRBs) and Independent 
Ethics Committees (IECs), and to the Investigators. 
Further interim exploration of safety may be performed, if deemed necessary, at any 
time during the conduct of the study.
3.1.3
End of Study
The end of the study is defined as the date when the last patient last observation (LPLO) 
occurs. LPLO is expected to occur 28 weeks (German sites: 36 weeks) after the last 
patient is enrolled.
3.2
RATIONALE FOR STUDY DESIGN
3.2.1
Rationale for Design
The study comprises three double-blind parts which will be run sequentially: Part 1 is an 
initial safety cohort intended to establish the safety and tolerability of repeat dosing of 
RO7123520 in patients with RA receiving MTX and anti-TNF-therapy; Part 2 is 
intended to demonstrate the effectiveness of RO7123520 as a treatment for RA; while 
Part 3 is intended to characterize the dose vs. response relationship to identify the dose 
of RO7123520 with the optimal benefit-risk profile. The three part structure has been 
implemented to allow assessment of the safety and efficacy of RO7123520 in a 
staggered manner which minimizes the number of individuals exposed to study drug at 
each step. In particular, Part 1 is an initial safety cohort in a small number of patients 
(6 active, 3 placebo) to generate pharmacokinetic, safety and tolerability data before 
commencing with dosing in a larger number of patients in Part 2. 
While Study SDP051-001 provided clinical experience of administration of single doses 
to healthy volunteers, this study represents the first study to test repeat dosing of 
RO7123520 in patients with RA also receiving MTX and anti-TNF-therapy. Therefore, 
Part 1 includes design elements intended to minimize the potential risk to individual 
participants. These include use of a low dose of study drug (see Section 3.2.2), use of 
staggered dosing, a period of in-clinic residency and close medical supervision after 
each dosing, extensive safety monitoring measures, ongoing generation and review of 


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pharmacokinetic data, and periodic review of unblinded data by an IMC/SOC including 
members independent of the Sponsor. 
Part 2 will only proceed if pre-specified safety criteria are met, and the IMC/SOC confirm 
that the study design remain appropriate (e.g., observed pharmacokinetic exposure data 
support original dose selection). Furthermore, Part 2 also includes a period of in-clinic 
residency and close medical supervision for first dosing for the first 15 patients enrolled,
as well as review of unblinded data by an IMC/SOC. In this regard, the procedures for 
Parts 1 and 2 encompass all of the design elements typically expected in the early 
clinical development program for a new pharmaceutical agent with a novel mechanism 
of action.
The study also includes the possibility for patients who complete double-blind treatment 
to participate in an optional 12 week extension period in which all participants will 
receive RO7123520 treatment. This extension period is included to allow generation of 
data on longer-term use of RO7123520, and thereby help to characterize the benefit-risk 
profile from longer periods of treatment.
3.2.2
Rationale for Dosage Selection
Selection of the proposed dosing algorithm, dosing regimen and range of doses to be 
investigated has been based primarily on modelling of pharmacokinetic data from the 
Phase I study SDP051-001 and simulations to predict RO7123520 exposures from 
multiple dosing under a variety of different dosing scenarios. Direct extrapolation of 
pharmacokinetic data from healthy volunteers to a patient population is possible based 
on the linear pharmacokinetic behavior of RO7123520 in Study SDP051-001 and the 
apparent absence of saturable pharmacokinetic processes (such as Fc receptor 
involvement in clearance) in the relevant concentration range. The available clinical 
safety and non-clinical pharmacology and toxicology data have also been used to inform 
the selection. Overall, doses have been selected which are predicted to produce 
exposures similar to those already studied in humans, and which also maintain margins 
versus NOAEL exposures in preclinical toxicology studies (see also Section 1.3.2).
3.2.2.1
Dosing Algorithm Selection
The pharmacokinetic model of data from Study SDP051-001 was used to explore the 
influence of intrinsic factors on RO7123520 pharmacokinetics and specifically to 
evaluate the need for a dosing algorithm incorporating body weight (i.e., mg/kg dosing). 
There was no apparent relationship between body weight and any of the four 
pharmacokinetic model parameters (V, CL, V2, or CL2). Similarly there was also no 
clear relationship between body weight and primary (V and CL) or secondary (AUCinf, 
Cmax, t1/2) pharmacokinetic parameters estimated by non-compartmental methods. Hence, 
it is concluded that based on the available data from dosing in healthy volunteers, total 
body weight is not a good predictor of RO7123520 exposure. This is supported by 
simulations comparing the performance of body weight-adjusted dosing against a 
uniform “flat” dose (i.e., mg/kg dosing vs. same dose for all individuals regardless of 


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body weight). There were no apparent differences in average exposures, or 
corresponding ranges of exposures, between the two different algorithms (Figure 2). 
Therefore, a dosing algorithm based on individual body weight is not anticipated to 
reduce inter-individual variability in exposure compared with a uniform fixed dose.
Figure 2
Simulated Plasma Concentration versus Time Profiles from 10 mg/kg 
and 800 mg Dosing Algorithms
Body-weight dosing
Fixed dose
Black lines represent arithmetic mean, red lines represent associated 95% CIs.
3.2.2.2
Dosing Regimen Selection
To inform selection of an appropriate dosing regimen and dose, the same 
pharmacokinetic model was used to simulate RO7123520 plasma concentrations from a 
variety of different dosing schemes. These simulations predict that the proposed dosing 
regimen will lead to achievement of steady state after the second dose (i.e., Day 14 
dose) (Figure 2) and no further significant accumulation in either the central or peripheral 
compartments is predicted even with continued monthly dosing. Simulations have been 
used to predict steady state RO7123520 exposures for different doses using the 
proposed dosing regimen (Figure 3).




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significantly exceed the range of exposures already demonstrated to be well tolerated in 
healthy volunteers. 
Doses between 90 mg/dose and 810 mg/dose are anticipated to encompass a 
clinically-effective dose-range. Quantitative predictions of a clinically-effective 
dose-range have been based on in vivo studies in a relevant murine model of 
rheumatoid arthritis involving synovitis (the KBN model). RO7123520 reduced swelling 
of joints and joint destruction in a dose-dependent manner. At 10 mg/kg, RO7123520 
significantly reduced joint inflammation, with a trend towards reduced joint swelling also 
at 3 mg/kg (see RO7123520 Investigator’s Brochure). The reduction of joint swelling by 
RO7123520 was correlated with a reduction in joint destruction (e.g., reduced cartilage 
erosion, bone erosion and decreased inflammatory cell infiltrates) and a reduction in the 
levels of some cytokines implicated in rheumatoid arthritis pathogenesis in humans. 
Although there has been no formal exposure versus response analysis, the observed 
serum concentrations of RO7123520 at doses which produce efficacy in the KBN model 
permits estimation of a potentially clinically efficacious exposure range in humans. A 
10 mg/kg dose of RO7123520 produced average circulating concentrations of 
125 g/mL. Based on the observation that RO7123520 demonstrates similar binding to 
human and mouse Cad-11-expressing cells, and assuming that the relative distribution 
of RO7123520 into synovial joints is consistent between animals with KBN-induced 
arthritis and human patients with rheumatoid arthritis, it is considered that a serum 
concentration of approximately 100 g/mL is a relevant exposure target to maximize the 
potential for detecting a treatment effect on efficacy parameters. 
Using the pharmacokinetic model described above to simulate exposures from different 
doses (Figure 2 and Figure 3), it is predicted that 810 mg/dose will provide serum 
exposures which achieve this target in most individuals e.g., average serum 
concentrations exceed 100 g/mL throughout the dosing interval. For this reason, 
810 mg/dose has been selected as the dose for Part 2. However, this prediction does 
not preclude the possibility that clinically-relevant treatment effects may be achieved 
from lower exposures, and therefore the dose-range-finding in Part 3 will also explore a
range of lower doses in order to characterize the clinical exposure versus response 
relationship and establish the minimally effective dose. The lowest dose planned to be 
tested is 90 mg/dose, meaning that that overall a 9-fold range of doses will be tested.
3.2.3
Rationale for Study Population
Although there are a number of efficacious standard-of-care treatments (i.e., cDMARDs 
and biologics) for RA patients, many patients still experience significant ongoing disease 
activity. For example, a meta-analysis of different cDMARD and anti-TNF-studies 
revealed that only 22%58% (mean 39%) of RA patients achieve an ACR50
improvement, indicating that there are many patients who continue to have active 
disease (Bergmann et al 2010). Synovial fibroblasts are the major non-immune cell
population of the inflamed RA joint and are thought to play a significant role in cartilage 


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destruction and in tissue inflammation. Therefore, targeting synovial fibroblasts 
comprises an attractive and novel non-immunosuppressive approach for interrupting 
pathophysiology of the RA joint, particularly if combined with existing DMARDS and 
biologics as an adjunctive approach to increase efficacy without increasing 
immunosuppressive side effects. Therefore, evaluating the efficacy and safety of 
RO7123520 as an adjunctive treatment in patients who have an inadequate response to 
the immunosuppressive therapy using MTX plus an anti-TNF-therapy is reasonable.
Patients with RA will also potentially be taking a number of concomitant medications. 
These will include the protocol-specified anti-arthritis background therapy of the non-
biologic DMARD, MTX, and biologic anti-TNF-therapies (e.g., etanercept, adalimumab, 
certolizumab pegol, golimumab, etc.) but also miscellaneous other therapies for co-
morbid conditions. There are no data available on the use of RO7123520 with MTX or 
biologic anti-TNF-therapies, but clinically important drug-drug interactions are not 
anticipated for the following reasons:

There is limited potential for pharmacokinetic drug-drug interactions between 
monoclonal antibodies and other therapies (Ferri et al 2016). Although it has been
reported that MTX treatment reduces the clearance of some antibody based 
therapies used in RA (e.g., infliximab and adalimumab), this is hypothesized to arise 
from changes in target mediated drug distribution as a consequence of 
methotrexate-mediated reductions in TNF-levels (Xu et al 2015, Ternant et al 
2015). This mechanism is considered not relevant for RO7123520.

Based on the mode of action of RO7123520 (i.e., targeting the extracellular domain 
of the Cad-11 cell adhesion molecule), clinically important pharmacokinetic drug-
drug interactions are not anticipated. In particular, RO7123520 has a novel mode of 
action that is distinct from those of MTX and anti-TNF-therapies and other 
therapies currently in use for management of rheumatoid arthritis. Although it is 
reported that the COX2 selective non-steroidal anti-inflammatory drug celecoxib 
also inhibits Cad-11 (Assefina et al 2014), no other currently approved medications
have the same mode of action. Therefore there is limited likelihood of direct 
pharmacodynamic interactions between RO7123520 and other medications.

There is believed to be limited risk of interactions leading to clinically important 
safety concerns with other biologic therapies. RO7123520 does not appear to have 
direct effects on the immune system and PD effects are anticipated to be localized 
to those tissues where Cad-11 is expressed (i.e., predominantly the synovial joints). 
In the absence of systemic immunosuppressive effects from RO7123520, there is 
believed to be limited risk of clinically important immunosuppression from 
RO7123520 treatment, even when used in conjunction with immunosuppressive 
biologic therapies.
3.2.4
Rationale for Control Group
A placebo control group in Parts 1, 2, and 3 is justified in this early phase of 
development, as it will minimize the potential bias in reporting of adverse events, the 


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assessment of outcome measurements and assessment of laboratory abnormalities 
during the course of this study. Patients in the control group will be on placebo for 12 
weeks, which is acceptable according to the EMA and FDA guidance for clinical trials in 
RA. Outcome measures in RA trials involve elements of subjective measures (e.g., 
patient’s assessment of diseases status, pain, global function in ACR criteria) and 
therefore carry a high rate of placebo response (e.g., up to 11% non-specific ACR50 
response) (Azaïs et al 2016). Therefore, the use of a placebo group in this randomized,
double-blind, placebo-controlled trial is the most rigorous test for evaluating treatment 
efficacy of RO7123520.
3.2.5
Rationale for Biomarker Assessments
The biomarker strategy applied in this study aims to measure molecular markers that 
may be useful to define the prognosis and disease severity of the patients, to assess the 
mode of action/PD effects and to potentially identify predictive biomarkers. Specific 
blood cell markers will also be used as safety biomarkers.
All patients will be contributing mandatory serum, plasma and urine samples for
biomarker measurements. Biomarkers may also be measured in synovial fluid and 
synovial tissue in patients who consent to fluid sampling (optional) and/or tissue biopsies 
(optional). 
The potentially prognostic and disease severity markers measured will help to better 
characterize the patients in this study and will include the multi-biomarker disease 
activity (MBDA) test and type II collagen C-telopeptide (CTX-II). The MBDA test has
been developed to analyze 12 protein biomarkers in serum, including interleukin-6 (IL-6)
and C-reactive protein (CRP) (Centola et al 2013) and was identified as a good predictor 
for one year radiographic progression in early RA (Hambardzumyan et al 2015). Patients 
with high urinary CTX-II levels were found as having a higher risk for the progression of 
joint damage over one year (Qvist et al 2011).
The safety blood biomarkers, which will include T cells, B cells, NK cells, granulocyte
and monocyte markers, will be monitored during treatment to confirm the 
non-immunosuppressive profile of RO7123520.
The selected PD biomarkers are expected to reflect the changes upon treatment in the 
various tissues and cellular components involved in the damaged joint affected by the 
disease, complementing the traditional efficacy endpoints (e.g., disease activity score 28 
[DAS28], clinical disease activity index [CDAI], etc.) and imaging techniques used in the 
study. In particular, the bone remodeling and cartilage markers may include but will not 
be limited to C-terminal telopeptide of type I collagen (CTX-I), aminoterminal propeptide 
of type I collagen (PINP) and osteocalcin. Inflammatory, synovial and angiogenesis 
markers may also be measured, which are expected to be regulated upon Cad-11 
engagement. The exploratory analysis of those markers should allow better 
understanding of the mode of action of RO7123520.


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In addition, the potential utility of synovial fluid and synovial protein, and RNA 
biomarkers may be investigated to facilitate the understanding of the target and mode of 
action of RO7123520. The RNA biomarkers may be measured with next-generation 
sequencing (NGS) methods.
Cadherin-11 expression in synovium and synovial fluid might differ from patient to 
patient which might impact the response to the treatment. The expression of Cad-11 in 
the synovium might be measured by tissue staining while the soluble form of Cad-11 will 
be measured (shed Cad-11) in the synovial fluid of patients who consented to the 
sampling. Blood soluble Cad-11 concentrations which might vary upon treatment may 
be measured by immunoassay.
MRI scans will be performed to assess disease severity for patients in Study Part 2. 
Inflammatory lesions in the joints and the bone erosion will be evaluated, and soft tissue 
and bone marrow involvement will be assessed. The readings will be done centrally, by 
a blinded reader. 
As active synovitis of the hand/wrist as determined by MRI is an inclusion criterion for 
active disease in Part 2 (Section 4.2.2), the central reader will also give the confirmation 
that this criterion is met.
3.2.6
Rationale for Pharmacokinetic Assessments
Samples will be collected at each visit for measurement of serum concentrations of 
RO7123520. These data will be used for population PK and PK/PD modelling at the end 
of Parts 2 and 3 of the study, but samples will be analyzed on an on-going basis and 
concentration data will also be reviewed as part of the periodic IMC/SOC reviews to 
verify that RO7123520 exposures are within the expected ranges.
RO7123520 concentrations will also be measured in synovial fluid samples collected at 
the end of treatment. These data will provide information on tissue distribution and drug 
exposures at the site of action. In addition, because the bioanalytical assay only detects 
free RO7123520 molecules that are not bound to Cad-11, synovial concentrations also 
have the potential serve as a surrogate marker of target engagement (i.e., detectable 
synovial RO7123520 concentrations implies a surplus of drug and complete target 
engagement).
3.3
OUTCOME MEASURES 
3.3.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature and severity of adverse events, including targeted adverse events, 
number of participants with SAEs, treatment-related SAEs, SAEs leading to 
discontinuation, treatment-related AEs, or AEs leading to discontinuation


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
Incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results

ECGs

Vital signs

Assessment of bone remodeling and cartilage markers (e.g., CTX-I, PINP and 
osteocalcin)

Assessment of blood cell markers (including, but not limited to, CD4, CD8, CD19,
CD16/56, CD3, CD45, CD14)

Anti-drug antibodies (ADA)

Bone mineral density lumbar spine L1-L4 by dual energy X-ray absorptiometry 
(DEXA) scans, which involves the exposure of a very small amount of X-ray 
radiation around one to six microSievert (μSv).
3.3.2
Pharmacokinetic Outcome Measures
RO7123520 serum and synovial fluid concentration data will be pooled with 
corresponding data from other studies (e.g., SDP051-001) for population PK and PK/PD 
modelling of the exposure versus response relationship.
3.3.3
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure:

Proportion of patients achieving an ACR50 response at Week 12
Secondary Outcome Measures:

Change from baseline in CDAI Score at Week 12

Change from baseline in DAS28 at Week 12

Proportion of patients achieving DAS28 remission at Week 12

Proportion of patients achieving CDAI remission at Week 12

Proportion of patients achieving an ACR20 response at Week 12

Proportion of patients achieving an ACR70 response at Week 12

Simple Disease Activity Index (SDAI) Score at Week 12

Change from baseline in the Stanford Health Assessment Questionnaire Disability 
Index (HAQ-DI) at Week 12


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3.3.4
Exploratory Outcome Measures
The exploratory outcome measures for this study include but are not limited to the 
following:

Proportion of patients achieving an ACR50 response at Week 24

CDAI Score at Week 24

DAS28 at Week 24

Proportion of patients achieving DAS28 remission at Week 24

Proportion of patients achieving CDAI remission at Week 24

Proportion of patients achieving an ACR20 response at Week 24

Proportion of patients achieving an ACR70 response at Week 24

Proportion of patients achieving a mACR50 response at Weeks 12 and 24

Proportion of patients achieving a mACR20 response at Weeks 12 and 24

Proportion of patients achieving a mACR70 response at Weeks 12 and 24

SDAI Score at Week 24

Change from baseline in the Stanford HAQ-DI at Week 24

Change from baseline in Short-form 36 health questionnaire Physical and Mental 
Health component scores (SF36V2 standard recall) at Weeks 12 and 24

Change from baseline in Brief Fatigue Inventory (BFI) total and item scores at 
Weeks 12 and 24

Change from baseline in patient global assessment of disease activity at Weeks 12 
and 24

Change from baseline in patient global assessment of pain at Weeks 12 and 24

Change from baseline in Cad-11 synovium level in synovial fluid and blood soluble
Cad-11 concentration at Weeks 12 and 24

Change from baseline of the PD biomarkers (e.g., bone remodeling and cartilage 
markers) at Weeks 12 and 24

Change from baseline in synovitis, osteitis, joint erosions, cartilage loss, bone 
marrow edema, total damage and total inflammation at Weeks 12 and 24 evaluated 
by rheumatoid arthritis MRI score (RAMRIS) of the hand/wrist
4.
MATERIALS AND METHODS
4.1
CENTER
This is a multi-center study to be conducted in multiple countries. Additional site(s) may 
be included for back-up purposes and may be activated if needed.
Administrative and Contact Information, and List of Investigators are provided separately.


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4.2
STUDY POPULATION
4.2.1
Recruitment Procedures 
Patients will be identified for potential recruitment using pre-screening enrollment logs, 
IEC/IRB approved newspaper/radio/television/internet advertisements, social media,
mailing lists, and referral letters to other physicians.
4.2.2
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Able and willing to provide written consent by signing the Informed Consent Form 
(ICF), and to comply with the study protocol according to ICH and local regulations.
2.
Adult men and women, of more than 18 years of age.
3.
Diagnosis of adult-onset RA as defined by the American College of Rheumatology 
(ACR) 2010 criteria (Aletaha et al 2010), for at least 6 months before screening.
4.
Moderately to severely active RA as defined by at least 4/28 tender joints and at 
least 4/28 swollen joints (Note: surgically treated joints cannot be counted in 
TJC/SJC for enrollment purposes).
5.
For Part 2 only: Active synovitis and/or osteitis as determined by contrast-enhanced
MRI.
6.
Patients must be taking one of the following anti-TNF-therapies: certolizumab, 
golimumab, etanercept, adalimumab, infliximab or approved biosimilars of these, 
given at a recommended and stable dose for at least 12 weeks before randomization, 
and have experienced in the opinion of the Investigator an inadequate response to 
anti-TNF-therapy with a DAS28 3.2.
Note: prior use of other anti-TNF-therapies is allowed.
7.
Patients must be taking MTX (PO, SC, or IM) for at least 12 weeks before 
randomization and must be on a stable dose for at least 4 weeks before 
randomization (5.0 to 25 mg/week). 
Note: The dose of MTX is expected to remain stable throughout the study and may 
be adjusted only for safety or intolerability reasons. Local standard-of-care should 
be followed for concomitant administration of folic acid.
8.
Patients on glucocorticoids (10 mg/day PO prednisone or equivalent) are 
permitted if doses are stable within 6 weeks of planned randomization. 
Note: Patients should remain on stable doses of glucocorticoids throughout the 
duration of study unless for medical reasons (e.g., safety, intolerability, RA flare, etc).
9.
Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) intermittently 
(e.g., up to 2-3 times weekly) for short-term relief of pain are allowed, and patients 
on regular NSAID use (i.e., on stable dose for 4 weeks) are allowed.
Note: NSAIDs must not be taken for at least 2 days before clinical assessments in 
the study for patients with intermittent use of NSAIDs. If needed for symptomatic 
relief, paracetamol (up to 3 g/day) is permitted.


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10. Negative pregnancy test at screening and baseline (women only), and agreement to 
comply with measures to prevent pregnancy and restrictions on sperm donation as 
follows:

Male or female patients: The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.

For males: men with female partners of childbearing potential or pregnant female 
partners must remain abstinent or use a condom during the treatment period and up 
to the post-treatment follow-up visit to avoid exposing the embryo. Men must refrain 
from donating sperm during this same period.

For females: Females are eligible to participate if not pregnant and not 
breastfeeding. A woman of childbearing potential and female partners with 
childbearing potential of male patients must agree to remain abstinent (refrain from 
heterosexual intercourse) or use one highly effective form of contraception that 
results in a failure rate of 1% per year during the treatment period and up to the 
post-treatment follow-up visit. A woman is considered to be of childbearing potential 
if she is post-menarcheal, has not reached a post-menopausal state (12 
continuous months of amenorrhea with no identified cause other than menopause), 
and has not undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.

Male and female patients should continue to use contraception after the last study 
drug administration until the end of relevant systemic exposure (i.e., ~115 days).
4.2.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Parenteral glucocorticoids administration (IM, IV) of 50 mg within 6 weeks or 
≤50 mg within 4 weeks prior to planned randomization, or scheduled parenteral 
administrations during the study.
2.
Joint(s) injected with intra-articular glucocorticoids within 6 weeks prior to planned 
randomization.
3.
Active inflammatory diseases of the joints not related to RA: Gout, reactive arthritis, 
psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease
4.
Systemic autoimmune disease other than RA: Systemic lupus erythematosus, 
Crohn's disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, 
mixed forms of connective tissue inflammatory diseases.
5.
Juvenile idiopathic arthritis or juvenile RA and/or RA developed before the age of 16.


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6.
Active fibromyalgia that makes appropriate assessment of RA disease activity 
challenging in the opinion of the Investigator.
7.
RA patients functional status class IV according to the ACR 1991 criteria 
(i.e., largely or wholly incapacitated permitting little or no self-care, such as being 
bedridden or confined to wheelchair).
8.
Patients with severe chronic or recurrent viral, bacterial, parasitic or fungal infections.
9.
History of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV) infection.
10. Any identified confirmed congenital or acquired immunodeficiency.
11. Abnormal laboratory values:
o
Hemoglobin level is less than 80 g/L.
o
Leucocyte level is less than 2.5 109/L.
o
Absolute neutrophil count is less than 1.0 109/L.
o
Thrombocyte level is less than 75 109/L.
12. Laboratory test results for liver function meeting criteria for marked abnormality 
(ULN: upper limit of normal): Alkaline phosphatase: 3 ULN; aspartate 
aminotransferase: 3 ULN; alanine aminotransferase: 3 ULN; -glutamyl 
transferase: 3 ULN.
13. Other unstable somatic diseases apart from RA that can increase the probability of 
adverse events during the study; mask, enhance or alter the symptoms of RA or 
cause clinical or laboratory symptoms similar to that of RA.
14. Major surgery within 28 days prior to randomization, or planned major surgery 
(e.g., elective joint replacement surgery) during the trial.
15. Any mental disorder, including major depressive disorder and/or suicidal thoughts in 
anamnesis that can, in the Investigator's opinion, create a risk for the patient or 
influence the patient's ability to follow the study protocol.
16. Myocardial infarction within less than 6 months prior to participation in the study.
17. Severe central or peripheral nervous system diseases.
18. Chronic drug or alcohol abuse.
19. Known hypersensitivity to any components of the medications used in the study. 
20. Acute forms of any infectious diseases or history of chronic infections with severe 
clinical manifestations that would increase risk in participation of trial in the opinion 
of the Investigator.
21. Presence of malignant neoplasm, with the exception of adequately treated basal cell 
carcinoma and cervical carcinoma in situ and any malignancy with complete 
remission of more than 5 years.
22. Simultaneous participation in any other clinical trial, as well as former participation in 
other clinical trials within 3 months before this study initiation; and previous study 
drug administration in this study.


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23. German sites: Patients who are institutionalized due to regulatory or juridical order.
24. German sites: Patients who are occupationally or medically dependent on the 
Sponsor, the Investigator, or the medical site.
4.3
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Randomization will be performed centrally by an Interactive (voice/web) response 
system (IxRS) vendor. Patients will be stratified by the duration of prior anti-TNF-
therapy (3-12 months vs. 12 months) for Study Parts 2 and 3.
The first 12 weeks of the study will be double-blind. Blinding to study treatment allocation 
will be achieved through administration of placebo (i.e., saline only) infusions. Neither 
the patient, nor the Investigator, nor the CRO and Sponsor personnel directly involved in 
managing the study, except for the members of the IMC/SOC, will be aware of the 
treatment allocation. The randomization list will, however, be made available to the staff 
at bioanalytical laboratories, and to the Sponsor personnel responsible for 
pharmacokinetic and pharmacodynamic bioanalysis, as well as members of the 
IMC/SOC. Access to data that are potentially unblinding (e.g., pharmacokinetic 
concentration data) will be restricted accordingly. The qualified individual responsible for 
dispensing the study drug will not be blinded.
Patients entering the Extension Period following 12 weeks in Study Part 1 will receive 
open-label RO7123520 360 mg throughout the Extension Period. Patients entering the 
Extension Period following 12 weeks in Study Part 2 will receive open-label RO7123520 
810 mg throughout the Extension Period. Patients entering the Extension Period 
following 12 weeks in Study Part 3 will receive RO7123520 throughout the Extension 
Period and the RO7123520 dose level will be blinded to both the patient and Investigator 
(see Section 3.1.1.4 for details).
If unblinding is necessary for patient management (in the case of a serious adverse 
event), the Investigator will be able to break the treatment code by contacting the IxRS. 
Treatment codes should not be broken except in emergency situations. If the 
Investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly. The Investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a SAE).
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs (see Section 5.1) that are considered by the Investigator 
to be related to study drug.


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4.4
STUDY TREATMENT
4.4.1
Formulation, Packaging, and Handling
RO7123520 drug product (30 mg/mL) will be provided as a sterile, colorless to 
brown-yellowish liquid and contains no preservatives. Each single-use, 6 mL vial with a 
nominal 3.0 mL fill contains 90 mg (nominal) of RO7123520 formulated as 30 mg/mL in 
L-histidine/HCl buffer solution containing sodium chloride and polysorbate 20. For IV
infusion, RO7123520 concentrate for solution for infusion should be diluted in 0.9% (w/v) 
sodium chloride solution prior to administration. The recommended storage conditions 
for the drug product are between 2°C-8°C and protected from light. The drug product 
must not be frozen.
Patients randomized to placebo will receive IV infusions of saline alone, therefore no 
actual matching placebo will be provided. It is not possible to differentiate between the IV 
bags which contain only saline and those which have RO7123520 added.
Study drug packaging will be overseen by the Roche clinical trial supplies department
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.
The study drug must be stored according to the details on the product label. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery.
For further details, see the RO7123520 Investigator’s Brochure and the Pharmacy 
Manual.
4.4.2
Dosage, Administration and Compliance
Infusions will be administered IV over approximately 60 minutes or longer until the IV 
bag is empty. For further details on the preparation of RO70123520 for dosing, see the 
Pharmacy Manual. The administration of RO7123520 must be separated by at least one 
hour (end of administration first drug to start of administration second drug) from any 
other parenteral administration (anti-TNF-α, MTX or other).
Patients who receive active treatments in Study Parts 1, 2 or 3 and chose to participate 
in the optional extension period will continue on the same dose of RO7123520 they 
previously received in Parts 1, 2 or 3. Patients who receive placebo treatment in Part 1 
and choose to participate in the optional extension will receive a 360 mg dose, while 
patients on placebo in Parts 2 or 3 will receive an 810 mg dose of RO7123520 although 
a lower dose may be employed at the recommendation of the IMC/SOC.


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The qualified individual responsible for dispensing the study drug will prepare the correct 
dose according to the randomization schedule. This individual will write the date 
dispensed and patient number and initials on the study drug vial label and on the Drug 
Accountability Record. This individual will also record the study drug batch number
received by each patient during the study.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.
4.4.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study 
(RO7123520) will be provided by the Sponsor. The investigational site will acknowledge 
receipt of IMPs, to confirm the shipment condition and content. Any damaged shipments 
will be replaced.
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the patient to whom the study drug was dispensed (for example,
patient initials and date of birth)

All records and drug supplies must be available for inspection by the Roche Monitor 
[at every monitoring visit]
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons. In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Written documentation of destruction must contain the following:

Identity [batch number] of investigational product[s] destroyed

Quantity of investigational product[s] destroyed

Date of destruction


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
Method of destruction

Name and signature of responsible person [or company] who destroyed 
investigational product[s]
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.4.4
Post-Trial Access to RO7123520
The Sponsor does not intend to provide RO7123520 or other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal.
4.5
CONCOMITANT THERAPY
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
drugs, approved dietary and herbal supplements, nutritional supplements used by a 
patient from 30 days prior to screening until the follow-up visit. All concomitant 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF).
All medications (prescription and over-the-counter [OTC]) taken within 30 days of study 
screening will be recorded on the appropriate eCRF.
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF.
Patients must be receiving stable regimens of MTX (i.e., 5.0 to 25 mg/week, per oral, 
subcutaneous, or intra-muscular application) and at least one anti-TNF-therapy (from 
the following certolizumab, golimumab, etanercept, adalimumab, infliximab or approved 
biosimilars of these) in order to be eligible for the study. The recommended dose of anti-
TNF-therapy should be stable for at least 12 weeks, and the dose of MTX should be 
stable for at least 4 weeks before randomization. The doses should not be adjusted 
during the study except for safety or intolerability reasons.
Local standard-of-care should be followed for concomitant administration of folic acid.
Where possible all other concomitant medications (e.g., glucocorticoids, NSAIDs) should 
be kept stable during the study and only adjusted where clinically indicated, e.g., as in 
RA flare.
All prohibitions and requirements for treatment with anti-TNF-therapies and MTX as 
described in local approved labelling are to be complied with by the Investigator and the 
patient.


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4.5.1
Prohibited Therapy
The following medications are prohibited after randomization:

Live vaccines, including herpes zoster vaccination. Non-live seasonal vaccinations 
and/or emergency vaccination, such as rabies or tetanus vaccinations, are allowed.

Any biologic therapy such as anti-IL-1, anti-IL-6, or T-cell or B-cell targeted 
therapies for any indication.

Any interferon therapy for any indication.

Any parenteral corticosteroid administered by IV injection.
4.5.2
Vaccination
Investigators should follow relevant local guidelines and standards of care for 
immunization of individuals with RA receiving MTX and anti-TNF-therapy.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the schedule of 
assessments outlined in Appendix 1 and Appendix 2.
4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, reproductive status, smoking 
history, use of alcohol and drugs of abuse. All medications (e.g., prescription drugs, OTC
drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient
within 30 days prior to the screening visit will be recorded. The use of anti-TNF-α therapy 
in the last 12 weeks should be recorded.
Demographic data will include age, sex, and self‑reported race/ethnicity.
4.6.1.2
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, and neurological systems and should be done as indicated 
in Appendix 1.
Any abnormality identified at baseline should be recorded on the appropriate eCRF.
Height (screening only) and weight will be recorded.
Additionally, or as clinically indicated, limited, symptom-directed physical examinations 
should be performed. Changes from baseline abnormalities should be recorded in 
patient’s notes. New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF.


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4.6.1.3
Skin Examination
A thorough skin examination will be conducted at every visit with detailed recording of 
findings. Patients will disrobe entirely and the entire skin, including the scalp, will be 
examined. Photographs may be taken for skin adverse events reported.
Detailed findings will be recorded in the eCRF.
4.6.1.4
Vital Signs
Blood pressure (BP), pulse rate, respiratory rate and body temperature will be recorded 
at the time-points specified in the Schedule of Assessments (Appendix 1 and 
Appendix 2).
On days when study medication is administered, vital signs will be recorded pre-infusion, 
every 15 minutes during the infusion and at the end of the infusion.
Blood pressure, pulse rate and respiratory rate should be obtained in a quiet room at a 
comfortable temperature, with the patient's arm unconstrained by clothing or other
material. All measurements will be obtained from the same arm and, with the same cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (the “ideal” cuff should have a bladder length that is 80% and a width that is at 
least 40% of arm circumference [a length-to-width ratio of 2:1]). The automatic cuff 
should be placed on the designated arm at least 10 minutes prior to dosing. The patient
should be asked to remove all clothing that covers the location of cuff placement. The 
individual should be comfortably seated, with the legs uncrossed, and the back and arm 
supported, such that the middle of the cuff on the upper arm is at the level of the right 
atrium (the mid-point of the sternum). After the patient has been resting in supine 
position for at least 5 minutes, blood pressure, pulse rate and respiratory rate will be 
obtained.
4.6.1.5
Electrocardiograms
Triplicate ECG recordings (i.e., three useful ECGs without artifacts) will be obtained 
within approximately 2-5 minutes at each specified time‑point. The average of the three 
readings will be used to determine ECG intervals (e.g., PR, QRS, QT). Whenever
possible, the same brand/model of a standard high‑quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements 
should be used for each patient. The conditions should be as close as possible to 
pre-dose time-points; this includes but is not limited to food intake, activity level, 
stressors and room temperature.
To minimize variability, it is important that patients be in a resting position for 
10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre‑ECG 
resting period and during ECG recording. ECGs should be performed prior to meals and 


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any scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the patient’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcB (Bazett’s correction), QTcF (Fridericia’s correction) and 
RR will be calculated by the Sponsor/recorded on the eCRF. Changes in T‑wave and 
U-wave morphology and overall ECG interpretation will be documented on the eCRF. 
T-wave information will be captured as normal or abnormal, U-wave information will be 
captured in two categories: absent/normal or abnormal.
4.6.1.6
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points specified 
in the Schedule of Assessments (Appendix 1 and Appendix 2).
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for an abnormal
urine or blood test, the test could be repeated.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the central laboratory. Local 
laboratory analysis should only be used for study parameters related to AE/SAE. 
Erythrocyte sedimentation rate (ESR) may be performed locally.
Samples for the following blood and urine laboratory tests will be collected and sent to 
the appropriate laboratory for analysis according to the lab manual:

Hematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)
ESR, HsCRP


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
Serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, urea, 
creatinine, protein, albumin, phosphate, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, urate, LDH

Coagulation: international normalized ratio (INR), activated partial thromboplastin 
time (aPTT), prothrombin time (PT)

Viral serology:
o
HIV (specific tests HIV-1 Antibody, HIV-1/2 Antibody, HIV-2 Antibody)
o
Hepatitis B surface antigen (HBsAg)
o
Total hepatitis B core antibody (HBcAb)
o
Hepatitis C virus (HCV) antibody

Lipids: cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein 
(HDL) cholesterol, triglycerides

Quantitative immunoglobulins: IgA, IgG, IgM, IgE

Pregnancy test
All women of childbearing potential (including those who have had a tubal ligation) 
will have a blood pregnancy test at screening. Urine pregnancy tests will be 
performed at all subsequent visits. If a urine pregnancy test is positive, it must be
confirmed by a blood pregnancy test.

Anti-drug antibodies

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, red blood cells [RBCs], white blood cells 
[WBCs], casts, crystals, epithelial cells, bacteria). Microscopy should only be 
performed when there are clinically significant positive or strong positive dipstick 
results.

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)
Based on continuous analysis of the data in this study, any sample type not considered 
to be critical for safety may be stopped at any time if the data from the samples collected 
does not produce useful information.
4.6.1.7
Additional Samples
The following samples will be collected for exploratory research:

Whole blood for DNA and RNA analysis.

Serum and plasma samples.
These samples will be destroyed no later than 15 years after the date of final clinical 
study report.
The residual material from PK, PD and exploratory biomarker samples will be destroyed 
within 3 years after the date of final clinical study report.


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The synovial fluid and synovial tissue (collected from consenting patients from approved 
centers only) samples will be destroyed within 3 years after the date of final clinical study 
report. If the patient provides consent for optional exploratory research, the synovial 
tissue and fluid samples will be destroyed no later than 15 years after the date of final 
clinical study report or until no longer needed or used up.
For sampling procedures, storage conditions, and shipment instructions, see the 
separate laboratory manual.
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
4.6.1.8
Immunogenicity Assessments
Blood samples for anti-drug antibodies (ADA) will be taken as described in the SoA 
(Appendix 1 and Appendix 2). Samples collected from placebo treated patients will not 
be analyzed in the first instance, but retained for subsequent analysis if appropriate. 
ADA in serum will be determined using a validated enzyme-linked 
electrochemiluminescent assay (ECLA) method. Unused sample material may also be 
used for the purposes of concurrent assay improvement. 
Details on sampling procedures, sample storage and shipment are given in the Sample 
Handling Manual.
4.6.1.9
PK Assessments 
Blood samples for measurement of serum concentrations of RO7123520 will be 
collected at on-treatment visits as specified in the SoA (Appendix 1 and Appendix 2). 
Samples will be collected at any convenient time before dosing, and one hour after the 
completion of the IV drug infusion. In addition, samples of synovial fluid collected will be 
used for measurement of synovial fluid concentrations of RO7123520. 
RO712520 serum and synovial fluid concentrations will be measured by a specific and 
validated enzyme-linked immunosorbent assay (ELISA) method. Samples collected from 
placebo treated patients will not be analyzed in the first instance, but retained for 
subsequent analysis if appropriate. Unused sample material may also be used for the 
purposes of concurrent assay improvement. Details on sampling procedures, sample 
storage, and shipment are given in the Sample Handling Manual.


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4.6.1.10
Biomarker Assessments
Blood, Urine, Plasma and Serum Samples
Whole Blood, urine, plasma and serum samples will be collected for the following 
assessments:

Multi-biomarker disease activity (MBDA) test

Bone remodeling and cartilage markers (e.g., CTX-I, PINP and osteocalcin)

Safety biomarkers which will include T cells, B cells, NK cells, granulocyte and 
monocyte markers.
Plasma/serum samples may also be used for analysis of inflammatory, synovial and 
angiogenesis markers.
Urine samples will be collected to measure CTX-II.
Synovial Fluid Samples
Synovial fluid aspiration, which will be done at two timepoints (or three in case of 
optional extension; see Appendix 1 and Appendix 2), can be performed from the same 
joint being biopsied but should precede the biopsy. Samples will be processed for 
several protein biomarkers assessments and may be used for measuring RNA expression.
The joint used for fluid aspiration is at the Investigator’s discretion. If possible, the 
same joint should be aspirated during the study.
Synovial Biopsy Samples
Synovial biopsy samples will be taken by arthroscopy under local at two timepoints (or 
three in case of optional extension; Appendix 1 and Appendix 2). Samples will be 
processed for routine histology, immunohistochemistry and potentially to assess RNA 
expression. The joint used for synovial biopsy is at the Investigator’s discretion. If 
possible, the same joint should be assessed during the study.
Protein Biomarkers in Synovial Fluid
Protein biomarkers may include the following markers: MMP1, MMP3. Synovial fluid 
samples may also be used for analysis of inflammatory, synovial and angiogenesis 
markers.
Immunohistochemistry of Synovial Tissue
The immunohistochemical analyses may include the following markers: CD106, CD55.
Analyses will include but not be limited to the above and involve further investigation in 
populations potentially involved in the etiopathogenesis of RA and related autoimmune 
conditions.


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RNA Expression of Biomarkers in Synovial Tissue
RNA expression levels may be analyzed in synovial tissue by next generation 
sequencing (NGS) methods.
4.6.1.11
Disease-Specific Assessments
Swollen/Tender Joint Count (SJC/TJC)
An assessment of 66 joints for swelling and 68 joints for tenderness will be made. Joints 
will be assessed and classified as swollen/not swollen and tender/not tender by pressure 
and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused 
joints will not be taken into consideration for swelling or tenderness. The joints to be 
assessed for swelling and tenderness are given in Appendix 9.
Acute Phase Reactants 
HsCRP will be analyzed centrally. Erythrocyte sedimentation rate (ESR) will be analyzed
locally according to the standardized Westergren method.
MRI
For Part 2 only: Fat-suppressed, T1-weighted 3D gradient-echo and short tau inversion 
recovery (STIR) images of hand/wrist will be obtained with and without gadolinium 
contrast using 1.5T MRI and a hand frame to ensure reproducible positioning.
4.6.1.12
Patient-Reported Outcomes and Clinician-Reported Outcomes 
Patient-reported outcomes (Patient Global Assessment of Disease Activity [PtGA], 
Patient Global Assessment of Pain [PtPA], HAQ-DI, Short Form Health Survey Version 2 
[SF-36v2], and Brief Fatigue Inventory [BFI]) and clinician-reported outcomes (PGA) will 
be collected to help to characterize the clinical profile of RO712520. 
The global assessment visual analogue scale (VAS) items (PtGA, PtPA and PGA) will 
be included in all composite assessments requiring these items (DAS28, CDAI and 
SDAI).
The instruments will be translated as required in the local language and completed in 
their entirety at specified time-points during the study. Patients will complete 
questionnaires using an electronic ePRO device, specific to each study visit day/week. 
To ensure instrument validity and that data standards meet Health Authority 
requirements, questionnaires will be self-administered before the patient receives any 
information on disease status, prior to the performance of non-PRO and clinician-
reported outcome assessments, and prior to the administration of study treatment, 
unless otherwise specified.
Patient Global Assessment of Disease Activity (PtGA)
The PtGA represents the patient’s overall assessment of their current disease activity on 
a 100 mm horizontal visual analogue scale (VAS). The extreme left end of the line is
described as no disease activity (symptom-free and no arthritis symptoms) and the 


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extreme right end as maximum disease activity (maximum arthritis disease activity)
(Appendix 3). Visually-impaired patients unable to complete the VAS will be asked to
give the score verbally.
Physician Global Assessment of Disease Activity (PGA)
The PGA represents the physician’s assessment of the patient’s current disease activity 
on a 100 mm horizontal VAS. The extreme left end of the line is described as no disease 
activity (symptom-free and no arthritis symptoms) and the extreme right end as 
maximum disease activity (Appendix 4). 
Patient’s Global Assessment of Pain (PtPA)
The PtPA represents the patient’s assessment of his/her current level of pain on a
100 mm horizontal VAS. The extreme left end of the line is described as no pain and the 
extreme right end as most severe pain (Appendix 5).
Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI will be used to assess patient’s physical functioning. The HAQ-DI is a
20-item, validated questionnaire used to assess difficulty in performing activities of daily
living (Fries 1983). The HAQ-DI refers to the previous week and assesses eight domains
of physical functioning: Dressing and Grooming (2 items), Hygiene (3 items), Arising 
(2 items), Reach (2 items), Eating (3 items), Grip (3 items), Walking (2 items), Common 
Daily Activities (3 items). The questions assess usual abilities ranging from 0 “without 
any difficulty” to 3 “unable to do.” A lower HAQ-DI score indicates better quality of life 
(Appendix 6).
Short-form Health Survey (SF-36v2)
The SF-36v2 will be used to assess health-related quality of life (HRQoL; Ware and 
Sherbourne 1992). The 36-item questionnaire consists of 8 domains: Physical 
Functioning (10 items), Role-Physical (4 items), Bodily Pain (2 items), General Health 
(5 items), Vitality (4 items), Social Functioning (2 items), Role-Emotional (3 items),
Mental Health (5 items), and an additional item on reported health transition. The
SF-36v2 has a recall specification of 4 weeks and items are assessed on Yes/No and 5-
to 6-point Likert scales. A higher score indicates better health (Appendix 7).
Brief Fatigue Inventory (BFI)
The BFI will be used to assess the level and impact of fatigue experienced by patients 
(Mendoza et al 1999). The BFI is comprised of 4 items: the first is a single-item not
included in scoring. The second is a single-item assessing patient’s usual level of fatigue, 
the third rates the patient’s fatigue at its worst in the past 24 hours, and the final item is 
comprised of 4 questions which rate the interference from fatigue. Items 2, 3 and 4 
comprise the total BFI score. All items are rated on an 11-point numeric rating scale 
(NRS-11), with 0 as “no fatigue/interference” and 10 “bad as you can imagine/complete 
interference.” The BFI is appropriate for use in an RA population (Wolfe et al 2004) 
(Appendix 8).


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Morning Stiffness
The patient’s assessment of morning stiffness will be collected as duration (hours and 
minutes) of morning stiffness (Appendix 10).
4.6.1.13
Samples for Research Biosample Repository
Overview of the Research Biosample Repository
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage and analysis of these specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens will be collected from patients who give specific consent to participate in this 
optional Research Biosample Repository. Collected specimens will be used to achieve 
the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression.

To increase knowledge and understanding of disease biology.

To study drug response, including drug effects and the processes of drug absorption 
and disposition.

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body. If a site has not been granted approval for RBR sampling, this section 
of the protocol will not be applicable at that site.
Sample Collection
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers:

Residual synovial tissue and fluid from any patient who consents to their collection 
and to store in RBR post-study

Plasma and serum to assess for biomarkers

Blood for DNA and RNA extraction to assess for biomarkers
The following samples will be collected for identification of genetic (inherited) biomarkers:

Blood for DNA extraction to assess for biomarkers


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The samples collected for DNA extraction may be used for whole genome sequencing 
(WGS) and other genetic analysis and may be sent to one or more laboratories for 
analysis.
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate laboratory manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The Research Biosample Repository storage period will be in accordance 
with the IRB/EC‑approved Informed Consent Form and applicable laws (e.g., Health 
Authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Section 8.4).
Confidentiality
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche Monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RBR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RBR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Patients will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
investigators or patients unless required by law.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR. Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period. A separate, specific signature will be 
required to document a patient’s agreement to provide optional RBR specimens. 
Patients who decline to participate will not provide a separate signature.
The Investigator should document whether or not the patient has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a patient who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
Withdrawal from the Research Biosample Repository
Patients who give consent to provide specimens for the RBR have the right to withdraw 
their specimens at any time for any reason. If a patient wishes to withdraw consent to 
the testing of his or her specimens, the Investigator must inform the Medical Monitor in 
writing of the patient’s wishes using the RBR Withdrawal Form and, if the trial is ongoing, 
must enter the date of withdrawal on the Research Biosample Repository Withdrawal of 
Informed Consent eCRF. The patient will be provided with instructions on how to 
withdraw consent after the trial is closed. A patient's withdrawal from Study BP39261
does not, by itself, constitute withdrawal of specimens from the RBR. Likewise, a 
patient’s withdrawal from the RBR does not constitute withdrawal from Study BP39261. 
Data already generated before time of withdrawal of consent to Research Biosample 
Repository will still be used.
Monitoring and Oversight
Specimens collected for the Research Biosample Repository will be tracked in a manner 
consistent with Good Clinical Practice by a quality-controlled, auditable, and 
appropriately validated laboratory information management system, to ensure 
compliance with data confidentiality as well as adherence to authorized use of 
specimens as specified in this protocol and in the Informed Consent Form. Roche 
Monitors and auditors will have direct access to appropriate parts of records relating to 
patient participation in Research Biosample Repository for the purposes of verifying the 
data provided to Roche. The site will permit monitoring, audits, IRB/EC review, and 
Health Authority inspections by providing direct access to source data and documents 
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4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled patient and for patients who are not subsequently enrolled will be maintained 
at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed within 28 days prior to 
Day 1, unless otherwise specified. Patients who fail screening may be able to re-screen
once. In order to re-screen a patient, all inclusion and exclusion criteria should be re-
evaluated and all applicable screening assessments, including MRI scan, should be 
repeated if done more than 28 days before randomization. There is no need to repeat 
bone mineral density if it has been done for the study within 6 months before re-
screening.
4.6.2.2
Assessments during Treatment
Under no circumstances will patients who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments must be performed as per SoA (see Appendix 1 and Appendix 2). 
Assessments scheduled on the day of study treatment administration should be 
performed prior to administration of study treatment, unless otherwise noted in the 
schedule of assessments. The exact assessments may vary by specific visit date and 
the sequence will be standardized as follows (at visits as specified in the SOA):
1.
Patients will complete health outcomes assessments using an electronic ePRO 
device, specific to each study visit day/week. 

SF36v2

HAQ-DI

BFI

PtPA (pain VAS)

PtGA (Global Assessment of disease activity VAS)


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2.
Laboratory samples for safety, efficacy, PD and PK; must be drawn after patient 
self-assessments are completed, at least 30 min before Investigator assessments or 
at any time after nurse/Investigator assessments but prior to study drug infusion.
Note: providing all listed restrictions are met, the lab samples can be collected 
before or after the joint count is performed.
3.
Investigator assessments:

Joint counts

Physician’s global assessment of disease activity VAS, safety assessments 
(adverse events, vital signs, concomitant medications, review of laboratory data)
4.
RO7123520/placebo infusion
5.
Post-dose vital signs, post-dose PK (at the visits scheduled), adverse events.
4.6.2.3
Safety Follow-up Phone Call
Patients in Study Parts 1 and 2 will receive a safety follow-up telephone call two weeks 
after each dose of the study medication, at the timepoints shown in the SoA (Appendix 1
and Appendix 2), if they are not otherwise visiting the Study Center.
4.6.2.4
Assessments at Study Completion/Early Termination Visit
Patients who complete the study or discontinue from the study early will be asked to 
return to the clinic 8 weeks (German sites: 8 and 16 weeks) after the last dose of study 
drug for a follow‑up visit.
4.6.2.5
Follow-Up Assessments
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 5.5 and 5.6.
4.6.2.6
Assessments at Unscheduled Visits
Assessments at unscheduled visits are based on the medical need of the patient. 
Assessments that are conducted at regular scheduled visits can be conducted at 
unscheduled visits at the discretion of the Investigator.
4.7
PATIENT, STUDY, AND SITE DISCONTINUATION
4.7.1
Patient Discontinuation
The Investigator has the right to discontinue a patient from RO7123520 or withdraw a 
patient from the study at any time. In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason. Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient


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
Patient non-compliance: Patients who miss more than one scheduled dose or miss 
the Week 8 scheduled dose of study medication should be withdrawn from the study.
4.7.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Severe skin adverse reactions

Severe hypersensitivity reactions

Reduction in bone mineral density of clinical significance (e.g., significant loss of 
height over the course of the study, back pain suspected to be caused by fractured 
or collapsed vertebra, fragility)
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
study completion/early termination visit (see Section 4.6.2.4) and may undergo follow‑up 
assessments (see Section 4.6.2.5). The primary reason for premature study drug 
discontinuation should be documented on the appropriate eCRF. Patients who 
discontinue study drug prematurely will not be replaced.
4.7.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
Patients will not be followed for any reason after consent has been withdrawn.
When a patient voluntarily withdraws from the study, or is withdrawn by the Investigator, 
samples collected until the date of withdrawal will be analyzed, unless patient specifically 
requests for these to be discarded or local laws require their immediate destruction. A 
patient's withdrawal from Study BP39261 does not, by itself, constitute withdrawal of 
specimens donated to the Research Biosample Repository.
Patients who withdraw from the study for safety reasons will not be replaced. Patients 
who withdraw from the study for other reasons will not be replaced.
4.7.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.


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
Enrollment and study progression from Part 1 to Part 2 or from Part 2 to Part 3 will 
be put on hold pending full data review if more than 30% of patients on active study 
drug experience drug-related SAEs of similar nature (see Sections 3.1.1.1
and 3.1.1.2). The study will be stopped if the benefit-risk ratio changes to be 
unacceptable in this indication as judged by the Sponsor and the IMC/SOC.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.1.2.
5.1.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline.


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
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X‑ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies).
5.1.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death).

Life-threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death).
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10).

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions).

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.

Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe); the event itself may be of 
relatively minor medical significance (such as severe headache without any further 
findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 


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event; see Section 5.4.2 for reporting instructions). Adverse events of special interest for 
this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of the study drug is suspected.
5.2
SAFETY PLAN
5.2.1
Management of Specific Adverse Events
For the adverse events listed below, standard-of-care should be provided at the 
Investigator’s discretion. For more details please refer to the RO7123520 Investigator’s 
Brochure.
5.2.1.1
Contact Dermatitis
In the Phase I study SDP051-001, there were 6 cases of mild contact dermatitis plus one 
case of application site reaction, all in the active treatment groups. A thorough skin 
examination will be performed at every visit with detailed recording of findings. 
Photographs may be taken for skin adverse events reported. Dermatology consultation 
and biopsy will be taken on an ad hoc basis. Study drug will be discontinued in patients 
with skin adverse reactions that are considered Severe.
5.2.1.2
Headache
In the Phase I study SDP051-001, there were 4 cases of mild headache in the active 
treatment group and none in placebo. Adverse event reports will be monitored.
5.2.1.3
Hypersensitivity
Hypersensitivity is a theoretical risk for all biologic compounds. Adverse events will be 
monitored and treatment given according to standard of care. Study drug will be 
discontinued in patients with severe adverse reactions.
5.2.1.4
Reduced Bone Density
This is a theoretical risk for reduced bone mineral density as Cad-11 is expressed in 
osteoblasts. Bone density will be measured during this study. There are no inclusion or 
exclusion criteria regarding this event and no specific discontinuation criteria.
5.2.1.5
Impaired Wound Healing
There is a theoretical risk that inhibition of Cad-11 can impair fibroblast function and 
wound healing. Adverse events will be monitored, especially in patients who develop 


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wounds or have surgical procedures. There are no inclusion or exclusion criteria 
regarding recent surgery and no specific discontinuation criteria.
5.2.1.6
Decreased Fertility
Cad-11 is believed to play a role in trophoblast implantation. This is a theoretical risk in 
female patients. Female patients of childbearing potential are required to use highly 
effective birth control.
5.2.1.7
Teratogenicity
This is a theoretical risk based on the role of Cad-11 on mesenchymal tissue and organ 
development. Highly effective birth control is to be used by female patients, and male 
patients are to use condoms to avoid a vaginal dose.
5.2.1.8
Serious Infection
Infections are not expected with anti-Cad-11 but are known to be a risk for concomitant 
medications being used in this study. Adverse event reports will be closely monitored.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.1.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 to Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical record. Adverse events will then be reported on the Adverse Event 
eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures, such as biopsies). Any 
other adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the follow-up visit after the last dose of study drug.
After the last dose of study drug and until the follow-up visit, Investigators should 
report any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (see Section 5.6).


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time‑points. Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
Table 1 provides guidance for assessing adverse event severity.
Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer 
to definition of a serious adverse event (see Section 5.1.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study drug, or reintroduction of study drug

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patient receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
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5.3.5.1
Diagnosis versus Signs and Symptoms
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug RO7123520 infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF. If possible, 
avoid ambiguous terms such as "systemic reaction". Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF. If a patient 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF.
Other Adverse Events
For adverse events other than infusion-related reactions, a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF. If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time‑points. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between patient evaluation time‑points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the Investigator’s judgment
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] associated 
with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded on the 
Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 2
ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). This 
includes death attributed to progression of RA.


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Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the general medical history and baseline 
conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”).
5.3.5.9
Lack of Efficacy or Worsening of Rheumatoid Arthritis
Medical occurrences or symptoms of deterioration that are anticipated as part of RA
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of RA on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated RA”).
5.3.5.10
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), except as outlined below.
The following hospitalization scenarios are not considered to be serious adverse events:

Hospitalization for respite care

Planned hospitalization required by the protocol


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not suffered an adverse event
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
5.3.5.11
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data. However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice. If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest

Pregnancies

Accidental overdoses or medication errors (see Section 5.4.4. for details on 
reporting requirements).
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery


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
Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
To ensure the safety of study patients, access to the Medical Monitor is available 24 
hours a day 7 days a week. Medical Monitor contact details are listed in the “Protocol 
Administrative and Contact Information & List of Investigators”.  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the SAE Responsible immediately 
(i.e., no more than 24 hours after learning of the event).
5.4.2.2
Events That Occur after Study Drug Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3) that occur after initiation of study drug, investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest /Serious 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to the Sponsor’s Safety Risk Management
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the SAE Responsible immediately (i.e., no more than 24 hours after 
learning of the event).  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 115 days after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed by 
the investigator and submitted to the sponsor within 24 hours after learning of the 
pregnancy. Pregnancy should not be recorded on the Adverse Event eCRF. The 
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of the pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy.
5.4.3.2
Pregnancies in Female Partners of Male Patient
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
115 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed by the investigator and submitted to the sponsor within 24 hours 
after learning of the pregnancy. Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug. The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. 
Once the authorization has been signed, the investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of the 
pregnancy. An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no
more than 24 hours after learning of the event; see Section 5.4.2).


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5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error  (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with RO7123520, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For RO7123520, each adverse event associated with a special situation should be 
recorded separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4).  For 
RO7123520, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the patient 
is lost to follow-up, or the patient withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 8 weeks [German sites: 16 weeks]
after the last dose of study drug). 
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the adverse event reporting period, if the event is believed to be related to prior 
study drug treatment the event should be reported directly to the Sponsor or its designee, 
either by faxing or by scanning and emailing the Serious Adverse Event Reporting Form 
using the fax number or email address provided to investigators. 


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO7123520 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
Part 1:
No formal sample size estimation was performed for Part 1 of the study. A total of 9 
patients (6 on the RO7123520 arm and 3 on the placebo arm) is deemed sufficient to 
provide initial safety information on RO7123520 in RA patients.
Part 2:
A total of 90 patients will be randomized 2:1 to either the RO7123520 or placebo arm. 
The probability of observing a difference of at least 15% between the RO7123520 and 
placebo Week 12 ACR50 response rates is approximately 0.73, assuming that the true
ACR50 response rate on placebo is 15% and 35% on RO7123520. With 60 patients 
receiving RO7123520 810 mg, there is at least a 95% chance of observing an AE with 
true incidence of 5%. Ninety patients will therefore give a reasonable assessment of 
the safety and efficacy of RO7123520 before progressing to Part 3.
Part 3:
Following the decision to initiate Part 3 at the interim analysis of Part 2 of the study or 
after the end of Part 2 (when all 90 patients have reached the Week 12 visit) 
(Section 6.9), 105 patients will be randomized 2:2:2:1 to one of 3 selected RO7123520 
doses, and placebo (or 5:5:5:5:1 if four RO7123520 doses and placebo are selected). 


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The total sample size for the combined Study Parts 1, 2 and 3 will be 204 patients (either 
60, 30, 30, 30 receiving different doses of RO7123520, plus 6 RO7123520 patients from 
Study Part 1, and 48 receiving placebo, or 60, 25, 25, 25, 25 receiving different doses of 
RO7123520, plus 6 RO7123520 patients from Study Part 1, and 38 receiving placebo). 
This provides approximately 80% power of observing a positive dose response curve 
with a maximum effect of RO7123520 compared to placebo of -8.0 in change from 
baseline in CDAI score at Week 12 (placebo change from baseline in CDAI is assumed 
to be -10.0, with a common standard deviation of 15.0), allowing for a 10% drop-out rate 
and using a two-sided alpha level of 0.1.
If conflicting results are observed from Study Part 2 of the study between the change 
from baseline in CDAI at Week 12 endpoint and ACR50 response at Week 12 endpoint, 
then the following sample size for Part 3 will be undertaken and the dose-response 
analysis will be based on ACR50 at Week 12:
A total sample size of 150 patients will be recruited into Part 3 of the study. Therefore 
the total sample size for the combined Study Parts 1, 2 and 3 will be 249 patients (either 
60, 45, 45, 45 receiving different doses of RO7123520, plus 6 RO7123520 patients from 
Study Part 1, and 48 receiving placebo, or 60, 36, 36, 36, 36 receiving different doses of 
RO7123520, plus 6 RO7123520 patients from Study Part 1, and 39 receiving placebo), 
which provides approximately 80% power of observing a positive dose response curve 
using a two-sided alpha level of 0.1, and assuming a placebo ACR50 response of 15% 
and active RO7123520 response of 35%, i.e., a delta effect size of 20%.
6.2
SUMMARIES OF CONDUCT OF STUDY
The numbers of patients, who enroll, discontinue, and complete the study, will be 
tabulated by treatment group. Reasons for premature study discontinuation will be listed 
and summarized by treatment group. Any major protocol deviations will be captured and 
listed.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All patients who have received at least one dose of the study medication, whether 
prematurely withdrawn from the study or not, will be included in the safety analysis 
population.
6.3.2
Efficacy Analysis Population
All randomized patients will be included in the efficacy analysis population.
6.3.3
Immunogenicity Analysis Population
The immunogenicity analyses will include patients with at least one predose ADA 
assessment, with patients grouped according to treatment received and dose level.


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The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up visit will be summarized by treatment group and 
dose level.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and pretreatment characteristics such as age, sex, race, ethnicity, duration 
of RA, previous and background therapies for RA, weight, DAS28 score, CDAI score, 
CRP, ESR, joint counts, HAQ-DI score, physician’s global assessment of disease 
activity, patient’s global assessment of disease activity, and patient’s assessment of pain 
will be summarized by treatment group and dose using the efficacy analysis population. 
The potentially prognostic and disease severity biomarkers MBDA and CTX-II 
(Section 3.2.5) will also be summarized by treatment group and dose using the efficacy 
analysis population.
Continuous data (e.g., age, body weight, and DAS28) will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum). For 
categorical data (e.g., race and sex), the number and percentage of participants in each 
category will be presented. 
Baseline will be defined as the latest assessment prior to the first infusion of 
RO7123520/placebo.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population and reported by the 
treatment group and dose actually received.
6.5.1
Adverse Events
The original terms recorded on the eCRF by the investigator for adverse events will be 
standardized by the sponsor.
Adverse events will be summarized by mapped term and appropriate thesaurus level.
Incidence, nature and severity of adverse events, including targeted adverse events, 
number of participants with serious adverse events (SAEs), treatment-related SAEs,
SAEs leading to discontinuation, treatment-related AEs, or AEs leading to 
discontinuation will be tabulated by treatment group and dose.
6.5.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Patient listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 


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d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
6.5.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
6.5.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in patient listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a patient, the midpoint of the standard reference range will be used as the
patient’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low.
6.5.3
Vital Signs
Vital signs and weight data will be presented by individual listings with flagging of values 
outside the normal ranges and flagging of marked abnormalities. In addition, tabular 
summaries will be used, as appropriate.
6.5.4
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate.


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6.5.5
Concomitant Medications
The original terms recorded on the patients’ eCRFs by the investigator for concomitant 
medications will be standardized by the sponsor by assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
6.6
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all patients in the efficacy 
analysis population, with patients grouped according to the treatment and dose assigned 
at randomization.
6.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint to demonstrate the proof of concept of RO7123520 is the 
proportion of patients achieving an ACR50 response at Week 12 using RO7123520 as 
adjunct therapy to MTX+anti-TNF-compared to MTX+anti-TNF-plus placebo.
An ACR50 response is defined by achieving an improvement of 50% compared to 
baseline in the American College of Rheumatology (ACR) core set of outcome measures 
in both SJC and TJC as well as in 3 out of 5 additional parameters: physician’s global  
assessment of disease activity (PGA, Section 4.6.1.12), patient’s global assessment of 
disease activity (PtGA, Section 4.6.1.12), patient’s assessment of pain (PtPA), HAQ-DI, 
and acute phase reactant (CRP will be used as the ACR APR in this study).
Patients who withdraw from the study prior to the Week 12 ACR assessment, and all 
patients in whom the Week 12 ACR50 response cannot be determined for any reason, 
will be considered non-responders for the summaries of ACR50.
The proportion of patients achieving an ACR50 response at Week 12 will be 
summarized descriptively by treatment/dose arm.
6.6.2
Secondary Efficacy Endpoints
Clinical Disease Activity Index (CDAI) Score
The CDAI is a composite endpoint score including swollen 28-joint count (SJC28), 
tender 28-joint count (TJC28), PtGA and PGA. CDAI score is calculated as follows: 
CDAI = SJC28 + TJC28 + PtGA + PGA
The change from baseline in CDAI score at Week 12 will be included in the dose-
response assessment at the end of Part 3 of the study. The dose-response relationship 
will be assessed using a MCP-mod approach (Bretz et al 2005), including the data from 
all three study parts. The candidate models will be fitted to the change from baseline in 
CDAI at Week 12 and multiple contrast tests (two-sided =0.1) will be produced along 
with the corresponding multiplicity adjusted p-values. From the statistically significant 


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candidate models, the most appropriate (based on Akaike information criterion [AIC]) will 
be selected and the target dose will be the dose which demonstrates a change from 
baseline in CDAI at Week 12 of -8.0 relative to the placebo change from baseline value. 
Full details will be included in the study statistical analysis plan (SAP).
If conflicts in the change from baseline in CDAI and ACR50 response results are 
observed at the time of the Part 2 interim analysis (Section 6.9), then the ACR50 
response (Section 6.6.1) may be chosen as the endpoint for assessing the dose-
response. The methodology will be the same as for the change from baseline in CDAI 
dose-response as described above. If ACR50 response is used for the dose-response 
endpoint then the target dose will be selected as the dose which demonstrates a 15% 
difference between the RO7123520 response rate and the placebo response rate.
The change from baseline in CDAI at Week 12 and the actual CDAI score at Week 12 
will also be summarized descriptively by treatment/dose arm.
Missing CDAI scores will not be imputed.
ACR20, ACR70
Achievement of an ACR20 requires a 20% improvement in the same parameters as 
ACR50 (see Section 6.6.1) and an ACR70 requires a 70% improvement.
The proportion of patients achieving an ACR20 response at Week 12 and the proportion 
achieving an ACR70 response at Week 12 will be summarized in the same manner as 
for the ACR50 endpoint described in Section 6.6.1.
Patients who withdraw from the study prior to the Week 12 ACR assessment, and all 
patients in whom the Week 12 ACR20/ACR70 response cannot be determined for any 
reason, will be considered non-responders for the summaries of ACR20/ACR70.
Disease Activity Score (DAS28)
The DAS28 is a combined index for measuring disease activity in RA. The index 
includes swollen and tender joint counts, acute phase response (ESR will be used as the 
DAS28 APR in this study), and general arthritis disease activity status. The index is 
calculated using the following formula:
DAS28 = 0.56 √(TJC28) + 0.28 √(SJC28) + 0.70 ln (ESR) + 0.014 PtGA
Where, TJC28 = tender joint count on 28 joints, SJC28 = swollen joint count on 28 joints, 
ln = natural log, ESR = Erythrocyte sedimentation rate (mm/hr), and PtGA 
(Section 4.6.1.12). The DAS28 scale ranges from 0 to 10, where higher scores represent 
higher disease activity.


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The change from Baseline in DAS28 score at Week 12 will be summarized descriptively 
by treatment/dose arm.
Missing DAS28 scores will not be imputed.
DAS28 Remission
The proportion of patients achieving DAS28 remission at Week 12 will be summarized 
descriptively by treatment/dose arm.
DAS28 remission is defined as a DAS28 score 2.6.
Patients who withdraw from the study prior to the Week 12 visit, and all patients in whom 
the Week 12 DAS28 score cannot be determined for any reason, will be considered non-
responders for the summaries of DAS28 remission.
CDAI Remission
The proportion of patients achieving CDAI remission at Week 12 will be summarized 
descriptively by treatment/dose arm.
CDAI remission is defined as a CDAI score 2.8.
Patients who withdraw from the study prior to the Week 12 visit, and all patients in whom 
the Week 12 CDAI score cannot be determined for any reason, will be considered non-
responders for the summaries of CDAI remission.
Simple Disease Activity Index (SDAI) Score
The SDAI is the numerical sum of five outcome parameters: tender and swollen joint 
count (based on a 28‐joint assessment), PtGA (Section 4.6.1.12), PGA 
(Section 4.6.1.12) and level of CRP (mg/dl) as follows:
SDAI = SJC28 + TJC28 + PtGA + PGA + CRP
The change from Baseline in SDAI at Week 12 and also the actual SDAI score at Week 
12 will be summarized descriptively by treatment/dose arm.
Missing SDAI scores will not be imputed.
Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI is a self-completed questionnaire described in Section 4.6.1.12.
The change from Baseline in HAQ-DI at Week 12 will be summarized descriptively by 
treatment/dose arm.


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Missing HAQ-DI scores will not be imputed.
6.7
PHARMACOKINETIC ANALYSES
RO7123520 concentration data will be pooled with data from other studies 
(e.g., SDP051-001) for population PK and PK/PD modelling. The methods and results of 
that population modelling will be reported separately.
6.8
EXPLORATORY ANALYSES
Modified ACR20, ACR50, ACR70
Modified ACR20, mACR50 and mACR70 include the same components as ACR20, 
ACR50 and ACR70, except excludes the acute-phase reactants, i.e. CRP. Therefore a 
mACR50 is based on at least a 50% improvement in TJC and SJC as well as two of the 
four remaining criteria; similarly 20% improvement is used for mACR20 and 70% 
improvement for mACR70 (Greenburg et al 2009).
The proportion of mACR20/mACR50/mACR70 responders at Week 12 and Week 24 will 
be summarized descriptively using the efficacy analysis population.
Patients who withdraw from the study prior to the Week 12 ACR assessment, and all 
patients in whom the Week 12 mACR20/mACR50/mACR70 response cannot be 
determined for any reason, will be considered non-responders for the summaries of 
mACR20/mACR50/mACR70. Similarly missing mACR20/mACR50/mACR70 at Week 24 
will be imputed with non-responder status.
Short-form Health Survey (SF-36v2)
The SF-36v2 is a self-completed questionnaire described in Section 4.6.1.12.
The change from Baseline in SF-36v2 mental component score (MCS) and physical 
component score (PCS) at Week 12 and Week 24 will be summarized descriptively by 
treatment/dose arm using the efficacy analysis population.
No imputation for missing MCS or PCS will be performed.
Brief Fatigue Inventory (BFI)
The BFI is a self-completed PRO questionnaire described in Section 4.6.1.12.
The change from Baseline in BFI items 2, 3 and 4, as well as total score will be
summarized descriptively at Week 12 and Week 24 by treatment/dose arm using the 
efficacy analysis population.
No imputation for missing BFI scores will be performed.


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Patient and Physician VAS items
In addition to being included in composite RA disease scores, the PtGA VAS and PGA 
VAS will be presented individually to describe, respectively, the patient and physician 
global assessment of disease activity changes from baseline at Week 12 and Week 24 
using the efficacy analysis population.
The PtPA VAS change from baseline at Week 12 and Week 24 will also be presented 
using the efficacy analysis population.
PtGA, PGA and PtPA VAS changes from baseline will be summarized descriptively.
Missing PtGA and PtPA scores will not be imputed.
Potentially Prognostic and Disease Severity Biomarkers
The potentially prognostic and disease severity biomarkers (MBDA and CTX-II, 
Section 3.2.5) will be summarized descriptively at Baseline by treatment/dose arm. In 
addition, the synovium cadherin-11 data, synovial fluid and blood soluble cadherin-11 
data will be summarized descriptively by visit and treatment/dose arm. Those 
biomarkers will be summarized using the efficacy analysis population.
The relationship between the potentially prognostic and disease severity biomarkers and 
efficacy endpoints will also be analyzed and reported descriptively.
Bone remodeling and cartilage markers
Bone remodeling and cartilage markers (including but not limited to CTX-1, PINP and 
osteocalcin) will be summarized descriptively by visit and treatment/dose arm. Those 
biomarkers will be summarized using the efficacy analysis population.
The relationship between the markers mentioned above and efficacy endpoints will also 
be analyzed and reported descriptively.
Safety Biomarkers
The safety biomarkers (T cells, B cells, NK cells, granulocyte and monocyte markers, 
Section 3.2.5) will be summarized descriptively by visit and treatment/dose arm using 
the safety analysis population.
Disease activity as assessed by MRI (Part 2 only)
The OMERACT RA MRI scoring system (RAMRIS) will be used for the evaluation of 
inflammatory and destructive changes in RA hands and wrists at baseline, Week 12 and 
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assess cartilage loss (Peterfy et al 2012), and total damage and total inflammation 
scores will be calculated (Peterfy et al 2016).
The change from baseline in synovitis, osteitis, bone erosions, bone marrow edema, 
cartilage loss, total damage and total inflammation will be summarized descriptively by 
visit and treatment arm using the efficacy analysis population. 
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analyses
An interim analysis of the primary efficacy outcome measure (ACR50 at Week 12) will 
be carried out after the first 50% of the patients within Part 2 of the study have 
completed their Week 12 assessment visit. The data will be reviewed by the IMC and
SOC.
The difference in ACR50 response rate at Week 12 between the RO7123520 810 mg 
dose group and the placebo group will be compared descriptively. If no difference 
between the treatment arms is observed for ACR50 (i.e., the difference is 0%) then, the 
study may be stopped for futility. If a positive difference is observed then, the Sponsor 
will determine whether to start Part 3 of the study at this point (also continuing Part 2 
recruitment until completion) or wait until all of the Part 2 patients have been recruited 
and have completed the Week 12 visit, where the decision will be revisited.
Once all of the patients in Study Part 3 have completed their Week 12 visit, a data 
snapshot will be taken for the purpose of the dose-response analysis (Section 6.6.2). 
The study will not be modified at this point and will continue until all patients have 
completed the final follow-up visit.
6.9.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two additional interim efficacy analyses (i.e., beyond what is specified in 
Section 6.9.1).  The decision to conduct an optional interim analysis and the timing of the 
analysis will be documented in the Sponsor’s trial master file prior to the conduct of the 
interim analysis.  The interim analysis will be performed and interpreted by members of 
the Sponsor study team and appropriate senior management personnel, who will be 
unblinded at the treatment group level.  Access to treatment assignment information will 
follow the Sponsor’s standard procedures.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the EDC system.


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A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the investigator.
The Sponsor will produce a Data Handling Manual and a Data Management Plan that 
describe the quality checking to be performed on the data. Central laboratory data and 
other electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line Electronic Data Capture (EDC) system. 
The data collected in the source documents is entered onto the study eCRF. An audit 
trail will maintain a record of initial entries and changes made; reasons for change; time 
and date of entry; and user name of person authorizing entry or change. For each 
Patient enrolled, an eCRF must be completed and electronically signed by the principal 
investigator or authorized delegate from the study staff. If a Patient withdraws from the 
study, the reason must be noted on the eCRF. If a Patient is withdrawn from the study 
because of a treatment‑limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor/CRO in the eCRFs and in all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patients will use an electronic device to capture PRO data. The data will be transmitted 
to a centralized database maintained by the electronic device vendor.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived. The Investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the
study records as source data. Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.


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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X‑rays, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer. After that 


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period of time, the documents may be destroyed, subject to local regulations. No records 
may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or 
moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.


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A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. In 
addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety‑related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.


RO7123520 —F. Hoffmann-La Roche Ltd
107/Protocol BP39261, Version 4
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
Roche shall also submit an Development Safety Update Report (DSUR) once a year to 
the IEC and CAs according to local regulatory requirements and timelines of each 
country participating in the study.
It is the understanding of the sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an Institutional Review Board (IRB). This board must operate in accordance with the 
current Federal Regulations. The sponsor will be sent a letter or certificate of approval 
prior to initiation of the study, and also whenever subsequent amendments 
/modifications are made to the protocol. Roche shall also submit an IND Annual Report 
to FDA according to local regulatory requirements and timelines.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs. The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.


RO7123520 —F. Hoffmann-La Roche Ltd
108/Protocol BP39261, Version 4
9.3
ADMINISTRATIVE STRUCTURE
Vendors for the IxRS, the MRI reading and the ePRO management will be selected. The 
Site Management is outsourced to 
 UK. 
 will 
manage the samples centrally.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission. This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement.
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.5
PROTOCOL AMENDMENTS
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.


RO7123520 —F. Hoffmann-La Roche Ltd
109/Protocol BP39261, Version 4
10.
REFERENCES
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an 
American College of Rheumatology/European League Against Rheumatism 
collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.
Assefnia S, Dakshanamurthy S, Guidry Auvil JM, et al. Cadherin-11 in poor prognosis
malignancies and rheumatoid arthritis: common target, common therapies. 
Oncotarget. 2014;5:1458-74.
Azaïs J, Vergne-Salle P, Bonnet C, et al. Meta-Analysis of the Clinical Efficacy of the 
Placebo Effect from Tumour-Necrosis-Factor Inhibitors to Treat Rheumatoid 
Arthritis after Methotrexate Failure. J Rheum Dis Treat 2016;2:032.
Bergmann GJD, Hochberg MC, Boers M, et al. Indirect comparison of tocilizumab and 
other biologic agents in patients with rheumatoid arthritis and inadequate response 
to disease-modifying antirheumatic drugs. Semin Arthritis Rheum 2010;39:425-441.
Bretz F, Pinheiro J, Branson M. Combining multiple comparisons and modeling 
techniques in dose response studies. Biometrics 2005; 61:738-748.
Centola MG, Cavet Y, Shen S, et al. Development of a multi-biomarker disease activity 
test for rheumatoid arthritis. PLoS One 2013;e60635.
Chang SK, Noss EH, Chen M, et al. Cadherin-11 regulates fibroblast inflammation. 
PNAS 2011;108:8402-07.
Charles-Schoeman C, Burmester G, Nash P, et al. Efficacy and safety of tofacitinib 
following inadequate response to conventional synthetic or biological disease-
modifying antirheumatic drugs. Ann Rheum Dis. 2016 Jul;75(7):1293-301.
Ferri N, Bellosta S, Baldessin L, Boccia D, Racagni G, Corsini A. Pharmacokinetics 
interactions of monoclonal antibodies. Pharmacol Res. 2016 Jul 18;111:592-599.
Fries JF. Measuring the quality of life in relation to arthritis therapy. Postgrad 
Med. 1983;Spec No:49-56.
Greenberg JD, Harrold LR, Bentley MJ, et al. Evaluation of composite measures of 
treatment response without acute-phase reactants in patients with rheumatoid 
arthritis. Rheumatology 2009;48:686–690.
Hambardzumyan KR, Bolce S, Saevarsdottir SE, et al. Pretreatment multi-biomarker 
disease activity score and radiographic progression in early RA: results from the 
SWEFOT trial. Ann Rheum Dis. 2015;74(6):1102-1109.
Investigator’s Brochure RO7123520 Fourth Version, September 2016.
Lee DM, Kiener HP, Agarwal SK, et al. Cadherin-11 in synovial lining formation and 
pathology in arthritis. Science 2007;315:1006-10.
Mendoza TR, Wang S, Cleeland CS, et al. The Rapid Assessment of Fatigue Severity in 
Cancer Patients:  Use of the Brief Pain Inventory. Cancer 1999;85:1186-96.


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Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT rheumatoid arthritis magnetic 
resonance imaging studies. core set of MRI acquisitions, joint pathology 
definitions, and the OMERACT RA-MRI scoring system. J Rheumatol
2003;30:1385–6.
Peterfy CG, DiCarlo JC, Olech E, et al. Evaluating joint-space narrowing and cartilage 
loss in rheumatoid arthritis by using MRI. Arthritis Res Ther 2012;14:R131.
Peterfy C, Emery P, Tak PP, et al. MRI assessment of suppression of structural damage 
in patients with rheumatoid arthritis receiving rituximab: results from the 
randomised, placebo-controlled, double-blind RA-SCORE study. Ann Rheum Dis 
2016;75:170-177.
Qvist P, Bay-Jensen AC, Christiansen C, et al. Molecular serum and urine marker 
repertoire supporting clinical research on joint diseases. Best Pract Res Clin 
Rheumatol. 2011;25(6):859-72. 
SDP051-001. A Randomized, Double-blind, Placebo-controlled, Ascending Single-dose 
Safety, Tolerability, and Pharmacokinetic Study of SDP051 in Healthy Adult 
Volunteers. 3 February 2014.
Singh JA, Saag KG, Bridges SL, et al. American College of Rheumatology Guideline for 
the Treatment of Rheumatoid Arthrit. Arthritis Care & Research 2016;68(1):1–25.
Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the
management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 
2014;73:492-505.
Ternant D, Bejan-Angoulvant T, Passot C, et al. Clinical Pharmacokinetics and
Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid 
Arthritis. Clin Pharmacokinet 2015;54:1107-23.
Valencia X, Higgins JM, Kiener HP, et al. Cadherin-11 provides specific cellular 
adhesion between fibroblast-like synoviocytes. J Exp Med. 2004;200(12):1673-9.
Voll RE and Kalden JR. Do we need new treatment that goes beyond tumor necrosis 
factor blockers for rheumatoid arthritis? Ann NY Acad Sci 2005;1051:799-810.
Ware JE, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36), I: 
conceptual framework and item selection. Med Care. 1992;30:473–83.
Wolfe F. Fatigue assessments in rheumatoid arthritis: comparative performance of visual 
analogue scales and longer fatigue questionnaires in 7760 patients. J Rheumatol 
2004;31:1896-1902.
Xu Z, Davis HM, Zhou H. Clinical impact of concomitant immunomodulators on biologic 
therapy: Pharmacokinetics, immunogenicity, efficacy and safety. J Clin Pharmacol 
2015;55:S60-74.


RO7123520 —F. Hoffmann-La Roche Ltd
111/Protocol BP39261, Version 4
Appendix 1 Schedule of Assessments for Parts 1, 2 and 3 
(without Extension) 
Week
Screening
Screening Baseline Week 1a,b Week 2 Week 3a Week 4 Week 5a Week 6a Week 8 Week 9a Week 10 Week 12c Week 16d Week 24k
Early 
Termination 
Safety Visit
Day
D-28 to D-7
D-7 to D-1
Day 1
Day 2
Day 14
Day 15
Day 28
Day 29
Day 42
Day 56
Day 57
Day 70
Day 84
Day 112
Day 168
Time Relative (h)
0
24
312
336
648
672
984
1320
1344
1656
1992
2664
4008
Visit Window
notime
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
Assessments
Informed Consent
x
Demography
x
Medical History
x
x
Substance Use
x
Inclusion/Exclusion
x
Randomisation
x
SF-36 v2e
x
x
HAQ-DIe
x
x
x
x
x
x
x
x
BFIe
x
x
Patient’s Global Assessment of Pain 
(PtPA)e
x
x
x
x
x
x
x
x
Patient Global Assessment of 
Disease Activity (PtGA)e
x
x
x
x
x
x
x
x
x
Morning Stiffnesse
x
x
x
x
x
x
x
x
Physical Examinationl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Skin Examination (incl. foot soles and 
palms of the hand)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signsf
x
5
x
5
x
5
x
x
5
x
x
x
x
x
ECG-12 Lead (Triplicate)
x
x
x
x
x
x
x
x
x
Bone Mineral Density (Lumbar Spine 
L1-L4)
x
x
MRI Scang
x
x
Hematology
x
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
x
x
x
Coagulation
x
x
x
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
x
x
x
Serology
x
Serum Pregnancy Test
x
Urine Pregnancy Test
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
Rheumatoid Factor
x
x
x
x
x
x
x
x
x
ACPA
x
x
x
x
x
x
x
HsCRP
x
x
x
x
x
x
x
x
x
ESR (Westergren method)h
x
x
x
x
x
x
x
x
x
Immunoglobulin Levels (IgG/A/M)
x
x
x
x
x
PK RO7123520 (Synovial Fluid)i
x
x
Synovial Fluid for RNA Profilingi
x
x
Synovial Fluid for PD Biomarkersi
x
x
Synovial Biopsies for RNA Profilingi
x
x
Synovial Biopsiesi
x
x
PK RO7123520 (Serum)
2
2
2
2
x
x
x
Anti-Drug Antibody (ADA)
x
x
x
Serum Sampling for PD Biomarkers
x
x
x
Plasma Sampling for PD Biomarkers
x
x
x
Urine Sampling for PD Biomarkers
x
x
x
Whole Blood (RNA) Sampling for RBR
x
x
Whole Blood (DNA) Sampling for RBR
x
Serum Sampling for RBR
x
x
Plasma Sampling for RBR
x
x
Safety Biomarkers (blood cell 
markers)
x
x
x
x
x
x
x
Bone Biomarkers (CTX-1, PINP, 
osteocalcin)
x
x
x
x
x
Swollen/Tender Joint Count (66/68 
joints)e
x
x
x
x
x
x
x
x
x
Physician Global Assessment of 
Disease Activity (PGA)e
x
x
x
x
x
x
x
x
Administration of Study Medication
x
x
x
x
Safety Follow-up Phone Callj
x
x
Adverse Events
Previous and Concomitant 
Treatments
x
x


RO7123520 —F. Hoffmann-La Roche Ltd
112/Protocol BP39261, Version 4
Appendix 1 Schedule of Assessments for Parts 1, 2 and 3 
(without Extension) (cont.)
a
Part 1 only: Assessments performed in Part 1.
b
Part 2: Overnight stay required following first dose for the first 15 subjects.
c
Efficacy and safety assessments for patients who do not enter the Extension Phase.
d
Follow up for patients who do not enter the Extension Phase.
e
Questionnaires are self-administered before the patient receives any information on disease status, 
prior to the performance of non-PRO and ClinRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. Collected using ePRO device or paper PRO.
f
Vital signs at the start of the infusion, every 15 minutes during the infusion, and then at the end of 
infusion.
g
Part 2 only: MRI of the hand including wrist, contrast-enhanced, RA of hands need to be queried first.
h
All sites must do this locally.
i
Optional assessment; performed at selected centers only.
j
Performed in Part 1 and Part 2 only.
k
German sites only.
l
Physical examination may include an extended examination (i.e., symptom-directed, as clinically 
indicated) as per Investigator’s discretion. 


RO7123520 —F. Hoffmann-La Roche Ltd
113/Protocol BP39261, Version 4
Appendix 1 Schedule of Assessments Detail for Part 1, 2 and 3 (without Extension) (cont.)
a
Optional assessment; performed at selected centers only.
b
Part 2 only: MRI of the hand including wrist, contrast-enhanced, RA of hands needs to be queried first.
c
German sites only.
Week
Day
Scheduled Time (h)
Vital Signs
ECG-12 
Lead 
(Triplicate)
HsCRP
Safety 
Biomarkers 
(blood cell 
markers)
Bone 
Biomarkers 
(CTX-1, PINP, 
osteocalcin)
PK 
RO7123520 
(Synovial 
Fluid)
a
Synovial 
Fluid for 
RNA 
Profiling
a
Synovial 
Fluid for PD 
Biomarkers
a
Synovial 
Biopsies for 
RNA 
Profiling
a
Synovial 
Biopsies
a
PK 
RO7123520 
(Serum)
Anti-Drug 
Antibody 
(ADA)
Serum 
Sampling 
for PD 
Biomarkers
Plasma 
Sampling 
for PD 
Biomarkers
Urine 
Sampling 
for PD 
Biomarkers
MRI Scan
b
Whole 
Blood 
(RNA) 
Sampling 
for RBR
Whole 
Blood 
(DNA) 
Sampling 
for RBR
Serum 
Sampling 
for RBR
Plasma 
Sampling 
for RBR
D-28 to D-7
x
x
x
D-7 to D-1
x
Predose
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Week 1
Day 2
x
Predose
x
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Week 3
Day 15
x
Predose
x
x
x
x
x
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Week 5
Day 29
x
Week 6
Day 42
x
x
x
x
Predose
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Week 9
Day 57
x
Week 12
Day 84
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Week 16
Day 112
x
x
x
x
x
x
x
Week 24
c
Day 168
x
Early 
Termination 
Safety Visit
x
x
x
x
x
x
x
Week 8
Day 56
Screening
Baseline
Day 1
Week 2
Day 14
Week 4
Day 28


RO7123520 —F. Hoffmann-La Roche Ltd
114/Protocol BP39261, Version 4
Appendix 2 Schedule of Assessments for Optional Extension 
for Parts 1, 2 and 3 
Week
Week 12
Week 14 Week 16 Week 18 Week 20 Week 22 Week 24 Week 28 Week 36g
Early 
Termination 
Safety Visit
Day
Day 84
Day 98
Day 112
Day 126
Day 140
Day 154
Day 168
Day 196
Day 252
Time Relative (h)
1992
2328
2664
3000
3336
3672
4008
4680
6024
Visit Window
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
Assessments
Informed Consent
x
SF-36 v2a
x
x
HAQ-DIa
x
x
x
x
x
x
BFIa
x
x
Patient’s Global Assessment of Pain 
(PtPA)a
x
x
x
x
x
x
Patient Global Assessment of 
Disease Activity (PtGA)a
x
x
x
x
x
x
Morning Stiffnessa
x
x
x
x
x
x
Physical Examinationh
x
x
x
x
x
x
x
Skin Examination (incl. foot soles and 
palms of the hand)
x
x
x
x
x
x
x
Vital Signsb
5
5
5
x
x
x
x
ECG-12 Lead (Triplicate)
x
x
x
x
x
x
Bone Mineral Density (Lumbar Spine 
L1-L4)c
x
x
MRI Scan
x
x
Hematology
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
Coagulation
x
x
x
x
x
x
Lipids
x
x
x
x
x
x
Urine Pregnancy Test
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
Rheumatoid Factor
x
x
x
x
x
x
ACPA
x
x
x
HsCRPd
x
x
x
x
x
x
ESR (Westergren method)
x
x
x
x
x
x
Immunoglobulin Levels (IgG/A/M)
x
x
x
x
PK RO7123520 (Synovial Fluid)e
x
x
Synovial Fluid for RNA Profilinge
x
x
Synovial Fluid for PD Biomarkerse
x
x
Synovial Biopsies for RNA Profilinge
x
x
Synovial Biopsiese
x
x
PK RO7123520 (Serum)
2
2
2
x
x
x
Anti-Drug Antibody (ADA)
x
x
x
Serum Sampling for PD Biomarkers
x
x
x
x
x
Plasma Sampling for PD Biomarkers
x
x
x
x
x
Urine Sampling for PD Biomarkers
x
x
x
x
x
Safety Biomarkers (blood cell 
markers)
x
x
x
x
x
Bone Biomarkers (CTX-1, PINP, 
osteocalcin)
x
x
x
x
x
Swollen/Tender Joint Count (66/68 
joints)a
x
x
x
x
x
x
Physician Global Assessment of 
Disease Activity (PGA)a
x
x
x
x
x
x
Administration of Study Medication
x
x
x
Safety Follow-up Phone Callf
x
x
x
Adverse Events
Previous and Concomitant 
Treatments
x
x


RO7123520 —F. Hoffmann-La Roche Ltd
115/Protocol BP39261, Version 4
Appendix 2 Schedule of Assessments for Optional Extension 
for Parts 1, 2 and 3 (cont.)
a
Questionnaires are self-administered before the patient receives any information on disease status, 
prior to the performance of non-PRO and ClinRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. Collected using ePRO device or paper PRO.
b
Vital signs at the start of the infusion, every 15 minutes during the infusion, and then at the end of 
infusion.
c
Part 2 only: MRI of the hand including wrist, contrast-enhanced, RA of hands need to be queried first.
d
All sites must do this locally.
e
Optional assessment; performed at selected centers only.
f
Performed in Part 1 and Part 2 only.
g
German sites only.
h
Physical examination may include an extended examination (i.e., symptom-directed as clinically 
indicated) as per Investigator’s discretion.


RO7123520 —F. Hoffmann-La Roche Ltd
116/Protocol BP39261, Version 4
Appendix 2 Schedule of Assessments Detail for Optional Extension for Parts 1, 2 and 3 (cont.)
a
Optional assessment; performed at selected centers only.
b
Part 2 only: MRI of the hand including wrist, contrast-enhanced, RA of hands needs to be queried first.
c
German sites only.
Week
Day
Scheduled Time (h)
Vital Signs
ECG-12 
Lead 
(Triplicate)
HsCRP
Safety 
Biomarkers 
(blood cell 
markers)
Bone 
Biomarkers 
(CTX-1, PINP, 
osteocalcin)
PK 
RO7123520 
(Synovial 
Fluid)
a
Synovial 
Fluid for 
RNA 
Profiling
a
Synovial 
Fluid for PD 
Biomarkers
a
Synovial 
Biopsies for 
RNA 
Profiling
a
Synovial 
Biopsies
a
PK 
RO7123520 
(Serum)
Anti-Drug 
Antibody 
(ADA)
Serum 
Sampling 
for PD 
Biomarkers
Plasma 
Sampling 
for PD 
Biomarkers
Urine 
Sampling 
for PD 
Biomarkers
MRI Scan
b
Predose
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Predose
x
x
x
x
x
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Predose
x
x
x
x
0.25
x
0.5
x
0.75
x
EOI
x
EOI +1
x
Week 24
Day 168
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Week 28
Day 196
x
x
x
x
x
x
x
x
x
x
Week 36
c
Day 252
x
Early 
Termination 
Safety Visit
x
x
x
x
x
x
x
x
x
x
Week 12
Day 84
Week 16
Day 112
Week 20
Day 140


RO7123520 —F. Hoffmann-La Roche Ltd
117/Protocol BP39261, Version 4
Appendix 3 Visual Analogue Scale
Patient Global Assessment of Disease Activity (PtGA)
Considering all the ways your rheumatoid arthritis affects you, how are you 
feeling today?


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Appendix 4 Visual Analogue Scale
Physician Global Assessment of Disease Activity (PGA)
Considering all the aspects of the patient’s current disease activity, how do you 
rate them at this time?




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Appendix 6 Health Assessment Questionnaire (HAQ-DI)


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Appendix 6 Health Assessment Questionnaire (HAQ-DI) (cont.)


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Appendix 6 Health Assessment Questionnaire (HAQ-DI) (cont.)


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Appendix 7 Short-form Health Survey (SF-36v2)


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Appendix 7 Short-form Health Survey (SF-36v2) (cont.)


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Appendix 7 Short-form Health Survey (SF-36v2) (cont.)


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Appendix 7 Short-form Health Survey (SF-36v2) (cont.)


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Appendix 7 Short-form Health Survey (SF-36v2) (cont.)


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Appendix 7 Short-form Health Survey (SF-36v2) (cont.)


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Appendix 8 Brief Fatigue Inventory (BFI)


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Appendix 9 Swollen/tender joint count (SJC/TJC)
The joints to be evaluated for tenderness (68) and swelling (66) consist of the following: 

Temporomandibular joint 

Sternoclavicular joint 

Acromioclavicular joint 

Shoulders 
a 

Elbows 
a 

Wrists 
a 

Interphalangeal on digit 1 
a 

Distal interphalangeal joints on digits 2–5 

Proximal interphalangeal joints on digits 2–5 
a 

Metacarpophalangeal joints on digits 1–5 
a 

Hips (tenderness only) 

Knees 
a 

Ankles 

Tarsus

Metatarsophalangeal joints on  toes 1–5 

Interphalangeal joints on toes 1–5 
a Includes the 28 joints used to calculate the Disease Activity Score (DAS)28