Clinical trial NCT03052322
Conditions: Moderate to Severe Rheumatoid Arthritis
Sponsor: Fresenius Kabi SwissBioSim GmbH
Start date: 2017-01-31; Completion date: 2018-08-27
Enrollment: 288 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy, safety and immunogenicity of MSB11022 and Humira® in adult participants with rheumatoid arthritis (RA).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: MSB11022 intervention 2: EU-Humira
Intervention descriptions: intervention 1: Participants received MSB11022 (modified buffer and stabilizer) subcutaneously at dose of 40 milligram (mg) every other week from Day 1 up to Week 48. intervention 2: Participants received EU-Humira subcutaneously at dose of 40 mg every other week from Day 1 up to Week 48.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
Clinical Trial Protocol Number
MS200588-0004
Title
A multicenter, randomized, double-blind, phase III 
trial to evaluate the safety, immunogenicity, and 
efficacy of MSB11022 compared with Humira® in 
patients 
with 
moderately 
to 
severely 
active 
rheumatoid arthritis
Phase
III
IND Number
EudraCT Number
2016-002852-26
Coordinating Investigator
Sponsor
For sites in the US:
EMD Serono Research & Development Institute, 
Inc.
45A Middlesex Turnpike, 
Billerica, MA 01821, US
For all countries except the US:
Merck KGaA, Frankfurter Strasse 250,
64293 Darmstadt, Germany
Medical Responsible
Ares Trading S.A (an affiliate of Merck Serono S.A. 
– Merck Serono is a division of Merck)
Z.I. de l'Ouriettaz
1170 Aubonne, Switzerland
Clinical Trial Protocol Version
11 July 2017 / Version 2.0 including Amendment 2
Replaces Version
09 September 2016 / Version 1.0
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................11
2
Sponsor, Investigators and Trial Administrative Structure ................23
3
Background Information.....................................................................23
3.1
Adalimumab .......................................................................................23
3.2
Rheumatoid Arthritis ..........................................................................25
3.3
Safety and tolerability.........................................................................26
3.4
Risk-Benefit Assessment....................................................................27
4
Trial Objectives ..................................................................................27
4.1
Primary Objective...............................................................................27
4.2
Secondary Objectives .........................................................................28
4.2.1
Key Secondary Objective ...................................................................28
4.2.2
Other Secondary Objectives ...............................................................28
4.3
Exploratory Objective.........................................................................28
5
Investigational Plan ............................................................................28
5.1
Overall Trial Design and Plan ............................................................28
5.2
Discussion of Trial Design .................................................................29
5.2.1
Scientific Rationale for Study Design ................................................31
5.2.2
Justification for Dose..........................................................................32
5.2.3
Rationale for Endpoints......................................................................32
5.3
Selection of Trial Population..............................................................36
5.3.1
Inclusion Criteria ................................................................................36
5.3.2
Exclusion Criteria...............................................................................37
5.4
Criteria for Patient Withdrawal ..........................................................40
5.4.1
Withdrawal from Trial Therapy..........................................................40
5.4.2
Withdrawal from the Trial..................................................................41
5.5
Premature Termination of the Trial ....................................................42
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5.6
Definition of End of Trial...................................................................42
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................42
6.1
Description of the Investigational Medicinal Product........................42
6.2
Dosage and Administration ................................................................42
6.3
Assignment to Treatment Groups.......................................................43
6.4
Concomitant Medications and Therapies ...........................................43
6.4.1
Permitted Medicines...........................................................................43
6.4.2
Prohibited Medicines..........................................................................44
6.4.3
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................45
6.5
Packaging and Labeling of the Investigational Medicinal Product....46
6.6
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................46
6.7
Investigational Medicinal Product Accountability.............................47
6.8
Assessment of Investigational Medicinal Product Compliance .........48
6.9
Blinding ..............................................................................................48
6.10
Emergency Unblinding.......................................................................48
6.11
Treatment of Overdose .......................................................................49
6.12
Medical Care of Patients after End of Trial........................................49
7
Trial Procedures and Assessments......................................................49
7.1
Schedule of Assessments....................................................................49
7.1.1
Screening Procedures and Assessments .............................................49
7.1.2
Baseline Assessments and Treatment Period .....................................50
7.1.3
Early Termination Visit ......................................................................51
7.1.4
Safety Follow-up Period.....................................................................51
7.2
Demographic and Other Baseline Characteristics ..............................51
7.2.1
Demographic Data..............................................................................51
7.2.2
Medical History ..................................................................................51
7.2.3
Tuberculosis Status.............................................................................52
7.2.4
Immunogenicity..................................................................................52
7.2.5
Other Baseline Assessments...............................................................52
7.3
Efficacy Assessments .........................................................................52
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7.3.1
Disease Activity Assessments ............................................................52
7.4
Assessment of Safety..........................................................................56
7.4.1
Safety Monitoring Committee............................................................56
7.4.2
Adverse Events ...................................................................................56
7.4.3
Pregnancy and In Utero Drug Exposure.............................................61
7.4.4
Clinical Laboratory Assessments .......................................................61
7.4.5
Vital Signs, Physical Examinations, and Other Assessments.............62
7.5
Pharmacokinetics................................................................................63
7.6
Biomarkers..........................................................................................63
7.7
Other Assessments..............................................................................63
7.7.1
HAQ-DI..............................................................................................64
7.7.2
Visual Analog Scales..........................................................................64
7.7.3
SF-36...................................................................................................65
7.7.4
EQ-5D-5L...........................................................................................65
8
Statistics..............................................................................................65
8.1
Sample Size ........................................................................................65
8.2
Randomization....................................................................................66
8.3
Endpoints............................................................................................66
8.3.1
Primary Endpoint................................................................................66
8.3.2
Secondary Endpoints ..........................................................................66
8.3.3
Exploratory Endpoints........................................................................67
8.4
Analysis Sets.......................................................................................68
8.4.1
Enrolled...............................................................................................68
8.4.2
Intention-to-Treat................................................................................68
8.4.3
Per-Protocol ........................................................................................68
8.4.4
Safety..................................................................................................68
8.5
Description of Statistical Analyses.....................................................69
8.5.1
General Considerations.......................................................................69
8.5.2
Analysis of Primary Endpoint ............................................................69
8.5.3
Analysis of Secondary Endpoints.......................................................69
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8.6
Interim and Additional Planned Analyses ..........................................71
8.7
Missing Data.......................................................................................72
9
Ethical and Regulatory Aspects..........................................................72
9.1
Responsibilities of the Investigator ....................................................72
9.2
Patient Information and Informed Consent ........................................72
9.3
Patient Identification and Privacy.......................................................73
9.4
Emergency Medical Support and Patient Card...................................73
9.5
Clinical Trial Insurance and Compensation to Patients......................74
9.6
Independent Ethics Committee or Institutional Review Board..........74
9.7
Health Authorities...............................................................................74
10
Trial Management...............................................................................74
10.1
Case Report Form Handling...............................................................74
10.2
Source Data and Patient Files.............................................................75
10.3
Investigator Site File and Archiving...................................................75
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................76
10.5
Changes to the Clinical Trial Protocol................................................76
10.6
Clinical Trial Report and Publication Policy......................................76
10.6.1
Clinical Trial Report...........................................................................76
10.6.2
Publication..........................................................................................76
11
References Cited in the Text...............................................................77
12.
Appendices .........................................................................................83
Appendix A:
Contraceptive Guidance and Woman of Childbearing Potential........84
Appendix B:
Signature Pages and Responsible Persons for the Trial......................86
Signature Page – Protocol Lead.........................................................................................87
Signature Page – Coordinating Investigator ......................................................................88
Signature Page – Principal Investigator.............................................................................89
Sponsor Responsible Persons not Named on the Cover Page ...........................................90
Appendix C:
Blood and Urine Volumes ..................................................................91
Appendix D:
Joint Count Assessment Forms (66/68 Joint Evaluation)...................92
Appendix E:
Protocol Amendments and List of Changes .......................................93
Amendment No.
1 ..........................................................................................................94
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Amendment No.
2 ..........................................................................................................95
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Table of In-Text Tables
Table 1
Schedule of Assessments....................................................................18
Table 2
Population PK Table of Assessments.................................................22
Table 3
Clinical Laboratory Assessments .......................................................62
Table of In-Text Figures
Figure 1
Schematic of the Trial Design ............................................................29
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List of Abbreviations
ACPA
Anti-citrillinated Protein Antibodies
ACR20
American College of Rheumatology 20% Response Criteria
ACR50
American College of Rheumatology 50% Response Criteria
ACR70
American College of Rheumatology 70% Response Criteria
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANC
Absolute Neutrophil Count
ALT
Alanine Aminotransferase 
ARA
American Rheumatology Association
AST
Aspartate Aminotransferase
AUC(0-last)
Area Under the Plasma Concentration Time Curve from Zero to the Last 
Measurable Time Point
AUC(0-inf)
Area Under the Plasma Concentration Time Curve from Zero to Infinity
CDAI
Clinical Disease Activity Index
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CRF
Case Report Form
CRP
C-reactive protein
CT
Computerized Tomography
DAS28-ESR
Disease Activity Score Based on a 28 Joint Count
DMARDs
Disease-Modifying Antirheumatic Drugs
ECG
Electrocardiogram
EQ-5D-5L
Euro-Quality of Life – 5 Dimensions -5 Levels
EMA
European Medicines Agency
ESR
Erythrocyte Sedimentation Rate
EU
European Union
EULAR
European League Against Rheumatism
GCP
Good Clinical Practice
HAQ-DI
Health Assessment Questionnaire – Disability Index
HIV
Human Immunodeficiency Virus
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IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT
Intention To Treat
IWRS
Interactive Web Response System
JIA
Juvenile Idiopathic Arthritis
LS
Least Squares
LTBI
Latent TB Infection
MRI
Magnetic Resonance Imaging
MTX
Methotrexate 
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NYHA
New York Heart Association
PD
Pharmacodynamics
PK
Pharmacokinetics
PRO
Patient-Reported Outcome
QFT
QuantiFERON-TB Gold test
QoL
Quality of Life
RA
Rheumatoid Arthritis
RF
Rheumatoid Factor
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SDAI
Simplified Disease Activity Index
SF-36
36-item Short Form Health Survey
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TNF
Tumor Necrosis Factor
US
United States
VAS
Visual Analog Scale
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WBC
White Blood Cell
WOCBP
Woman of Childbearing Potential
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1
Synopsis
Clinical Trial Protocol Number
MS200588-0004
Title
A multicenter, randomized, double-blind, Phase 
III trial to evaluate the safety, immunogenicity, 
and efficacy of MSB11022 compared with 
Humira® in patients with moderately to severely 
active rheumatoid arthritis
Trial Phase
III 
IND Number
FDA covered trial
Yes
EudraCT Number
2016-002852-26
Coordinating Investigator
Sponsor
For sites in the US:
EMD Serono Research & Development Institute, 
Inc.
45A Middlesex Turnpike, 
Billerica, MA 01821, US
For all countries except the US:
Merck KGaA, Frankfurter Str. 250, 
64293 Darmstadt, Germany
Medical Responsible:
Ares Trading S.A, an affiliate of Merck Serono 
S.A
Telephone: 
Trial centers/countries
Approximately 50 trial sites in approximately
6 countries in Europe
Planned trial period
(first patient in-last patient out)
First patient in: Quarter I 2017
Last patient out: Quarter III 2018
Trial Registry
All required registries
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Objectives: 
Primary Objective
The primary objective of this study is to evaluate the safety profile of MSB11022-
 
compared to Humira® in patients with moderately to severely active rheumatoid arthritis (RA) 
up to Week 52.  
Secondary Objectives
The key secondary objective is to compare the efficacy of MSB11022-
 to Humira® at
Week 12 in patients with moderately to severely active RA.
Other secondary objectives include:
! To evaluate the immunogenicity profile of MSB11022-
 compared to Humira® in 
patients with moderately to severely active RA up to Week 52
! To further compare the efficacy and safety of MSB11022-
 compared to Humira® in 
patients with moderately to severely active RA up to Week 52
! To compare quality of life (QoL) and physical function on MSB11022-
 with Humira®
in patients with moderately to severely active RA
! To compare injection site pain levels of MSB11022-
 versus Humira®
Exploratory Objective
The exploratory
objective is to evaluate population pharmacokinetics (PK) on 
MSB11022-
 and Humira® in patients with moderately to severely active RA.
Methodology: This trial is a two-arm, randomized, multicenter, double-blind, parallel group 
trial designed to compare the safety, immunogenicity, and efficacy of MSB11022-
 with 
Humira® in approximately 260 randomized patients with moderately to severely active RA 
during a 52 week period.
Baseline is defined as the day on which the first dose of the investigational medicinal product 
(IMP) (blinded trial drug) is administered (Week 0). The trial will include a pre-trial evaluation 
period (screening period, from 28 days to 3 days prior to drug administration), a double-blind 
48-week treatment period to evaluate long-term safety and immunogenicity, a 4-week safety 
follow-up visit, and a 4-month safety evaluation period. The primary safety endpoint will be 
assessed up to Week 52, key secondary efficacy endpoint will be assessed at Week 12. The 
analysis for the key secondary efficacy endpoint will be descriptive.
Re-screening will be allowed once for those patients who do not meet the inclusion/exclusion 
criteria within the above specified time limits. The Medical Monitor must promptly inform the 
Sponsor about requests and reasons for re-screening. An Independent Data Monitoring 
Committee (IDMC) will review the safety data from this trial on an ongoing basis.
Eligible patients will be randomized in permuted blocks in a 1:1 ratio by an interactive web 
response system (IWRS) to receive either MSB11022-
 subcutaneous (s.c.) or Humira®
s.c. at a dose of 40 mg every other week starting at baseline up to and including Week 48. 
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Randomization will be stratified by the type of systemic therapy previously received: 
non-biological (biologic naïve patients) versus biological (biologic experienced patients). 
Patients who previously received both (biological and non-biological systemic therapies) will 
be assigned to the “biological” group. The exposure to previous biological agents will be 
limited to one tumor necrosis factor (TNF) inhibitor other than adalimumab. The participation 
of patients in the previous biological systemic therapy stratum will be capped at 20% of the 
total number of patients randomized. Capping will be enforced through application of an 
IWRS.
The first 2 doses of IMP will be administered on site by the Investigator or other qualified 
personnel and the patient will be educated on the correct process. The third dose of IMP will 
be administered on-site by the patient. Patients will be monitored for 1 hour following the first 
3 IMP administrations. If the Investigator judges it appropriate after proper training, the patient
(or a caregiver) may continue to self-inject/inject the treatment for the remaining doses. 
Injection site pain will be assessed after doses 3 to 5. If a patient self-administers, the injection 
should not be given in the arm. The remaining doses of IMP will be dispensed, and written 
instructions on proper dosage, administration, storage, and recording will be provided to the 
patient/caregiver. Administrations performed at home will be recorded in a diary with the 
accurate dosing information (dosing date and time). 
The 52-week double-blind period will allow for the collection of long-term comparative safety, 
immunogenicity, and efficacy data for MSB11022-
 versus Humira®.
Patients who achieve less than 20% improvement in both swollen and tender joint counts at 
Week 24 (non-responders) will be discontinued from the IMP. These patients will remain in 
the trial safety analysis set and participate in the safety and immunogenicity assessments. After 
Week 24, patients with less than 20% improvement in both swollen and tender joint counts at 
any scheduled visit up to Week 52 will also be discontinued. Patients may continue at 
Investigator discretion from Week 24 to Week 52 as long as they maintain more than 20% 
improvement in both swollen and tender joint counts.
Patients who discontinue from study medication (but remain in the trial and continue for the 
safety/immunogenicity visits) before the Week 52 visit will immediately complete an Early 
Termination visit and return for a Safety/Follow-up visit 4 weeks after the last dose of IMP. 
During this 4-week Safety Follow-up period, no excluded treatment for RA (as defined in this 
protocol) should be administered. Patients will return for an additional safety evaluation
4 months after the last dose of IMP. Treatment for RA from the 4-week Safety Follow-up visit 
to the 4-month Safety Evaluation visit will be at the discretion of the Investigator following 
institutional standard of care. The 4-week and 4-month Safety Follow-up visits will not be 
duplicated if either of these visits falls within 2 weeks of an otherwise scheduled visit. If the 
4-week and 4-month Safety Follow-up since last IMP are completed within the 52-week visit 
schedule, these will not be repeated thereafter.
A subset of 60 patients (30 per treatment arm) will be randomly selected to participate in 
population PK analysis. 
The anticipated duration of the entire trial is approximately 2 years.
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Visit schedules for safety, immunogenicity, and efficacy assessments are detailed in the 
Schedule of Assessments.
Planned number of patients: Approximately 260 randomized patients
Primary endpoint: 
! Treatment-emergent adverse events of special interest (AESI) including and up to Week 52
Secondary endpoints: 
Key secondary endpoint
! American College of Rheumatology 20% response criteria (ACR20) at Week 12 (An 
ACR20 response is defined as an improvement of at least 20% in the number of tender joints 
and swollen joints, and at least 20% improvement in 3 out of the remaining 5 ACR core-set 
measures: patient assessment of arthritis pain, Patient’s and Physician’s Global Assessment
of Disease Activity, physical function via the Health Assessment Questionnaire-Disability 
Index [HAQ-D1], acute-phase reactants).
Other secondary endpoints
Safety
! Occurrences of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) including and up to Week 52
! Clinical laboratory values including hematology, chemistry, and urinalysis
! Vital signs
! Physical exam
! 12-lead electrocardiogram (ECG)
Immunogenicity
! ADA to adalimumab and ADA titer including and up to Week 52
! Neutralizing ADA to adalimumab including and up to Week 52
Efficacy
! ACR20 at Weeks 2, 4, 8, 24, and 52
! American College of Rheumatology 50% Response Criteria (ACR50) and American 
College of Rheumatology 70% Response Criteria (ACR70) at Weeks 2, 4, 8, 12, 24, and 52
! Disease Activity Score based on a 28 joint count (DAS28)-ESR mean change from baseline
at Weeks 2, 4, 8, 12, 24, and 52
! Proportion of patients with low disease activity as measured by DAS28-ESR, and remission 
at Weeks 2, 4, 8, 12, 24, and 52
! Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) 
mean change from baseline at Weeks 2, 4, 8, 12, 24, and 52
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! ACR/European League Against Rheumatism (EULAR) Boolean remission rates at Weeks 
2, 4, 8, 12, 24, and 52
Quality of life
! Health Assessment Questionnaire – Disability Index (HAQ-DI) questionnaire at screening, 
baseline, and Weeks 2, 4, 8, 12, 24, and 52
! 36-item Short Form Health Survey (SF-36) questionnaire at baseline and Weeks 12, 24, and 
52
! Euro-Quality of Life – 5 Dimensions and 5-levels (EQ-5D-5L) questionnaire at baseline and 
Weeks 12, 24, and 52
Injection-site pain
! Mean change in injection site pain on a visual analog scale (VAS), evaluated during 
3 administrations of IMP (doses 3 to 5) (immediately post-injection, 15 minutes 
post-injection, and 1 hour post-injection)
Exploratory endpoints
Population pharmacokinetics 
! Absorption profile characterization, if it is supported by the data
! Apparent clearance (CL/F)
! Volume of distribution (Vz/F)
! Ctrough levels at Day 14 after first dose, at Week 4, 12 and 24 pre-dose, and at Day 14 after 
dose of Week 24
Pharmacokinetics: All patients will have PK samples taken pre-first dose, and then prior to 
dosing on Weeks 2, 4, 12, 24, 36, and 52. In addition, a subset of 60 patients (30 per arm) will 
have additional samples to support the population PK analysis taken on Days 2 (24 h post first 
dose), 4, and 9, and Days 2 (24 h post Week 24 dose), 4, 9, and 14 (Week 26 pre-dose) after 
the Week 24 dose (see Table 2).
Diagnosis and key inclusion and exclusion criteria:
Key inclusion criteria
Male or female patients ≥18 years old with a clinical diagnosis of moderately to severely active 
RA with disease duration of at least 6 months from confirmed diagnosis (defined by the 2010 
revised ACR/EULAR 2010 criteria or the 1987 Criteria of American Rheumatology 
Association) despite methotrexate (MTX) therapy (defined as ≥6 swollen joints and ≥6 tender 
joints (from the 66/68 joint count system) at screening and randomization and either 
erythrocyte sedimentation rate (ESR) ≥28 mm/h or serum C-reactive protein (CRP) 
≥1.0 mg/dL at screening. Patient must have been treated with MTX for a total of at least 
12 weeks prior to baseline and must have been on both a stable route of administration (oral or 
parenteral) and stable dose of MTX (10 to 25 mg/week) for at least 4 weeks prior to screening. 
Patients must be adalimumab naïve and have discontinued infliximab (either originator or 
investigational or approved biosimilar), certolizumab pegol (either originator or investigational 
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or approved biosimilar) or golimumab (either originator or investigational or approved 
biosimilar) 8 weeks prior to screening, or etanercept (either originator or investigational or 
approved biosimilar) 4 weeks prior screening.
Key exclusion criteria
A patient will be excluded if he or she is considered ACR functional class IV as defined by the 
ACR classification of functional status or wheelchair/bedbound or has diagnoses of Felty’s 
syndrome or any other inflammatory arthritides/systemic autoimmune disease other than 
secondary Sjögren’s syndrome. The patient must not have received therapy with leflunomide 
within 12 weeks prior to baseline (Day 1); disease-modifying antirheumatic drugs other than 
MTX including but not limited to oral or injectable gold, sulfasalazine, azathioprine, 
penicillamine, cyclosporine, or tacrolimus within 4 weeks prior to baseline; or increasing doses 
of non-steroidal anti-inflammatory drugs (including low dose aspirin and COX-2 inhibitors) in 
the 2 weeks prior to baseline; had prior exposure to alkylating agents, such as chlorambucil or 
cyclophosphamide; use oral glucocorticoids > 10 mg/day prednisone or equivalent (dose must 
have been stable for the 4 weeks prior to baseline); or received any intra-articular, intravenous, 
or intramuscular use of corticosteroids in the 6 weeks prior to baseline. The patient will also be 
excluded if they have a history of an ongoing, chronic, or recurrent infectious disease (including 
active or latent tuberculosis [TB]); history of active or latent TB; or a history of hypersensitivity 
to any component of the IMP formulation, comparable drugs, or latex. The patient will be 
excluded if they have a concomitant diagnosis or history of congestive heart failure (New York 
Heart Association [NYHA] class III or IV).
Investigational Medicinal Product: dose/mode of administration/dosing schedule: 
MSB11022-
 will be administered at a dose of 40 mg s.c. every other week starting from 
baseline.
Reference therapy: dose/mode of administration/dosing schedule: Humira® will be 
administered at a dose of 40 mg s.c. every other week starting from baseline.
Planned trial and treatment duration per patient: The planned trial duration per patient is 
approximately 17 months: a screening period of 28 days to 3 days prior to IMP administration, 
a double-blind 48-week treatment period to evaluate long-term safety and immunogenicity, a 
safety follow-up visit 4 weeks after the last dose of IMP, and an additional safety evaluation at 
4 months following the last dose of IMP. During the 4-week Safety Follow-up period, no 
excluded treatment for RA (as defined in this protocol) should be administered. Treatment for 
RA from the 4-week Safety Follow up visit to the 4-month Safety Evaluation visit will be at 
the discretion of the Investigator following institutional standard of care.
Statistical 
methods:
According 
to 
EMA 
recommendation
(EMA/CHMP/SAWP/
200743/2016), a total of 100 patients/arm should be adequate for a study primarily focusing on 
safety. To account for drop outs, this descriptive study will include 260 randomized patients in 
total (130/arm) in order to ensure 200 subjects in the study at Week 52. This sample size will 
allow to provide a precision of 12.0% (injection site reactions) and 9.0% (rash) for the AESIs 
incidence of 26.0% and 11.0% respectively.
Eligible patients will be randomized in a 1:1 ratio by an IWRS to receive either 
MSB11022-
 s.c. or Humira® s.c. at a dose of 40 mg every other week starting at baseline 
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up to and including Week 48. Randomization will be stratified by the type of systemic therapy 
previously received. The participation of patients in the previous biological systemic therapy 
stratum will be capped at 20% of the total number of patients randomized.
The Intention-to-Treat (ITT) Analysis Set will include all patients randomly allocated to a 
treatment, based on the intention to treat “as randomized” principle (ie, the planned treatment 
regimen rather than the actual treatment given in case of any difference). The Per-protocol (PP)
analysis set includes all randomized and treated patients (hence a subgroup of the ITT analysis 
set) who do not have any important protocol deviations per regulatory definition.
The Safety Analysis Set will include all randomized patients who receive at least one dose of 
trial treatment. The PK Analysis Set will include all patients who receive at least 1 dose of trial 
treatment and have at least 1 valid post-dose pharmacokinetic assessment without protocol 
deviations which could potentially affect PK.
Safety endpoints will be summarized by treatment group using the Safety analysis set. The 
incidence with 95% CI of AESIs will be provided for each treatment group.  The half width of 
95% CIs of the difference for the most common AESI incidence between the 2 treatment groups 
will also be calculated. 
Adverse events will be coded with the latest version of the Medical Dictionary for Regulatory 
Activities and summarized by treatment group overall, by severity, and by relationship to 
MSB11022-
 or Humira®. The nature, severity, and frequency of the adverse drug 
reactions in patients who receive MSB11022-
 will be compared with those who receive 
Humira® to evaluate comparability of safety. 
Descriptive statistics of the immunogenicity assessment per treatment arm will be given with 
reference to the Safety Analysis Set.
The proportion of patients with an ACR20 response in both the treatment groups at Week 12 
as well as 95% CIs for their difference will be reported in the ITT and Per protocol analysis 
sets.
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Table 1
Schedule of Assessments
Day/Week
Screening 
Day 1
Week 0
(Baseline)
W2
W4
W6
W8
W12
W24a
W36
W48
W52b
ETb
4-week 
safety FU
(4 weeks 
after last 
dose of 
IMP)c
4-month 
safety 
evaluation
(4 months 
after last 
dose of 
IMP)c
Visit window (days)
-28 days 
to
-3 days
None
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 7
± 7
± 7
Informed consent
X
Demographics, 
medical historyd
X
Xe
Inclusion/exclusion 
criteria
X
Xf
Randomization
X
IMP dispensedg
X
X
X
X
X
IWRS contacted
X
X
X
X
X
X
X
X
X
Trial medication 
administered at siteg
X
X
X
X
X
X
X
X
Physical examination 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (including 
blood pressure, 
height,h and weight, 
body temperature, 
respiratory rate, heart 
rate)
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry, 
hematology, 
urinalysis 
X
X
X
X
X
X
X
X
X
X
X
Follicle-stimulating 
hormone testi
X
Pregnancy test 
(serum β-hCG)j
X
Urine pregnancy testj
X
X
X
X
X
X
X
X
X
X
Antibody tests: ANA, 
anti-dsDNA, RF and 
ACPAk
X
X
X
X
X
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Day/Week
Screening 
Day 1
Week 0
(Baseline)
W2
W4
W6
W8
W12
W24a
W36
W48
W52b
ETb
4-week 
safety FU
(4 weeks 
after last 
dose of 
IMP)c
4-month 
safety 
evaluation
(4 months 
after last 
dose of 
IMP)c
Visit window (days)
-28 days 
to
-3 days
None
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 7
± 7
± 7
Viral serologyl
X
Tuberculosis 
Quantiferon-Gold 
testm
X
Xm
Xm
Xm
Chest X-rayn
X
12-lead ECGo
X
X
X
X
X
Patient’s Global 
Assessment of 
Disease Activityp
X
X
X
X
X
X
X
X
X
Physician’s Global 
Assessment of 
Disease Activityp
X
X
X
X
X
X
X
X
X
Patient assessment 
of arthritis painp
X
X
X
X
X
X
X
X
X
HAQ-DIp
X
X
X
X
X
X
X
X
X
Tender joint count
X
X
X
X
X
X
X
X
X
Swollen joint count
X
X
X
X
X
X
X
X
X
C-Reactive protein
X
X
X
X
X
X
X
X
X
Erythrocyte 
sedimentation rateq
X
X
X
X
X
X
X
X
X
Sampling for 
immunogenicityr
Xs
X
X
X
X
X
X
X
X
PK sampler
X
X
X
X
X
X
X
X
Injection site pain 
(VAS)t
X
Xu
X
Adverse events, 
concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
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Day/Week
Screening 
Day 1
Week 0
(Baseline)
W2
W4
W6
W8
W12
W24a
W36
W48
W52b
ETb
4-week 
safety FU
(4 weeks 
after last 
dose of 
IMP)c
4-month 
safety 
evaluation
(4 months 
after last 
dose of 
IMP)c
Visit window (days)
-28 days 
to
-3 days
None
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 7
± 7
± 7
Infectious disease 
specialist 
/pulmonologist 
consultationv
X
X
SF-36p
X
X
X
X
X
EQ-5D-5Lp
X
X
X
X
X
Collection and review 
of patient diaryw
X
X
X
X
X
X
ACPA = anti-citrullinated protein antibodies; Β-hCG = beta-human chorionic gonadotropin; dsDNA = double-stranded DNA; ECG = electrocardiogram; 
EQ-5D-5L = EuroQol in 5 dimensions-5 levels; ET = early termination; FU = follow up; HAQ-DI = Health Assessment Questionnaire – Disability Index;
SF-36 = 36-item Short Form Health Survey; RA = rheumatoid arthritis; RF = rheumatoid factor; VAS = visual analog scale; W = week.
a
For patients who do not achieve a reduction in both swollen and tender joints of ≥ 20% at Week 24 or at any other later-scheduled time point, the IMP will be
discontinued. These patients will remain in the trial safety analysis set and participate in the safety and immunogenicity assessments.
b
The treatment termination information must be recorded during the Week 52 visit and the ET visit, and trial termination information must be recorded during 
the Safety Follow-up visit.
c
Patients who discontinue from treatment will immediately have an ET visit and return for a safety follow-up visit 4 weeks after the last dose of IMP. Patients 
will return for an additional safety evaluation 4 months after the last dose of IMP. The 4-week and 4-month Safety Follow-up visits will not be duplicated if 
either of these visits falls within 2 weeks of an otherwise scheduled visit. If the 4-week and 4-month Safety Follow-up since last IMP are completed within the 
52 week visit schedule, these will not be repeated thereafter.
d
Medical history must include the following: disease phenotype, disease duration, infectious complications, disease localization, previous treatment(s) including 
identification of any previous biologic and nonbiologic RA therapy or history of treatment for latent or active TB, previous surgery/surgeries and smoking 
status. 
e
Review & update medical history only, to ensure patient remains qualified for the study.
f
Screening results should be re-checked (particularly virus serology and TB tests) to ensure that the patient remains eligible for the trial.
g
IMP will be administered every other week. During weeks with scheduled trial site visits, IMP will be administered at the site. During all other weeks, the 
patient (or a caregiver) will self-inject/inject IMP at home. Patients must be monitored for 1 hour following IMP administration on Day 1 of Week 0, Week 2,
and Week 4. Last dose of IMP will be at Week 48.
h
Height will be measured at screening only. 
i
Follicle-stimulating hormone test will be performed to confirm postmenopausal status of women with continuous amenorrhea ≥12 months.
j
For women of child-bearing potential only, a qualitative serum pregnancy test will be performed at screening and an on-site urine test performed at baseline; 
Weeks 4, 8, 12, 24, 36, 48, and 52; the ET visit and the safety follow-up visit. When there is no site visit, the patients will perform urine pregnancy tests 
themselves at home, ie, at Weeks 16, 20, 28, 32, 40, and 44.
k
RF and ACPA will only be collected at screening.
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l
Blood samples for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus will be obtained at screening.
m
The tuberculosis Quantiferon-Gold test will only be performed in patients whose previous test was negative. Continuation of study medication will be excluded 
in patients who were QFT negative at randomization, but subsequently become QFT positive at Week 24.
n
If a bi-directional X-ray is available from the last 3 months before planned randomization, the exam will not be repeated at screening.
o
The ECG will be repeated at the ET or 4-week/4-month Safety/Follow-up visit only if in the opinion of the Investigator it is clinically warranted.
p
Patient reported outcome questionnaires and the Physician’s Global Assessment of Disease Activity must be performed prior to any other assessments at all 
visits.
q
Performed locally.
r
All blood samples for immunogenicity assessment and IMP concentration must be drawn prior to administration of the IMP, which will be performed at the 
site for these visits. The date and exact time of sample collection must be recorded.
s
For assay validation purposes only, no result(s) will be reported.
t
Injection site pain (VAS) immediately post-injection, 15 min post-injection, and 1 hour post-injection. If the pain has not resolved by 1 hour post-injection, the 
patients will be asked to record when the pain resolves. Injection site pain during 3rd, 4th, and 5th injection will be reported as adverse event similar to any 
injection site reactions at other time point of IMP administration. The first 2 injections will be administered by qualified personnel.  The next three doses of 
IMP (3-5) will be self-administered by the patient and injection site pain will be assessed. Pain will be recorded immediately after, 15 minutes after, and 1 hour 
after the injections received by the patient.
u
Injection site pain will be recorded by the patient at home.
v
Subjects who were QFT negative at randomization but subsequently become QFT positive at Week 24 or Week 52 will be referred by Investigators for a 
consultation with an infectious disease specialist/pulmonologist to assess whether TB re-activation occurred during the trial.
w
Subject diaries will be collected at the visits indicated and reviewed by the site staff.
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Table 2
Population PK Table of Assessments
Day/Week
Screening
Day 1
Week 0
(Baseline)
Day 2 
Week 0
Day 4 
Week 0
Day 9 
Week 0 W2 W4 W6 W8 W12 W24
Day 2 
Week 24
Day 4 
Week 24
Day 9 
Week 24 W26+ W36 W48 W52
ET
4-week 
safety FU
(4 weeks 
after last 
dose of
IMP)
4-month 
safety 
evaluation
(4 months 
after last 
dose of 
IMP)
Population 
PK 
sampling@
X
X
X
X
X
X
X
@
Blood for population pharmacokinetic assessment will be collected in a subset of 60 patients (30 per treatment arm). Patients in the population PK analysis 
will have additional samples taken on Days 2 (24 h post first dose), 4, and 9, and Days 2 (24 h post Week 24 dose), 4, 9, and 14 (Week 26 pre-dose) after 
the Week 24 dose.  The date and exact time of sample collection must be recorded.
+
At Week 26 an additional sample for immunogenicity assessment is to be collected.
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2
Sponsor, Investigators and Trial Administrative Structure
The Sponsor of this clinical trial with MSB11022 is EMD Serono Research & Development 
Institute, Inc. (EMD Serono R&D), Billerica, MA, in the United States of America (USA) and 
Merck KGaA, Darmstadt, Germany, in rest of world.  
The trial will be conducted at approximately 50 sites in 6 countries in Europe.
The Coordinating Investigator represents all Investigators for decisions and discussions regarding 
this trial, consistent with the International Council for Harmonisation (ICH) Topic E6 Good 
Clinical Practice (GCP; hereafter referred to as ICH GCP). The Coordinating Investigator will
provide expert medical input and advice relating to trial design and execution and is responsible 
for the review and signoff of the clinical trial report. 
Signature pages for the Protocol Lead and the Coordinating Investigator as well as a list of Sponsor 
responsible persons are in Appendix B.
The trial will appear in the following clinical trial registries: Clinicaltrials.gov, EU clinical trial 
registry and national registries as per local regulations.
A contract research organization (CRO), 
, will undertake the 
operational aspects of this trial with oversight by the Sponsor. Details of such structures and 
associated procedures will be defined in a separate Integrated Project Management Plan (IPMP).  
The IPMP will be prepared by the 
 Clinical Project Manager in cooperation with other 
 Operational Team Leads. Clinical quality assurance will be performed under the 
responsibility of the Development Quality Assurance department at Merck KGaA Darmstadt.
An Independent Data Monitoring Committee (IDMC) will be established to continually review 
available safety and tolerability data. The IDMC will be composed of independent physicians and 
an independent biostatistician. The full list of IDMC members and IDMC responsibilities will be 
included in the IDMC charter. 
The investigational medicinal products (IMP) will be supplied by the Clinical Trial Supply 
Department of the Sponsor and packaged and labeled by 
. 
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader.
3
Background Information
3.1
Adalimumab
Adalimumab is a tumor necrosis factor (TNF) inhibitor indicated in the European Union (EU) and 
United States (US) for the treatment of multiple medical conditions, including rheumatoid arthritis 
(RA), polyarticular juvenile idiopathic arthritis (JIA), enthesitis-related JIA (EU only), psoriatic 
arthritis, ankylosing spondylitis, axial spondyloarthritis (EU only), Crohn’s disease, ulcerative 
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colitis, plaque psoriasis, pediatric plaque psoriasis (EU only), pediatric Crohn’s disease, 
hidradenitis suppurativa, and uveitis. It is a recombinant human monoclonal antibody expressed 
in Chinese Hamster Ovary cells which binds specifically to TNF and neutralizes the biological 
function of TNF by blocking its interaction with the cell surface TNF receptors, p55 and p75.
MSB11022 is a proposed biosimilar of adalimumab (Humira®). To establish biosimilarity per 
international regulations, the biological product must be highly similar to the reference product 
notwithstanding minor differences in clinically inactive components and there must be no 
clinically meaningful differences between the biological product and the reference product in 
terms of the safety, purity, and potency of the product (1). Development of a biosimilar generally 
includes a comparison of the proposed product and the reference product with respect to structure, 
function, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity
and clinical safety and effectiveness. If a product meets the requirements of biosimilarity and upon 
scientific justification, the potential exists for the proposed product to be approved for additional 
indications of use for which the reference product is approved. (2, 3, 4).
MSB11022 has previously undergone extensive analytical characterization compared to the 
reference product. In a recently conducted Phase I study, EMR200588-001, a citrate-based 
formulation (MSB11022-citrate) that showed a high degree of similarity has demonstrated PK 
similarity to the EU-approved and US-licensed reference products in healthy volunteers. In that 
study, the 90% confidence intervals (CIs) of the geometric least squares (LS) mean ratios 
(MSB11022-citrate/US-licensed 
Humira, 
MSB11022-citrate/EU-approved 
Humira®, 
and 
US-licensed Humira®/EU-approved Humira®) for area under the plasma concentration time curve 
from zero to the last measurable time point (AUC[0-last]), area under the plasma concentration time 
curve from zero to infinity (AUC[0-inf]), and maximum plasma concentration (Cmax) were all 
entirely contained within the predefined equivalence interval of 80.00% to 125.00%. Therefore, 
MSB11022-citrate showed an equivalent PK profile to the 2 reference treatments, US-licensed 
Humira® and EU-approved Humira®; and US-licensed Humira® showed an equivalent PK profile 
to EU-approved Humira®, following a single subcutaneous (s.c.) injection administration of 
40 mg. The safety and immunogenicity data supported the clinical similarity of MSB11022 to both 
US-licensed Humira® and also EU-approved Humira®.
EMR200588-002, a pivotal Phase III study designed to demonstrate equivalent efficacy of 
MSB11022-citrate versus EU-approved Humira® is currently ongoing in patients with moderate 
to severe chronic plaque psoriasis. Studies EMR200588-001 and EMR200588-002 will together 
constitute the core package for dossier submission for marketing authorization for the citrate-based 
formulation of MSB11022.
For potential commercialization, a new (
based) formulation has been developed. A 
thorough compatibility exercise has been performed between the two MSB11022 formulations, 
MSB11022-citrate and MSB11022-
 Results from extensive characterization of the drug 
substance and product batches showed comparable characteristics. Therefore the product used in 
the Phase I EMR200588-001 and Phase III EMR200588-002 clinical trials is representative of the 
product, MSB11022-
 to be used in the proposed Phase III MS200588-004 clinical trial. The 
planned MS200588-0004 study will use this new 
 formulation and will offer supportive 
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evidence by providing safety, immunogenicity, and efficacy data in a major approved indication 
for adalimumab, RA. 
Refer to the Investigator’s Brochure (IB) for further information about the nonclinical and clinical 
programs and guidance for the Investigator.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and 
any additional applicable regulatory requirements.
Based on the available quality, nonclinical and clinical data to date, the conduct of the trial
specified in this protocol is considered justified (see Section 5.2.1).
3.2
Rheumatoid Arthritis
Rheumatoid arthritis is a chronic autoimmune disorder affecting about 1% of the adult population 
worldwide (5). It is characterized by chronic inflammation of the synovial joints, particularly the 
small joints of hands and feet, which often leads to destruction of articular cartilage and 
juxta-articular bone. Most patients have a progressive course that eventually leads to considerable 
functional disability. A wide array of factors including geographical location, age, gender, 
infection, oxidative stress and genetic predisposition are known to be involved in the list of 
causative agents of RA (6, 7).
Juvenile idiopathic arthritis affects individuals up to 16 years of age, and often persists throughout 
adult life; both the systemic (sJIA) and the poly-articular (pJIA) forms of the JIA may be 
considered as the pediatric counterparts of the adult forms of RA. The destructive potential of both 
RA and JIA can be observed even in the earliest stage of the disease. While joints constitute the 
main target of the anatomical damage, both RA and JIA are systemic conditions and they are often 
accompanied by extra-articular manifestations such as fever, anemia, fatigue, and osteoporosis. 
The pathogenesis of these diseases is complex and involves both humoral and cellular reactions 
including immune-complex formation, vascular reactions and infiltration of lymphocytes and 
monocytes into the synovium. These infiltrating cells and synoviocytes release pro-inflammatory 
cytokines that perpetuate inflammation and destruction through effects on other cell types in the 
synovium and periarticular structures (8). 
Reactive oxygen and nitrogen species have been shown to cause tissue injury and 
pathophysiological consequences in chronic inflammatory conditions such as RA and other 
rheumatic diseases (9). The basic pathology in the synovium of RA is hyperplasia, increased 
vascularity and inflammatory cell infiltration. The principal cells among the infiltrates are 
activated CD4+ T-cells which produce cytokines such as IL-1, IL-6 and TNF-α. TNF-α is a potent 
cytokine involved in normal inflammatory and immune response. Individuals with RA have high 
levels of TNF-α in the synovial fluid and it plays an important role in inflammation and joint 
destruction that are hallmarks of RA. Anti-TNF-α therapy induces a shift in the cytokine 
equilibrium producing more anti-inflammatory cytokines. Studies have demonstrated dramatic 
improvement in synovial inflammation in RA patients after treatment with neutralizing anti-TNF-α 
Abs or soluble TNF receptors, and decreased joint destruction after treatment with IL-1Ra. 
Immunosuppressive and anti-inflammatory cytokines, including TGFβ, IL-10 and IL-1Ra are 
highly and consistently expressed during RA synovitis. Production of these cytokines has been 
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proposed to reflect the patient's attempts to contain or control inflammation and achieve 
homeostasis (10).
In particular, IL-6 is a pleiotropic cytokine playing a pivotal role in the pathogenesis of both RA 
and JIA (11). For example its role for the process of B-cell maturation and the consequent 
production of auto-antibodies has been demonstrated. It also directly triggers the production of 
C-reactive protein (CRP) from hepatocytes. In animal models of autoimmune diseases, IL-6 also 
plays a critical role in the generation of Th17 pro-inflammatory lymphocytes. In patients with 
established RA, many of the articular and systemic manifestations could be explained by the 
biologic effect of IL-6 (8).
3.3
Safety and tolerability
The expected safety profile for MSB11022 is that known for EU-approved and US-licensed 
Humira®. The exclusion criteria for this trial take the known side-effect profile for adalimumab 
into consideration.
Adalimumab is known to compromise host defenses against pathogenic organisms, resulting in 
possible reactivation of tuberculosis (TB), invasive fungal infections, or susceptibility to 
opportunistic pathogens such as Legionella or Listeria. Upper respiratory tract and pulmonary 
infections feature prominently within the AE profile (12, 13, 14, 15, 16, 17, 18). Explicit screening 
for TB before exposure to Humira® is included in the trial procedures. No serious infections were 
reported in the first-in-human Trial EMR200588-001. 
Minor differences in structural features such as glycosylation profiles cannot be excluded between 
2 batches of closely related biological molecules targeting the same cell functions. For most 
biological systems, such minor variations is not expected to adversely impact the compound’s 
ability to perform the biological role. In contrast, the immune system is uniquely sensitive to small 
biological variations and has the ability to distinguish between almost identical molecular entities. 
Accordingly, immunogenicity, such as anti-drug antibodies (ADAs), will be measured in this trial, 
and the results will be compared between the trial treatment arms. Differences in immunogenicity 
as ascertained in highly sensitive laboratory experiments may be indicative of a difference in the 
propensity to trigger clinically meaningful reactions of the immune system, eg, injection site 
reactions, or other forms of hypersensitivity (19).
The nonclinical pharmacodynamics properties of MSB11022 were investigated in vitro using 
binding and functional assays, which supported similarity of MSB11022 to Humira®. In addition, 
a comparative repeat-dose toxicity study was performed in a relevant animal model (cynomolgus 
monkeys), which proved comparability between MSB11022 and Humira®. Please refer to the 
current IB for complete nonclinical data.
MSB11022 was found to be equivalent in terms of PK to EU-approved Humira® and US-licensed 
Humira® and to have a comparable safety profile in Trial EMR200588-001.
In Trial EMR200588-001, no deaths and no SAEs related to the trial medications were observed. 
Similar proportions of subjects had treatment-emergent adverse events (TEAEs) in the MSB11022 
trial arm (64.1%), the US-licensed Humira® arm (57.5%), and the EU-approved Humira® arm 
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(62.0%). Most of the TEAEs were considered to be mild in severity and not related to the trial 
medications. The most frequently reported TEAE considered to be related to the trial medications 
was headache.
No serious infections were reported in the trial. A higher proportion of subjects in the EU-approved 
Humira® arm had hypersensitive reactions compared with the other arms (2 subjects [2.6%] in the 
MSB11022 arm, 2 subjects [2.5%] in the US-licensed Humira® arm, and 6 subjects [7.6%] in the 
EU-approved Humira® arm).
No safety concerns based on laboratory measurements, vital signs, 12-lead electrocardiogram 
(ECG), or local tolerability were reported.
Please refer to the current IB for more details on the results of Trial EMR200588-001.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and 
any additional applicable regulatory requirements.
3.4
Risk-Benefit Assessment
MSB11022 shows structural concordance with EU-approved and US-licensed Humira®, pointing 
towards a commonality of benefits and risks between them. It is thus expected that the benefits 
and the risks associated with MSB11022 are those described for EU-approved and US-licensed 
Humira®. Minor variations in the safety profile between Humira® and MSB11022 cannot be 
excluded due to subtle differences in micro-structure. Investigators should consider the known 
risks for Humira® as equally applicable for MSB11022.
The risk-benefit relationship was carefully considered in the planning of the trial. Based on the 
nonclinical data for MSB11022, the results of the PK equivalence Trial EMR200588-001, and 
clinical data for Humira® available to date, as well as the thorough comparability exercise which 
has been performed between the two MSB11022 formulations, MSB11022-citrate and 
MSB11022-
 the conduct of this trial is considered justifiable using the dose and dosage 
regimen of the IMPs as specified in this clinical trial protocol. The trial will be discontinued in the 
event of any new findings that indicate a relevant deterioration of the risk benefit relationship and 
would render continuation of the trial unethical.
4
Trial Objectives
4.1
Primary Objective
The primary objective of this study is to evaluate the safety profile of MSB11022-
compared 
to Humira® in patients with moderately to severely active RA up to Week 52.
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4.2
Secondary Objectives
4.2.1
Key Secondary Objective
The key secondary objective is to compare the efficacy (ACR20) of MSB11022-
 compared 
to Humira® at Week 12 in patients with moderately to severely active RA.
4.2.2
Other Secondary Objectives
Other secondary objectives are as follows:
! To evaluate the immunogenicity profile of MSB11022-
 compared to Humira®in patients 
with moderately to severely active RA up to Week 52
! To further compare the efficacy and safety of MSB11022-
 compared to Humira® in 
patients with moderately to severely active RA up to Week 52
! To compare quality of life (QoL) and physical function on MSB11022-
 with Humira®
in patients with moderately to severely active RA
! To compare injection site pain levels of MSB11022-
 versus Humira®.
4.3
Exploratory Objective
The exploratory objective is to evaluate population PK on MSB11022-
 and Humira® in 
patients with moderately to severely active RA.
5
Investigational Plan
5.1
Overall Trial Design and Plan
A schematic of the trial design is presented in Figure 1.
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Figure 1
Schematic of the Trial Design
A detailed schedule of study procedures/assessments is provided in Table 1.
5.2
Discussion of Trial Design
This trial is a two-arm, randomized, multicenter, double-blind, parallel group trial designed to 
compare the safety, immunogenicity, and efficacy of MSB11022-
 with Humira® in 
approximately 260 randomized patients with moderately to severely active RA during a 52-week 
period.
Baseline is defined as the day on which the first dose of the IMP (blinded trial drug) is 
administered. The trial will include a pre-trial evaluation period (screening period, from 28 days 
to 3 days prior to IMP administration), a double-blind 48-week treatment period to evaluate 
long-term safety and immunogenicity, a 4-week safety follow-up visit, and a 4-month safety 
evaluation period.
Primary safety and immunogenicity endpoints will be assessed up to Week 52, key secondary 
efficacy endpoint will be assessed at Week 12. The analysis for the key secondary efficacy 
endpoint will be descriptive.  
Re-screening will be allowed once for those patients who do not meet the inclusion/exclusion 
criteria within the above specified time limits. The Medical Monitor must promptly inform the 
Sponsor about requests and reasons for re-screening. An IDMC will review the safety data from 
this trial on an ongoing basis. Re-screened subjects will undergo all screening procedures.
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Eligible patients will be randomized in permuted blocks in a 1:1 ratio by an interactive web 
response system (IWRS) to receive either MSB11022-
 subcutaneous (s.c.) or Humira® s.c. 
at a dose of 40 mg every other week starting at baseline (Day 1/Week 0) up to and including 
Week 48. Patients will be stratified by the type of systemic therapy previously received: 
non-biological (biologic naïve patients) versus biological (biologic experienced patients). Patients
who previously received both (biological and non-biological systemic therapies) will be assigned 
to the “biological” group. The exposure to previous biological agents will be limited to one TNF 
inhibitor other than adalimumab. The participation of patients in the previous biological systemic 
therapy stratum will be capped at 20% of the total number of patients randomized. This is in accord 
with what registered in other trials with biological agents in different rheumatic indications (63, 
64, 65). Capping will be enforced through application of an IWRS.
The first 2 doses of IMP will be administered on site by the Investigator or other qualified 
personnel and the patient will be educated on the correct process. The third dose of IMP will be 
administered on-site by the patient. Patients will be monitored for 1 hour following the first 3 IMP
administrations. If the Investigator judges it appropriate after proper training, the patient (or a 
caregiver) may continue to self-inject/inject the treatment for the remaining doses. Injection site 
pain will be assessed after doses 3 to 5. If a patient self-administers, the injection should not be 
given in the arm. The remaining doses of IMP will be dispensed, and written instructions on proper 
dosage, administration, storage, and recording will be provided to the patient/caregiver. 
Administrations performed at home will be recorded in a diary with the accurate dosing 
information (dosing date and time). In the case that there is a delay in the administration of IMP 
at home, there will be no delay to scheduled visits. During weeks with scheduled trial site visits, 
the IMP will be administered at the site.
The 48-week double-blind treatment period will allow for the collection of long-term comparative 
safety, immunogenicity, and efficacy data for MSB11022-
 versus Humira®. 
Patients who achieve less than 20% improvement in both swollen and tender joint counts at 
Week 24 (non-responders) will be discontinued from the IMP. These patients will remain in the 
trial safety analysis set and participate in the safety and immunogenicity assessments. For the 
management of these patients, see Section 5.4.1.
After Week 24, patients with less than 20% improvement in both swollen and tender joint counts 
at any scheduled visit up to Week 52 will also be discontinued. Patients may continue at 
Investigator discretion from Week 24 to Week 52 as long as they maintain more than 20% 
improvement in both swollen and tender joint counts.
Patients who discontinue from the study medication but remain in the trial and continue for the 
safety/immunogenicity visits before the Week 52 visit will immediately complete an Early 
Termination visit and return for a Safety/Follow-up visit 4 weeks after the last dose of IMP. During 
this 4-week Safety Follow-up period, no excluded treatment for RA (as defined in this protocol) 
should be administered. Patients will return for an additional safety evaluation 4 months after the 
last dose of IMP. Treatment for RA from the 4-week Safety Follow-up visit to the 4-month Safety 
Evaluation visit will be at the discretion of the Investigator following institutional standard of care.
The 4-week and 4-month Safety Follow-up visits will not be duplicated if either of these visits
falls within 2 weeks of an otherwise scheduled visit. If the 4-week and 4-month Safety Follow-up 
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since last IMP are completed within the 52 week visit schedule, these will not be repeated 
thereafter.
All patients will have PK samples taken pre-first dose, and then prior to dosing on Weeks 2, 4, 12, 
24, 36, and 52. In addition, a subset of 60 patients (30 per arm) will have additional samples to 
support the population PK analysis taken on Days 2 (24 h post first dose), 4, and 9, and Days 2 
(24 h post Week 24 dose), 4, 9, and 14 (Week 26 pre-dose) after the Week 24 dose (see Table 2).  
An IDMC will review the safety data from this trial on an ongoing basis.
Visit schedules for safety, immunogenicity, and efficacy assessments are detailed in the Schedule 
of Assessments in Table 1.
5.2.1
Scientific Rationale for Study Design
A double-blind, two-arm, parallel-group design represents an ideal setting to provide comparative 
long-term immunogenicity and safety data for the new 
 formulation versus Humira®. 
Regulatory agencies are aware of the difficulty to power for safety and immunogenicity. 
According to EMA “the investigation of safety is a multidimensional problem. Although some 
specific adverse effects can usually be anticipated and specifically monitored for any drug, the 
range of possible adverse effects is very large, and new and unforeseeable effects are always 
possible. Further, an adverse event (AE) experienced after a protocol violation, such as use of an 
excluded medication, may introduce a bias. This background underlies the statistical difficulties 
associated with the analytical evaluation of safety and tolerability of drugs, and means that 
conclusive information from confirmatory clinical trials is the exception rather than the rule. In 
most trials the safety implications are best addressed by applying descriptive statistical methods to 
the data, supplemented by calculation of confidence intervals wherever this aids interpretation.” 
(20).
Concerning immunogenicity assessment, regulatory agencies currently prefer to focus on a 
comprehensive, yet descriptive, presentation and correlation of the immunogenicity data generated 
in clinical studies (21, 22, 23, 24, 25).
According to regulatory guidance and literature, data captured in the study should allow 
exploration of the possible correlation of the immunogenicity assessment to PK (eg, Ctrough), safety 
(eg, injection site reactions), and/or efficacy (eg, reduced or loss of clinical response) (26, 27). In 
addition, the kinetics of an immune response (time to anti-drug antibodies [ADA], titer over time, 
persistent or transient ADA) observed will be used to compare the proposed biosimilar with the 
reference product to contribute to the totality of evidence and to the biosimilarity claim.
For all these reasons, the proposed study cannot be powered to demonstrate equivalence in safety 
and immunogenicity. 
In this study, RA patients must have active disease, and be inadequate responders to methotrexate 
(MTX). The patients will continue to use MTX at a stable dose in combination with adalimumab 
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over the entire duration of the study. Previous treatment with up to 4 disease-modifying 
antirheumatic drugs (DMARDs) including MTX is allowed. Up to 20% of patients may have been 
treated with 1 TNF inhibitor (other than adalimumab, adalimumab biosimilar investigational 
products, or innovator investigational products). This patient population was chosen because it 
was the most robustly studied population in Phase III studies and likely represents the majority of 
patients receiving adalimumab. Additionally, as confirmed in a recent EMA consultation
(April 2016), RA represents a sensitive setting to investigate potential differences in 
immunogenicity (28).
The inclusion and exclusion criteria (see Sections 5.3.1 and 5.3.2, respectively) have been chosen 
to ensure patient safety by identifying patients with a history of specific medical conditions or 
those receiving specific medications that may pose a risk based on the mechanism of action of this 
class of drugs.
5.2.2
Justification for Dose
The dose and regimen selected are those approved for Humira® for the treatment of RA.
5.2.3
Rationale for Endpoints
5.2.3.1
Primary Endpoint
Incidence of AESI (Hypersensitivity) including and up to Week 52
In order to provide long-term safety and immunogenicity data in patients to support the new 
 
formulation, this descriptive study will evaluate the safety and immunogenicity profile of 
MSB11022-
compared to the Humira® in patients with moderately to severely active RA 
who have had an inadequate response to MTX. In such a population, the rate of most commonly 
observed hypersensitivity events is 26.5% for the injection site reactions and 11% for rash (29).
5.2.3.2
Key Secondary Endpoint
The endpoints and schedule for the efficacy assessment reflect the most up-to-date regulatory 
guidance and evidence-based recommendations for this indication (30, 31). Additionally, an 
intensive efficacy assessment up to Week 12 is appropriate to properly evaluate the response 
curves before a plateau is reached.
American College of Rheumatology 20% response criteria (ACR20) – An ACR20 response, 
the most extensively used criterion for response in RA, is defined as an improvement of at least 
20% in the number of tender joints and swollen joints, and at least 20% improvement in 3 out of 
the remaining 5 ACR core-set measures (patient assessment of arthritis pain, Patient’s and 
Physician’s Global Assessment of Disease Activity, physical function [HAQ-DI], and acute phase 
reactants). Data on efficacy and safety of adalimumab in combination with MTX against placebo, 
in patients affected by RA, were mainly evaluated from 6 multicenter, randomized, double-blind, 
controlled studies (29, 32, 33, 34, 35, 36). These trials were all conducted in adult RA patients 
with long-standing, moderately to severely active disease. ACR20 has been extensively studied 
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also in the recent Amgen’s proposed biosimilar adalimumab ABP501 (37), Samsung’s proposed 
biosimilar adalimumab SB5 (38), Celltrion’s biosimilar infliximab CT-P13 (39).
5.2.3.3
Other Secondary Endpoints
Safety
Incidence of TEAEs and SAEs including and up to Week 52
In a population of MTX insufficient responders, the rate of TEAEs and SAEs at Week 52 has been 
reported up to 91% and 15-17%, respectively (40, 41, 42).
Immunogenicity
Numbers of patients who develop ADA, the ADA titer, and numbers of patients who develop 
anti-adalimumab neutralizing antibodies
An important objective of this clinical study is to investigate whether the
based formulation 
of MSB11022 displays a comparable immune response when compared to Humira®. The 
appearance of an immune response will be assessed in terms of formation of anti-drug-antibodies 
(ADA) and in terms of clinical manifestations.
Efficacy
ACR50, ACR70 – These are defined as an improvement of at least 50% and 70% respectively, in 
the number of tender joints and swollen joints, and at least 50% (ACR50) and 70% (ACR70) 
improvement in 3 out of the remaining 5 ACR core-set measures (patient pain, Patient’s and 
Physician’s Global Assessment of Disease Activity, physical function, acute phase reactants, 
respectively).
DAS28-ESR – The Disease Activity Score calculated on 28 joints (DAS28-ESR) is a composite 
score derived from 4 measures (43). Components of DAS28-ESR are:
! The number of swollen joints (out of the 28),
! The number of tender joints (out of the 28),
! Erythrocyte sedimentation rate (ESR),
! Patient’s Global Assessment of Disease Activity on a visual analog scale (VAS). 
The results are then fed into a formula to produce the overall disease activity score. A DAS28-ESR
of > 5.1 implies active disease, < 3.2 low disease activity, and < 2.6 remission. A change of 1.2 
(twice the measurement error) is defined as a significant change of the disease activity state (44). 
Yet, a change of 0.6 may be already be considered as a clinically meaningful variation in the 
context of defining response to therapy: indeed DAS28 is the core element of the EULAR response 
criteria. It is validated for use in clinical research and it is extensively used in clinical practice as 
well (45). 
SDAI – The Simplified Disease Activity Index (SDAI) is the numerical sum of 5 outcome 
parameters: tender and swollen joint count (based on a 28-joint assessment), Patient’s and 
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Physician’s Global Assessment of Disease Activity (VAS) and level of CRP (mg/dL, normal 
< 1 mg/dL). The SDAI is a valid and sensitive assessment of disease activity and treatment 
response that is comparable with the DAS28 and ACR response criteria; it is easy to calculate and 
therefore a viable tool for day-to-day clinical assessment of RA treatment (46, 47).
CDAI – The Clinical Disease Activity Index (CDAI) is a composite index (without acute-phase 
reactant) for assessing disease activity. CDAI is based on the simple summation of the count of 
swollen and tender joint counts of 28 joints along with Patient’s and Physician’s Global 
Assessment of Disease Activity (VAS) for estimating disease activity. The CDAI ranges from 0 
to 76. The greater advantage associated with CDAI is its potential to be employed in evaluation of 
patients with RA consistently with close frequency and independently of any calculating device, 
therefore, it can essentially be used everywhere and anytime for disease activity assessment in RA 
patients (46, 47).
ACR/EULAR Boolean remission – Following the Boolean-based definition of remission of 
ACR/EULAR, at any time point, a patient must satisfy all of the following: tender joint count ≤1, 
swollen joint count ≤1, CRP ≤1 mg/dL, and Patient’s Global Assessment Of Disease Activity ≤1 
(0-10 VAS). The Boolean criteria appear more stringent than the DAS28 remission and have been 
specifically created for use in clinical trials (48). Emery et al. showed that a significantly greater 
proportion of patients achieved remission when receiving a combination of a TNF inhibitor 
(golimumab) in combination with MTX as compared with those receiving MTX monotherapy 
(49).
Quality of Life (QoL)
HAQ-DI – The Health Assessment Questionnaire-Disability Index is a validated patient reported 
outcome measure for the evaluation of physical function. There are 8 sections: dressing, arising, 
eating, walking, hygiene, reach, grip, and activities. There are 2 or 3 questions for each section. 
Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section,
the score given to that section is the worst score within the section, eg, if 1 question is scored 1 
and another 2, then the score for the section is 2. In addition, if an aid or device is used or if help 
is required from another individual, then the minimum score for that section is 2. If the section 
score is already 2 or more then no modification is made. The 8 scores of the 8 sections are summed 
and divided by 8. The result is the disability index (DI) or functional disability index (FDI) (50). 
The HAQ-DI has been validated for use in RA over 3 decades (51). 
36-item Short-Form Health Survey – The Short Form (36) Health Survey (SF-36) is a validated 
36-item, patient-reported indication of overall health status not specific to any age, disease or 
treatment group (52). It has been extensively studied in RA, and a significant association between 
the physical functioning score of the SF36 and the HAQ-DI score, as well as with other measures 
of disease activity and severity, and co-morbidities has been demonstrated (53). 
The SF-36 includes 1 multi-item scale measuring each of the following 8 health concepts: (1) 
physical functioning; (2) role limitations because of physical health problems; (3) bodily pain; (4) 
social functioning; (5) general mental health (psychological distress and psychological wellbeing); 
(6) role limitations because of emotional problems; (7) vitality (energy/fatigue); and (8) general 
health perceptions.
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Questions in the standard version of the SF-36 refer to a 4-week time period. Scales are scored 
according to the Likert method. Lower scores equate to higher disability and higher scores equate 
to lower disability. 
EQ-5D-5L – The EuroQoL-5 dimension-5 levels instrument is a short, easy to use, generic 
questionnaire used to measure health-related quality of life (HRQoL). It consists of a 
self-assessment questionnaire and VAS. It assesses the patient’s current health in 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The patient is asked 
to grade their own current level of function in each dimension into 1 of 5 levels (no problems, 
slight problems, moderate problems, severe problems and unable to/extreme problems). The 
EQ-VAS is a self-rated health status using a vertical VAS. The EQ-VAS records the patient’s 
perceptions of their own current overall health in a range from 0 (worst imaginable health state) to 
100 (best imaginable health state) and can be used to monitor changes with time. The EQ-VAS 
addition to the EQ-5D-5L provides an insight into patients’ perception of their own overall current 
health (54). EQ-5D-5L is also recognized by the National Institute of Health and Care Excellence 
(NICE) in the United Kingdom for monitoring HRQoL and is used in cost-utility analyses. The 
EQ-5D-5L is one the most extensively validated measures for use in patients with RA (55).
Evaluation of injection site pain – Information regarding injection site pain following s.c. 
injection with the MSB11022-
formulation vs. Humira® will be collected. The patient’s 
reported perception of pain will be measured on a VAS where the slash drawn by the patient
represents pain of increasing intensity (56). The first 2 injections will be administered by qualified 
personnel. The next three doses of IMP (3-5) will be self-administered by the patient and injection 
site pain will be assessed. Pain will be recorded immediately after, 15 minutes after, and 1 hour 
after the injections received by the patient.
 
 
 
 
 
 
 
 
 
 
 
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5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as patients. Prior to performing any trial assessments not part of the patient’s routine medical care, 
the Investigator will ensure that the patient or the patient’s legal representative has provided written 
informed consent following the procedure described in Section 9.2.
5.3.1
Inclusion Criteria
1. Must voluntarily give written informed consent. Patients must read and fully understand 
the Informed Consent Form (ICF) and the requirements of the trial and must be willing to 
comply with all trial visits and assessments.
2. Moderately to severely active diagnosis of RA with disease duration of at least 6 months 
from confirmed diagnosis, as defined by the 2010 revised ACR/EULAR 2010 criteria or
the 1987 ARA criteria (Criteria of American Rheumatology Association) (present or past).
3. Have moderately to severely active disease despite MTX therapy defined as:
a.
≥ 6 swollen joints and ≥ 6 tender joints (from the 66/68 joint count system) at screening 
and randomization.
b. Either ESR (Westergren) ≥28 mm/h or serum CRP ≥ 1.0 mg/dL at screening.
4. Must have been treated with MTX for a total of at least 12 weeks prior to baseline and must 
have been on both: a stable route of administration (oral or parenteral) and stable dose of 
MTX (10 to 25 mg/week) for at least 4 weeks prior to screening.
5. Age 18 and older.
6. Must be adalimumab naïve and must not have received a non-marketed experimental 
biological agent for their RA in the past, or any biological agent not belonging to the class 
of TNF inhibitors. Patients who have received no more than 1 TNF inhibitor (either 
originator or investigational biosimilar candidate that underwent comparison with EU or 
US reference compounds) other than adalimumab are allowed to participate in the trial.
7. Must have discontinued infliximab (either originator or investigational or approved 
biosimilar), certolizumab pegol (either originator or investigational or approved biosimilar)
or golimumab (either originator or investigational or approved biosimilar) 8 weeks prior to 
screening, or etanercept (either originator or investigational or approved biosimilar) 
4 weeks prior screening.
8. A female patient is eligible to participate if she is not pregnant (see Appendix A), not breast 
feeding, and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix A
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OR
b. A WOCBP who agrees to use a highly effective contraception (ie, methods with a 
failure rate of less than 1% per year) as detailed in Appendix A of this protocol 
3 months before the start of the first dose of the IMP, during the treatment period, and 
for at least 5 months after the last dose of the IMP.
9. Female patients must not be pregnant and if of childbearing potential, must have a negative 
serum pregnancy test at screening and a negative urine pregnancy test at baseline before 
randomization.
10. Female patients must not be lactating or breast-feeding at screening through at least 
5 months after the last treatment with IMP.
11. Male patients must be either surgically sterile (vasectomy with documented confirmation 
of aspermia) or must agree to use a condom and have their female partners use a highly 
effective contraception (ie, methods with a failure rate of less than 1% per year) as detailed 
in Appendix A for 3 months before the first dose of IMP, during the treatment period and 
for at least 5 months after the last dose of IMP, unless their partners are infertile or 
surgically sterile. Male patients must agree to continue to practice adequate contraception 
for 5 months after the administration of the IMP and refrain from donating sperm during 
this period.
12. Patient must be able and willing to self-administer s.c. injections.
5.3.2
Exclusion Criteria
1. ACR functional class IV as defined by the ACR classification of functional status or 
wheelchair/bedbound.
2. A diagnosis of Felty’s syndrome.
3. A diagnosis of any other inflammatory arthritides/systemic autoimmune disease other than 
secondary Sjögren’s syndrome.
4. Received therapy with leflunomide within 12 weeks prior to baseline unless patient has 
undergone a drug elimination procedure with cholestyramine or activated charcoal powder, 
in which case the wash-out period is a minimum of 4 weeks.
5. Received DMARDs other than MTX including but not limited to oral or injectable gold, 
sulfasalazine, azathioprine, penicillamine, cyclosporine, or tacrolimus within 4 weeks prior 
to baseline. Patients may be taking oral hydroxychloroquine provided that the dose is not 
greater than 400 mg/day, or chloroquine provided that the dose is not greater than 
250 mg/day and that doses have been stable for a minimum of 12 weeks prior to baseline. 
The hydroxychloroquine or chloroquine treatment will need to be continued at a stable dose 
for the duration of the study.
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6. Received increasing doses of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 
(including low dose aspirin and COX-2 inhibitors) in the 2 weeks prior to baseline.
7. Prior exposure to alkylating agents, such as chlorambucil or cyclophosphamide.
8. Use oral glucocorticoids > 10 mg/day prednisone or equivalent. Doses up to 10 mg/day are 
allowed if have been kept stable for the 4 weeks prior to baseline.  
9. Any intra-articular, intravenous, or intramuscular use of corticosteroids in the 6 weeks prior 
to baseline.
10. High potency opioid analgesics (eg, methadone, hydromorphone, oxycodone, fentanyl, or 
morphine) are prohibited during the study; other analgesics are allowed (eg, propoxyphene, 
tramadol, codeine, or aspirin), although not within 12 hours of study visits.
11. History of tuberculosis (TB), presence of active tuberculosis, or latent tuberculosis as 
detected by imaging (eg, chest X-ray, chest Computerized Tomography [CT] scan, 
Magnetic Resonance Imaging [MRI]) and/or positive QuantiFERON-TB Gold test (QFT)
and/or clinical examination or has had latent TB disease at any time in the past.
Patients will be evaluated for latent TB infection (LTBI) by the QFT enzyme-linked 
immunosorbent assay and by chest X-ray. If a patient tests positive for LTBI at screening, 
the patient will be screen failed and will not be randomized. Patients with indeterminate 
QFT test result may be re-tested once within the screening period:
i.
If the re-test is negative, the patient is eligible to take part in the trial.
ii.
If the re-test is positive, the patient will not be eligible to participate in the 
trial.
iii.
If the re-test is again indeterminate, the patient will be considered as having 
LTBI and will not be eligible to participate in the trial. No further QFT will 
be performed.
12. Received a live vaccine within 3 months prior to IMP administration or intends to receive 
a live vaccination during the trial or within 3 months after the last dose of IMP.
13. History of hypersensitivity to any component of the IMP formulation, comparable drugs, 
or latex.
14. Any infection as follows:
a.
Requires treatment with oral antibiotics within 14 days prior to IMP administration.
b. A serious infection defined as requiring hospitalization or treatment with intravenous 
antibiotics within 8 weeks prior to IMP administration.
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c.
Has had herpes zoster or any opportunistic infection (eg, histoplasmosis, 
coccidioidomycosis, blastomycosis, pneumocystis, listeriosis, legionellosis, or 
parasitic infections) within 6 months prior to administration of IMP.
d. A history of persistent chronic infection or recurrent infections (3 or more of the same 
type of infection in any rolling 12 month period, eg, urinary tract or upper respiratory 
tract infections).
e.
Have documentation of seropositivity for human immunodeficiency virus (HIV), or
positive hepatitis C antibody test or hepatitis B surface antigen test and/or core antibody 
test for IgG and/or IgM or total Ig at screening.
15. History of lymphoproliferative disease or previous malignancy. Curatively treated basal or 
squamous cell carcinoma of the skin is not excluded, unless it occurred within 12 months 
of randomization. Curatively treated localized in situ carcinoma of the cervix is also not 
excluded, if there is no evidence of recurrence within the last 5 years prior to 
randomization.
16. Has a poorly controlled medical condition, such as but not limited to, poorly controlled 
diabetes, unstable ischemic heart disease, uncontrolled hypertension (systolic ≥160 mmHg 
and/or diastolic ≥95 mmHg), or other relevant medical disease, such as a neurological, 
pulmonary, gastrointestinal, or endocrine disease or a history of clinically significant 
hematological, renal, or liver disease or any other condition that, in the opinion of the 
Investigator, would put the patient at risk by participation in the trial.
17. Any major surgery (including arthroplasty) performed within the 6 weeks prior to the first 
dose of IMP.
18. Have presence of a solid organ or bone marrow transplant (with the exception of a 
successful corneal transplant > 3 months prior to screening).
19. Have a concomitant diagnosis or history of congestive heart failure (New York Heart 
Association [NYHA] class III or IV).
20. Have a known history, family history of or symptoms consistent with a demyelinating 
disease, such as multiple sclerosis, or optic neuritis, or symptoms suggestive of such a 
disorder.
21. Laboratory abnormalities deemed clinically significant by the Investigator or any of the 
following at screening:
a.
Hemoglobin < 8 g/dL for women or 8.5 g/dL for men.
b. White blood cells (WBCs) < 3.5 x 109/L.
c.
Absolute neutrophil count (ANC) < 1.5 x 109/L.
d. Platelet count < 100 x 109/L.
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e.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the 
upper limit of normal.
f.
Creatinine > 1.5 mg/dL if < 65 years old, or > upper limit of normal if ≥65 or with 
proteinuria 4+ or greater by dipstick.
22. Women who are pregnant, lactating, or planning pregnancy within 6 months after the last 
dose of IMP.
23. Legal incapacity or limited legal capacity.
24. Patient is considered by the Investigator, for any reason, to be an unsuitable candidate for 
the trial.
25. Patient has participated in any nonbiological investigational clinical trial within 12 weeks 
or 5 drug half-lives (whichever is longer) before first administration of IMP in this trial or 
planned intake of an investigational drug during the course of this trial.
26. History of clinically significant drug or alcohol abuse within the last 2 years.
5.4
Criteria for Patient Withdrawal
5.4.1
Withdrawal from Trial Therapy
A patient will no longer receive the study medication in the event of any of the following 
circumstances:
a.
Any events that unacceptably endanger the safety of the patient, including but not limited to 
the following:
! Use of prohibited treatment that in the opinion of the Investigator or Sponsor 
necessitates the patient treatment to be interrupted
! Occurrence of an exclusion criterion that is clinically relevant and affects the patient’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
! Anaphylactic or other serious allergic reactions
! Development of active or latent TB
! New or worsening symptoms of congestive heart failure
! Biopsy confirmation of any malignancy other than non-melanoma skin cancer, such as 
basal cell carcinoma and squamous cell carcinoma.
! Symptoms suggestive of lupus-like syndrome
! Pregnancy
b. Interruption of MTX more than twice in a period of 4 weeks, or for a period of interruption 
longer than 4 months.
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c.
Noncompliance or protocol violations that in the opinion of the Investigator or Sponsor 
necessitates the patient being withdrawn. The decision to withdraw the patient should be taken 
in consultation with the Medical Monitor. 
d. Participation in any other trial during the duration of this trial.
e.
If the whole trial is discontinued prematurely.
f.
Lost to follow-up.
If a patient is lost to follow-up, every possible effort must be made by trial center personnel to 
contact the patient and determine the reason for discontinuation. The measures taken to follow-up 
must be documented. If a patient discontinues before completion of trial procedures, the reason for 
discontinuation must be documented in the CRF and source documents.
Patients who discontinue from study medication (but continue safety/immunogenicity visits) 
before the Week 52 visit will immediately complete an Early Termination visit and return for a 
Safety/Follow-up visit 4 weeks after the last dose of IMP. During this 4-week Safety Follow-up 
period, no excluded treatment for RA (as defined in this protocol) should be administered. Subjects 
will return for an additional safety visit 4 months after the last dose of IMP. Treatment for RA 
from the 4-week Safety Follow-up visit to the 4-month Safety Evaluation visit will be at the 
discretion of the Investigator following institutional standard of care. The 4-week and 4-month 
safety Follow-up visits will not be duplicated if either of these visits falls within 2 weeks of an 
otherwise scheduled visit. If the 4-week and 4-month safety Follow-up visit since last IMP are 
completed within the 52 week visit schedule, these will not be repeated thereafter.
Withdrawn patients will not be replaced.
5.4.2
Withdrawal from the Trial
Patients may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. The Investigator should make every attempt to clarify 
the level of withdrawal: eg, whether or not banked samples can still be retained and evaluated, if 
the patient can still be contacted by phone for checking his/her status (eg, alive or not), or to return 
for safety visits. In case of withdrawal from the trial for reasons other than consent withdrawal, 
the assessments scheduled for the early termination visit should be performed immediately and 
return for a Safety/Follow-up visit 4 weeks after the last dose of IMP. Patients will return for an 
additional safety visit 4 months after the last dose of IMP. In any case, the appropriate CRF section 
must be completed. Patients will be asked to confirm that any samples collected but not yet 
analyzed can be utilized. 
Patients withdrawn from IMP will continue the safety and immunogenicity follow-up until the end 
of the trial (also see Section 5.4.1 for specific details). These patients will be managed based on 
the Investigator’s clinical judgment and per local guidelines, and any new medication prescribed 
in such a period will be recorded. In any case, the appropriate case report form (CRF) section must 
be completed. 
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5.5
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment. The Sponsor
may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, for poor 
enrollment, or because of discontinuation of clinical development of MSB11022 or withdrawal of 
Humira® from the market.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
5.6
Definition of End of Trial
The end of the trial is defined as the last patient’s end of trial visit.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “IMP” refers to an active substance or a placebo being tested or used as a reference
therapy in a clinical trial, including products that have a marketing authorization but are packaged
or administered differently from the authorized form, used for an unauthorized indication, or used 
to gain further information about the authorized form.  
6.1
Description of the Investigational Medicinal Product
 
 
 
 
 
 
 
 
 
.
6.2
Dosage and Administration
MSB11022-
 will be administered at a dose of 40 mg s.c. every other week starting from 
baseline up to and including Week 48.
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The Humira® will be administered at a dose of 40 mg s.c. every other week starting from baseline
up to and including Week 48.
6.3
Assignment to Treatment Groups
A patient is eligible for randomization only if he/she fulfills all the inclusion criteria and none of 
the exclusion criteria and their eligibility is confirmed on Day 1/Week 0. The patient will be 
randomized by a central IWRS on Day 1/Week 0 after all eligibility criteria are confirmed in a 
1:1 ratio to receive MSB11022-
 or Humira® in a double-blind manner. Randomization will 
be stratified by the type of systemic therapy previously received.
A treatment kit labeled with individual kit/medication numbers will be provided to each trial site. 
See Sections 6.9 and 6.10 for methods of blinding and emergency unblinding. In the event of 
change in the reference product and the further supply is not guaranteed, the sponsor will have an 
established process to avoid any bias in the blinding. The IMP will be administered every other 
week. The IMP will be administered at the site at the visits indicated in the Schedule of 
Assessments after all assessments have been completed and the patient is determined to be eligible 
to remain in the trial. At each visit when IMP is dispensed, the trial staff will contact the IWRS 
after the Investigator confirms that the patient has met the criteria to continue in the trial to obtain 
appropriate kit numbers, and the specified kits will then be dispensed.
6.4
Concomitant Medications and Therapies
All concomitant medications taken by the patient during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the CRF, noting the name, dose, 
duration, and indication of each drug. Nondrug interventions and any changes to a concomitant 
medication or other intervention should also be recorded in the CRF.
6.4.1
Permitted Medicines
Permitted medicines will not be provided by the sponsor as they are considered standard of care 
background medications. 
It is important that medication dosages taken during the study period remain stable. This includes, 
but it is not limited to, the dosage of corticosteroids and NSAIDs. However, reductions in these 
treatments will be allowed as clinically required for safety reasons.
Methotrexate: All patient should maintain a stable MTX dose (10 to 25 mg/week, PO, IM, or SC) 
during the study period. Any modification of the route of administration is not allowed. However, 
a dose reduction of MTX will be allowed in case of AEs. Temporary interruptions administration 
are allowed for up to 14 days (can be interrupted up to twice because MTX is administered once 
weekly). See withdrawal criteria related to interruptions in Section 5.4.1.
Folic Acid: It is possible that certain AEs that are commonly associated with MTX treatment 
occur. In order to minimize MTX toxicity, all patients treated with MTX should receive folic acid 
or equivalent at a dose of at least 5 mg/week according to local guidelines. This can either be given 
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as a single dose weekly or be divided into daily doses to achieve at least 5 mg folic acid per week. 
It is the Investigator’s decision as to which dosing regimen is used.
Hydroxychloroquine or chloroquine: as per inclusion and exclusion criteria.
Oral corticosteroids (≤ 10 mg/day prednisone or equivalent) and NSAIDs are permitted during the 
study.
NSAID: patients may be treated with NSAIDs (including low dose aspirin and COX-2 inhibitors) 
for symptomatic treatment of their arthritis up to the maximum recommended dose per local 
labeling throughout the study (including COX-2 inhibitors). Drug must be at a stable dose for at 
least 2 weeks prior to baseline. Increases in the NSAID dose during the study are not allowed. 
However, discontinuation or reduction is allowed in case of NSAID-related toxicity. In patients 
who receive NSAIDs, prophylactic treatment with proton pump inhibitors or H2-receptor blockers 
is recommended. 
NSAIDS, up to the maximum recommended dose per local labeling, are also allowed for the 
management of AEs not related to RA such as colds or sprains throughout the study (including 
COX-2 inhibitors).
Analgesics (other than NSAIDs) up to the maximum recommended doses may be used for pain 
control as required except for high potency opioids as delineated below. However, patients should 
not take analgesics within 12 hours prior to a visit where clinical efficacy assessments are 
performed.
Any medications that are considered necessary to protect patient welfare and will not interfere with 
the IMP may be given at the Investigator’s discretion.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions, or anticipated emergency situations.
Any concomitant medications (including over-the-counter medications, herbal medications, 
preventive vaccines, vitamins, and food supplements) and procedures must be recorded. A 
description of the type of drug or procedure, the amount, duration, reason for administration of 
drug, and the outcome of any procedure must be documented. AEs related to the administration of 
a concomitant medication or the performance of a procedure must also be recorded.
6.4.2
Prohibited Medicines
The use of prohibited medications will require the patient to be withdrawn from the IMP.
All biological and non-biological DMARDs other than MTX and hydroxychloroquine or 
chloroquine are prohibited during the study and must be discontinued prior to the initiation of IMP
in accordance with specifications as per the inclusion and exclusion criteria.
High potency opioid analgesics (eg, methadone, hydromorphone, oxycodone, fentanyl, or 
morphine) as per the inclusion and exclusion criteria. 
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Intravenous, intramuscular or intra-articular corticosteroids: Intravenous or intramuscular 
corticosteroids are not permitted during the study. Intra-articular corticosteroids are not permitted 
within 6 weeks prior to baseline. Injection of intraarticular steroids while on blinded study 
medication is discouraged, but may be used in a limited fashion. No more than 1 joint per 24-week 
period may be injected during the core period of the study and should not be given 8 weeks or less 
before the Week 24 visit. No single injection should exceed 40 mg of triamcinolone (or 
equivalent).
6.4.3
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed for this trial. Standard medical care will be provided at the trial 
site for all AEs occurring during the trial.
6.4.3.1
Management of Latent Tuberculosis Infection Diagnosed 
During the Study
It is highly recommended to adhere to national/institutional guidelines to manage and treat subjects 
diagnosed as LTBI during the study.
Patients with a positive QFT at screening will be ineligible for the trial. Investigators may treat 
them per local/national guidance for LTBI outside of the study.
If a patient with a negative QFT during screening develops a positive QFT during the trial (ie, at 
Week 24), treatment with IMP should be stopped and an early termination visit completed. Such 
patients continue safety/immunogenicity visits (see Table 1 for schedule of assessments). The 
patient will return for a safety follow-up visit 4 weeks after the last dose of IMP and an additional 
safety evaluation visit 4 months after the last dose of IMP.
During this 4-week safety follow-up period no excluded treatment for RA (as defined in the 
protocol) should be administered. Patients will return for an additional safety follow-up visit 
4 months after the last dose of IMP. Treatment for RA from the 4-week safety follow-up visit to 
the 4-month visit will be at the discretion of the Investigator following institutional standard of 
care. The 4-week and 4-month safety follow-up visits will not be duplicated if either of these visits
falls within 2 weeks of an otherwise scheduled visit. If the 4-week and 4-month safety follow-up 
visits since the last IMP are completed within the 52-week visit schedule, these will not be repeated 
thereafter.
Patients who were QFT-negative at randomization but subsequently become QFT-positive at 
Week 24 should, at the safety follow-up visit (4 weeks after the last IMP administration), be 
referred by the Investigator for a consultation with an infectious disease specialist/pulmonologist 
as necessary in order to assess whether TB re-activation occurred during the trial. 
Patients who were QFT-negative at randomization and at Week 24 but subsequently became 
QFT-positive at Week 52 should be referred by the Investigator for a consultation with an 
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infectious disease specialist/pulmonologist as necessary in order to assess whether TB 
re-activation occurred during the trial.
If a patient develops active TB disease during the trial, treatment with IMP should be stopped 
immediately.
6.5
Packaging and Labeling of the Investigational Medicinal 
Product
MSB11022-
 drug product will be manufactured by the Sponsor, and Humira® will be 
sourced by the Sponsor from a wholesaler. Packaging and labeling will be in accordance with 
applicable local regulatory requirements and applicable Good Manufacturing Practice guidelines.
Packaging of all IMPs for the trial will be done by the Sponsor’s contract manufacturing 
organization, 
.
MSB11022-
 and Humira® will be provided in single-use prefilled syringes. Each prefilled 
syringe with plunger rod assembly will be packed in a carton box that will be closed with a 
tamper-evident seal. The IMPs will be packaged in a blinded fashion, or the sponsor will put in 
place a process to avoid any bias in the blinding. Full re-traceability according to current Good 
Manufacturing Practice guidelines will be provided based on the unique medication number on the 
labels together with packaging documentation.
The IMPs will be shipped and stored under controlled conditions according to the storage 
requirements (2°C to 8°C/36°F to 46°F).
The IWRS will support the logistics of the IMP.
6.6
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
Handling instructions will be provided in a prepared handling guideline for MSB11022-
 
and in the Summary of Product Characteristics document for Humira®.
All IMPs must be stored in a secure area with limited access under controlled conditions at 2°C to 
8°C/36°F to 46°F and protected from light. The IMP must not be frozen, and rough shaking of the 
solution must be avoided.
Patients or family members/caregivers who receive appropriate training will be permitted to 
administer medication in this trial. To ensure compliance with recommended storage conditions, 
all patients will be provided with cooler bags to transport the IMP home. Patients will be provided 
with instructions on proper storage, including instructions to store their trial treatment under 
refrigeration at 2°C to 8°C (36°F to 46°F) and not to leave their medication unattended or in a 
place that might get too hot, eg, inside a car. Patients should have access to refrigeration to store 
the IMP. Patients will also receive sharps containers and handling instructions.
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The IMPs will be supplied in single-use prefilled syringes and no further preparation is required. 
The syringes must be kept in the original outer packaging until administration.
The preparation should be carefully inspected before injection (it should be a homogenous looking 
clear solution, free of visible particles).
In the event of a temperature deviation at the clinical site, the site must contact the clinical research 
associate without delay for further evaluation and assessment by the designated quality assurance 
personnel at Merck KGaA or their delegate. The medication with the temperature excursion should 
still be stored at the required temperature but quarantined during the investigations and must be 
appropriately labeled as “quarantine storage”.
Additional details on the instructions for handling and storage will be described in the drug 
administration instructions and provided to patients as required for administration at home.
The IMP should not be administered after the date of expiration indicated on the product 
packaging.
6.7
Investigational Medicinal Product Accountability
The Investigator (or designee) is responsible for ensuring IMP accountability, including 
reconciliation of drugs and maintenance of records.
! Upon receipt of IMP, the responsible person will check for accurate delivery and acknowledge 
receipt by signing or initialing and dating the appropriate documentation and storing it in the 
Pharmacy File as well as entering it into the IWRS.
! IMP dispensing, which will be triggered by the IWRS, will be recorded on the appropriate drug 
accountability forms so that accurate records will be available for verification at each 
monitoring visit.
! Trial site IMP accountability records will include the following:
! Confirmation of IMP receipt, in good condition and in the defined temperature range.
! The inventory of IMP provided for the clinical trial.
! The use of each dose by each patient.
! The disposition (including return, if applicable) of any unused IMP.
! Dates, quantities, batch numbers, kit/syringe numbers, use-by dates, and the individual 
patient trial numbers.
The Investigator site should maintain records, which adequately document that patients were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
The IWRS should only be contacted after all scheduled assessments are completed and the 
patient’s eligibility to remain in the trial is confirmed. Unused IMP must not be discarded or used 
for any purpose other than the present trial. No IMP that is dispensed to a patient may be dispensed 
to a different patient. 
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The monitor will periodically collect the IMP accountability forms and will check all returns (both 
unused and used containers) before authorizing their destruction by the trial site. The preferred 
option is always to destroy used/unused medication at the trial site. Only in exceptional cases can 
the medication be returned to the Sponsor or designee for destruction.
6.8
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered at the site on the trial visit days defined in Table 1. All other dosing 
will be done by the patient or patient’s caregiver at home throughout the rest of the trial. Patients 
will be asked to record the date and time dispensed, date and time of dosing, location of 
administration, and injection site reaction (yes/no) in a patient diary. Diaries will be collected and 
reviewed at the trial visits specified in Table 1.
Patients will be instructed to bring all IMP, including the used packaging, to each trial visit to 
allow for the assessment of compliance with trial treatment. Prior to discharge from each scheduled 
visit, patients will be given sufficient IMP for at-home dosing until the next scheduled visit.
6.9
Blinding
This trial will be double-blinded. Blinding will be maintained throughout the trial duration, unless 
an emergency unblinding is necessary. In the event of a change in the reference product (eg,
introduction in the market of the new 0.4 mL Humira® formulation) prior to the completion of this 
study, the sponsor will put in place a process to avoid any bias in the blinding. Randomization data 
will be kept strictly confidential, accessible only to authorized staff, until the time of unblinding. 
The trial blind may be broken for an individual only if knowledge of the IMP is essential for 
clinical management of an incurred SAE; however, unblinding is discouraged as knowledge of the 
treatment received has limited influence on the treatment of AEs. If the Investigator breaks the 
blind, he must contact the medical monitor immediately, and no later than 24 hours after 
performing the unblinding, without sharing any treatment assignment information. The 
Investigator must promptly explain the reason for any unblinding of an IMP to the Sponsor without 
revealing the result to any Sponsor employee except the designated Drug Safety representative. 
The Investigator must record the date of unblinding and the reason in the CRF. Under certain 
circumstances, Drug Safety may be required to unblind the treatment assignment for an individual 
patient following an SAE or other serious event; for example, if an expedited regulatory report is 
required. The CRO Medical Monitor will not break the blind.
All breaks of the trial blind must be adequately documented.
6.10
Emergency Unblinding
The trial blind may be broken for an individual only if knowledge of the IMP assignment is 
essential for clinical management of the patient. The Investigator must promptly explain the reason 
for any unblinding of an IMP to the Sponsor without revealing the result to any Sponsor employee 
except the designated Drug Safety representative (using the Emergency Unblinding Notification 
Form). The Investigator must record the date of unblinding and the reason in the CRF. Contact 
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information for breaking the blind in an emergency is given on the patient emergency card 
provided to each patient (see Section 9.4).
Under certain circumstances, Drug Safety may be required to unblind the treatment assignment for 
an individual patient following a serious adverse event (SAE) or other serious event; for example,
if an expedited regulatory report is required. See Section 7.4 for further details on expedited 
reporting and SAEs.
6.11
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol. In the event of an overdose, patients should receive appropriate supportive medical care 
and be followed until resolution/stabilization of any clinical issues.
Even if it does not meet other criteria for an SAE, any overdose must be recorded in the trial 
medication section of the CRF and reported to Drug Safety in an expedited manner using the 
appropriate reporting form, and following the procedure in Section 7.4. 
6.12
Medical Care of Patients after End of Trial
The Sponsor will not provide any additional care to patients after they leave the trial. After patients
leave the trial, medical care will be at the discretion of the Investigator following institutional 
standard of care.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Assessments during the trial will be performed according to Table 1. Patient reported outcome 
questionnaires must be performed prior to any other assessments at all visits. For volumes of blood 
collected, see Appendix C.
Prior to performing any trial assessments that are not part of routine medical care for the patient, 
the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening Procedures and Assessments
The screening procedures will be completed within 28 to 3 days prior to drug administration.
The IWRS must be notified within 5 days of patients who fail screening. The following 
information, at a minimum, should be collected in the eCRF for patients who failed screening: 
informed consent, inclusion/exclusion criteria, basic demographics, reason for screen failure, AEs 
from the date of informed consent until patient is considered to have failed screening by the 
Investigator, and the Investigator’s signature.
During screening, a serum β-human chorionic gonadotropin (β-hCG) pregnancy test will be 
performed for females of childbearing potential, and blood HIV, hepatitis B virus, and hepatitis C 
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virus tests will be performed for all screening patients as these conditions are trial entry exclusion 
criteria (see Section 5.3.2). Testing for TB will be performed as described in the exclusion criteria.
Patients who do not meet the inclusion/exclusion criteria within the specified time limits (ie, 
28 days to 3 days prior to drug administration) and fail screening may undergo re-screening once,
if approved by the Medical Monitor. If the patient is re-screened, the patient will receive a new 
patient identification number and will be asked to sign a new ICF. Such re-screened patients will 
undergo complete screening assessments.
Patients with test results that do not meet the inclusion/exclusion criteria may have testing repeated 
once only if the results are thought to represent a laboratory error or a reversible or clinically 
insignificant intermittent condition. If testing is repeated for such patients, all screening tests will 
need to be repeated except for the chest X-ray, ECG, TB test, HIV, and hepatitis testing, which 
may be repeated separately from the other tests as necessary. The Medical Monitor may also give 
permission for tests to be repeated separate from other tests as necessary. If inclusion/exclusion 
criteria are not met based on the results of the repeated tests, the patient should be considered a 
screen failure and not be enrolled in the trial. Repeat tests should be conducted and results available 
within 28 to 3 days prior to baseline.
7.1.2
Baseline Assessments and Treatment Period
During the 52-week period, patients will be asked to visit the trial site at the visits indicated in the 
Schedule of Assessments (Table 1). Except for the Day 1/Week 0 (baseline) visit, a time window 
of up to 2 days before or after (±2 days) the scheduled day will be permitted for all trial visits
during the treatment period.
Demographics, medical history, and inclusion/exclusion criteria will be reviewed to ensure that 
patients remain eligible for the trial.
An Emergency Medical Support card will be handed out on Day 1/Week 0 (baseline).
The IWRS will be contacted on Day 1/Week 0 (baseline) for patient randomization after all 
eligibility criteria have been confirmed. Patients will be randomized to receive either 40 mg 
MSB11022-
or 40 mg Humira® every other week starting on Day 1/Week 0 (baseline) and 
continuing up to and including Week 48. If the IMP is well tolerated as per medical judgment, and 
reflects the expected safety profile during these visits, the remainder of the patients will be dosed. 
The IMP is administered at the trial site for the first 3 doses; at Weeks 0, and 2, the patient or a 
caregiver will be trained for self-injection/injection and at Week 4, the patient will self-inject. 
Patients will be monitored for 1 hour following IMP administration on Day 1/Week 0, Week 2, 
and Week 4. Patients or their caregivers will administer the IMP for all subsequent doses and 
record the dosing date and time in a diary. 
Patients who achieve less than 20% improvement in both swollen and tender joint counts at 
Week 24 (non-responders) will be discontinued from IMP and must immediately perform the 
assessments listed for the early termination visit and return for the safety follow-up visit 4 weeks 
after the last dose of IMP in addition to a safety follow-up visit 4 months after the last dose of 
IMP.
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Patients who discontinue from the study medication (but remain in the trial and continue 
safety/immunogenicity visits) before the Week 52 visit will immediately complete an Early 
Termination visit and return for a Safety/Follow-up visit 4 weeks after the last dose of IMP. During 
this 4-week Safety Follow-up period, no excluded treatment for RA (as defined in this protocol) 
should be administered. Patients will return for an additional safety evaluation 4 months after the 
last dose of IMP. Treatment for RA from the 4-week Safety Follow-up visit to the 4-month Safety 
Evaluation visit will be at the discretion of the Investigator following institutional standard of care.
The 4-week and 4-month Safety Follow-up visits will not be duplicated if either of these visits
falls within 2 weeks of an otherwise scheduled visit. If the 4-week and 4-month Safety Follow-up 
visits since last IMP are completed within the 52 week visit schedule, these will not be repeated 
thereafter.
7.1.3
Early Termination Visit
Patients who discontinue the trial for any reason other than consent withdrawal before the Week 52 
visit must undergo an early termination visit immediately upon discontinuation.
Assessments scheduled during the early termination visit are presented in Table 1.
7.1.4
Safety Follow-up Period
All patients will have a subsequent safety follow-up visit scheduled 4 weeks (±1 week) after the 
last dose of IMP, in addition to a safety follow-up visit 4 months (±1 week) after the last dose of 
IMP. The assessment for these visits are presented in Table 1. 
7.2
Demographic and Other Baseline Characteristics
7.2.1
Demographic Data
At screening, the following demographic data will be collected: date of birth, sex (gender), race, 
and ethnicity.
7.2.2
Medical History
A complete medical history of each patient will be collected and documented during screening, 
which will include, but may not be limited to, the following:
! Past and concomitant diseases (nonmalignant and malignant) and treatments
! All medications (including herbal medications) taken and procedures carried out within 28 days 
prior to screening. The site should document any biologic ever used by the patient.
For trial entry, all of the patients must fulfill all inclusion criteria described in Section 5.3.1, and 
none of the patients should fulfill any exclusion criterion from the list described in Section 5.3.2. 
Significant findings that are observed after the patients signs the ICF and that meet the definition 
of an AE must be recorded in the AE section of the CRF.
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7.2.3
Tuberculosis Status
Assessment of TB status will be required before randomization.
7.2.3.1
Imaging
Bi-directional chest X-ray will be used to determine eligibility. If the QFT test is negative, a 
bi-directional chest X-ray, chest high-resolution CT, or chest MRI obtained within 12 weeks prior 
to randomization will be acceptable. If needed to rule out active TB, chest high-resolution CT or 
chest MRI could be subsequently performed.
If imaging evaluated by a qualified physician shows evidence of ongoing infectious disease, signs 
of active TB, or evidence of any malignant process, the patient will not be eligible to enter the trial.
7.2.3.2
QuantiFERON-TB Gold In-Tube assay
A QFT will be performed to assess the TB status during screening for all patients. Additional tests 
will be performed according to the Schedule of Assessments for patients whose previous QFT was 
negative. The QFT test will be supplied and analyzed by the central laboratory. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided in 
the Laboratory Manual. Refer to Section 6.4.3.1 for guidance on treatment for patients with TB.
7.2.4
Immunogenicity
A blood sample will be collected at screening for assay validation purposes only, no results will 
be reported and at baseline (on Day 1/Week 0 before IMP administration).
7.2.5
Other Baseline Assessments
All other baseline measurements, such as vital signs, a complete physical examination, clinical 
laboratory parameters, chest X-ray, and 12-lead ECG, will be assessed. Screening assessments will 
be rechecked to confirm eligibility for the trial. If the ECG findings are clinically relevant and 
would prevent the patient from participating in the trial, the patient should not receive IMP.
7.3
Efficacy Assessments
The following tests and procedures have been selected to evaluate the efficacy of 
MSB11022-
 and describe clinical improvement in patients with RA and will be performed 
according to the Schedule of Assessments (Table 1).
7.3.1
Disease Activity Assessments
Assessments for RA disease activity will include ACR response criteria, DAS28-ESR, CDAI, and 
SDAI, which are described below.
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7.3.1.1
American College of Rheumatology Response Rates
The individual components that make up the ACR Core Set of measures for RA are described 
below. Relief of signs and symptoms will be assessed using the ACR Responder Index, a 
composite of clinical, laboratory, and functional measures in RA. The ACR responses are 
presented as the minimal numerical improvement from baseline in multiple disease assessment 
criteria. The response criteria is based on the 68-joint tender/painful joint count, the 66-joint 
swollen joint count, and the CRP level.
ACR Core Set
a.
Tender Joint Count (TJC)
For ACR measures, the number of tender and painful joints will be determined by examination of 
68 joints (34 joints on each side of the patient’s body; see Appendix D). The 68 joints to be assessed 
and classified as tender or not tender include: 2 temporomandibular joints, 2 sternoclavicular 
joints, 2 acromioclavicular joints, 2 shoulder joints, 2 elbow joints, 2 wrist joints, 
10 metacarpophalangeal joints, 2 interphalangeal joints of the thumb, 8 proximal interphalangeal 
joints of the hands, 8 distal interphalangeal joints of the hands, 2 hip joints, 2 knee joints, 2 ankle 
joints, 2 tarsus, 10 metatarsophalangeal joints of the feet, 2 great toes (first proximal 
interphalangeal joint of the feet), and 8 proximal interphalangeal joints of the feet. 
Joints will be assessed for tenderness by pressure and joint manipulation on physical examination. 
The patient will be asked for pain sensations on these manipulations and watched for spontaneous 
pain reactions. Any positive response on pressure, movement, or both will then be translated into 
a single tender-versus-nontender dichotomy. Joint assessments of 1 particular patient should be 
performed (if at all possible) by the same assessor throughout the trial to minimize inter-observer 
variation.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at the 
screening visit and will be excluded from evaluation during the trial. The locations (or a listing) of 
surgical procedures should be documented in the patient’s source documents/CRF pages.
b.
Swollen Joint Count (SJC)
For ACR measures, the number of swollen joints will be determined by examination of 66 joints 
(33 joints on each side of the patient’s body). The 66 joints to be assessed and classified as swollen 
or not swollen include: 2 temporomandibular joints, 2 sternoclavicular joints, 2 acromioclavicular 
joints, 2 shoulder joints, 2 elbow joints, 2 wrist joints, 10 metacarpophalangeal joints, 
2 interphalangeal joints of the thumb, 8 proximal interphalangeal joints of the hands, 8 distal 
interphalangeal joints of the hands, 2 knee joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal 
joints of the feet, 2 great toes (first proximal interphalangeal joint of the feet), and 8 proximal 
interphalangeal joints of the feet.
Joints will be classified as either swollen or not swollen. Swelling is defined as palpable fluctuating 
synovitis of the joint. Swelling secondary to osteoarthrosis will be assessed as not swollen, unless 
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there is unmistakable fluctuation. Joint assessments of 1 particular patient should be performed by 
the same assessor (if at all possible) throughout the trial to minimize inter-observer variation.  
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at the 
screening visit and will be excluded from evaluation during the trial. The locations (or a listing) of 
surgical procedures should be documented in the patient’s source documents/CRF pages.
Any joint which will have received an intra-articular steroid injection will be excluded by the joint 
count and will be documented as “not done” (ND) for the following 12 weeks. After this time the 
joint may be assessed again.
c.
CRP
CRP will be the ACR Core Set measure of acute phase reactant. It will be measured at the central 
laboratory to help assess the effect of MSB11022-
or Humira® on the patient’s RA.
ACR20
The ACR20 is a primary efficacy measure for which a patient must have at least 20% improvement 
in the following ACR Core Set values.
! TJC (68 joint count) and
! SJC (66 joint count) and
! An improvement of at least 20% in at least 3 of the following 5 assessments:
! Patient’s Global Assessment of Disease Activity 
! Patient’s Assessment of Arthritis Pain
! Patient’s Assessment of Physical Function as measured by the HAQ-DI
! Physician’s Global Assessment of Disease Activity
! Acute phase reactant as measured by CRP.
In this trial, ACR20 response calculations will use the HAQ-DI for the patient’s assessment of 
physical function and CRP as the measure of acute phase reactant.
ACR50 and ACR70
ACR50 and ACR70 are defined in the same way as the ACR20 using at least 50% and 70% 
improvement, respectively.
7.3.1.2
DAS28-ESR
The DAS28-ESR is a measures of disease activity in 28 joints that consists of a composite 
numerical score of the following variables: TJC, SJC, or ESR, and Patient’s Global Assessment of 
Disease Activity (57).  
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For DAS28-ESR, the 28 joints to be examined and assessed as tender or not tender for TJC and to 
be examined and assessed as swollen or not swollen for SJC include 14 joints on each side of the 
patient’s body: 2 shoulders, 2 elbows, 2 wrists, 10 metacarpophalangeal joints, 2 interphalangeal 
joints of the thumb, 8 proximal interphalangeal joints, and 2 knees (58).
DAS28 will be derived using the following formulas from the DAS28 website (59):
DAS28 =  0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.70*ln(ESR)
Where:
! TJC28 = 28 joint count for tenderness
! SJC28 = 28 joint count for swelling
! ln(ESR) = natural logarithm of ESR
! GH = the general health component of the DAS (ie, Patient’s Global Assessment of Disease 
Activity on a scale of 1 to 10 where 10 is maximal activity).
7.3.1.3
CDAI
The CDAI is calculated based on the following formula (46):
CDAI =  SJC28 + TJC28 + GH + PGA
Where:
! TJC28 = 28 joint count for tenderness
! SJC28 = 28 joint count for swelling
! GH = the general health component of the DAS (ie, Patient’s Global Assessment of Disease 
Activity on a scale of 1 to 10 where 10 is maximal activity).
! PGA = Physician’s Global Assessment of Disease Activity on a scale of 1 to 10 where 10 is 
maximal activity
7.3.1.4
SDAI
The SDAI is calculated based on the following formula (46):
SDAI =  SJC28 + TJC28 + GH + PGA +CRP
Where:
! TJC28 = 28 joint count for tenderness
! SJC28 = 28 joint count for swelling
! GH = the general health component of the DAS (ie, Patient’s Global Assessment of Disease 
Activity on a scale of 1 to 10 where 10 is maximal activity).
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! PGA = Physician’s Global Assessment of Disease Activity on a scale of 1 to 10 where 10 is 
maximal activity
! CRP = C-reactive protein in mg/dL
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting, and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each patient will be performed 
from the time of giving informed consent and throughout the trial. The Investigator will report any 
AEs, whether observed by the Investigator or reported by the patient (see Section 7.4.2.2). The 
reporting period for AEs is described in Section 7.4.2.3.
7.4.1
Safety Monitoring Committee
An IDMC will review the safety data of this trial on ongoing basis (see Section 2). The IDMC is 
responsible for monitoring the safety of the trial participants and making appropriate 
recommendations based on the data reviewed. Details regarding the review process will be 
available in the relevant IDMC charter.
7.4.2
Adverse Events
7.4.2.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be 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. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
Injection site pain during 3rd, 4th, and 5th injection administration will be reported as an AE similar 
to any injection site reactions at other time points of IMP administration.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute – Common Terminology Criteria for AEs 
(NCI-CTCAE), version 4.03 (publication date: 14 June 2010), a descriptive terminology that can 
be used for AE reporting.
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A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
The 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening
! Grade 5 or Death 
Investigators must also systematically assess the causal relationship of AEs to IMP(s)/study 
treatment (including any other non-IMPs, radiation therapy, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP include, but may 
not be limited to, temporal relationship between the AE and the IMP, known side effects of IMP, 
medical history, concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the IMP. AE could medically (pharmacologically/clinically) 
be attributed to the IMP under study in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death.
! Is life-threatening. (Note: The term “life-threatening” refers to an event in which the patient is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
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! Requires inpatient hospitalization or prolongs an existing hospitalization.
! Results in persistent or significant disability or incapacity.
! Is a congenital anomaly or birth defect.
! Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in Section 7.4.2.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are not to be considered AEs.
Adverse Events of Special Interest
The following is considered pre-defined AESIs for this trial:
Hypersensitivity (defined by Standardized MedDRA Query [SMQ] narrow as per the latest 
MedDRA version).
7.4.2.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the patient will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the patient’s condition will be recorded as AEs, 
whether reported by the patient or observed by the Investigator. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the CRF. 
All SAEs must be additionally documented and reported using the appropriate SAE Report Form 
as described in Section 7.4.2.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times when it is important to assess the time of AE onset relative to the 
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recorded treatment administration time), its severity, its causal relationship with the trial treatment, 
any other potential causal factors, any treatment given or other action taken, including dose 
modification or discontinuation of the IMP, and its outcome. In addition, serious cases should be 
identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the CRF Completion and Monitoring Conventions provided by 
the Sponsor.
7.4.2.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the patient is initially included in the 
trial (date of first signature of informed consent/date of first signature of first informed consent) 
and continues until the 4-month safety follow-up/end of trial visit. 
Any SAE assessed as related to IMP and all AESIs must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration of IMP. 
7.4.2.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest and Dose Limiting Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be provided immediately thereafter.
Relevant pages from the CRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the CRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
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Adverse Events of Special Interest
The AESIs have to reported in an expedited manner (like the SAEs outlined above) using the AESI 
form.
7.4.2.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial patients to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of patients, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.
7.4.2.6
Monitoring of Patients with Adverse Events
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.2.3) and are 
assessed for final outcome at the 4-month safety follow-up visit. All SAEs ongoing at the 4-month 
safety follow-up visit must be monitored and followed up by the Investigator until stabilization or 
until the outcome is known, unless the patient is documented as “lost to follow-up.” Reasonable 
attempts to obtain this information must be made and documented. It is also the responsibility of 
the Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. 
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7.4.3
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example,
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.2.4 must be recorded by convention in the AE page/section of the CRF. The same rule 
applies to pregnancies in female patients and to pregnancies in female partners of male patients. 
The Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using 
the Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.4.2.4. 
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the patients are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the paper Pregnancy 
Report Form. If an abnormal outcome occurs, the SAE Report Form will be used if the patient
sustains an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains 
an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.2.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a patient occurring during the course of the trial, the patient must be 
discontinued from IMP immediately. The Sponsor/designee must be notified without delay and 
the patient must be followed as mentioned above.
7.4.4
Clinical Laboratory Assessments
Blood and urine samples will be collected for the following clinical laboratory tests, following the 
timing noted in the Schedule of Assessments (Table 1) and sent to the central laboratory for 
analysis. All samples should be clearly identified.
The Sponsor should receive a list of laboratory normal ranges before shipment of trial drug. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor or designee 
in a timely manner.
For women of childbearing potential, a qualitative serum pregnancy test will be performed at 
screening only, and an on-site urine test will be performed at baseline, Weeks 4, 8, 12, 24, 36, 48, 
and 52, the early termination visit, and the safety follow-up visits. The dipstick and urine 
pregnancy testing will be done locally only. If abnormal dipstick findings are observed, a urine 
sample will be sent to the central laboratory for microscopy. When there is no site visit, the female 
patients will perform urine pregnancy tests themselves at home, ie, at Weeks 16, 20, 28, 32, 36, 
40, and 44. The patient should be instructed to immediately contact the Investigator if she identifies 
a positive urine pregnancy test result.
The ESR will be assessed locally only.
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Local clinical laboratory samples may be collected for emergency safety evaluations but are not 
required to be collected/recorded in the CRFs. 
The blood samples listed in Table 3 will be drawn, processed, and stored in accordance with the 
directions provided in the Laboratory Manual (also see Appendix C).
Table 3
Clinical Laboratory Assessments
Hematology
White blood cell count, red blood cell count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin concentration, platelet 
count, erythrocyte sedimentation rate, neutrophils (absolute and percentage), 
lymphocytes (absolute and percentage), monocytes (absolute and percentage), 
eosinophils (absolute and percentage), basophils (absolute and percentage)
Biochemistry
Sodium, potassium, blood urea nitrogen, creatinine, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transferase, lactate dehydrogenase, serum albumin, calcium, phosphate, 
glucose, creatine kinase, uric acid, total bilirubin, total serum protein, 
cholesterol, triglycerides, C-reactive protein, coagulation (activated partial 
thromboplastin time and prothrombin time)
Urinalysis
Dipstick, including macroscopic appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, and 
urobilinogen. Full urinalysis (dipstick plus microscopic evaluation) at the 
Investigator’s discretion only if warranted by an abnormal dipstick finding.
Viral serology
Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, HIV
types 1 and 2
Other
Pregnancy test (women only), rheumatoid factor (RF), anti-citrillinated protein 
antibodies (ACPA), anti-nuclear antibody, anti-dsDNA, QuantiFERON Gold 
tuberculosis test
The following laboratory assessments will not be entered into the database: rheumatoid factor, 
pregnancy test, and viral serology.
7.4.5
Vital Signs, Physical Examinations, and Other Assessments
Vital signs including body temperature, respiratory rate, and heart rate (after 5-minute rest) will 
be measured once at screening and throughout the trial at the visits indicated in the Schedule of 
Assessments. Arterial blood pressure (after 5-minute rest) will be measured twice using a validated 
device and recorded at the visits indicated in the Schedule of Assessments (Table 1). 
A complete physical examination (including, eg, general appearance, skin, head/neck, pulmonary, 
cardiovascular, gastrointestinal, external genitourinary, lymphatic, musculoskeletal system, 
extremities, eyes [inspection and vision control], nose, throat, and neurologic status) will be 
performed at screening and at subsequent visits as documented in the Schedule of Assessments 
(Table 1) and the abnormal results documented in the CRF. All clinically significant abnormalities 
occurring before signature of informed consent should be recorded in the Medical History section 
and/or Disease History; all abnormalities occurring or worsening after signature of informed 
consent should be recorded in the Adverse Events section. Abnormal findings are to be reassessed 
at subsequent visits.
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Body weight will be recorded at screening and at subsequent visits as indicated in the Schedule of 
Assessments (Table 1) and documented in the CRF. Height will be measured at screening only.
A 12-lead ECG and chest X-ray will be recorded as indicated in the Schedule of Assessments
(Table 1).
All newly diagnosed or worsening conditions, signs, and symptoms observed from screening, 
whether related to trial treatment or not, are to be reported as AEs.
For women of childbearing potential, a serum β-hCG pregnancy test will be carried out during the 
screening phase only, and a urine pregnancy test will be performed at the on-site visits (baseline, 
Weeks 4, 8, 12, 24, 36, 48, and 52, the early termination visit and the safety follow-up visit) and
at home (Weeks 16, 20, 28, 32, 36, 40, and 44) as indicated in the Schedule of Assessments
(Table 1).
7.5
Pharmacokinetics
The timing of sampling for PK analysis is based on available steady-state data from RA patients 
treated with 40 mg adalimumab s.c. These data showed that adalimumab steady-state 
concentrations were reached approximately 20 weeks after the beginning of adalimumab treatment 
(60, 61). Sparse sampling for population PK analysis will be collected in a subset of patients (at 
least 30/arm) in this trial.
All patients will have PK samples taken pre-first dose, and then prior to dosing on Weeks 2, 4, 12, 
24, 36, and 52. In addition, a subset of 60 patients (30 per arm) will have additional samples to 
support the population PK analysis taken on Days 2 (24 h post first dose), 4, and 9, and Days 2 
(24 h post Week 24 dose), 4, 9, and 14 (Week 26 pre-dose) after the Week 24 dose (see Table 2).  
7.6
Biomarkers
Not applicable.
7.7
Other Assessments
Patient-reported outcomes (PROs) and the Physician’s Global Assessment of Disease Activity will 
be assessed at the visits indicated in Table 1. The PROs consist of the HAQ-DI, Patient’s Global 
Assessment of Disease Activity, Patient’s Assessment of Arthritis Pain, SF-36, and EQ-5D-5L
dimension instruments. The PRO/QoL questionnaires and the Physician’s Global Assessment of 
Disease Activity are recommended to be completed prior to any of the other trial-related 
assessments being performed, that is, physical examinations, blood draws, trial treatment 
administration, etc. Data will be collected by the Contract Research Organization (CRO) and 
housed in a database. Validated translated versions of the PROs/QoL questionnaires will be used 
for each country participating in this trial
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7.7.1
HAQ-DI
The HAQ-DI is a patient-reported questionnaire that is commonly used in RA to measure disease 
associated disability (assessment of physical function). It consists of several questions referring to 
8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities (62, 
63).
The disability section of the questionnaire scores the patient’s self-perception on the degree of 
difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 
3 = unable to do) covering the following domains: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and performing other daily activities. The reported use of special aids or 
devices and/or the need for assistance of another person to perform these activities is also assessed. 
The scores for each of the functional domains will be averaged to calculate the functional disability 
index. 
7.7.2
Visual Analog Scales
Visual analog scales will include the Patient’s and Physician’s Global Assessment of Disease 
Activity, Patient’s Assessment of Arthritis Pain and injection site pain. 
Patient’s Global Assessment of Disease Activity
The patient’s overall assessment of his or her arthritis during the last 24 hours will be recorded 
using the horizontal VAS where the left end represents no disease activity (symptom free and no 
arthritis symptoms) and the right end represents maximum disease activity (maximum arthritis 
disease activity).
The patient will be asked to give an overall assessment of how the arthritis is affecting him/her at 
present by marking a vertical tick on a VAS from “no arthritis activity” to “extremely active 
arthritis.”
Physician’s Global Assessment of Disease Activity
The physician’s overall assessment of the patient’s arthritis during the last 24 hours will be 
recorded using the horizontal VAS where the left end represents no disease activity (symptom free 
and no arthritis symptoms) and the right end represents maximum disease activity (maximum 
arthritis disease activity).
The physician will give an overall assessment of how the arthritis is affecting the patient at present 
by marking a vertical tick on a VAS from “no arthritis activity” to “extremely active arthritis.”
Patient’s Assessment of Arthritis Pain
The patient will be asked to assess his or her current level of pain by marking a vertical tick on a 
horizontal VAS with the left end marked as “no pain” and the right end marked as “worst possible 
pain.” The scale should be administered prior to the tender and swollen joint count examination.
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Injection Site Pain
The patient’s reported perception of pain will be measured on a VAS where the slash drawn by the 
patient represents pain of increasing intensity. The first 2 injections will be administered by 
qualified personnel. The next three doses of IMP (3-5) will be self-administered by the patient and 
injection site pain will be assessed. Pain will be recorded immediately after, 15 minutes after, and 
1 hour after the injections received by the patient.
Results will be expressed in millimeters measured between the left end of the scale and the crossing 
point of the vertical line of the tick. This procedure is applicable for all VAS scales used in the 
trial.
7.7.3
SF-36
Patients will complete the SF-36 v2, standard version, a generic, health survey consisting of 
36 questions, yielding 8 health-related quality of life (HRQoL) domains (physical functioning, 
role-physical, bodily pain, general health, vitality, social function, role emotional, mental health) 
as well as a psychometrically based physical component score (PCS) and mental component score 
(MCS).
7.7.4
EQ-5D-5L
Patients will complete the EQ-5D, a standardized measure of health status. It consists of 
5 questions (mobility, self-care, usual activity, pain/discomfort and anxiety/depression) - the 
EQ-5D descriptive system, rated on a 5-point scale (no problems, slight problems, moderate 
problems, severe problems and unable to/extreme problems) and a health state VAS of 0 (Worst 
imaginable health state) to 100 (Best imaginable health state).
8
Statistics
8.1
Sample Size
According to EMA recommendation
(EMA/CHMP/SAWP/200743/2016),
a total of 
100 patients/arm should be adequate for a study primarily focusing on safety. To account for drop 
outs, this descriptive study will include 260 randomized patients in total (130/arm) in order to 
ensure 200 subjects in the study at Week 52. In fact, based on averaged originator’s dropout rates 
at Week 52, a 20% rate of drop-out overall is included in the sample size (29, 40, 41). This sample 
size will permit an informative assessment of the occurrence of most common AESI (> 1/10) such 
as injection site reactions, and rash with a precision of 12.0% and 9.0% for the AESIs incidence 
of 26.0% and 11.0% respectively (29).
A subset of 60 patients (30 per treatment arm) will be randomly selected to participate in 
population PK analysis.
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8.2
Randomization
Eligible patients will be randomized in permuted blocks in a 1:1 ratio by an IWRS to receive either 
MSB11022-
 s.c. or Humira® s.c. at a dose of 40 mg every other week starting at baseline 
up to and including Week 48.
Randomization will be stratified by previous disease-modifying therapy use. Patients will be 
stratified by the type of systemic therapy previously received: non-biological (biologic naïve 
patients) versus biological (biologic experienced patients). Patients who previously received both 
(biological and non-biological systemic therapies) will be assigned to the “biological” group. The 
exposure to previous biological agents will be limited to 1 TNF inhibitor other than adalimumab. 
The participation of patients in the previous biological systemic therapy stratum will be capped at 
20% of the total number of patients randomized. This is in accord with what registered in other 
trials with biological agents in different rheumatic indications (64, 65, 66).
8.3
Endpoints
8.3.1
Primary Endpoint
! Safety
! Incidence of AESIs including and up to Week 52 (AEs will be recorded at each visit: 
screening, baseline [Week 0], and Weeks 2, 4, 8, 12, 24, 36, 48, and 52)
8.3.2
Secondary Endpoints
Key Secondary Endpoint
! Efficacy
! ACR20 at Week 12
Other Secondary Endpoints
! Safety
! Occurrences of TEAEs and SAEs including and up to the 4-month Safety Evaluation visit
(AEs will be recorded at each visit: screening, baseline [Week 0], and Weeks 2, 4, 8, 12, 24, 
36, 48, and 52, and 4-week and 4-month Safety Follow-up)
! Vital signs at screening, baseline and at Weeks, 2, 4, 8, 12, 24, 36, 48, and 52
! Physical examination at screening, baseline and at Weeks 2, 4, 8, 12, 24, 36, 48, and 52
! Hematology, urinalysis and biochemistry analysis at screening, baseline and at Weeks 2, 4, 
12, 24, 36, 48, and 52
! ANA and anti-dsDNA at baseline and at Weeks 24 and 52
! 12-lead ECG at screening, Weeks 12, 24, and 52 
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! Immunogenicity
! ADA to adalimumab and ADA titer including and up to Week 52
! Neutralizing ADA to adalimumab including and up to Week 52
! Efficacy
! ACR20 at Weeks 2, 4, 8, 24, and 52
! ACR50 response rates at Weeks 2, 4, 8, 12, 24, and 52
! ACR70 response rates at Weeks 2, 4, 8, 12, 24, and 52
! Change from baseline in DAS28-ESR to Weeks 2, 4, 8, 12, 24, and 52
! Proportion of patients with DAS28 low disease activity and remission at Weeks 2, 4, 8, 12, 
24, and 52
! Change from baseline in SDAI at Weeks 2, 4, 8, 12, 24, and 52
! Change from baseline in CDAI at Weeks 2, 4, 8, 12, 24, and 52
! ACR/EULAR Boolean remission rates at baseline, Weeks 2, 4, 8, 12, 24, and 52
! Quality of Life (QoL) and Physical Function
At baseline, then at Weeks 12, 24, and 52:
! HAQ-DI - Health Assessment Questionnaire – Disability Index 
! SF-36 - 36-item Short-Form Health Survey 
! EQ-5D-5L - The EuroQoL-5D-5L dimension instrument 
! Injection site pain
! Mean change in injection site pain on a VAS, evaluated during 3 (doses 3-5) administrations 
of IMP 
8.3.3
Exploratory Endpoints
! Pharmacokinetic endpoints from a population PK analysis
! Absorption profile characterization, if it is supported by the data
! Apparent clearance (CL/F)
! Apparent volume of distribution (Vz/F)
! Ctrough levels at Day 14 after first dose, at Weeks 4, 12, and 24 predose, and at Day 14 after 
dose at Week 24.
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8.4
Analysis Sets
8.4.1
Enrolled
All participants who sign informed consent.
8.4.2
Intention-to-Treat
The Intention-to-Treat (ITT) Analysis Set will include all patients randomly allocated to a 
treatment, based on the intention to treat “as randomized” principle (ie, the planned treatment 
regimen rather than the actual treatment given in case of any difference). Patients will be analyzed 
according to their randomized treatment. 
8.4.3
Per-Protocol
The Per-Protocol (PP) analysis set includes all randomized and treated patients (hence a subgroup 
of the ITT analysis set) who do not have any important clinical protocol deviations (67).
Patients will be analyzed according to their randomized and received treatment, as receipt of a 
different treatment from that assigned is an important protocol deviation.
The following are criteria for inclusion in the PP analysis set:
! Received the randomized treatment;
! Compliance with all entry criteria;
! Absence of important clinical trial protocol violations per regulatory definition;
! Adequate compliance with and sufficient exposure to IMP;
The criteria for the PP population will be defined in detail in the SAP; major protocol violators 
excluded from the PP analysis set will be identified.
Patients who achieve less than 20% improvement in both swollen and tender joint counts at 
Week 24 (non-responders) will be discontinued from the treatment. These patients will remain in 
the trial safety analysis set and participate in the safety and immunogenicity assessments.
8.4.4
Safety
The Safety Analysis Set will include all randomized patients who receive at least one dose of trial 
treatment. Patients will be analyzed according to the actual treatment they receive during the trial.
8.4.5
Population Pharmacokinetics
The Pharmacokinetic Analysis Set will include all patients who receive at least 1 dose of trial 
treatment and have at least 1 valid post-dose pharmacokinetic assessment without protocol 
deviations which could potentially affect PK.
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8.5
Description of Statistical Analyses
8.5.1
General Considerations
Full details of all planned analyses will be provided in the SAP, to be finalized and approved prior 
to database lock.
Baseline is defined as the day on which the first dose of the IMP (blinded trial drug) is 
administered. 
Descriptive statistics will be given with reference to the analysis set deemed appropriate for each 
particular endpoint.
The following descriptive statistics will be used to summarize the trial data per treatment group on 
the basis of their nature unless otherwise specified:
! Continuous variables: n (number of non-missing observations), mean, standard deviation, 95% 
confidence interval (CI), median, minimum, and maximum
! Categorical variables: Frequencies and percentages
! Time to event variables: Kaplan-Meier estimates and 95% CIs
No correction for multiplicity is anticipated.
8.5.2
Analysis of Primary Endpoint
The primary safety (safety population) endpoint will be summarized by treatment group using the 
Safety analysis set. Incidence of AESIs and 95% CIs will be provided for each treatment group. 
Half width of 95% CIs for the difference in incidence for the most commonly observed clinical 
events of AESI (hypersensitivity) will also be calculated.
8.5.3
Analysis of Secondary Endpoints
8.5.3.1
Analysis of Key Secondary Efficacy Endpoint
The proportion of patients with an ACR20 response in both the treatment groups at Week 12 will 
be reported along with 95% CIs.
The analyses will be carried out on both the ITT and the PP analysis sets.
8.5.3.2
Analysis of Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints will be summarized descriptively according to the type of 
outcome.
The proportion of patients with ACR20, ACR50, and ACR70, DAS28 low disease activity and 
remission, and ACR/EULAR Boolean remission rates, will be reported along with 95% CIs.
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Continuous outcomes (eg, DAS28, SDAI, and CDAI mean change from baseline) will be 
summarized using descriptive statistics.
The summaries will be presented on both the ITT and the PP analysis sets.
8.5.3.3
Analysis of Safety Endpoints
Safety endpoints below will be summarized by treatment group:
! Treatment-emergent AEs, SAEs, AESIs, and deaths
! Clinical laboratory values including hematology, chemistry, and urinalysis
! Vital signs
! Physical exam
! 12-lead ECG
Adverse events will be coded with the latest version of the Medical Dictionary for Regulatory 
Activities and summarized by treatment group overall, by severity, and by relationship to 
MSB11022-
 or Humira®.
The nature, severity and frequency of the adverse drug reactions in patients who received 
MSB11022-
 will be compared with those who receive Humira® to evaluate comparability 
of safety.
AEs and concomitant medications will be recorded at each visit: screening, baseline (Week 0), and 
Weeks 2, 4, 8, 12, 24, 36, 48, and 52.
Summary statistics will be used to present changes from baseline in continuous laboratory and 
vital sign variables. 
Shift tables will be used to present changes in categorical laboratory variables.
All clinical laboratory data will be stored in the database in the units in which they were reported 
and using the laboratory reference ranges. Patient listings and summary statistics at each 
assessment time will be presented using the International System of Units (SI units). Laboratory 
data not reported in SI units will be converted to SI units before processing.
Safety endpoints will be analyzed using the safety analysis set.
8.5.3.4
Analysis of Quality of Life Endpoints
Patient reported outcomes (PRO) quality of life and physical function endpoints, HAQ-DI, SF-36,
and EQ-5D-5L, at baseline and Weeks 12, 24, and 52, will be summarized using descriptive 
statistics. 
The summaries will be presented using both the ITT and the PP analysis sets.
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8.5.3.5
Analysis of Immunogenicity Endpoints
Descriptive statistics of the immunogenicity assessment per treatment arm will be given with 
reference to the Safety Analysis Set unless otherwise specified in the SAP. 
! Number and percentage of ADA positive patients at any time
! ADA titer
! Number and percentage of NAb positive patients
! Time to ADA
! Change of titer over time 
! Persistent or transient ADA for patients with a treatment period ≥ 6 months
Presentations will include summaries of PK, safety, and efficacy endpoints over time for ADA
positive and negative patients.
Correlation of PK, safety, and efficacy endpoints versus treatment group split by upper and lower 
quartile patients, based on their maximum ADA titer values, may be presented as exploratory 
analyses. 
ADA status, titer, and NAb status will be listed and summarized by treatment and time point of 
collection.
8.5.3.6
Analysis of Pharmacokinetic Endpoints
Serum concentrations of MSB11022-
 and Humira® will be listed and summarized by 
treatment and time point of collection. Summary statistics in the tabulation will include n, mean, 
standard deviation, coefficient of variation, median, minimum, maximum, geometric mean, and 
geometric coefficient of variation.
8.5.4
Analysis of Population Pharmacokinetics Endpoints
Pharmacokinetic parameters (absorption profile, apparent clearance, apparent volume of 
distribution, and Ctrough levels) of MSB11022-
 and Humira®, with their intra- and 
inter-individual variability in the patient population, will be derived by population PK data analysis 
using a nonlinear mixed effects modeling approach, based on sparse sampling. The influence of 
covariates, such as standard demographic covariates, treatment (MSB11022-
 or Humira®),
and immunogenicity, will be explored graphically and statistically to explain potential random 
inter- and intra-individual variability in PK parameters.
8.6
Interim and Additional Planned Analyses
No interim analyses are planned.
An IDMC will review the safety data from this trial on an ongoing basis.
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8.7
Missing Data
Details of the handling of missing data for all secondary endpoints will be provided in the SAP.
Sensitivity analyses for the key secondary endpoint based on different missing data mechanism 
assumptions may be explored and will be pre-specified in detail in the SAP and documented prior 
to database lock.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that only 
patients who have given informed consent are included in the trial.
According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration for marketing approval and could contribute significantly to the demonstration of 
efficacy and safety of an IMP (which are considered “covered clinical trials” by the FDA), the 
Investigator and all subinvestigators are obliged to disclose any financial interest which they, their 
spouses or their dependent children may have in the Sponsor or the Sponsor’s product under study. 
This information is required during the trial and for 12 months following completion of the trial.
9.2
Patient Information and Informed Consent
An unconditional prerequisite for each patient prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the patient by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. Prior to blood sampling for 
immunogenicity assessment at screening, subjects must give written informed consent that their 
sample may be used to validate the assays used in the immunogenicity assessment. A separate 
specific ICF will be provided to subjects who agree to participate in the PK sub-trial.
A patient information sheet must be prepared in the local language in accordance with ICH GCP
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition to 
providing this written information to a potential patient, the Investigator or a designate will inform 
the patient verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The patient will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the patient
about the trial and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
patient and the Investigator. 
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The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing and 
inspection purposes. A copy of the signed and dated information and ICF should be provided to 
the patient prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the patient information sheet and any other written information to be
provided to the patients and submit them to the IRB for review and opinion. Using the approved 
revised patient information sheet and other written information, The Investigator will explain the 
changes to the previous version to each trial patient and obtain new written consent for continued 
participation in the trial. The patient will be given sufficient time to read the information and the 
opportunity to ask questions and to request additional information and clarification about the 
changes.
9.3
Patient Identification and Privacy
A unique number will be assigned to each patient, immediately after informed consent has been 
obtained. This number will serve as the patient’s identifier in the trial as well as in the clinical trial 
database. All patient data collected in the trial will be stored under the appropriate patient number. 
Only the Investigator will be able to link trial data to an individual patient via an identification list 
kept at the site. For each patient, original medical data will be accessible for the purposes of source 
data verification by the monitor, audits and regulatory inspections, but patient confidentiality will 
be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing patient data. Patients will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Patient Card
Patients will be provided with Emergency Medical Support cards supplied by the Sponsor for use
during trial participation in order to provide clinical trial patients with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any
information about this participation that may be needed to determine the course of medical 
treatment for the patient. The information provided on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected patient. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (for example, unblinding) will follow the standard process 
established for Investigators.
In cases where the Investigator is not available, the Sponsor provides the appropriate means to 
contact a Sponsor physician. This includes the provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor physician 
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to assist with the medical emergency and to provide support for the potential unblinding of the 
patient concerned.
9.5
Clinical Trial Insurance and Compensation to Patients
Insurance coverage will be provided for each country participating to the trial. Insurance conditions 
shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents, such as the ICF, to the responsible IEC or IRB for its 
favorable opinion or approval, which will be filed in the Investigator Site File. A copy will be filed 
in the Sponsor Trial Master File at the CRO.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version and 
the Patient Information and ICF version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Patient Information and ICF) will be submitted or notified to the 
Health Authorities in accordance with all local and national regulations for each site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for CRF handling guidelines.  
The main purpose of the CRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible, and timely manner. The data in the CRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the CRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any patient names.
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For PRO data such as QoL and pain assessments, ePRO and/or paper CRF will be used.
The data will be entered into a validated database. The Contract Research Organization will be 
responsible for data processing, in accordance with the Contract Research Organization data 
management procedures. Database lock will occur once quality control and quality assurance 
procedures have been completed. PDF files of the CRFs will be provided to the Investigators after
the completion of the trial.
10.2
Source Data and Patient Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every patient in the trial. It must be possible to identify each patient by using this patient file. 
This file will contain the demographic and medical information for the patient listed below and 
should be as complete as possible. 
! Patient’s full name, date of birth, sex, height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Trial identification, that is, the Sponsor trial number for this clinical trial, and patient number
! Dates for entry into the trial (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in this clinical trial protocol
! All AEs
! Date that the patient left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to CT or MRI scan 
images, ECG recordings, and laboratory results. Such documents must bear the patient number 
and the date of the procedure. If possible, this information should be printed by the instrument 
used to perform the assessment or measurement. As necessary, medical evaluation of such records 
should be performed; all evaluations should be documented, signed, and dated by the Investigator.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years (or longer, per local requirements or as otherwise notified by the Sponsor) after the end 
of the trial. The documents to be archived include the Patient Identification List and the signed 
patient ICFs. If archiving of the Investigator Site File is no longer possible at the site, the 
Investigator must notify the Sponsor/designee.
All original patient files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
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GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP and any other applicable regulations. 
The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be patient to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed CRFs, all IMP and
IMP accountability records, and the original medical records or files for each patient.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to the Health Authorities and to the relevant IEC/IRB for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the patient’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a final clinical trial report will be written by the Sponsor in 
consultation with the Coordinating Investigator following the guidance in ICH Topic E3. 
10.6.2
Publication
The first publication will include the results of the analysis of the main endpoints and will include 
data from all trial sites that provided evaluable data. The Investigator will inform the Sponsor in 
advance about any plans to publish or present data from the trial. Any publications and 
presentations of the results (abstracts in journals or newspapers, oral presentations, etc.), either in 
whole or in part, by Investigators or their representatives will require review by the Sponsor before 
submission. The Sponsor will not suppress publication, but maintains the right to delay publication 
in order to protect intellectual property rights.
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Posting of data on ClinicalTrials.gov and the EU Clinical Trials Register is planned and will occur 
12 months after the last clinic visit of the final trial patient or another appropriate date to meet 
applicable requirements.
11
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65.
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12. Appendices
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Appendix A:
Contraceptive Guidance and Woman of Childbearing 
Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with one of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note:  Documentation can come from the study site staff’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at screening.
! Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use one of the non-hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctlya. 
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation
!
oral 
!
intravaginal 
!
transdermal.
!
Progestogen-only hormonal contraception associated with inhibition of ovulation
!
oral 
!
injectable
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Highly Effective Methods That Are User Independent 
!
implantable progestogen-only hormonal contraception associated with inhibition of ovulation
!
intrauterine device (IUD)
!
intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion.
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.)
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the IMP. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
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Appendix B:
Signature Pages and Responsible Persons for the Trial
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Signature Page – Principal Investigator
Trial Title
A multicenter, , randomized, double-blind, phase III 
trial to evaluate the safety, immunogenicity, and 
efficacy of MSB11022 compared with Humira® in 
patients 
with 
moderately 
to 
severely 
active 
rheumatoid arthritis
IND Number
EudraCT Number
2016-002852-26
Clinical Trial Protocol Date / 
Version
11 July 2017 / Version 2.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name:
Function / Title:
Principal Clinical Trial Lead
Institution:
Merck KGaA
Address:
Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
Telephone number:
E-mail address:
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
E-mail address:
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Appendix C:
Blood and Urine Volumes
Blood will be drawn on 12 separate days/occasions. On the day of PK/PD sampling, patients will have an intravenous catheter inserted 
to facilitate obtaining the multiple samples required. The planned maximum volume of blood to be drawn in this trial is approximately 
390 mL over the screening period, 52-week trial period, 4-week follow-up period, and 4-month safety follow-up period (approximately 
68 weeks total).
Assay
Approximate 
Sample Volume 
(mL)
Number of 
Samplesa
Approximate 
Subtotal Volume 
(mL)
Clinical chemistry, hematology (blood sample)
7
9
63
Urinalysis 
10
9
90
Antibody tests: ANA, anti-dsDNA (blood sample)
5
6
30
Pregnancy test (serum β-hCG) (blood sample)
3
1
3
Urine pregnancy test 
5
11
55
Virus screen (HIV,HBV and HCV) (blood sample)
3.5
1
QFT (blood sample)
3
1
3
High sensitivity C-reactive protein (blood sample)
3
8
24
Erythrocyte Sedimentation Rate (blood sample)
2
1
2
ADAs, NAbs (blood sample)
5
10
50
PK sample (blood sample)b
5
14
70
Total
51.5
71
390
ADA = anti-drug antibody; ANA = anti-nuclear antibody; β-hCG = beta human chorionic gonadotropin; dsDNA = double-stranded DNA; HBV = hepatitis B virus;
HCV = hepatitis C virus; HIV = human immunodeficiency virus; NAb = neutralizing antibody; PK = pharmacokinetics; QFT = QuantiFERON-TB Gold test.
a) Includes samples taken at screening or during double-blind period.
b) Blood for population pharmacokinetic assessment will be collected in a subset of 60 patients (30 per treatment arm). Patients in the population PK analysis will 
have additional samples taken on Days 2 (24 h post first dose), 4, and 9, and Days 2 (24 h post Week 24 dose), 4, 9, and 14 (Week 26 pre-dose) after the 
Week-24 dose (see Table 2). The date and exact time of sample collection must be recorded.
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Appendix D:
Joint Count Assessment Forms (66/68 Joint Evaluation)
Patient Right
Patient Left
Pain/Tenderness
Swelling
Pain/Tenderness
Swelling
JOINTa
(Circle Correct Answer)
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
1.  Temporomandibular
0
1
9
0
1
9
0
1
9
0
1
9
2.  Sternoclavicular
0
1
9
0
1
9
0
1
9
0
1
9
3.  Acromio-clavicular
0
1
9
0
1
9
0
1
9
0
1
9
4.  Shoulder
0
1
9
0
1
9
0
1
9
0
1
9
5.  Elbow
0
1
9
0
1
9
0
1
9
0
1
9
6.  Wrist
0
1
9
0
1
9
0
1
9
0
1
9
7.  Metacarpophalangeal I
0
1
9
0
1
9
0
1
9
0
1
9
8.  Metacarpophalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
9.  Metacarpophalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
10. Metacarpophalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
11. Metacarpophalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
12. Thumb Interphalangeal
0
1
9
0
1
9
0
1
9
0
1
9
13.  Proximal Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
14.  Proximal Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
15.  Proximal Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
16.  Proximal Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
17.  Distal Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
18.  Distal Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
19.  Distal Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
20.  Distal Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
21.  Hip
0
1
9
N/A
0
1
9
N/A
22.  Knee
0
1
9
0
1
9
0
1
9
0
1
9
23.  Ankle
0
1
9
0
1
9
0
1
9
0
1
9
24.  Tarsus
0
1
9
0
1
9
0
1
9
0
1
9
25.  Metatarsophalangeal I
0
1
9
0
1
9
0
1
9
0
1
9
26.  Metatarsophalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
27.  Metatarsophalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
28.  Metatarsophalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
29.  Metatarsophalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
30.  Great Toe
0
1
9
0
1
9
0
1
9
0
1
9
31.  Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
32.  Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
33.  Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
34.  Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
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Appendix E:
Protocol Amendments and List of Changes
Previous Protocol Amendments 
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
Amendment 1
N
31 January 2017
Germany
N
Amendment 2
N
11 July 2017
Global
Y
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Amendment No.
1
Scope
Local (Germany)
Date of Protocol Amendment
31 January 2017
A summary of changes specific for Germany is included in the local German protocol V1.1.
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Amendment No.
2
Scope
Global
Date of Protocol Amendment
11 July 2017
Current Trial Protocol
11 July 2017/Version 2.0
Version
Rationale 
This global protocol amendment was prepared to include some clarifications and corrections in 
various sections, as well as to globally implement the changes which were requested by the 
 
(and implemented in the local protocol amendment 1) in order to 
conform pregnancy and contraception language to the Clinical Trial Facilitation Group guidelines 
and to remove an inadequate sentence from Section 6.9.
List of Changes
Changes were made to conform the language regarding pregnancy and contraception to Clinical 
Trial Facilitation Group guidelines and provide a new appendix regarding contraceptive methods.
Some sections of the clinical study protocol needed to be corrected as they were found inaccurate, 
and some other sections needed to be clarified.
Administrative and editorial changes were undertaken to correct typographical errors that do not 
impact the design or execution of the study.
Changes to the clinical study protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical study protocol text was already bold, changes are 
shown in bold and underlined, deletions are marked using strike through.
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Comparison with Clinical Study Protocol Version 1.0, 09 September 2016
Change
Section
Page
Previous Wording
New Wording
To update the 
number of sites 
and countries
Synopsis
2.0 Sponsor, 
Investigators and 
Trial 
Administrative 
Structure
9
21
Approximately 60 50 trial sites in 8 6 countries in North 
America and Europe.
Approximately 50 trial sites in 6 countries in Europe.
To update to 
the planned trial 
period
Synopsis 
9
Planned trial period (first patient in-last patient out): 
First patient in: Quarter IV 2016 I 2017
Last patient out: Quarter II III 2018
Planned trial period (first patient in-last patient out): 
First patient in: Quarter I 2017
Last patient out: Quarter III 2018
To correct the 
alignment of PK 
objective and 
endpoints found 
in the synopsis 
and protocol 
body
Synopsis, 4.0 
Trial Objectives
10, 
26
Secondary Objectives
The key secondary objective is to compare the efficacy of 
MSB11022-
 to Humira® at Week 12 in patients with 
moderately to severely active RA.
Other secondary objectives include:
!
To evaluate the immunogenicity profile of 
MSB11022-
 compared to Humira® in 
patients with moderately to severely active RA up 
to Week 52
!
To further compare the efficacy and safety of 
MSB11022-
 compared to Humira® in 
patients with moderately to severely active RA up 
to Week 52
!
To evaluate population pharmacokinetics (PK) on 
MSB11022-
 and Humira® in patients with 
moderately to severely active RA
!
To compare quality of life (QoL) and physical 
function on MSB11022-
 with Humira® in 
patients with moderately to severely active RA
!
To compare injection site pain levels of MSB11022-
 versus Humira®
Exploratory Objective
!
The exploratory objective is to evaluate 
population pharmacokinetics (PK) on 
MSB110220-
 and Humira® in patients 
with moderately to severely active RA
Secondary Objectives
The key secondary objective is to compare the 
efficacy of MSB11022-
 to Humira® at Week 
12 in patients with moderately to severely active 
RA.
Other secondary objectives include:
!
To evaluate the immunogenicity profile of 
MSB11022-
 compared to Humira®
in patients with moderately to severely 
active RA up to Week 52
!
To further compare the efficacy and safety 
of MSB11022-
 compared to 
Humira® in patients with moderately to 
severely active RA up to Week 52
!
To compare quality of life (QoL) and 
physical function on MSB11022-
 
with Humira® in patients with moderately to 
severely active RA
!
To compare injection site pain levels of 
MSB11022-
 versus Humira®
Exploratory Objective
!
The exploratory objective is to evaluate 
population pharmacokinetics (PK) on 
MSB11022 
 and Humira® in 
patients with moderately to severely active 
RA
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Change
Section
Page
Previous Wording
New Wording
Synopsis
13
Population pharmacokinetics (PK)
!
Absorption rate constant (ka)
!
Apparent clearance (CL/F)
!
Volume of distribution (Vz/F)
!
Ctrough levels at Day 14 after first dose, at Week 4, 
12 and 24 pre-dose, and at Day 14 after dose of 
Week 24
Quality of Life
!
Health Assessment Questionnaire – Disability 
Index (HAQ-DI) questionnaire at screening, 
baseline, and Weeks 2, 4, 8, 12, 24, and 52
!
36-item Short Form Health Survey (SF-36) 
questionnaire at baseline and Weeks 12, 24, and 
52
!
Euro-Quality of Life – 5 Dimensions and 5-levels 
(EQ-5D-5L) questionnaire at baseline and Weeks 
12, 24, and 52
Injection site pain
!
Mean change in injection site pain on a visual 
analog scale (VAS), evaluated during 3 
administrations of IMP (doses 3 to 5) (immediately 
post-injection, 15 minutes post injection, and 1 hour 
post injection)
Exploratory endpoints
Population pharmacokinetics (PK)
!
Absorption profile characterization, if it is 
supported by the data
!
Apparent clearance (CL/F)
!
Volume of distribution (Vz/F)
!
Ctrough levels at Day 14 after first dose, at Week 
4, 12 and 24 pre-dose, and at Day 14 after dose 
of Week 24
Quality of Life
!
Health Assessment Questionnaire –
Disability Index (HAQ-DI) questionnaire at 
screening, baseline, and Weeks 2, 4, 8, 
12, 24, and 52
!
36-item Short Form Health Survey (SF-36) 
questionnaire at baseline and Weeks 12, 
24, and 52
!
Euro-Quality of Life – 5 Dimensions and 
5-levels (EQ-5D-5L) questionnaire at 
baseline and Weeks 12, 24, and 52
Injection site pain
!
Mean change in injection site pain on a 
visual analog scale (VAS), evaluated 
during 3 administrations of IMP (doses 3 to 
5) (immediately post-injection, 15 minutes 
post injection, and 1 hour post injection)
Exploratory endpoints
Population pharmacokinetics (PK)
!
Absorption profile characterization, if it is 
supported by the data
!
Apparent clearance (CL/F)
!
Volume of distribution (Vz/F)
!
Ctrough levels at Day 14 after first dose, at 
Week 4, 12 and 24 pre-dose, and at 
Day 14 after dose of Week 24
8.3.2 Secondary 
Endpoints
65
!
Injection site pain
!
Mean change in injection site pain on a VAS, 
evaluated during 3 (doses 3-5) administrations of 
IMP 
!
Pharmacokinetics
!
Injection site pain
!
Mean change in injection site pain on a 
VAS, evaluated during 3 (doses 3-5) 
administrations of IMP 
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Change
Section
Page
Previous Wording
New Wording
To align title 
and objectives 
with text 
describing 
evidence 
provided.
Synopsis, 5.2 
Discussion of Trial 
Design
10, 
27
This trial is a two-arm, randomized, multicenter, double-
blind, parallel group trial designed to compare the safety,
immunogenicity, safety, and efficacy of MSB11022-
 
with Humira® in approximately 260 randomized patients with 
moderately to severely active RA during a 52 week period.
This trial is a two-arm, randomized, multicenter, 
double-blind, parallel group trial designed to 
compare the safety, immunogenicity, and efficacy of 
MSB11022-
 with Humira® in approximately 
260 randomized patients with moderately to 
severely active RA during a 52 week period
Synopsis
11
The 52-week double-blind period will allow for the collection 
of long-term comparative safety, immunogenicity, safety,
and efficacy data for MSB11022-
 versus Humira®.
The 52-week double-blind period will allow for the 
collection of long-term comparative safety, 
immunogenicity, and efficacy data for 
MSB11022-
 versus Humira®.
3.1 Adalimumab
22
The planned MS200588-0004 study will use this new 
 formulation and will offer supportive evidence by 
providing safety, immunogenicity, safety, and efficacy data 
in a major approved indication for adalimumab., RA.
The planned MS200588-0004 study will use this 
new 
 formulation and will offer supportive 
evidence by providing safety, immunogenicity, and 
efficacy data in a major approved indication for 
adalimumab., RA.
5.2 Discussion of 
Trial Design
28
The 48-week double-blind treatment period will allow for the 
collection of long-term comparative safety, immunogenicity, 
safety, and efficacy data for MSB11022-
 versus 
Humira®.
The 48-week double-blind treatment period will 
allow for the collection of long-term comparative 
safety, immunogenicity, and efficacy data for 
MSB11022-
 versus Humira®.
To clarify that 
analysis of the 
key secondary 
endpoint at 
Week 12 will be 
descriptive.
Synopsis, 
5.2, Discussion of 
Trial Design
10,
27
The Pprimary safety endpoints will be assessed up to 
Week 52, key secondary efficacy endpoint will be assessed 
at Week 12. A descriptive analysis will be performed for the 
key secondary efficacy endpoint at Week 12 and the final 
analysis will be performed at Week 52The analysis for the 
key secondary efficacy endpoint will be descriptive.
The primary safety endpoint will be assessed up to 
Week 52, key secondary efficacy endpoint will be 
assessed at Week 12. The analysis for the key 
secondary efficacy endpoint will be descriptive.
Addition of text 
to clarify that 
third dose of 
IMP will be 
administered 
on-site by the 
patient
Synopsis, 5.2 
Discussion of Trial 
Design
11, 
28
The first 2 doses of IMP will be administered on site by the 
Investigator or other qualified personnel and the patient will 
be educated on the correct process. The third dose of IMP 
will be administered on-site by the patient. Patients will 
be monitored for 1 hour following the first 3 IMP 
administrations. If the Investigator judges it appropriate after 
proper training, the patient (or a caregiver) may continue to
self-inject/inject the treatment. The next three for the 
remaining doses. of IMP (3-5) will be self-administered by 
the patient and iInjection site pain will be assessed after 
doses 3 to 5. The remaining doses of IMP will be 
dispensed, and written instructions on proper dosage, 
administration, storage, and recording will be provided to the 
patient/caregiver.
The first 2 doses of IMP will be administered on site 
by the Investigator or other qualified personnel and 
the patient will be educated on the correct process. 
The third dose of IMP will be administered on-site 
by the patient. Patients will be monitored for 1 hour 
following the first 3 IMP administrations. If the 
Investigator judges it appropriate after proper 
training, the patient (or a caregiver) may continue to 
self-inject/inject the treatment for the remaining 
doses. Injection site pain will be assessed after 
doses 3 to 5. The remaining doses of IMP will be 
dispensed, and written instructions on proper 
dosage, administration, storage, and recording will 
be provided to the patient/caregiver.
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Change
Section
Page
Previous Wording
New Wording
To clarify that 
either of the 
4-week and 
4-month Safety 
Follow-up visits 
will not be 
duplicated if 
they fall within 
2 weeks of a 
scheduled visit.
Synopsis,
footnote c in 
Schedule of 
Assessments,
Section 5.2 
Discussion of Trial 
Design,
Section 5.4.1 
Withdrawal from 
Trial Therapy,
Section 6.4.3.1 
Management of 
Latent 
Tuberculosis 
Infection 
Diagnosed During 
the Study,
Section 7.1.2 
Baseline 
Assessments and 
Treatment Period
11, 
18, 
28, 
39, 
43, 
49
The 4-week and 4-month Safety Follow-up visits will not be 
duplicated if this visit either of these visits falls within 
2 weeks of an otherwise scheduled visit.
The 4-week and 4-month Safety Follow-up visits will 
not be duplicated if either of these visits falls within 
2 weeks of an otherwise scheduled visit.
To remove 
incorrect 
reference to 
neutralizing 
ADA titer
Synopsis
12
Immunogenicity
!
ADA to adalimumab and ADA titer including and up 
to Week 52
!
Neutralizing ADA to adalimumab and neutralizing 
ADA titer including and up to Week 52
Immunogenicity
!
ADA to adalimumab and ADA titer 
including and up to Week 52
!
Neutralizing ADA to adalimumab including 
and up to Week 52
To correct 
reference from
Week 50 to 
Week 52
Synopsis, 8.3.2 
Secondary 
Endpoints
12-
13, 
65
Efficacy
!
ACR20 at Weeks 2, 4, 8, 24, and 50 52
!
American College of Rheumatology 50% Response 
Criteria (ACR50) and American College of 
Rheumatology 70% Response Criteria (ACR70) at 
Weeks 2, 4, 8, 12, 24, and 50 52
!
Disease Activity Score based on a 28 joint count 
(DAS28)-ESR mean change from baseline at 
Weeks 2, 4, 8, 12, 24, and 50 52
Efficacy
!
ACR20 at Weeks 2, 4, 8, 24, and 52
!
American College of Rheumatology 50% 
Response Criteria (ACR50) and American 
College of Rheumatology 70% Response 
Criteria (ACR70) at Weeks 2, 4, 8, 12, 24, 
and 52
!
Disease Activity Score based on a 28 joint 
count (DAS28)-ESR mean change from 
baseline at Weeks 2, 4, 8, 12, 24, and 52
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Change
Section
Page
Previous Wording
New Wording
!
Proportion of patients with low disease activity as 
measured by DAS28-ESR, and remission at Weeks 
2, 4, 8, 12, 24, and 50 52
!
Clinical Disease Activity Index (CDAI) and 
Simplified Disease Activity Index (SDAI) mean 
change from baseline at Weeks 2, 4, 8, 12, 24, and 
50 52
!
ACR/European League Against Rheumatism 
(EULAR) Boolean remission rates at Weeks 2, 4, 8, 
12, 24, and 50 52
!
Proportion of patients with low disease 
activity as measured by DAS28-ESR, and 
remission at Weeks 2, 4, 8, 12, 24, and 52
!
Clinical Disease Activity Index (CDAI) and 
Simplified Disease Activity Index (SDAI) 
mean change from baseline at Weeks 2, 4, 
8, 12, 24, and 52
!
ACR/European League Against 
Rheumatism (EULAR) Boolean remission 
rates at Weeks 2, 4, 8, 12, 24, and 52
Removal of text 
to correct 
statement 
regarding PK 
analysis. This 
information will 
be provided in 
the PK 
statistical 
analysis plan.
Synopsis, Table 2 
Population PK 
Table of 
Assessments 
footnote @, 5.2 
Discussion of Trial 
Design, and 7.5 
Pharmacokinetics, 
Appendix B 
(Appendix C in 
amended
protocol) 
footnote b
13, 
20, 
29,
61,
87
In addition, a subset of 60 patients (30 per arm) will have 
additional samples to support the population PK analysis 
taken on Days 2 (24 h post first dose), 4, and 9 of Week 0, 
and Days 2 (24 h post Week 24 dose), 4, 9, and 14 (Week 
26 pre-dose) after the Week 24 dose (see Table 2). All PK 
samples will be included into the population PK analysis.
In addition, a subset of 60 patients (30 per arm) will 
have additional samples to support the population 
PK analysis taken on Days 2 (24 h post first dose), 
4, and 9, and Days 2 (24 h post Week 24 dose), 4, 
9, and 14 (Week 26 pre-dose) after the Week 24 
dose (see Table 2).
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Change
Section
Page
Previous Wording
New Wording
Edit of text to 
correct that the 
immunogenicity 
assessment will 
be analyzed 
using the Safety 
Analysis Set 
and to clarify 
the descriptive 
statistics.
Synopsis
15
Descriptive statistics of the immunogenicity assessment per 
treatment arm will be given with reference to the ITT 
analysis set.Safety Analysis Set.
Descriptive statistics of the immunogenicity 
assessment per treatment arm will be given with 
reference to the Safety Analysis Set.
8.5.3.5 Analysis of 
Immunogenicity 
Endpoints
69
Descriptive statistics of the immunogenicity assessment per 
treatment arm (ITT) will be given with reference to the ITT 
analysis set Safety Analysis Set unless otherwise specified 
in the SAP.
!
Number and percentage of ADA positive patients at 
any time
!
ADA titer
!
Number and percentage of NAb positive patients
!
Time to ADA
!
Change of titer over time 
!
Persistent or transient ADA for patients with an 
ADA result a treatment period ≥ 6 months
Descriptive statistics of the immunogenicity 
assessment per treatment arm will be given with 
reference to the Safety Analysis Set unless 
otherwise specified in the SAP.
!
Number and percentage of ADA positive 
patients at any time
!
ADA titer
!
Number and percentage of NAb positive 
patients
!
Time to ADA
!
Change of titer over time 
!
Persistent or transient ADA for patients 
with a treatment period ≥ 6 months
Removal of 
non-applicable 
footnote.
Synopsis, Table 1 
Schedule of 
Assessments
18
Day/Week
W52b ETb
4-week safety 
FU
(4 weeks 
after last 
dose of IMP)c
4-month safety 
evaluation
(4 months after 
last dose of 
IMP)c
Visit window (days)
± 2
± 7
± 7
± 7
Infectious disease 
specialist 
/pulmonologist 
consultationv
XU
X
XU
X
Day/Week
W52
b
ETb
4-week 
safety FU
(4 weeks 
after last 
dose of 
IMP)c
4-month 
safety 
evaluation
(4 months 
after last 
dose of 
IMP)c
Visit window 
(days)
± 2
± 7
± 7
± 7
Infectious 
disease 
specialist 
/pulmonologist 
consultationv
X
X
Modification of 
footnote i in 
Schedule of 
Assessments to 
match 
contraceptive 
guidance
Synopsis 
Schedule of 
Assessments
18
Follicle-stimulating hormone test will be performed to 
confirm postmenopausal status of women with continuous 
amenorrhea for at least 2 years ≥ 12 months.
Follicle-stimulating hormone test will be performed 
to confirm postmenopausal status of women with 
continuous amenorrhea ≥12 months.
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Change
Section
Page
Previous Wording
New Wording
To correct the 
list of approved 
indications for 
Humira
3.1 Adalimumab
22
Adalimumab is a tumor necrosis factor (TNF) inhibitor 
indicated in the European Union (EU) and United States 
(US) for the treatment of multiple medical conditions, 
including rheumatoid arthritis (RA), polyarticular juvenile 
idiopathic arthritis (JIA), enthesitis-related JIA (EU only), 
psoriatic arthritis, ankylosing spondylitis, axial 
spondyloarthritis (EU only), Crohn’s disease, ulcerative 
colitis, plaque psoriasis, pediatric plaque psoriasis (EU only), 
and pediatric Crohn’s disease and, hidradenitis suppurativa, 
and uveitis.
Adalimumab is a tumor necrosis factor (TNF) 
inhibitor indicated in the European Union (EU) and 
United States (US) for the treatment of multiple 
medical conditions, including rheumatoid arthritis 
(RA), polyarticular juvenile idiopathic arthritis (JIA), 
enthesitis-related JIA (EU only), psoriatic arthritis, 
ankylosing spondylitis, axial spondyloarthritis (EU 
only), Crohn’s disease, ulcerative colitis, plaque 
psoriasis, pediatric plaque psoriasis (EU only),
pediatric Crohn’s disease, hidradenitis suppurativa, 
and uveitis.
Modification of 
inclusion criteria 
as per the 
request from 
PEI
5.3.1 Inclusion 
Criteria
34-35
8.
A female patient is eligible to participate if she is 
not pregnant (see Appendix A), not breastfeeding, 
and at least one of the following conditions applies:
Women of childbearing potential must use highly 
effective methods of contraception to prevent 
pregnancy for 4 weeks before randomization and must 
agree to continue to practice adequate contraception for 
5 months after the last dose of IMP.
For the purposes of this trial, women of childbearing 
potential are defined as all female patients after onset of 
puberty unless they are:
a.
Not a woman of childbearing potential 
(WOCBP) as defined in Appendix A
Postmenopausal, defined by continuous 
amenorrhea for at least 2 years and confirmed by 
follicle-stimulating hormone at screening, or
OR
b.
A WOCBP who agrees to use a highly effective 
contraception (ie, methods with a failure rate of 
less than 1% per year) as detailed in Appendix 
A of this protocol 3 months before the start of 
the first dose of the IMP, during the treatment 
period, and for at least 5 months after the last 
dose of the IMP. Surgically sterile (tubal ligation is 
acceptable as a method of surgical sterilization if it 
has been performed at least 1 year prior to 
screening without reversal)
8.
A female patient is eligible to participate if she 
is not pregnant (see Appendix A), not 
breastfeeding, and at least one of the following 
conditions applies:
a.
Not a woman of childbearing potential 
(WOCBP) as defined in Appendix A 
OR
b.
A WOCBP who agrees to use a highly 
effective contraception (ie, methods with a 
failure rate of less than 1% per year) as 
detailed in Appendix A of this protocol 
3 months before the start of the first dose 
of the IMP, during the treatment period, 
and for at least 5 months after the last 
dose of  the IMP.
9.
Female patients must not be pregnant and if of 
childbearing potential, must have a negative 
serum pregnancy test at screening and a 
negative urine pregnancy test at baseline 
before randomization.
10. Female patients must not be lactating or 
breast-feeding at screening through at least 
5 months after the last treatment with IMP.
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Highly effective contraception is defined as use of 2 barrier 
methods (eg, female diaphragm and male condoms) or 1 
barrier method with spermicide or an intrauterine device or 
hormonal contraceptives (eg, implant, injectable, patch or 
oral*), or total abstinence from intercourse (when this is in 
line with the preferred and usual lifestyle of the patient).
*If contraception is oral, patients should have been stable on 
the same contraceptive pill for a minimum of 3 months 
before initiation of trial treatment. 
9.
Women Female patients must not be pregnant and if of 
childbearing potential, must have a negative serum 
pregnancy test at screening and a negative urine 
pregnancy test at baseline before randomization.
10. Women Female patients must not be lactating or 
breast-feeding at screening through at least 5 months 
after the last treatment with IMP.
11. Male patients must be either surgically sterile 
(vasectomy with documented confirmation of aspermia) 
or must agree to use a condom and have their 
female partners use a highly effective contraception 
(ie, methods with a failure rate of less than 1% per 
year) as detailed in Appendix A for 3 months before 
the first dose of IMP, during the treatment period 
and for at least 5 months after the last dose of IMP, 
unless their partners are infertile or surgically 
sterile. Male patients must agree to continue to 
practice adequate contraception for 5 months after 
the administration of the IMP and refrain from 
donating sperm during this period. willing to use a 
condom in addition to having their female partner use 
another form of contraception (such as an intra-uterine 
device, barrier method with spermicide, or hormonal 
contraceptive [eg, implant, injectable, patch or oral]), 
unless their partners are infertile or surgically sterile.
11. Male patients must be either surgically sterile 
(vasectomy with documented confirmation of 
aspermia) or must agree to use a condom and 
have their female partners use a highly 
effective contraception (ie, methods with a 
failure rate of less than 1% per year) as 
detailed in Appendix A for 3 months before the 
first dose of IMP, during the treatment period 
and for at least 5 months after the last dose of 
IMP, unless their partners are infertile or 
surgically sterile. Male patients must agree to 
continue to practice adequate contraception for 
5 months after the administration of the IMP 
and refrain from donating sperm during this 
period. 
Clarifying what 
items the 
patient should 
be expected to 
receive with 
their IMP.
6.6 Preparation, 
Handling, and 
Storage of the 
Investigational 
Medicinal Product
45
Patients should have access to refrigeration to store the 
IMP. Patients will also receive sharps containers and 
handling instructions and leaflets.
Patients should have access to refrigeration to store 
the IMP. Patients will also receive sharps 
containers and handling instructions.
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Removal of 
1 sentence 
asking the 
Investigator to 
contact the 
medical monitor 
for unblinding, 
as per the 
request from 
PEI.
6.9 Blinding
46
The trial blind may be broken for an individual only if 
knowledge of the IMP is essential for clinical management of 
an incurred SAE; however, unblinding is discouraged as 
knowledge of the treatment received has limited influence on 
the treatment of AEs. The Investigator should attempt to 
contact the medical monitor to discuss in advance the 
possibility of unblinding. If the Investigator breaks the blind, 
he must contact the medical monitor immediately, and no 
later than 24 hours after performing the unblinding, without 
sharing any treatment assignment information.
The trial blind may be broken for an individual only 
if knowledge of the IMP is essential for clinical 
management of an incurred SAE; however, 
unblinding is discouraged as knowledge of the 
treatment received has limited influence on the 
treatment of AEs. If the Investigator breaks the 
blind, he must contact the medical monitor 
immediately, and no later than 24 hours after 
performing the unblinding, without sharing any 
treatment assignment information.
Clarification of 
the overdose 
definition by 
removal of an 
incorrect 
sentence. 
6.11 Treatment of 
Overdose
47
An overdose is defined as any dose greater than the highest 
daily dose included in a clinical trial protocol. Any dose taken 
outside of ±2 days of the schedule will qualify as overdose 
for the next dose. In the event of an overdose, patients 
should receive appropriate supportive medical care and be 
followed until resolution/stabilization of any clinical issues.
An overdose is defined as any dose greater than 
the highest daily dose included in a clinical trial 
protocol. In the event of an overdose, patients 
should receive appropriate supportive medical care 
and be followed until resolution/stabilization of any 
clinical issues.
Addition of text 
to clarify where 
the IMP doses 
will be given for 
the first 3 doses 
and by whom.
7.1.2 Baseline 
Assessments and 
Treatment Period
48
If the IMP is well tolerated as per medical judgment, and 
reflects the expected safety profile during these visits, the 
remainder of the patients will be dosed. The IMP is 
administered at the trial site for the first 2 3 doses; at 
Weeks 0, and 2, the patient or a caregiver will be trained for 
self-injection/injection and at Week 4, the patient will 
self-inject. Patients will be monitored for 1 hour following 
IMP administration on Day 1/Week 0, Week 2, and Week 4.
If the IMP is well tolerated as per medical judgment, 
and reflects the expected safety profile during these 
visits, the remainder of the patients will be dosed. 
The IMP is administered at the trial site for the first
3 doses; at Weeks 0, and 2, the patient or a 
caregiver will be trained for self-injection/injection 
and at Week 4, the patient will self-inject. Patients 
will be monitored for 1 hour following IMP 
administration on Day 1/Week 0, Week 2, and 
Week 4.
Addition of text 
to clarify assay 
validation 
sampling.
7.2.4 
Immunogenicity
50
A blood sample will be collected at screening for assay 
validation purposes only, no results will be reported and 
at baseline (on Day 1/Week 0 before IMP administration).
A blood sample will be collected at screening for 
assay validation purposes only, no results will be 
reported and at baseline (on Day 1/Week 0 before 
IMP administration).
Clarifying that 
CRP and not 
high-sensitivity 
CRP will be 
detected as part 
of the SDAI.
7.3.1.4 SDAI
53-54
SDAI =  SJC28 + TJC28 + GH + PGA +hsCRP CRP
Where:
!
TJC28 = 28 joint count for tenderness
!
SJC28 = 28 joint count for swelling
!
GH = the general health component of the DAS (ie, 
Patient’s Global Assessment of Disease Activity on 
a scale of 1 to 10 where 10 is maximal activity).
SDAI =  SJC28 + TJC28 + GH + PGA + CRP
Where:
!
TJC28 = 28 joint count for tenderness
!
SJC28 = 28 joint count for swelling
!
GH = the general health component of the 
DAS (ie, Patient’s Global Assessment of 
Disease Activity on a scale of 1 to 10 
where 10 is maximal activity).
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!
PGA = Physician’s Global Assessment of Disease 
Activity on a scale of 1 to 10 where 10 is maximal 
activity
!
hsCRP CRP = high sensitivity C-reactive protein in 
mg/dL
!
PGA = Physician’s Global Assessment of 
Disease Activity on a scale of 1 to 10 
where 10 is maximal activity
!
CRP = C-reactive protein in mg/dL
To more 
accurately 
define 
absorption 
endpoint
8.3.3 Exploratory 
Endpoints
65
!
Pharmacokinetic endpoints from a population PK 
analysis
!
Absorption rate constant (ka) profile 
characterization, if it is supported by the data
!
Pharmacokinetic endpoints from a population 
PK analysis
!
Absorption profile characterization, if it is 
supported by the data
8.5.4 Analysis of 
Population 
Pharmacokinetic 
Endpoints
69
Pharmacokinetic parameters (absorption rate constant
profile, apparent clearance, apparent volume of distribution, 
and Ctrough levels) of MSB11022-
 and Humira®, with 
their intra- and inter-individual variability in the patient 
population, will be derived by population PK data analysis 
using a nonlinear mixed effects modeling approach, based 
on sparse sampling.
Pharmacokinetic parameters (absorption profile, 
apparent clearance, apparent volume of 
distribution, and Ctrough levels) of 
MSB11022-
 and Humira®, with their 
intra- and inter-individual variability in the patient 
population, will be derived by population PK data 
analysis using a nonlinear mixed effects modeling 
approach, based on sparse sampling.
Inadvertent 
inclusion of PP 
safety analysis 
set, which will 
not be part of 
the data 
analyses.
8.4.3 Per-Protocol
66
Two PP populations will be described, one for efficacy, the 
other for safety assessment. The criteria for the PP 
population will be defined in detail in the SAP; major 
protocol violators excluded from the PP analysis set will be 
identified.
The criteria for the PP population will be defined in 
detail in the SAP; major protocol violators excluded 
from the PP analysis set will be identified.
Addition of text 
to specify 
covariate 
analysis of PK 
parameters.
8.5.4 Analysis of 
Population 
Pharmacokinetics 
Endpoints
69
Pharmacokinetic parameters (absorption profile, apparent 
clearance, apparent volume of distribution, and Ctrough levels) 
of MSB11022-
 and Humira®, with their intra- and 
inter-individual variability in the patient population, will be 
derived by population PK data analysis using a nonlinear 
mixed effects modeling approach, based on sparse 
sampling. The influence of covariates, such as standard 
demographic covariates, treatment (MSB11022-
 
or Humira®), and immunogenicity, will be explored 
graphically and statistically to explain potential random 
inter- and intra-individual variability in PK parameters.
Pharmacokinetic parameters (absorption profile, 
apparent clearance, apparent volume of 
distribution, and Ctrough levels) of 
MSB11022-
 and Humira®, with their intra-
and inter-individual variability in the patient 
population, will be derived by population PK data 
analysis using a nonlinear mixed effects modeling 
approach, based on sparse sampling. The influence 
of covariates, such as standard demographic 
covariates, treatment (MSB11022-
 or 
Humira®), and immunogenicity, will be explored 
graphically and statistically to explain potential 
random inter- and intra-individual variability in PK 
parameters.
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Addition of 
Contraceptive 
Guidance 
following the 
request from 
PEI
Appendix A 
Contraceptive 
Guidance and 
Woman of 
Childbearing 
Potential
82
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and 
until becoming postmenopausal unless permanently 
sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
Women in the following categories are not considered 
WOCBP
1.
Premenopausal female with one of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note:  Documentation can come from the study site 
staff’s: review of participant’s medical records, medical 
examination, or medical history interview.
2.
Premenarchal 
3.
Postmenopausal female
!
Females who are postmenopausal (age-related 
amenorrhea ≥ 12 consecutive months and 
increased follicle-stimulating hormone [FSH] 
> 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are 
exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be 
drawn at Screening.
!
Females on hormone replacement therapy 
(HRT) and whose menopausal status is in doubt 
will be required to use one of the non-hormonal 
highly effective contraception methods if they 
wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before 
study enrollment.
Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User 
Dependent 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche 
and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not 
considered WOCBP
1.
Premenopausal female with one of the 
following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note:  Documentation can come from the study site 
staff’s: review of participant’s medical records, 
medical examination, or medical history interview.
2.
Premenarchal 
3.
Postmenopausal female
!
Females who are postmenopausal 
(age-related amenorrhea ≥ 12 consecutive 
months and increased follicle-stimulating 
hormone [FSH] > 40 mIU/mL), or who 
have undergone hysterectomy or bilateral 
oophorectomy are exempt from pregnancy 
testing. If necessary to confirm 
postmenopausal status, an FSH will be 
drawn at Screening.
!
Females on hormone replacement therapy 
(HRT) and whose menopausal status is in 
doubt will be required to use one of the 
non-hormonal highly effective 
contraception methods if they wish to 
continue their HRT during the study. 
Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal 
status before study enrollment.
Contraceptive Guidance
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Failure rate of < 1% per year when used consistently and 
correctlya. 
!
Combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of 
ovulation 
!
oral 
!
intravaginal 
!
transdermal.
!
Progestogen-only hormonal contraception associated 
with inhibition of ovulation 
!
oral 
!
injectable
Highly Effective Methods That Are User Independent 
!
implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation
!
intrauterine device (IUD)
!
intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion.
!
Vasectomized partner 
(A vasectomized partner is a highly effective 
contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence 
of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used). 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated 
with the IMP. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those when 
used consistently and correctly. Use should be 
consistent with local regulations regarding the use of 
Highly Effective Contraceptive Methods That 
Are User Dependent 
Failure rate of < 1% per year when used 
consistently and correctlya. 
!
Combined (estrogen- and 
progestogen-containing) hormonal 
contraception associated with inhibition of 
ovulation 
!
oral 
!
intravaginal 
!
transdermal.
!
Progestogen-only hormonal contraception 
associated with inhibition of ovulation 
!
oral 
!
injectable
Highly Effective Methods That Are User 
Independent 
!
implantable progestogen-only hormonal 
contraception associated with inhibition of 
ovulation
!
intrauterine device (IUD)
!
intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion.
!
Vasectomized partner 
(A vasectomized partner is a highly effective 
contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and 
the absence of sperm has been confirmed. If not, 
an additional highly effective method of 
contraception should be used). 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective 
method only if defined as refraining from 
heterosexual intercourse during the entire period of 
risk associated with the IMP. The reliability of 
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contraceptive methods for participants participating in 
clinical studies. 
sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and 
usual lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those 
when used consistently and correctly. Use should 
be consistent with local regulations regarding the 
use of contraceptive methods for participants 
participating in clinical studies. 
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