Conditions: Rheumatoid Arthritis
Keywords: MSB11456 RoActemra®
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 604
Healthy volunteers: no

Brief summary:
The purpose of the study is to compare the efficacy, safety and immunogenicity of MSB11456 and EU approved RoActemra® in participants with moderately to severely active rheumatoid arthritis.

Participants will be randomized at the beginning of the Core Treatment Period (Baseline to Week 24) to receive either MSB11456 or EU approved RoActemra® once a week (QW). At the beginning of the Extended Treatment Period (Week 24 to Week 52), participants who received RoActemra® will be re-randomized to either continue receiving RoActemra® QW or switch to receive MSB11456 QW.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: MSB11456 intervention 2: EU-approved RoActemra
Intervention descriptions: intervention 1: Participants will receive MSB11456 subcutaneously, once a week. intervention 2: Participants will receive EU-approved RoActemra® subcutaneously, once a week.

Protocol document:
Prot_000.pdf: 
Protocol Number: FKS456-001 
Official Title: A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-
Arm Study to Evaluate the Efficacy, Safety and Immunogenicity of MSB11456 
Compared to European Union-approved RoActemra® in Patients with 
Moderately to Severely Active Rheumatoid Arthritis (APTURA I study) 
Document Date: 08 February 2021 
NCT Number: NCT04512001 


MSB11456 
Confidential
Sponsor Name: Fresenius Kabi Swiss BioSim GmbH 
Study Number: FKS456-001 
Version 1.0
 
CONFIDENTIAL INFORMATION 
 
 
16.1 
Study Information 
Page 1/337


MSB11456 
Confidential
Sponsor Name: Fresenius Kabi Swiss BioSim GmbH 
Study Number: FKS456-001 
Version 1.0
 
CONFIDENTIAL INFORMATION 
 
 
16.1.1 
Protocol and Protocol Amendments 
Protocol Version 3.0 (Global Amendment 2; substantial), dated 01 Feb 2021 
Protocol Version 3.2 (Incorporating Global Amendment 2 into Protocol Version 2.2 for 
the Czech Republic), dated 08 Feb 2021 
 
Page 2/337






































































































Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 51 of 166
 
 
4.4 
Study Schematic 
Abbreviations: EU-RMP=European Union-Approved Reference Medicinal Product=RoActemra®; FU=Follow-Up; MTX=methotrexate  
Page 53/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 52 of 166
 
 
4.5 
Schedule of Assessments 
Table 1 Schedule of Assessments – Main Study 
Trial Period 
Screening 
Core Treatment Period 
Extended Treatment 
Period 
Early 
Termination 
Safety 
Follow-Up 
End of Study Visit 
Visit number and week 
1 
2 
Base-
line 
3 
W1 
4 
W2 
5 
W4 
6 
W8 
7 
W12 
8 
W16 
9 
W24y 
10 
W30z 
11 
W42 
12 
W52 
(EOT 
+ 
1 wk) 
ETx 
13 
W55 
(4 weeks 
after the 
last study 
drug dose) 
14 
W63 
(12 weeks after the 
last study drug dose 
– Safety Evaluation 
Period) 
Visit Day/Window (days) 
-28 to -1 
days 
(n.a.) 
 
D1 
(None) 
D8 
(±2) 
D15 
(±2) 
D29 
(±2) 
D57 
(±2) 
D85 
(±2) 
D113 
(±2) 
D169 
(±2) 
D211 
(±2) 
D295 
(±4) 
D365 
(±4) 
 
D386 
(±7) 
D442 
(± 7) 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
Efficacy assessmentsb 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical Assessments 
Medical historyc 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
Xf 
Xg 
 
 
Xg 
 
Xg 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Vital signsh   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Xi 
Xi 
X 
Chest X-rayj 
X 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 
Xk 
Page 54/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 53 of 166
 
 
Trial Period 
Screening 
Core Treatment Period 
Extended Treatment 
Period 
Early 
Termination 
Safety 
Follow-Up 
End of Study Visit 
Visit number and week 
1 
2 
Base-
line 
3 
W1 
4 
W2 
5 
W4 
6 
W8 
7 
W12 
8 
W16 
9 
W24y 
10 
W30z 
11 
W42 
12 
W52 
(EOT 
+ 
1 wk) 
ETx 
13 
W55 
(4 weeks 
after the 
last study 
drug dose) 
14 
W63 
(12 weeks after the 
last study drug dose 
– Safety Evaluation 
Period) 
Visit Day/Window (days) 
-28 to -1 
days 
(n.a.) 
 
D1 
(None) 
D8 
(±2) 
D15 
(±2) 
D29 
(±2) 
D57 
(±2) 
D85 
(±2) 
D113 
(±2) 
D169 
(±2) 
D211 
(±2) 
D295 
(±4) 
D365 
(±4) 
 
D386 
(±7) 
D442 
(± 7) 
Concomitant medications and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reactionsm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection and review of patient 
diaryn 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic Sampling 
Pharmacokinetic trough 
concentration samplingo  
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments 
Clinical chemistryp, hematology, 
coagulation and lipid panel 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Erythrocyte sedimentation rate 
(as part of DAS28-ESR 
assessment)b 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Page 55/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 54 of 166
 
 
Trial Period 
Screening 
Core Treatment Period 
Extended Treatment 
Period 
Early 
Termination 
Safety 
Follow-Up 
End of Study Visit 
Visit number and week 
1 
2 
Base-
line 
3 
W1 
4 
W2 
5 
W4 
6 
W8 
7 
W12 
8 
W16 
9 
W24y 
10 
W30z 
11 
W42 
12 
W52 
(EOT 
+ 
1 wk) 
ETx 
13 
W55 
(4 weeks 
after the 
last study 
drug dose) 
14 
W63 
(12 weeks after the 
last study drug dose 
– Safety Evaluation 
Period) 
Visit Day/Window (days) 
-28 to -1 
days 
(n.a.) 
 
D1 
(None) 
D8 
(±2) 
D15 
(±2) 
D29 
(±2) 
D57 
(±2) 
D85 
(±2) 
D113 
(±2) 
D169 
(±2) 
D211 
(±2) 
D295 
(±4) 
D365 
(±4) 
 
D386 
(±7) 
D442 
(± 7) 
C-reactive protein (as part of the 
SDAI Score and DAS28-CRP)b 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Follicle-stimulating hormone 
test (women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testq 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Viral serologyr 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Anti-nuclear antibodies, 
anti-double-stranded DNA, 
rheumatoid factor, anti-cyclic 
citrullinated peptide antibodies 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
QuantiFERON®-TB Gold Plus 
tests 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Immunogenicity samplingt 
Xu 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
Treatments Administered 
Randomization 
 
X 
 
 
 
 
 
 
Xv 
 
 
 
 
 
 
Page 56/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 55 of 166
 
 
Trial Period 
Screening 
Core Treatment Period 
Extended Treatment 
Period 
Early 
Termination 
Safety 
Follow-Up 
End of Study Visit 
Visit number and week 
1 
2 
Base-
line 
3 
W1 
4 
W2 
5 
W4 
6 
W8 
7 
W12 
8 
W16 
9 
W24y 
10 
W30z 
11 
W42 
12 
W52 
(EOT 
+ 
1 wk) 
ETx 
13 
W55 
(4 weeks 
after the 
last study 
drug dose) 
14 
W63 
(12 weeks after the 
last study drug dose 
– Safety Evaluation 
Period) 
Visit Day/Window (days) 
-28 to -1 
days 
(n.a.) 
 
D1 
(None) 
D8 
(±2) 
D15 
(±2) 
D29 
(±2) 
D57 
(±2) 
D85 
(±2) 
D113 
(±2) 
D169 
(±2) 
D211 
(±2) 
D295 
(±4) 
D365 
(±4) 
 
D386 
(±7) 
D442 
(± 7) 
Trial medication administeredw 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
D=day; DAS28-CRP=Disease Activity Score-28 C-Reactive Protein; Disease Activity Score-28 Erythrocyte Sedimentation Rate; EOT=End of Treatment; ET=Early 
Termination; n.a.=not applicable; SDAI=Simplified Disease Activity Index; W/wk=week  
a. Informed consent must be obtained from each patient prior to performing any screening assessments.  Note: A separate Informed Consent Form (containing important 
information about COVID-19, clinical research study participation and patient consent) will be provided to and signed by each patient to provide information on the 
general risks of study participation related to COVID-19 and to document that it is understood by the patient.  Another separate Informed Consent Form will be required 
to be understood and signed by partners of male participating patients who become pregnant during the study or within 10 weeks after the participating patient’s last dose 
of study drug.   
b. Efficacy assessments: Tender Joint Count, Swollen Joint Count, erythrocyte sedimentation rate, C-reactive protein, Health Assessment Questionnaire-Disability Index, 
Patient Assessment of Arthritis Pain, Patient’s Global Assessment of Disease Activity and Physician’s Global Assessment of Disease Activity.  Patient-reported outcome 
questionnaires should be the first assessments performed after the temperature measurements at the visits for which they are scheduled.  Note: only Tender Joint Count 
and Swollen Joint Count assessments will be performed at screening (to confirm inclusion criterion 4 for at least six tender and swollen joints) and will be confirmed 
again at baseline.  After confirmation at baseline, Tender Joint Count and Swollen Joint Count assessments will be performed at the scheduled timepoints.  All other 
efficacy assessments will be performed only at baseline (once the patient has qualified) and then at the scheduled timepoints. 
c. Medical history must include rheumatoid arthritis disease phenotype and duration as well as date of first diagnosis, previous treatments including any previous biologic 
or non-biologic therapy for rheumatoid arthritis, history of tuberculosis or any treatment for active/latent tuberculosis, previous surgeries and smoking status. 
d. Review and update medical history only, to ensure the patient remains qualified for the study. 
e. Re-check screening results (including virus serology and tuberculosis test) to ensure the patient remains eligible to participate in the study. 
f. A complete physical examination including height and body mass index is performed at screening.  Weight will be measured at screening and baseline. 
g. Only physical examination and weight are performed at the indicated visits. 
Page 57/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 56 of 166
 
 
h. Vital signs (including body temperature, respiratory rate, heart rate [after a 5 minute rest] and arterial blood pressure [after a 5 minute rest]) will be measured using a 
validated device and will be recorded at the Screening Visit and throughout the study at the visits indicated in the Schedule of Assessments.  During the study, 
measurement of vital signs may be repeated at the discretion of the Investigator for safety reasons.  Axillary body temperature measurement should be performed first at 
each study visit and should precede every other assessment of each visit.  In the case of an elevated temperature, it is the Investigator’s decision to determine any further 
actions according to local practice and their medical judgment.    
i. The electrocardiogram will be repeated at the Safety Follow-Up Visit at Week 55 only if in the opinion of the Investigator it is clinically warranted (e.g., supported by 
corresponding signs and symptoms). 
j. If a bidirectional chest X-ray is available within the 3 months before randomization, the X-ray will not be required to be repeated at screening. 
k. Only if the QuantiFERON®-TB Gold Plus test is positive at the Early Termination Visit or the End of Study Visit.  If the QuantiFERON®-TB Gold Plus test is 
indeterminate, patients may be retested once.  If on retest the result is positive or indeterminate then the patient must undergo a chest X-ray.  
l. Confirmed COVID-19 cases should be considered by the Investigator as ‘otherwise medically important’ and accordingly reported as serious adverse events. 
m. In addition to the inspection of the injection site, the Investigator is also requested to ask the patient during the assessment about any such reactions that may have 
occurred since last assessment (see Section 7.13). 
n. Patients will receive their Patient Diaries on Visit 4. 
o. Pharmacokinetic trough concentration will be collected from all patients in conjunction with the immunogenicity sampling (except at Week 1 when only trough 
concentration sample is drawn).  These samples must be collected prior to the immunogenicity sampling and prior to the study drug administration. 
p. Additional unscheduled serum chemistry samples can be collected from those patients who receive anti-fungal drugs or any other medication with known liver toxicity 
during the study treatment phase. 
q. Urine pregnancy tests will be performed for women of childbearing potential at baseline before dosing with study drug and pre-dose at Weeks 4, 8, 12, 16, 24, 28, 32, 42 
and 52, Early Termination and Follow-Up Visit at Week 55.  When there is no site visit, the patients will perform the urine pregnancy tests at home every 4 weeks. 
r. Includes tests for human immunodeficiency virus subtype 1 (HIV-1) and subtype 2 (HIV-2), hepatitis B virus surface antigen, hepatitis B virus core antibody and 
hepatitis C virus antibody.  Note: Reflex testing for hepatitis C virus RNA and hepatitis B virus DNA is allowed if hepatitis C virus antibodies or hepatitis B virus 
antibodies are present without a positive result for hepatitis B virus surface antigen. 
s. Continuation of study medication will be excluded in patients who were QuantiFERON®-TB Gold Plus test negative at randomization, but subsequently become 
QuantiFERON®-TB Gold Plus positive at Week 24.  Patients whose QuantiFERON®-TB Gold Plus test is indeterminate at Week 24 may be retested once.  If on retest 
the result is positive or indeterminate then the patient must be withdrawn from the study.  The QuantiFERON®-TB Gold Plus test need not be repeated if the patient has 
had a QuantiFERON®-TB Gold Plus test performed within 4 weeks before the Early Termination Visit. 
t. Blood samples for immunogenicity assessments must be drawn prior to the administration of the study drug, which will be performed at the site for these visits.  Separate 
samples will be collected for antidrug antibody and neutralizing antidrug antibody assessments.  In order to evaluate antidrug antibodies in all patients who discontinue 
from the study at Week 24 (or any subsequent visit), a blood sample for immunogenicity assessment must be taken 4 weeks after last dose of study drug. 
u. No result will be reported; sample will only be used for method validation purposes and establishment of assay cut-off points for immunogenicity analysis.  These are 
required to statistically determine positive from negative samples. 
v. Re-randomization of patients (initially randomized to EU-approved RoActemra) to continue with RoActemra or being switched to MSB11456. 
w. On weeks with scheduled study visits, the study drug will be administered by the site staff.  On weeks with no scheduled study visit, the patient (or caregiver) will inject 
the study drug.  Patients will be monitored for 2 hours following the first, second and third doses of study drug at baseline (Day 1), and Weeks 1 and 2.  The last dose of 
study drug will be administered at Week 51 at home. 
x. Any patient who prematurely withdraws or is withdrawn from the study must complete the Early Termination procedures.  If a patient discontinues study drug prior to 
Week 24, the patient will remain in the study up to the completion of the Week 24 assessments to allow for the collection of efficacy, safety and immunogenicity data for 
the assessment of similarity for a full 24-week period before switching occurs.  If a patient discontinues study drug during the Extended Treatment Period, the patient will 
Page 58/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 57 of 166
 
be followed-up until the End of Study Visit.  They are NOT considered withdrawn from the study.  Patients that discontinue study drug prematurely should be followed 
for at least 4 weeks after the last study drug dose and either complete a 4-week Safety Follow-Up Visit or have the corresponding assessments completed at a suitable 
scheduled visit. 
y. All patients will remain in the study up to the completion of the Week 24 assessments to allow for the collection of efficacy, safety and immunogenicity data for the 
assessment of biosimilarity for a full 24-week period before switching occurs.  After the Week 24 Visit patients will be re-randomized and enter a further 28-week 
Extended Treatment Period (Day 169/Week 24 to Day 365/Week 52). 
z. Week 30 is the first clinic visit of the Extended Treatment Period after the Week 24 Visit. 
 
 
Page 59/337


Protocol Number: FKS456-001 
A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and 
Immunogenicity of MSB11456 Compared to European Union-approved RoActemra® in Patients with Moderately to Severely 
Active Rheumatoid Arthritis (APTURA I study) 
Confidential
MSB11456 
Page 58 of 166
 
 
Table 2 Schedule of Assessments – Population Pharmacokinetic Sub-Study 
 
 
Visit Day 
Day 1 
Day 1 
Day 5 
Day 9 
Day 13 
Day 14 
Day 16 
Day 24 
Time relative to previous dose in 
days (hours) 
0.5 
(12 hours 
±2 hours) 
1 
(24 hours 
±2 hours) 
4 
(96 hours 
±6 hours) 
1.5 
(36 hours 
±2 hours) 
5 
(120 hours 
±4 hours) 
6 
(144 hours 
±4 hours) 
1 
(24 hours 
±2 hours) 
2 
(48 hours 
±24 hours) 
Pharmacokinetics 
X 
X 
X 
X 
X 
X 
X 
X 
In addition to the trough samples collected from all patients shown in Table 1, samples specific for the pharmacokinetic sub-study analyses will be collected at the time points 
shown in this table.  Note: The time relative to the previous dose and visit window presented in this table supersede those of Table 1 if the patient is included in the sub-study.  
 
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SAP_001.pdf: 
Protocol Number: FKS456-001 
Official Title: A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-
Arm Study to Evaluate the Efficacy, Safety and Immunogenicity of MSB11456 
Compared to European Union-approved RoActemra® in Patients with 
Moderately to Severely Active Rheumatoid Arthritis (APTURA I study) 
Document Date: 15 June 2022 
NCT Number: NCT04512001 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
CONFIDENTIAL INFORMATION 
 
 
  
 1 / 61 
 
 
 
 
Statistical Analysis Plan (SAP) 
 
Protocol Title: 
A Randomized, Double-Blind, Multiple-Dose, 
Parallel-Group, Two-Arm Study to Evaluate the Efficacy, 
Safety and Immunogenicity of MSB11456 Compared to 
European Union-approved RoActemra® in Patients with 
Moderately to Severely Active Rheumatoid Arthritis 
(APTURA I study) 
Protocol Version No. / Date: 
Version 3.0 / 01 February 2021 and local Czech v3.1 / 08 
February 2022 
Version 2.0 (incorporating Global Amendment 1 - 
Substantial) 06 May 2020  
Version 1.0/ 12 February 2020  
 
 
 
CRF Version No. / Date: 
8.0 / 28 March 2022 
SAP Version No. / Date: 
Final 2.0 / 15 June 2022 
 
 
 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
CONFIDENTIAL INFORMATION 
 
 
  
 2 / 61 
 
 
 
 Approvals 
Sponsor 
Sponsor Name: 
Fresenius Kabi SwissBioSim GmbH 
Representative / 
Title: 
 
Signature / Date: 
 
 
Representative / 
Title: 
 
 
Signature / Date: 
 
 
Representative / 
Title: 
 
Signature / Date: 
 
 
Representative / 
Title: 
 
 
Signature / Date: 
 
 
 
Biostatistician / 
Title: 
 
Signature / Date: 
 
 
Biostatistician / 
Title: 
 
Signature / Date: 
 
 
 
 






FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
CONFIDENTIAL INFORMATION 
 
 
  
 3 / 61 
 
 
 
 Change History 
Version / Date 
Change Log 
Final Draft 1.0 / 30Dec2020 
Draft submitted for review by Health Authorities  
Draft 1.2/ 15Sep2021 
Draft 
Draft 1.3/ 12Nov2021 
Draft 
Final 1.1/ 13DEC2021 
Final SAP prior to Week 30 Database Lock 
Final 2.0/ 15Jun2022 
Final SAP prior to Week 55 Database Lock 
 
 
 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
CONFIDENTIAL INFORMATION 
 
 
  
 4 / 61 
 
 
 
 Table of Contents 
 Approvals .............................................................................................................................................. 2 
 Change History ..................................................................................................................................... 3 
 Table of Contents .................................................................................................................................. 4 
 Purpose................................................................................................................................................. 6 
 Scope .................................................................................................................................................... 6 
 Introduction ........................................................................................................................................... 6 
6.1 Changes from Protocol .................................................................................................................. 6 
 Study Objectives ................................................................................................................................... 7 
7.1 Primary .......................................................................................................................................... 7 
7.2 Secondary ...................................................................................................................................... 7 
7.3 Exploratory ..................................................................................................................................... 7 
 Study Design ......................................................................................................................................... 7 
8.1 Sample Size Considerations .......................................................................................................... 9 
8.1.1 Background Information ....................................................................................................... 9 
8.1.2 Sample Size Information .................................................................................................... 10 
8.2 Randomization ............................................................................................................................. 11 
 Study Estimands ................................................................................................................................. 11 
9.1 Efficacy Estimands and their Attributes ........................................................................................ 11 
9.1.1 Primary and Associated Supportive Estimands ................................................................. 13 
9.1.2 Key Secondary and Associated Supportive Estimands ..................................................... 15 
9.1.3 Early efficacy (Week 12) Estimands .................................................................................. 16 
9.1.4 Summary of Intercurrent Events ........................................................................................ 17 
9.2 Analysis Sets ............................................................................................................................... 18 
9.2.1 Study Periods..................................................................................................................... 18 
9.2.2 Intent-to-Treat Analysis Set ............................................................................................... 19 
9.2.3 Per Protocol Analysis Set .................................................................................................. 19 
9.2.4 Safety Analysis Set ............................................................................................................ 20 
9.2.5 Pharmacokinetic Analysis Set ............................................................................................ 20 
9.2.6 Summary ........................................................................................................................... 21 
 Conventions and Standards .............................................................................................................. 22 
10.1 Baseline and Change from Baseline .......................................................................................... 22 
10.2 Study Day .................................................................................................................................. 22 
10.3 Reporting Time Points ............................................................................................................... 22 
10.4 Windows .................................................................................................................................... 23 
10.5 Efficacy Measurements .............................................................................................................. 24 
10.5.1 DAS28-ESR ..................................................................................................................... 24 
10.5.2 DAS28-CRP ..................................................................................................................... 24 
10.5.3 ACR20/50/70 ................................................................................................................... 25 
10.5.4 Simplified Disease Activity Index ..................................................................................... 26 
10.5.5 Clinical Disease Activity Index ......................................................................................... 26 
10.6 Handling of Missing Dates ......................................................................................................... 27 
 Interim Analyses ............................................................................................................................... 28 
 Statistical Methods ............................................................................................................................ 28 
12.1 Patient Disposition ..................................................................................................................... 29 
12.2 Demographic and Baseline Characteristics ............................................................................... 29 
12.3 Treatments ................................................................................................................................. 30 
12.3.1 Extent of Study Drug Exposure ........................................................................................ 30 
12.3.2 Concomitant Medications and Procedures ...................................................................... 31 
12.4 Major Protocol Deviations .......................................................................................................... 31 
12.5 Efficacy Analyses ....................................................................................................................... 32 
12.5.1 Study Hypotheses ............................................................................................................ 32 
12.5.2 Hypothesis Testing Strategy and Multiplicity .................................................................... 33 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
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12.5.3 Time to Intercurrent Events .............................................................................................. 33 
12.5.4 Primary Estimand 1.0 (DAS28-ESR ITT) ......................................................................... 33 
12.5.5 Key Secondary Estimand ................................................................................................. 36 
12.5.6 Secondary Estimand 3.0 .................................................................................................. 38 
12.5.7 Subgroup Analyses .......................................................................................................... 39 
12.5.8 Secondary Analyses ........................................................................................................ 39 
12.5.9 Other Efficacy Analyses ................................................................................................... 40 
12.6 Immunogenicity and Pharmacokinetic Analyses ........................................................................ 41 
12.6.1 Antidrug Antibody Incidence Rate, Antidrug Antibody Titer, NAb Incidence Rate ............ 41 
12.6.2 Trough Concentration ...................................................................................................... 42 
12.7 Safety Analyses ......................................................................................................................... 43 
12.7.1 Adverse Events ................................................................................................................ 43 
12.7.2 Deaths and Serious Adverse Events ............................................................................... 45 
12.7.3 Laboratory Data ............................................................................................................... 46 
12.7.4 Vital Signs ........................................................................................................................ 46 
12.7.5 Physical Examinations, Electrocardiograms, and Other Observations Related to Safety 47 
 References ........................................................................................................................................ 48 
 Glossary of Abbreviations ................................................................................................................. 49 
Appendix ................................................................................................................................................... 51 
 Additional Conventions, Standards, Derivations and Definitions ....................................................... 51 
15.1 Timepoints and Windows ........................................................................................................... 51 
15.1.1 Study Days, Weeks, Visits, Incomplete Dates and Treatment-Emergent Adverse Events 
Definition ..................................................................................................................................... 51 
15.1.2 Baseline Visit Value ......................................................................................................... 53 
15.1.3 Core Period definition ...................................................................................................... 53 
15.1.4 Extended Period Definition .............................................................................................. 53 
15.2 Data Cut-off at W30 ................................................................................................................... 54 
15.3 Data Cut-off at W55 ................................................................................................................... 54 
15.4 Descriptive Statistics .................................................................................................................. 55 
15.4.1 Precision of Decimal Numbers for Additional Summary statistics .................................... 55 
15.4.2 Aligned Bar Charts ........................................................................................................... 55 
15.4.3 Aligned Histograms .......................................................................................................... 55 
15.4.4 Pyramid Table .................................................................................................................. 55 
15.5 Inferential Statistics .................................................................................................................... 56 
15.5.1 Secondary analyses: Mixed-Effect Repeated Measure Models ....................................... 56 
15.5.2 Newcombe Confidence Interval ....................................................................................... 56 
15.6 Baseline Measures .................................................................................................................... 56 
15.6.1 Demographic Data not Collected Due to Local Regulations ............................................ 56 
15.7 Efficacy Measurements .............................................................................................................. 57 
15.7.1 Patient’s Global Assessment of Disease Activity ............................................................. 57 
15.7.2 Patient’s Assessment of Arthritis Pain ............................................................................. 57 
15.7.3 Physician’s Global Assessment of Disease Activity ......................................................... 57 
15.7.4 Health Assessment Questionnaire-Disability Index.......................................................... 57 
15.8 Safety Measurements ................................................................................................................ 57 
15.8.1 Definition of Adverse Events of Special Interest .............................................................. 57 
15.9 Imputation of Missing Data......................................................................................................... 57 
15.9.1 Method for Missing Individual Joint Assessments ............................................................ 58 
15.9.2 Multiple Imputation Methodology – DAS28-ESR.............................................................. 58 
15.9.3 ACR ................................................................................................................................. 59 
15.9.4 Handling of Values in Text Format ................................................................................... 60 
15.10 Pooling of results ..................................................................................................................... 61 
15.11 Laboratory NCI-CTCAE Toxicity Grades (version 5) ................................................................ 61 
15.12 In-Text Tables for CSR ............................................................................................................ 61 
 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
Sponsor: Fresenius Kabi SwissBioSim GmbH 
 
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 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Fresenius Kabi SwissBioSim GmbH Protocol 
FKS456-001.This SAP describes all analyses planned to be included in the Week 30 clinical 
study report (CSR), Week 55 CSR, and Week 63 CSR Addendum. 
For details of the data included in the Week 30 CSR please see the Week 30 Data Cut Plan 
which is a separate document. 
 Scope 
The SAP outlines the following: 
• Study Objectives 
• Study Design 
• Study Estimands 
• Applicable Study Definitions 
• Statistical Methods 
 Introduction 
This SAP should be read in conjunction with the study protocol (current version: Version 3.0 / 
01 February 2021 and local Czech v3.1 / 08 February 2022), case report form (CRF) (current 
version: 8.0 dated 28-Mar-2022) and the Data Access Plan (current version: Version 2.0 dated 08 
December 2021). Any changes to the protocol or CRF may necessitate updates to the SAP. 
The SAP will be approved (by the Sponsor and 
) at two timepoints.  The first 
prior to W30 database lock and the second timepoint prior to W55 database lock.  For W63 
(safety follow-up) database lock, if further updates are needed, it will again be approved.  
Unblinding of study treatment codes to the unblinded team are defined in the Data Access Plan. 
6.1 Changes from Protocol 
Changes in study setup from protocol: 
• Active/latent tuberculosis will only be listed if at least one case is reported. 
Sub study post-dose PK concentrations analysis will not be conducted due to low recruitment 
during Covid-19 pandemic. Only listings will be provided.  
• Correction has been made to the null hypothesis of the primary analysis stated in the protocol 
as H0: (µT - µR) ≤ -0.6 or (µT - µR) ≥ 0.5. This has been updated to H0: (µT - µR) < -0.6 or (µT - µR) 
> 0.5 .  
 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
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 Study Objectives 
7.1 Primary 
The primary objective of the study is to demonstrate equivalent efficacy of proposed biosimilar 
tocilizumab MSB11456 and EU--approved RoActemra (both administered subcutaneously) in 
patients with moderately to severely active rheumatoid arthritis (RA). 
7.2 Secondary 
The secondary objective of the study is to compare the safety, immunogenicity and long-term 
efficacy of MSB11456 to EU--approved RoActemra. 
7.3 Exploratory 
The exploratory objectives of the study are:  
• To explore the effects of a single treatment transition (i.e., in patients who transitioned 
from EU--approved RoActemra to MSB11456) on efficacy, safety and immunogenicity 
and  
• To describe pharmacokinetic (PK) parameters of MSB11456 and EU-approved 
RoActemra 
 Study Design 
This is a multicenter, randomized (1:1), active-controlled, double-blind, multiple fixed-dose, 
multinational, two-arm, parallel-group study to compare the efficacy, safety and immunogenicity 
of the proposed biosimilar candidate MSB11456 versus EU-approved RoActemra (hereinafter 
referred to as “EU-RoActemra” only) in patients with moderately to severely active RA. In a 
separate sub-study, the population pharmacokinetics of MSB11456 and EU-RoActemra will be 
described. 
This study will enroll patients with moderately to severely active RA who have an inadequate 
response to ≥ 1 disease-modifying anti-rheumatic drug(s) which may include biologic 
disease--modifying anti-rheumatic drugs and who are currently receiving a stable dose of 
methotrexate. Patients who have previously received 1 or 2 biologic treatments in total for RA 
may be allowed to participate in the study. However, the population of patients with previous 
exposure to any biologic treatment will be capped at 10% of the total study population. Patients 
who have previously received more than 2 biologic treatments for RA will not be permitted to 
participate in the study. 
Patients must have received methotrexate for at least 12 consecutive weeks immediately prior to 
randomization and are on a stable dose between 10 and 25 mg / week methotrexate for the last 
8 weeks prior to screening. Patients will continue to take the same stable dose of methotrexate 
during the 52-week treatment period of the study. All other disease-modifying- anti-rheumatic 
drugs must be withdrawn prior to randomization.  


FKS456-001  
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MSB11456  
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The study will have a duration of up to 67 weeks and will include a Screening Period of a maximum 
of 28 days prior to first study drug administration, a double-blind 24-week Core Treatment Period 
(Day 1 to Day 169 / W24), an additional 28-week double-blind Extended Treatment Period 
(Day 169 / W24 to Day 365 / W52) and a 12-week Safety Evaluation Period. A Safety Follow-Up 
Visit will be performed at W55, 4 weeks after the last dose of study drug at W51 and a final End 
of Study Visit will be conducted at W63, 12 weeks after the last dose of study drug at W51. 
(Note: The 12-week Safety Evaluation starts at W51, after the last study drug injection and the 
Extended Treatment Period ends at W52.) The end of the study for each patient is defined as the 
patient’s last visit.  
Patients whose eligibility is confirmed at baseline will be randomized in a 1:1 ratio by an 
Interactive Response Technology (IRT) system to receive either MSB11456 or EU-RoActemra at 
a dose of 162 mg delivered by subcutaneous injection starting at Day 1, then weekly up to W51 
inclusive. Randomization will be stratified by previous exposure to biologic treatment for RA 
[yes/no]. 
The first 3 doses of study drug (162 mg at Day 1, Day 8 and Day 15) will be administered on-site. 
The subsequent 2 doses (on Day 22 and Day 29) will also be administered on-site in the Czech 
Republic only. Patients will be monitored for 2 hours following the on-site administrations of study 
drug. The following weekly doses of study drug can be self--administered if the patient is able to 
self-administer him / herself at the discretion of the Investigator. Patients will check their axillary 
temperature prior to the self-administration of study drug. In the case of an elevated temperature, 
it is the Investigator’s decision to determine any further actions according to local practice and 
their medical judgment.  
The primary efficacy endpoint will be evaluated at W24 (7 days after the 24th study drug 
administration), along with other endpoints. At W24, after all efficacy and safety assessments have 
been performed, patients will enter the Extended Treatment Period. Patients who were originally 
randomized to receive EU-RoActemra will be re-randomized in a 1:1 ratio to continue their weekly 
treatment with EU-RoActemra or to switch to MSB11456 starting at W24. Patients who were 
originally randomized to MSB11456 will continue this treatment for the complete 52 weeks of 
study treatment. During the Extended Treatment Period, efficacy, safety and immunogenicity data 
will be analyzed up to W52 with the last assessment performed 7 days after the last study drug 
administration (i.e., on W51). 
Safety data will be collected and analyzed at W55 and W63 (i.e., 4 and 12 weeks after the last 
study drug administration, respectively). Samples for immunogenicity analysis will be collected 
at W55. 
In order to minimize missing data in the evaluation of the treatment effect under the treatment 
policy strategy, patients who discontinue treatment early or violate the protocol should continue 
to be followed for all regularly scheduled visits for safety and efficacy assessments up to the end 
of the corresponding treatment period.  
Pharmacokinetic trough concentration samples will be collected from all study patients at 
scheduled visits. 


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Patients may be asked to participate in a population PK sub-study performed during the 24-week 
Core Treatment Period (Day 1 to Day 169 / W24) and contribute additional PK samples. 
Participation in the population PK sub-study is optional. 
A Data Monitoring Committee or Data Safety Monitoring Board will not be involved in this study. 
8.1 Sample Size Considerations 
8.1.1 Background Information 
In the absence of innovator studies comparing the weekly subcutaneous dosing regimen versus 
placebo, the dataset used to build the statistical assumptions has been extrapolated from the pivotal 
studies with the intravenous presentation. The subcutaneous 162 mg weekly regimen was shown 
to have comparable efficacy and safety to the intravenous presentation at a dose of 8 mg / kg every 
4 weeks (Burmester, 2014). 
In order to be in line with both the European Medicines Agency (EMA) and the Food and Drug 
Administration (FDA) requirements, different acceptance margins are predefined for the primary 
endpoint mean absolute change from baseline in Disease Activity Score 28-Erythrocyte 
Sedimentation Rate (DAS28-ESR) at W24.  
Equivalence margins of ± 0.6, correspond to the retention of approximately 65% of conservative 
estimates of treatment effect sizes relative to placebo for EU-RoActemra, based on the upper 
bound of 95% confidence interval from a meta-analysis performed by the Sponsor. The meta-
analysis was performed using the following publications Genovese, 2008; Smolen, 2008; Kremer, 
2011; Emery, 2008. The equivalence margins defined respectively for FDA and EMA are specified 
below: 
• For the FDA, the equivalence margins are set to [- 0.6, 0.5]. The FDA has recommended a 
stricter margin using 0.5 as the upper bound (FDA electronic correspondence 
19 October 2016). To help with the study feasibility the lower bound is set to - 0.6. A change 
of 0.6 in favor of MSB11456 is seen as a non-clinically significant difference as long as the 
safety and immunogenicity profile of MSB11456 demonstrates no more risk than EU-
RoActemra 
• For the EMA, the equivalence margins are set to ± 0.6 
The primary efficacy analysis is the change from baseline at W24 in DAS28-ESR which will be 
analyzed using an analysis of covariance with study drug and previous exposure to biologic 
treatment for RA [yes/no] stratum as fixed effects and baseline DAS28-ESR as a covariate. The 
difference between treatments is estimated by the least squares mean difference between 
MSB11456 and EU-RoActemra, with its 95% confidence interval for the EMA and its 90% 
confidence interval for the FDA. 
• For the FDA: MSB11456 will be considered equivalent to EU-RoActemra if the 90% 
confidence interval for the difference in mean change from baseline to W24 in DAS28-ESR 
between MSB11456 and EU-RoActemra lies entirely within the equivalence interval of 
[- 0.6, 0.5] in the Intent-To-Treat (ITT) Analysis Set 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
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• For the EMA: MSB11456 will be considered equivalent to EU-RoActemra if the 95 % 
confidence interval for the difference in mean change from baseline to W24 in DAS28-ESR 
between MSB11456 and EU-RoActemra lies entirely within the equivalence interval of [-0.6, 
0.6] in the ITT Analysis Set 
Specificities of Secondary Efficacy Endpoint “ACR20 at W24”: The treatment difference in 
American College of Rheumatology (ACR)20 at W24 will be assessed versus predefined margins. 
The equivalence margins are set to ± 15%. These proposed equivalence margins correspond to 
50% retention of conservative estimates of the effect size of EU-RoActemra relative to placebo 
(derived from Genovese, 2008; Smolen, 2008; Kremer, 2011; Emery, 2008 using meta-analysis). 
The primary and key secondary analyses will be performed on the ITT Analysis Set and repeated 
on the Per Protocol (PP) Analysis Set. 
8.1.2 Sample Size Information 
A sample size of 542 randomized patients (271 patients per arm) is chosen to provide 
approximately 460 patients (230 per arm) in the PP Analysis Set at W24, assuming a 15% drop-
out rate (including major protocol deviations).  
For the FDA: 
• A total of 460 evaluable patients (230 per arm) will provide 90% power to demonstrate 
equivalence between treatments for the primary endpoint, with equivalence margins of 
[- 0.6, 0.5] and a type I error of 5%, assuming no difference between the 2 treatment groups 
and a common standard deviation of 1.76 (derived from Genovese, 2008; Smolen, 2008; 
Kremer, 2011). 
For the EMA: 
• A total of 460 evaluable patients (230 per arm) will provide 90% power to demonstrate 
equivalence between treatments for the primary endpoint, with equivalence margins of 
± 0.6 and a type I error of 2.5%, assuming no difference between the 2 treatment groups 
and a common standard deviation of 1.76. 
• In addition, this sample size provides more than 80% power to demonstrate that the 95% 
confidence interval for the difference between treatments in the secondary efficacy 
endpoint ACR20 response rate at W24 will be included in the equivalence interval 
[- 15 %, + 15 %], assuming no difference between the 2 treatment groups and that both 
MSB11456 and EU-RoActemra have an ACR20 response rate of 60% at W24 (Genovese, 
2008; Smolen, 2008; Kremer, 2011). 
The drop-out/protocol deviation rate will be monitored on blinded data throughout the first 
24 weeks. If larger than anticipated (> 15 %), an investigation on the reasons for dropping out will 
be conducted. The number of randomized patients may be adjusted as a consequence.  With the 
exception of a potential increase in subjects in safety and ITT analysis sets, this blinded monitoring 
does not impact ITT or PP allocation. 
The sample size for the population PK sub-study will be a subset of approximately 30 patients per 
group, for a total of 60 patients (to ensure that approximately 50 patients complete the PK sub-
study). 


FKS456-001  
Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
Version Date: 15-June-2022 
 
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8.2 Randomization 
Randomization will be performed via a centralized IRT system. Eligible patients will be randomly 
assigned to either MSB11456 or EU-RoActemra in a 1:1 ratio, stratified by previous exposure to 
biological treatment for RA [yes/no], which is a prognostic factor (Strata for geographical region 
were planned in the IRT tool as well according to the study protocol, but all subjects will be 
randomized in the same European stratum.) 
Patients with previous exposure to any biologic treatment will be capped at 10% of the total study 
population.  
Randomization will be conducted in permuted blocks. 
Although the randomization is stratified,
 created only 1 random list that incorporates 
all strata. To ensure a balanced randomization the system will only assign full blocks to 
each stratum combination. 
At the W24 Visit, patients who were initially randomized to the EU-RoActemra group will be 
re-randomized in a 1:1 ratio to receive either MSB11456 or EU-RoActemra at the W24 Visit and 
weekly thereafter until W51. Re-randomization will use the same stratification factors as the 
original randomization. Patients who were initially randomized to the MSB11456 group will 
remain on weekly treatment with MSB11456 throughout the entire study. Patients who discontinue 
study drug before or at W24 will not be re-randomized at W24 and will discontinue the study. 
As the existence of a re-randomization number will unblind the reader to the patient’s treatment in 
the Core Treatment Period the re-randomization number will remain invisible to IRT users. As the 
nature of the random number might reveal details on the block size this is also not visible to IRT 
users. Patients will be identified by their screening numbers.   
Although only patients randomized to EU-RoActemra during the Core Period will be re-
randomized, in order to preserve the blind, it will appear that all patients have been re-randomized.  
Re-randomization will be silent, i.e., the re-randomization step will be hidden on the end user 
system. Hence, re-randomization will not impact the double-blind nature of the study as blinding 
will be kept.  
 Study Estimands 
This section describes the primary and secondary estimands, their attributes, and the proposed 
strategy to address the specified intercurrent events.  The estimands described in this SAP, 
although not defined in the protocol, are based on the planned objectives, endpoints, and analysis 
sets from the protocol. For data not collected (missing) or excluded from the assessment of a given 
estimand (e.g. hypothetical strategy after the onset of an intercurrent event), specific data 
imputation rules are defined in Section 12.5.  
9.1 Efficacy Estimands and their Attributes 
The following intercurrent events will be considered for the definition of the estimands in the core 
period; 
 


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1. Treatment discontinuation or interruption due to Adverse Events with a compliance of < 
80%: This includes subjects with either of the following two scenarios. 
Scenario 1 
AE record of: dose interruption or dose withdrawal.  
Scenario 2 
Disposition page record of discontinuation due to AE.  
2. Treatment discontinuation due to Lack of Efficacy: This includes subjects with a record of 
discontinuations due to lack of efficacy in the disposition page. 
3. Treatment discontinuation due to any other reason: This includes all discontinuations due 
to reasons other than those in 1) and 2) and also includes treatment interruptions or 
withdrawal due to adverse events as reported in AE page and treatment discontinuation as 
reported in disposition page but with a compliance of ≥ 80%.  
4. Prohibited medications: Prohibited medications (as defined in protocol) will be determined 
using the protocol deviation log by the medical team. In the determination of prohibited 
medications, COVID-19 related vaccinations will not be considered as a prohibited 
medication. 
5. Dose modification of Methotrexate: Subjects with a dose modification of Methotrexate will 
be determined by the medical team with the use of the Concomitant Medication dataset. 
Only Methotrexate used post baseline will be considered.  
6. COVID-19 vaccination: COVID-19 vaccination will be considered as a separate potential 
intercurrent event. Subjects with COVID-19 vaccinations will be determined 
programmatically with the use of the concomitant medication dataset. Only COVID-19 
vaccinations on or after first treatment date will be considered. 
 




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Statistical Analysis Plan (SAP) Final 2.0  
MSB11456  
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• 
Population of interest: Patients with moderately to severely active RA who were randomized: ITT 
Analysis Set  
• 
Variable / endpoint of interest: Absolute change from baseline at W24 for Disease Activity Score 
28-Erythrocyte Sedimentation Rate (DAS28-ESR) 
• 
Potential intercurrent events / strategy to address: 
o 
Treatment discontinuation or interruption prior to W24 
▪ 
Due to lack of efficacy or due to Adverse Event (AE) / hypothetical strategy 
▪ 
Due to any other reason / treatment policy strategy 
o 
Use of prohibited medication or change in permitted medications (other than Methotrexate) 
with the potential to impact W24 efficacy assessments / hypothetical strategy 
o 
Modification in Methotrexate, with the potential to impact W24 efficacy assessments/ 
hypothetical strategy 
o 
Covid-19 vaccination prior to W24 / treatment policy strategy 
• 
Population level summary: Difference between treatment groups on mean absolute change from baseline 
at W24 
This estimand targets the effect of treatment on the variable measurement in the target population should the 
patient who discontinued treatment due to study related events (lack of efficacy or AE) or took prohibited 
medication or had any dose modification would no longer benefit from treatment and measurements are projected 
as a worst case scenario as if the patient DAS28-ESR value returns to baseline levels immediately after the time 
of the intercurrent event (‘hypothetical’ strategy). For other intercurrent events a treatment policy strategy is 
followed.  
 
Supportive Estimand 1.3 (DAS28-ESR Hypothetical continuing per protocol ITT) 
• 
Treatment of interest: Subcutaneous injection of MSB11456 compared to EU-RoActemra 
• 
Population of interest: Patients with moderately to severely active RA who were randomized: ITT 
Analysis set.  
• 
Variable / endpoint of interest: Absolute change from baseline at W24 for Disease Activity Score 
28-Erythrocyte Sedimentation Rate (DAS28-ESR) 
• 
Potential intercurrent events / strategy to address: 
o 
Treatment discontinuation or interruption prior to W24 
▪ 
Due to lack of efficacy or due to Adverse Event (AE) / hypothetical strategy 
▪ 
Due to any other reason / hypothetical strategy 
o 
Use of prohibited medication with the potential to impact W24 efficacy assessments / 
hypothetical strategy 
o 
New or modification in permitted medications for management of the underlying disease, with 
the potential to impact W24 efficacy assessments/ hypothetical strategy 
o 
Covid-19 vaccination prior to W24 / treatment policy strategy 
• 
Population level summary: Difference between treatment groups on mean absolute change from baseline 
at W24. 
This estimand targets the effect of treatment on the variable measurement in the target population should the 
patient did not discontinued treatment for any reason and should the patient did not have taken prohibited 




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Statistical Analysis Plan (SAP) Final 2.0  
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• 
Population of interest: Patients with moderately to severely active RA who were randomized: ITT Analysis 
Set 
• 
Variable / endpoint of interest: ACR20 response at W24 
• 
Potential intercurrent events / strategy to address: 
o 
Treatment discontinuation prior to W24 
▪ 
Due to lack of efficacy or due to AE / hypothetical strategy 
▪ 
Due to any other reason / treatment policy strategy 
o 
Use of prohibited medication or change in permitted medications (other than Methotrexate) with the 
potential to impact W24 efficacy assessments / hypothetical strategy 
o 
Modification in Methotrexate, with the potential to impact W24 efficacy assessments/ hypothetical 
strategy 
o 
Covid-19 vaccination prior to W24 / treatment policy strategy 
 
• 
Population level summary: Difference between treatment groups on ACR20 response rate at W24 
This estimand targets the effect of treatment on the variable measurement in the target population should the patient 
who discontinued treatment due to study related events (lack of efficacy or AE) or took prohibited medication or had 
any dose modification would no longer benefit from treatment and measurements are projected as a worst case 
scenario as if the patient ACR20 is considered as non-responder immediately after the time of the intercurrent event ( 
‘hypothetical’ strategy). For other intercurrent events a treatment policy strategy is followed. 
 
 
 
9.1.3 Early efficacy (Week 12) Estimands 
 
The following estimands will be constructed based on DAS28-ESR at week 12; 
• 
Supportive Estimand 3.0 (Early DAS28-ESR ITT) will have the same attributes as Primary Estimand 1.0, 
except that week 24 (W24) will be replaced by Week 12 (W12) in all relevant attributes’ description. 
• 
Supportive Estimand 3.1 (Early DAS28-ESR PP) will have the same attributes as Supportive Estimand 1.1, 
except that W24 will be replaced by W12 in all relevant attributes’ description. 
• 
Supportive Estimand 3.2 (Early DAS28-ESR Hypothetical Continuing Per Protocol ITT) will have the same 
attributes as Supportive Estimand 1.3, except that W24 will be replaced by W12 in all relevant attributes’ 
description. 
 
 






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• The Week 12 Period is a subset of the Core Period. It begins on the day of initial 
randomization (Day 1) and includes assessments performed not later than W12 analysis visit 
(see Section 10.4). Data summaries for this period will be presented by Week 12 treatment 
group – MSB11456 and EU-RoActemra – and overall, when applicable.  
9.2.2 Intent-to-Treat Analysis Set 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to their 
randomized treatment. 
In the Extended Period (EP), the EP-ITT Analysis Set includes all patients who are re-randomized 
into the Extended Period. Patients will be analyzed according to their randomized treatment group; 
for patients initially randomized to EU-RoActemra, this will include both their initial and re-
randomization assignment. Subjects who are re-randomized but not dosed afterwards will have no 
data contributing to the Extended Period apart from the extended baseline data. 
9.2.3 Per Protocol Analysis Set 
In the Core Period, the PP Analysis Set includes all randomized and treated patients (hence a 
subgroup of the ITT Analysis Set) who completed the Core Period: attended the Week 24 visit 
with no clinically important protocol deviations before the primary efficacy endpoint analysis time 
point (W24) and who have a treatment compliance of ≥ 80% (including Methotrexate compliance) 
in the Core Treatment Period (refer to Section 12.3.1 for a definition of treatment compliance). A 
clinically important protocol deviation is a major protocol deviation likely to affect the efficacy of 
treatment. Patients will be analyzed according to their randomized and received treatment, as 
receipt of a different treatment from that assigned is a clinically important protocol deviation. 
Methotrexate compliance will be determined by the clinical team prior to W30 database lock and 
W55 database lock. Since Methotrexate detailed dosing data is not captured in the case report 
forms, the medical team will review concomitant medication data and flag subjects with 
Methotrexate compliance of less 80% prior to Week 12 and Week 24 for the W30 and W55 CSR, 
before unblinding. 
In the Week 12 Period, the W12-PP (Week 12 Per Protocol) Analysis Set includes all randomized 
and treated patients who attended the W12 visit, with no clinically important protocol deviations 
before Week 12 visit and who have a treatment compliance of ≥ 80% (including Methotrexate 
compliance) up to week 12 visit. 
In the Extended Period, the EP-PP Analysis Set includes all re-randomized and treated patients 
(hence a subgroup of the EP-ITT Analysis Set) who do not have any clinically important protocol 
deviations before W52 and who have a treatment compliance of ≥ 80% (including Methotrexate 
compliance) in both the Core Treatment Period and in the Extended Treatment Period. This is not 
applicable to the W30 CSR. Patients will be analyzed according to their randomized and received 
treatment after re-randomization, as receipt of a different treatment from that assigned is a 
clinically important protocol deviation.  
For the overall Period, an Overall PP Analysis set includes all randomized and treated patients 
who do not have any clinically important protocol deviations before W52 and who have a treatment 
compliance of ≥ 80% (including Methotrexate compliance) in both the Core Treatment Period and 


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in the Extended Treatment Period. The EP-PP Analysis Set and the Overall PP Analysis Set are 
the same.  Patients will be presented by treatment group after re-randomization.  For patients who 
were not re-randomized, they will be presented by treatment group according to initial 
randomization. 
Any subject that receives an incorrect treatment during the study will be excluded from the PP 
analysis set corresponding to the period in which the error took place. 
9.2.4 Safety Analysis Set 
The Safety Analysis (SAF) Set includes all patients who receive at least 1 dose of study drug 
(MBS11456 or EU-RoActemra) during the Core Treatment Period. Patients will be analyzed 
according to the actual treatment they receive.  
In the Extended Period, the EP-SAF Set includes all patients who receive at least 1 dose of study 
drug (MBS11456 or EU-RoActemra) during the course of the Extended Treatment Period. Patients 
will be analyzed according to the actual treatment they receive.   
Should a subject be assigned multiple treatments by error (both MSB11456 and EU-RoEctemra) 
after randomization or re-randomization, the treatment assigned the majority of times will be used 
as the actual treatment. 
9.2.5 Pharmacokinetic Analysis Set 
The PK Analysis Set includes all treated patients who have at least 1 measurement of trough 
concentration in the Core Period and without major protocol deviations impacting 
pharmacokinetics during the Core Treatment Period. The protocol deviations that impact 
pharmacokinetics data will be flagged by the clinical team in the protocol deviation log. 
In the Extended Period, the EP-PK Analysis Set includes all patients who have at least 1 
measurement of trough concentration during the Extended Period and without major protocol 
deviations impacting pharmacokinetics until (and including) W52. 
For the overall period, an Overall PK Analysis Set includes all subjects having at least one 
measurement of trough concentration during the study without major protocol deviations 
impacting pharmacokinetics during the treatment period. Patients will be presented by treatment 
group after re-randomization.  For patients who were not re-randomized, they will be presented by 
treatment group according to initial randomization. 
Patients will be analyzed according to the actual treatment they receive.  
 




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 Conventions and Standards 
Irrespective of being explicitly mentioned, all data collected on the eCRF will be presented in data 
listings. In those listings that are displayed by treatment group all patients who have started the 
Core Period on MSB11456 will be found in the MSB11456 section. Patients who have been on 
EU-RoActemra in the Core Period and have been re-randomized to MSB11456 will be found in 
the EU-RoActemra/MSB11456 section. Patients who have started the Core Period on EU-
RoActemra and have either discontinued before re-randomization or have been re-randomized to 
EU-RoActemra will be found in the EU-RoActemra section. 
An in-depth compendium on further conventions, standards, derivations and definitions can be 
found in the appendix. 
10.1 Baseline and Change from Baseline 
Unless stated otherwise, for each endpoint of interest, the baseline is defined as the last 
non-missing assessment taken prior to randomization and the first dose of study drug. In cases 
where baseline assessments are taken on the same day as the first dose of study drug and no times 
are reported, it will be assumed that these assessments are taken prior to study drug being 
administered. For patients who are randomized but not dosed after randomization, the baseline is 
defined as the last non-missing assessment prior to or on the date of randomization.  
Change from baseline is defined as (value at post-baseline visit – value at baseline). 
For analyses performed on some safety data in the Extended Period, baseline will be reset as the 
last non-missing assessment prior to or on the W24 treatment. This will be referred to as “extended 
baseline” to distinguish from the Core Period baseline described above.  
10.2 Study Day  
The first day of study drug administration is defined as Day 1.  In this study, the first study drug 
administration occurs on the day of randomization. For patients who are randomized but not dosed 
after randomization, Day 1 is defined only as the randomization date. 
Study day is defined as the number of days from Day 1, with the day prior to Day 1 defined as 
Day -1. 
• Before Day 1: Study Day = (Date of interest – Date of Day 1) 
• 
On or after Day 1: Study Day = (Date of interest – Date of Day 1) + 1 
10.3 Reporting Time Points  
There will be 3 analysis and reporting time points in the study: 
• W30 CSR: The primary efficacy analysis at W24 will be conducted after all patients have 
completed the W30 assessments or have terminated the study before W30. The report will 
include all data up to and including data from the W30 Visit. Extended period will not be 
completed for all subjects at this time, and hence the Extended Period PP cannot be defined 
for the W30 CSR. Refer to the Data Access Plan for further details regarding unblinding in 
the context of the W30 CSR. 




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10.5 Efficacy Measurements 
10.5.1 DAS28-ESR 
The DAS28-ESR is a measure of disease activity in 28 joints that consists of a composite numerical 
score of the following variables: Tender Joint Count, Swollen Joint Count, erythrocyte 
sedimentation rate and Patient’s Global Assessment of Disease Activity. DAS28-ESR will be 
derived using the following formula: 
DAS28_ESR = 0.56*√TJC28+0.28*√SJC28+0.014*GH+0.7* ln(ESR) 
Note: If ESR=0 then ESR=1 will be used for DAS28ESR derivation. It is clinically justified to 
carry out this imputation because an ESR value of 0 or 1 represents negligible inflammation. 
Where: 
• TJC28 = 28 joint count for tenderness 
• SJC28 = 28 joint count for swelling 
• ln(ESR) = natural logarithm of erythrocyte sedimentation rate [mm/hr] 
• GH = the general health component of the DAS (i.e., Patient’s Global Assessment of 
Disease Activity on a scale of 1 to 100 where 100 is maximal activity) 
The level of disease activity will be categorized as follows: 
• Remission: DAS28-ESR < 2.6 
• Low: 2.6 ≤ DAS28-ESR < 3.2 
• Moderate: 3.2 ≤ DAS28-ESR ≤ 5.1 
• High: DAS28-ESR > 5.1 
The imputation method for missing individual joint assessments is explained in Section 15.9.1 in 
the appendix. 
10.5.2 DAS28-CRP 
The Disease Activity Score 28-C-reactive protein (DAS28-CRP) is a measure of disease activity 
in 28 joints that consist of a composite numerical score of the following variables: Tender Joint 
Count, Swollen Joint Count, C-reactive protein and Patient’s Global Health Assessment of Disease 
Activity. 
DAS28_CRP = 0.56*√TJC28+0.28*√SJC28+0.014*GH+0.36* ln(CRP+1) +0.96 


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Note: CRP values below the LoQ (<0.3) will be imputed using the LLoQ. 
Where: 
• TJC28 = 28 joint count for tenderness 
• SJC28 = 28 joint count for swelling 
• CRP = C-reactive protein [mg/L] 
• GH = General Health of the DAS (i.e., Patient’s Global Assessment of Disease Activity 
on a scale of 1 to 100 where 100 is maximal activity) 
A patient will be further classified as a responder using The European League Against Rheumatism 
(EULAR) Boolean-based response criteria definition: 
At any timepoint, a patient must satisfy all of the following: 
• Tender joint count 28 ≤1 
• Swollen joint count 28≤1 
• C-reactive protein ≤1 mg/dL 
• Patient Global Assessment ≤1 (on a 0-10 scale) 
The imputation method for missing individual joint assessments is explained in Section 15.9.1 in 
the appendix. 
10.5.3 ACR20/50/70 
The ACR20 is an efficacy measure for which a patient must have at least 20 % improvement in 
the following ACR Core Set values: 
• Tender Joint Count (68 joint count) 
• Swollen Joint Count (66 joint count) 
• An improvement of at least 20 % in at least 3 of the following 5 assessments: 
o Patient’s Global Assessment of Disease Activity 
o Patient’s Assessment of Arthritis Pain 
o Patient’s Assessment of Physical Function as measured by the Health Assessment 
Questionnaire-Disability Index 
o Physician’s Global Assessment of Disease Activity 
o Acute phase reactant as measured by erythrocyte sedimentation rate or C-reactive 
protein 
ACR50 = 50 % improvement in at least 3 of the 5 measures and 50 % improvement in the 
Swollen and Tender Joint Count. 
ACR70 = 70 % improvement in at least 3 of the 5 measures and 70 % improvement in the 
Swollen and Tender Joint Count. 
The imputation method for missing individual joint assessments is explained in Section 15.9.1 in 
the appendix. 


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10.5.4 Simplified Disease Activity Index 
The Simple Disease Activity Index (SDAI) includes 5 items: 
• 28–Swollen Joint Count 
• 28–Tender Joint Count 
• Patient’s Global Assessment of Disease Activity on a Visual Analog Scale (0 to 10.0 scale) 
• Physician’s Global Assessment of Disease Activity on a Visual Analog Scale (0 to 10.0 
scale) 
• C-reactive protein level in mg / dL 
SDAI = SJC + TJC + PGA+ PhGA + CRP 
Since the visual analog scale used in the study is a 0 to 100 mm scale, the corresponding items will 
be divided by 10 before summing. 
The imputation method for missing individual joint assessments is explained in Section 15.9.1 in 
the appendix. 
The level of disease activity can be interpreted as: 
• Remission:  
SDAI ≤ 3.3 
• Low:        
3.3 < SDAI ≤ 11 
• Moderate:    
11 < SDAI ≤ 26 
• High:        
26 < SDAI 
10.5.5 Clinical Disease Activity Index 
The Clinical Disease Activity Index (CDAI) includes 4 items: 
• 28–Swollen Joint Count 
• 28–Tender Joint Count 
• Patient’s Global Assessment of Disease Activity on a Visual Analog Scale (0 to 10.0 scale) 
• Physician’s Global Assessment of Disease Activity on a Visual Analog Scale (0 to 10.0 
scale) 
CDAI = SJC + TJC + PGA + PhGA 
Since the visual analog scale used in the study is a 0 to 100 mm scale, the items will be divided by 
10 before summing. 
The imputation method for missing individual joint assessments is explained in Section 15.9.1 in 
the appendix. The level of disease activity can be interpreted as: 
• Remission:  
CDAI ≤ 2.8 
• Low:        
2.8 < CDAI ≤ 10 
• Moderate:    
10 < CDAI ≤ 22 
• High:        
22 < CDAI 


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10.6 Handling of Missing Dates  
In general, incomplete dates will not be imputed. If an imputation is required for analysis: 
• For dates where day only is missing, the first day of the month will be imputed for start dates 
and the last day of the month will be imputed for stop dates 
• For dates where day and month are missing, the first day of the year will be imputed for start 
dates and the last day of the year will be imputed for stop dates 
If start dates are missing or incomplete for an AE (including deaths) or medications, the following 
algorithm will be used for imputation: 
 
 
 
Start Date 
Stop Date 
Complete: yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
<1st dose 
≥1st dose 
<1st dose 
yyyymm 
≥1st dose 
yyyymm 
<1st dose 
yyyy 
≥1st dose 
yyyy 
 
 
Partial: 
yyyymm 
=1st dose 
yyyymm 
 
2 
1 
N/A 
1 
N/A 
1 
1 
≠1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
 
Partial: 
yyyy 
=1st dose 
yyyy 
 
3 
1 
 
3 
1 
N/A 
1 
1 
≠1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
 
4 
1 
4 
1 
4 
1 
1 
1=impute as the date of first dose; 2=impute as the first of the month; 3=impute as January 1 of 
the year; 4=impute as January of the stop year 
 
Imputation rules for missing or incomplete stop dates for AEs and medications: 
Initial imputation 
• For partial stop date “mmyyyy”, impute the last day of the month 
• For partial stop date “yyyy”, impute December 31 of the year 
• For completely missing stop date, do not impute 
• If the stop date imputation leads to a stop date that is after the death date, then impute the 
stop date as the death date 
• If the stop date imputation leads to a stop date that is before the start date, then there is a data 
error and do not impute the stop date 
Imputation rules for partial or missing death dates: 
• If death year and month are available but day is missing: 
o If “mmyyyy” for last contact date = “mmyyyy” for death date, set death date to the 
day after the last contact date 


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o If “mmyyyy” for last contact date < “mmyyyy” for death date, set death date to the 
first day of the death month 
o If “mmyyyy” for last contact date > “mmyyyy” for death date, data error and do not 
impute 
• If both month and day are missing for death date or a death date is totally missing, set death 
date to the day after the last contact date 
The imputed dates will be used to assess whether AEs should be considered as treatment-emergent 
and if medications should be included in the safety summaries as prior or concomitant, however 
the original partial dates will be included in data listings. 
 Interim Analyses 
An interim analysis is not planned for this study.   
As stated in Section 10.3, the primary analysis (including the primary efficacy analysis at W24) 
will be conducted after all patients have completed the W30 assessments or have terminated the 
study before W30. This analysis is considered a final analysis from a statistical perspective even 
though the study continues until W63.  
 Statistical Methods 
All analyses will use SAS version 9.4 or higher. 
The coding dictionaries available at date of first patient in are WHODRUG Dictionary Version 
WHODRUG2020MAR01_GLOBAL_B3 and MedDRA Version 23.0. For further details on 
coding dictionaries, please see the Data Management Plan and the Coding Conventions 
Specifications document. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages 
and include a missing category. Percentages will be rounded to 1 decimal place, except 100 % will 
be displayed without any decimal places and percentages will not be displayed for zero counts. 
Percentages will be based on the number of patients in the analysis set of interest (N). If the 
analysis is done by visits, percentages will be based on the number of patients still present in the 
study at the visit. 
Continuous variables will be summarized using the number of patients in the analysis set (N), 
number of observations (n), number of missing observations (N-n), mean, standard deviation (SD), 
median, minimum and maximum. The minimum and maximum values will be displayed to the 
same level of precision as the raw data; the mean and median to a further decimal place; and the 
SD to 2 additional decimal places. 
Unless otherwise described, all tables will either summarize  
• the Core Period (displayed by the 2 originally randomized treatment groups) 
• the Extended Period (displayed by the 3 treatment groups after re-randomization), or  
• the Overall Period (displayed by the 3 treatment groups after re-randomization but including 
data from the Core Period and the Extended Period) 


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Core and Overall Period outputs that are referring to a baseline will always use the Core Period 
baseline. Unless otherwise specified, extended period tables referring to a baseline will use the 
extended baseline. 
12.1 Patient Disposition 
The following information will be summarized for patient disposition by treatment group and in 
total: 
• Number of patients randomized at the initial randomization (2 treatment groups) tabulated by 
country, and center using the ITT analysis set 
• Patient disposition for the Core Period and the Extended Period (including, number screened, 
number of screen failures, number of patients not randomized and reasons, the number of 
patients who were randomized, treated with study drug, completed treatment, discontinued 
treatment with reason for discontinuation, completed period/study, and discontinued 
period/study with reason for discontinuation). The denominator of these percentages is based 
on the ITT Analysis Set for study discontinuation and the SAF Analysis Set for treatment 
discontinuation 
• The number of subjects receiving treatment at Week 12, Week 24 and Week 52 will be 
summarized 
• The reason for exclusion from the PP set at Week 12 and Week 24 will be summarized 
• Summaries of analysis sets with reason for exclusion using all screened subjects.  
• Note that EP-PP and EP-PK analysis sets will not be determined at the Week 30 lock and 
will not appear in the Week 30 CSR TFLs 
• Major protocol deviations prior to Week 12 and prior to Week 24 leading to exclusion from 
the PP and/or PK Analysis Sets 
• Randomization list of patients and their actual versus randomized treatment group and strata 
(previous exposure to biological treatment for RA) for all randomized and re-randomized 
patients 
12.2 Demographic and Baseline Characteristics 
Where permitted by local regulation the following demographic and baseline data will be 
summarized for the ITT and PP Analysis Set for the Core Period by treatment group and in total.   
• Age [in years, at day of patient signature on informed consent] 
• Race  
• Sex 
• Ethnicity 
• Height 
• Weight and  
• Body mass index  
General medical history will be coded according to MedDRA and will be summarized for the ITT 
Analysis Set and PP Analysis Set by system organ class (SOC) and preferred term (PT) for the 
Core Period by treatment group and in total.  


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RA history will be summarized using the ITT and PP Analysis Set. RA history variables include: 
• RA functional class 
• Previous exposure to biologic treatment for RA [yes/no] 
• Time since symptom onset 
• Time since first RA diagnosis  
• Time from first symptoms to diagnosis and 
• Presence and type of extra-articular manifestations 
In addition, baseline efficacy endpoint data as well as Antidrug Antibody (ADA) status will be 
summarized using the ITT and PP Analysis Set. 
General prior medications and prior medications for disease under study will be coded using 
WHODRUG and will be summarized for the ITT Analysis Set by medication preferred name and 
medication category (Anatomic Therapeutic Classification (ATC) levels 2 and 4) for the Core 
Period by treatment group and in total.   
Prior medications are defined as any medication discontinued prior to the first dose of study 
treatment. 
Tables will be sorted by decreasing order of frequency in the ATC groups and PTs within ATC 
groups in the total across all treatment groups. 
Prior procedures (i.e. surgeries etc.), defined as any procedure that occurred prior to randomization 
or the first dose of study treatment will be displayed in a data listing. 
Smoking status will be listed.  
12.3 Treatments 
12.3.1 Extent of Study Drug Exposure 
Summary statistics will be provided on the total number of doses administered and the total 
duration of exposure (date of last dose – date of first dose +7 day) for the Core Period (ITT, PP, 
and SAF Analysis Sets), Extended Period (EP-ITT, EP-PP, EP-SAF Analysis Sets), and Overall 
Period (ITT, EP-PP, SAF Analysis Sets) by treatment group and in total.  It should be noted that 
for the extended period related outputs in the Week 30 CSR, only the following exposure 
summaries will be presented, exposure from Week 24 to Week 30 (EP-ITT and EP-SAF) and 
exposure from Day 1 to Week 30 (EP-ITT and EP-SAF). 
In addition, treatment compliance will be estimated per patient by the proportion of the planned 
number of injections actually administered and be summarized as both a continuous and 
categorical variable for the Core Period (Week 12 and 24), Extended Period, and Overall Period 
by treatment group. Treatment compliance will be categorized as follows: < 80%, ≥80% to ≤ 100% 
and > 100%.  If a patient takes the treatment that they were not randomized to, for the purposes of 
compliance, that injection will be considered as missing for calculations. 
For the Core Period, 24 injections are planned for all patients. In the Extended Period 28 injections 
are planned. These planned numbers apply to all patients, irrespective of discontinuation of study 
or study drug. Therefore, the denominator for Core Period treatment compliance is 24, for 


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Extended Period treatment compliance is 28 (7 for the Week 30 CSR) and for Overall Period 
treatment compliance is 52 (31 for the Week 30 CSR). 
Additionally, cumulative exposure, calculated in patient-years, will be summarized. The duration 
of 1 year is defined as 365.25 days for that purpose.  Cumulative exposure is defined as follows: 
 
𝑌𝑒𝑎𝑟𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦= (
∑
(𝑙𝑎𝑠𝑡 𝑑𝑎𝑦−𝑑𝑎𝑦 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛+ 7)
𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑏𝑙𝑒
𝑎𝑛𝑎𝑙𝑦𝑠𝑖𝑠 𝑠𝑒𝑡
)/ 365.25 
 
12.3.2 Concomitant Medications and Procedures  
Concomitant medications, defined as those medications taken at any time on or after the first dose 
of study treatment, will be coded using WHODRUG and will be summarized for the ITT Analysis 
Set by medication group and medication subgroup (ATC Level 2 and 4) for the Core Period, 
Extended Period, and Overall Period by treatment group and overall. Core and Overall Period 
tables will utilize the ITT Analysis Set. Extended Period tables will utilize the EP-ITT Analysis 
Set. 
The number and percentage of patients using each medication will be displayed together with the 
number and percentage of patients using at least 1 medication within each medication group and 
subgroup. 
This display of medications will be provided for general concomitant medications and for when 
the intake reason is the disease under study.  
If a medication or procedure date is missing or partially missing and it cannot be determined 
whether the medication/procedure was prior or concomitant, it will be considered as concomitant. 
Tables will be sorted by decreasing order of frequency in the ATC groups and PTs within ATC 
groups in the total across all treatment groups. 
Concomitant procedures, defined as those procedures happening concurrently after the first dose 
of study treatment, will be displayed in a data listing. 
12.4 Major Protocol Deviations 
All protocol deviations data will be entered into the Clinical Trials Management System (CTMS). 
The study team and the Sponsor will conduct on-going reviews of the deviation data from CTMS. 
Details concerning handling and rating of protocol deviations can be found in the “Protocol 
Deviation Guidance” document.  
The list of major and clinically important protocol deviations will be finalized before the Week 30 
partial database lock for any deviations occurring before/at the Week 30 visit and again before the 
Week 55 database lock for deviations occurring during the remainder of the Extended Period.  
The PP (W12 and W24) and PK Analysis Sets must be finalized at the post-freeze data review 
meeting, prior to unblinding for the W30 CSR. The EP-PP and EP-PK Analysis Set must be 


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finalized at the post-freeze data review meeting and follow-up, prior to unblinding for the W55 
CSR, with the understanding that post lock discovery of any patient taking the incorrect treatment 
will exclude the patient from the EP-PP and EP-PK populations. 
Major protocol deviations will be summarized for the Core Period and Extended Period using the 
ITT and the EP-ITT Analysis Sets, respectively, by treatment group and in total.  
A listing of all protocol deviations (minor and major) will be provided. 
A table and listing detailing all COVID-19 related protocol deviations, summarized by the Core 
and Extended Period, will be provided. Categories will be based on missed visits or endpoints not 
collected in the manner described in the protocol. The COVID-19 situation continues to be 
monitored closely and additional COVID-19 related analyses may be warranted, in which case a 
SAP amendment would be prepared. The number of subjects with COVID-19 related vaccinations 
prior to Week 24 will be identified using the concomitant medication data and summarized. 
12.5 Efficacy Analyses 
All questionnaires and assessments that are conducted to support the below described analyses will 
be listed. These include:  
• Swollen and tender joint counts 28 and 66/68 
• Patient’s and Physician’s Global Assessment of Disease Activity 
• Health Assessment Questionnaire-Disability Index  
• Patient’s assessment of arthritis pain  
12.5.1 Study Hypotheses 
The hypothesis of the primary analysis in this study is as follows: 
Primary hypothesis for the FDA: 
H0: (µT - µR) < -0.6 or (µT - µR) > 0.5  
H1: -0.6 ≤ (µT - µR) ≤ 0.5  
where  
• µT = mean absolute change from baseline in DAS28-ESR at W24 for MSB11456 
• µR = mean absolute change from baseline in DAS28-ESR at W24 for EU-RoActemra 
• hypothesis test is based on 90% confidence intervals 
Primary hypothesis for the EMA: 
H0: (µT - µR) < -0.6 or (µT - µR) > 0.6 
H1: -0.6 ≤ (µT - µR) ≤ 0.6 
where  
• µT = mean absolute change from baseline in DAS28-ESR at W24 for MSB11456 


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• µR = mean absolute change from baseline in DAS28-ESR at W24 for EU-RoActemra 
• hypothesis test is based on 95% confidence intervals 
12.5.2 Hypothesis Testing Strategy and Multiplicity 
There is no adjustment for multiplicity because this study has only one primary endpoint, and study 
success will be evaluated according to the success criterion defined for each agency.  
12.5.3 Time to Intercurrent Events  
A Kaplan-Meier (K-M) plot will be provided to display the time of occurrence of intercurrent 
event(s). The following will be provided:  
• A plot, for each intercurrent event, displaying K-M curve for time to occurrence of the 
intercurrent event  
• A plot displaying the time to occurrence of first intercurrent event for patients with at least 
one intercurrent event.  
12.5.4 Primary Estimand 1.0 (DAS28-ESR ITT) 
The trial will compare subcutaneous injections of MSB11456 to EU-RoActemra. The primary 
estimand to demonstrate equivalent efficacy of MSB11456 and EU-RoActemra is based on the 
DAS28-ESR at W24 (see Section 9.1.1). The primary comparison of interest is the change from 
baseline at Week 24. The primary comparison will be made according to treatment policy 
regardless of whether patients discontinue treatment prior to W24, used any prohibited 
medications, had any Methotrexate dose modification prior to W24, or received a COVID-19 
related vaccine prior to Week 24, i.e., all available information at W24 will be included in the 
analysis.  
12.5.4.1 Imputation Methods  
According to the protocol patients who discontinue study treatment are asked to attend the W24 
visit, with the intention of reducing the amount of missing data for patients who discontinue 
treatment. Missing DAS28-ESR scores at W24 will be imputed by a multiple imputation (MI) 
procedure as described below and further detailed in Section 15.9.2 of the Appendix.  
For a subject with multiple IEs that are addressed with the hypothetical strategy the date of the 
first IE occurrence for the imputation of that estimand will be used for censoring. IEs that are 
addressed with treatment policy will not be considered in determining the date for censoring. 
Non-monotone missing data (i.e. interim missing DAS28-ESR scores for patients who have missed 
visits/endpoints but have returned for next visit) is assumed to be missing at random (MAR) and 
will be imputed separately for each treatment group using the Markov chain Monte Carlo (MCMC) 
option of SAS PROC MI.  
Then the monotone missing values for each treatment group will be imputed via the chained 
equation method, using SAS PROC MI option MONOTONE REG. First, all missing data for the 
first post-baseline visit are imputed; then missing data for the next visit are imputed using observed 
data plus the just imputed missing data; and so on to the W24 visit. The number of imputations 


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will be set to 500 and the PROC MI steps will always use the seed of 135984. Missing values for 
DAS28-ESR score will be imputed at each post-baseline visit. Baseline DAS28-ESR score and 
randomization stratification variable will be used to model the distribution of trajectory values.  
Imputed DAS28-ESR scores will be restricted such that the values are greater than zero.  Sample 
SAS code can be found in Section 15.9.2 of the appendix. 
12.5.4.2 Primary Analysis 
Change from baseline at W24 in DAS28-ESR will be analyzed using an analysis of covariance 
with treatment group and previous exposure to biologic treatment for RA [yes/no] as fixed effects 
and baseline DAS28-ESR as a covariate. Stratification variables will be used as entered in IRT. 
The difference between treatments will be estimated by the least squares mean difference between 
MSB11456 and EU-RoActemra, with its 95% confidence interval for the EMA and its 90% 
confidence interval for the FDA. 
• For the FDA: MSB11456 will be considered equivalent to EU-RoActemra if the 90% 
confidence interval for the difference in mean change from baseline to W24 in DAS28-ESR 
between MSB11456 and EU-RoActemra lies entirely within the equivalence interval of 
[-0.6, 0.5] 
• 
For the EMA: MSB11456 will be considered equivalent to EU-RoActemra if the 95% 
confidence interval for the difference in mean change from baseline to W24 in DAS28-ESR 
between MSB11456 and EU-RoActemra lies entirely within the equivalence interval of 
[-0.6, 0.6] 
The primary analysis is based on the Core Period using the ITT Analysis Set.  
A forest plot showing the 90% and 95% confidence intervals around the mean treatment difference 
of change from baseline to W24 in DAS28-ESR will be created for overall and the subgroup 
populations. 
12.5.4.3 Supportive Estimand 1.1 (DAS28-ESR Per-Protocol) 
The same ANCOVA analysis used for the primary estimand will be performed on the PP Analysis 
Set. All data available will be included in the analysis. No or little missing data is foreseen and 
hence it is not planned to impute missing values. However, if more than 5% of subjects included 
in the PP analysis set have missing DAS28-ESR assessments at Week 24 then the same MI applied 
to Estimand 1.0 will be performed. 
12.5.4.4 Supportive Estimand 1.2 (DAS28-ESR Hypothetical return-to-Baseline 
ITT) 
A similar analysis as for the primary estimand will be performed with the exception that 
measurements that occur after treatment discontinuation due to lack of efficacy or due to AE as 
well as after use of prohibited medication (or modification of permitted medications) that could 
impact W24 efficacy assessments will not be considered in the analysis.  Imputation of missing 
DAS28-ESR at W24 and imputation of discounted values due to the occurrence of relevant 
intercurrent events as described above will be based on a pattern-mixture model combining a 
baseline observation carried forward (BOCF) MI approach with MAR sequential imputation. 


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The BOCF MI approach will impute multiple values drawn from the baseline distribution of the 
endpoint values and will be used for DAS28-ESR assessments after patients’ discontinuation from 
study treatment prior to W24 due to lack of efficacy or due to an AE and/or for patients who used 
prohibited medication or modified their permitted medications prior to W24. For those patients, 
the assumption will be made that W24 DAS28-ESR would regress to the baseline value. The 
distribution of baseline values will be estimated using a regression model with baseline DAS28-
ESR score and randomization stratification variable as covariates while predictions from this 
model will be used to impute missing and discounted (observations affected by IE) DAS28-ESR 
at W24.  For other missing data, MAR sequential imputation will be used (as for the primary 
estimand). 
12.5.4.5 Supportive Estimand 1.3 (DAS28-ESR Hypothetical continuing per 
protocol ITT)  
A similar analysis as for the primary estimand 1.0 will be performed with the exception that the 
following DAS28-ESR assessments will be discounted and those now missing assessments will 
be imputed using MI as in the primary analysis: 
• DAS28-ESR values that occurred after treatment discontinuation due any reason  
• DAS28-ESR values that occurred after use of prohibited medication (or modification of 
permitted medications) that could impact W24 efficacy. 
For these intercurrent events a ‘hypothetical’ strategy is followed where measurements are 
projected as a per protocol scenario as if the patient had continued to follow the protocol after the 
time of the intercurrent event 
12.5.4.6 Sensitivity Analyses for the primary estimand 1.0 
The following sensitivity analyses to be performed on the ITT Analysis Set will be confirmed at 
the blinded data review meeting prior to the W30 partial database lock: 
• As little missing data is expected, the primary analysis of the primary estimand (DAS28-
ESR) will be performed with no imputation of missing values. 
• If data is not normally distributed as expected, a sensitivity analysis will be performed 
using appropriate non-parametric methods. 
• A listing will be produced comparing the previous exposure to biologic treatment for RA 
strata used in IRT versus the patient information recorded on the eCRF at the 
randomization visit. If randomized stratum versus actual has substantial differences, a 
sensitivity analysis for the primary estimand will be performed that uses the actual strata 
information instead of the those used in IRT. 
• To assess the robustness of the MAR assumption for the primary estimand, a tipping point 
analysis will be performed, based on the same analysis of covariance model as for the 
primary analysis. Missing changes from baseline at W24 in DAS28-ESR will be imputed 
by proc mi in SAS, accounting for treatment arm, randomization stratum and baseline 
DAS28-ESR as a continuous covariate (if baseline is also missing then the subject will be 
excluded from the analysis). 


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For the complete datasets obtained by proc mi the so-called 𝛿-method will be applied (Cro, 
2020). For pairs of the shift parameters, denoted by (𝛿1, 𝛿2), the shift parameter 𝛿1 will be 
added to each imputed value in the MSB11456 treatment arm, and the shift parameter 𝛿2 
will be added to each imputed value in the RoActemra treatment arm. 
500 series of imputations will be performed for each pair of shift parameters using the same 
seed as with the primary estimand 1.0, each complete dataset will then be analyzed by the 
original ANCOVA model, and the results of the analysis will be combined by proc 
mianalyze in SAS. 90% and 95% CIs will be calculated for the combined results. 
𝛿1 and 𝛿2 values will be incremented from -3 to 3 by steps of 1 (imputed value should not 
result in negative value for DAS28-ESR at week 24). Results for each pair (49 pairs in 
total) will be tabulated. The random seed initializing proc mi will be 135984. 
 
12.5.5 Key Secondary Estimand  
12.5.5.1 Key Secondary Estimand 2.0 (ACR20 ITT) 
12.5.5.1.1 Imputation Methods  
The comparison will be made according to treatment policy and all available information at W24 
will be included in the analysis (even if collected after occurrence of an intercurrent event). 
Missing ACR20 response data will be imputed using the LOCF method. All missing ACR20 
assessments will be imputed using the last non-missing assessment. Subjects who have just a 
baseline assessment will have their post baseline assessments imputed as non-responders. 
LOCF is proposed because few missing ACR assessments are expected at Week 24. However, a 
sensitivity analysis using MI is proposed to address any situation of a large number of missing 
values at week 24. 
12.5.5.1.2 Analysis Method  
The difference in ACR20 response rate at W24 will be compared using a 95 % stratified 
Newcombe confidence interval to adjust for the stratification factor previous exposure to biologic 
treatment for RA [yes/no] and assessed against an equivalence margin of [-15 %, 15 %]. Mantel-
Haenszel weights will be used to combine the stratum components 
This key secondary analysis will be performed on the ITT Analysis Set. 
12.5.5.2 Supportive Estimand 2.1 (ACR20 Per-Protocol Analysis)  
The same analysis method as the key secondary estimand (ACR20 ITT) will be performed on the 
PP Analysis Set. Very little missing data is expected and it is therefore not planned to impute 
missing values. However, if at least 5% of subjects in the per protocol analysis set have missing 
ACR20 assessments at Week 24 then the same LOCF method applied to Estimand 2.0 will be 
performed. 


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12.5.5.3 Supportive Estimand 2.2 (ACR20 Hypothetical Return to Baseline ITT)  
A similar analysis as that for the primary estimand will be carried out with the exception that 
measurements that occurred after treatment discontinuation due to lack of efficacy or due to AE 
as well as after use of prohibited medication (or modification of permitted medications) that could 
impact W24 efficacy assessments will not be considered in the analysis. Imputation of missing 
ACR response data at W24 and imputation of discounted values due to the occurrence of relevant 
intercurrent events as described above will be based on a combination of a non-responder approach 
with LOCF. The non-responder approach will be used for patients who discontinued from study 
treatment prior to W24 due to lack of efficacy or due to an AE and/or for patients who used 
prohibited medication or modified their permitted medications prior to W24. For other missing 
data, LOCF will be used (as for the key secondary estimand). 
12.5.5.4 Sensitivity Analyses for the key secondary estimand 2.0 
The following sensitivity analyses to be performed on the ITT Analysis Set will be confirmed at 
the blinded data review meeting prior to the W30 partial database lock: 
• The ACR20 response rate at week 24 analysis will be performed on the ITT Analysis Set with 
no imputation. 
• Missing ACR20 values will be imputed using the MI approach. 
This key secondary analysis will be performed on the ITT Analysis Set. Multiple imputation 
(MI) will be used to impute missing ACR20 response data at Week 24.  Multiple imputation 
of missing data ACR20 response will be performed by fully conditional specification (FCS) 
using PROC MI in SAS with the FCS option. The FCS MI specifies the multivariate imputation 
model on a variable-by-variable basis by a set of conditional densities. For each missing value 
at Week X, the FCS MI will generate values from a conditional distribution for the missing 
data given the other data prior to Week X. The FCS MI model will include treatment group 
and stratification factors for randomization. A total of 500 imputed (complete) datasets will be 
generated for the MI analysis. 
The difference in ACR20 response rate at W24 will be compared using a 95 % stratified 
Newcombe confidence interval to adjust for the stratification factor previous exposure to 
biologic treatment for RA [yes/no] and assessed against an equivalence margin of [-15 %, 
15 %] for each imputed dataset. SAS PROC MIANALYZE will be used to pool the results of 
the 95 % stratified Newcombe confidence intervals and generate an overall result by Rubin’s 
rules (1987). See code in Section 15.9.3.2 
• Tipping point analysis will further be used to assess the robustness of the primary study results.  
Different number of events between treatment groups will be assessed until the study 
conclusion is changed. All combinations of the number of responders and non-responders 
among the missing values will be evaluated. The stratification factor will not be taken into 
account in the generation of the combinations of responders and non-responders among 
missing data. Consequently, the selection of responders and non-responders will be only 
performed once for each combination. Each imputed value is initially imputed as a responder. 
The imputed values in the EU-RoActemra group will remain as responders while the 
MSB11456 imputed values are replaced as a nonresponders one at a time, therefore changing 


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the number of events between groups. Once all imputed values in the MSB11456 group have 
been replaced with nonresponders values, the data will reset to where the MSB11456 group 
imputed values are all responders and one by one the imputed values in the EU-RoActemra 
group are replaced with a nonresponder until all EU-RoActemra are nonresponders and all 
MSB11456 are responders.  
Furthermore, every pair of imputations between the EU-RoActemra and MSB11456 groups 
will be assessed similarly, creating a matrix of possible patterns. At each iteration, a similar 
analysis to that of the key secondary analysis is assessed, and the direction of the analysis is 
recorded. 
A graphical method will be used to present the tipping point analysis for ACR20 at week 24 
(Liublinska, 2014). On the two axes of the graph all the possible numbers of successes in 
between two treatment arms for subjects with missing data will be presented. For each pair of 
supposed outcome values the common risk difference across strata and its 95% CI will be 
estimated by the method specified for the LOCF key secondary analysis.  
12.5.6 Secondary Estimand 3.0 
12.5.6.1 Main Analysis 3.0 
The main analysis is similar to the primary analysis of Primary Estimand (DAS28-ESR ITT) but 
uses Change from baseline at W12 in DAS28-ESR. This will be analyzed using an analysis of 
covariance with study drug, and previous exposure to biologic treatment for RA [yes/no] as fixed 
effects and baseline DAS28-ESR as a covariate. Stratification variables will be used as entered in 
IRT. The difference between treatments will be estimated by the least squares mean difference 
between MSB11456 and EU-RoActemra, with its 95% confidence interval for the EMA and its 
90% confidence interval for the FDA. 
If the proportion of subjects with missing W12 change from baseline DAS28-ESR scores is above 
5%, then missing change from baseline in DAS28-ESR scores at W12 will be imputed by a 
multiple imputation (MI) procedure similar to the one described in 12.5.3.1 for the primary 
analysis. However, the proportion of missing data at W12 is expected to be low. 
12.5.6.2 Supportive Analysis 3.1 (Early DAS28-ESR Per Protocol) 
The same analysis as for the main analysis will be performed on the Week 12 PP Analysis Set. All 
data available will be included in the analysis.  No, or very little, missing data is foreseen, and no 
imputation of missing values is planned. 
12.5.6.3 Supportive Analysis 3.2 (Early DAS28-ESR Hypothetical Continuing Per 
Protocol ITT) 
The same analysis described in Section 12.5.4.5 will be performed on the ITT Analysis Set but for 
Week 12.  
12.5.6.4 Sensitivity Analysis – for main Estimand at Week 12 DAS28-ESR 
The same analysis for estimand 3.0 will be performed on DAS28-ESR at Week 12 with no 
imputation. 


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12.5.7 Subgroup Analyses 
Analyses on the primary and key secondary estimands (Estimand 1.0, and Estimand 2.0 as 
described in Section 9.1) will be performed for the following subgroups using the same methods 
as the main analyses, removing the strata from the model, when applicable: 
• Previous exposure to biologic treatment for RA [yes/no] as captured in IVRS 
• ADA positive/ADA negative 
o Neutralizing antibody (NAb) positive/NAb negative 
• Non COVID-19 vaccinated/COVID-19 vaccinated prior to Week 24  
• Non COVID-19 vaccinated/COVID-19 vaccinated prior to Week 12 for Estimand 3.0 
(DAS28 ESR at Week 12). 
Inferential statistics will be provided for each subgroup provided there are sufficient subjects to 
complete the analysis. 
ADA or NAb status will be defined as positive for a complete study period if the patient has at 
least 1 confirmatory positive result post-dose any time during this period. Otherwise the status is 
defined as negative for this complete study period. 
The estimate of the difference with the standard error, 90% and 95% confidence intervals will be 
presented. 
A forest plot will be displayed with the analysis by each of the subgroups as well as overall. 
12.5.8 Secondary Analyses 
Unless stated otherwise, secondary analyses will be performed on both the ITT and PP Analysis 
Sets. 
12.5.8.1 DAS28-ESR Change from Baseline 
The DAS28-ESR mean absolute change from baseline will be summarized descriptively over time 
and analyzed using a mixed-effect repeated measures model assuming an unstructured covariance 
matrix with treatment, visit, treatment-by-visit interaction, previous exposure to biologic treatment 
for RA (yes/no) included as factors and baseline DAS28-ESR from the Core Period as a covariate.  
For further details, see Section 15.5.1 of the Appendix. 
The mixed models will be performed on the Core Period, Extended Period (using the extended 
baseline data) and overall (using the Core Period baseline data). The Core Period tables will utilize 
the ITT and PP Analysis Sets. The Extended Period tables will utilize the EP-ITT and EP-PP 
Analysis Sets. The overall period tables will utilize the ITT and overall PP (combination of PP and 
EP-PP) analysis sets. The 95% confidence interval of the least-squared mean will be provided for 
each time point for the Core Period.  
A plot of the mean (SD) DAS28-ESR over time will be provided on the Overall Period.  
To provide an exploratory overview over the distribution of DAS28-ESR values over time, aligned 
histograms will be prepared for the Overall Period. 


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12.5.9 Other Efficacy Analyses 
No imputation of missing data will be performed on these other efficacy analyses. 
12.5.9.1 DAS28-CRP 
The DAS28-CRP mean absolute change from baseline will be summarized descriptively over time 
and analyzed using a mixed-effect repeated measures model with treatment, visit, treatment-by-
visit interaction, and previous exposure to biologic treatment for RA (yes/no) included as factors 
and baseline DAS28-CRP from the Core Period as a covariate.  
The mixed effects models on the Core Period and on the Extended Period, will be carried out as 
has been previously described for the DAS28-ESR change from baseline endpoint. The 95% 
confidence interval of the least-squared mean will be provided for each time point for the Core 
Period.  
The Core Period tables will utilize the ITT and PP Analysis Sets. Extended Period tables will 
utilize the EP-ITT and EP-PP Analysis Sets. 
12.5.9.2 ACR20 / ACR50 / ACR70 
The ACR20/ACR50/ACR70 response rate over time will be summarized descriptively using the 
LOCF imputed dataset and compared during the Core Period using 95% Newcombe confidence 
intervals for the difference stratified on previous exposure to biologic treatment for RA (yes/no).  
These summaries will be performed on the Core Period, and the Extended Period comparing to 
baseline from the Core Period. The Core Period tables will utilize the ITT and PP Analysis Sets. 
The Extended Period tables will utilize the EP-ITT and EP-PP Analysis Sets.     
To provide an exploratory overview over the distribution of ACR values over time, aligned bar 
charts will be prepared for the Overall Period. 
12.5.9.3 DAS28-ESR and DAS28-CRP Categorical Response 
The number and percentage of patients within each DAS28-ESR and DAS28-CRP disease 
activity/categorical response, as described in Section 10.5, will be provided for the Core Period, 
and Extended Period, by treatment group and visit. Categorical disease activity for DAS28-ESR 
is categorized as [remission/low/moderate/high], categorical response for DAS28-CRP is 
categorized as [yes/no] by the Boolean response criterion. The Core Period tables will utilize the 
ITT and PP Analysis Sets. The Extended Period tables will utilize the EP-ITT and EP-PP Analysis 
Sets.     
To provide an exploratory overview over the distribution of the DAS categorical responses over 
time, aligned bar charts will be prepared for the Overall Period. 
 
12.5.9.4 CDAI and SDAI 
The number and percentage of patients within each CDAI and SDAI level of disease category 
(remission/low/moderate/high), as described in Section 10.5, will be provided for the Core Period, 


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and Extended Period, by treatment group and visit. The Core Period tables will utilize the ITT and 
PP Analysis Sets. The Extended Period tables will utilize the EP-ITT and EP-PP Analysis Sets.     
To provide an exploratory overview over the distribution of the CDAI and SDAI over time, aligned 
bar charts will be prepared for the categorical responses and aligned histograms for the CDAI and 
SDAI values for the Core and Extended Periods on same graph. 
 
12.6 Immunogenicity and Pharmacokinetic Analyses 
Immunogenicity analyses will be performed on the SAF and EP-SAF Analysis Sets; PK analyses 
(i.e. trough concentration analyses) will be performed on the PK and EP-PK Analysis Sets. 
Participation in the population PK sub-study is optional. 
12.6.1 Antidrug Antibody Incidence Rate, Antidrug Antibody Titer, 
NAb Incidence Rate  
ADA or NAb status will be defined as positive for a given study period if the patient has at least 1 
positive result post-dose in the ADA confirmatory assay any time during this period. Otherwise 
the status is defined as negative for this study period. 
Treatment-induced ADA positive status is defined as: 
• In patients with an ADA negative pre dose sample, a treatment-induced ADA response is 
defined as any post dose sample being positive in the ADA confirmatory assay 
• 
In patients with an ADA positive pre dose sample, a treatment-induced ADA response is 
defined as a 1.808-fold increase in titers from the pre dose assessment to a post dose 
assessment. 
The ADA and NAb incidence rates over time as well as ADA titer over time will be summarized 
descriptively by visit (and overall for incidence) and treatment arm. The denominator for each visit 
will be the number of subjects with a valid immunogenicity assessment at that visit. This 
descriptive summary will be provided for the Core Period, the Extended and the Overall Period. 
The geometric mean, median minimum, and maximum values of ADA titer will be presented for 
overall and by visit. 
An additional table “treatment-induced” ADA positive status (without the pre dose time point) will 
be presented for the Core Period and the Extended Period.  
To provide a visual overview of overall ADA and NAb positive rates, aligned bar charts will be 
prepared on the Overall Period using the Safety Analysis Set. For the purpose of the bar chart a 
patient is defined as positive when he has at least 1 confirmatory positive result post-dose. ADA 
incidence over time and NAb incidence over time will also be presented in separate bar charts on 
the Overall Period. 
A descriptive summary (including the lower (T1) and upper tertile (T2)) of the maximum post 
baseline ADA titer of each subject will presented. Subjects with at least one post baseline 
confirmed ADA positive results and subjects with all negative ADA titer results will also be 


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summarized. The maximum post baseline ADA titer for all subjects will be categorized into three 
groups: Low titer (Maximum ADA Titer < T1), Mid titer (T1≤Maximum ADA Titer ≤T2), High 
Titer (Maximum ADA Titer>T2)  
Confirmed ADA titer for subjects with treatment-related hypersensitivity reactions will be 
summarized using the safety analysis set.  In addition, a boxplot of ADA titer over time on the 
log 2 scale will be provided for the Core and Overall Periods.  
12.6.2 Trough Concentration 
Trough concentration will be summarized descriptively on the PK Analysis Set for the Core 
Period, Extended Period, and Overall Period for each treatment group and timepoint. Core Period 
table will utilize the PK Analysis Set. Extended Period tables will utilize the EP-PK Analysis Set. 
Overall Period tables will utilize the Overall PK Analysis Set. 
For trough concentration the descriptive summary statistics additionally comprise: 
• Coefficient of variation 
• Geometric mean 
• Geometric coefficient of variation 
For the purpose of these analyses, values below the lower limit of quantitation (LLOQ) will be 
imputed as the ½LLOQ of the assay. Missing PK concentrations (e.g., no sample, insufficient 
sample volume for analysis, no result or result not valid) will be reported in a listing and classed 
as “N.R.” They will be excluded from summary statistics.  
Descriptive statistics for Ctrough will also be created by ADA status, ADA tertile subgroups, and 
NAb status (if sufficient data is available for the latter, to be confirmed at the first blinded data 
review meeting).  
To provide a visual overview over the distribution of trough concentration over time, the following 
figures will be displayed:  
• Mean concentration-over time by Overall Period on linear (+/- standard deviation) and semi 
logarithmic scales  
• Mean concentration-over time by Core Period on linear (+/- standard deviation) and semi 
logarithmic scales  
• Individual patient concentration-time data on the Overall Period by treatment group and visit 
week on linear and semi logarithmic scales 
• Mean concentration-over time on linear (+/- standard deviation) by ADA status and ADA 
tertile subgroups  
• Box plot of serum drug concentration at Week 24 and at Week 52 for the ADA negative vs. 
ADA positive in each treatment group 
 


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12.7 Safety Analyses 
All Safety Analyses will be provided for the Core Period, the Extended Period and Overall Period 
on the SAF Set. Core and Overall Period tables will utilize the SAF Analysis Set. Extended Period 
tables will utilize the EP-SAF Analysis Set. 
12.7.1 Adverse Events 
All AEs reported in the CRF will be coded using MedDRA. 
A summary of Treatment emergent adverse events (TEAEs) will be presented, including:  
• The number of events reported 
• The number and percentage of  
o Patients reporting at least 1 TEAE  
o Patients reporting at least 1 study drug related TEAE 
o Patients reporting at least 1 serious TEAE 
o Patients reporting at least 1 TEAE ≥ grade 3 
o Patients reporting at least 1 study drug related TEAE ≥ grade 3 
o Patients reporting at least 1 TEAE ≥ grade 4 
o Patients reporting at least 1 study drug related TEAE ≥ grade 4 
o Patients reporting any TEAE of special interest 
o Patients reporting any study drug related TEAE of special interest 
o Patients with withdrawal of study drug due to a TEAE 
o Patients with withdrawal of study drug due to a study drug-related TEAE 
o Patients with interruption of study drug due to a TEAE 
o Patients with interruption of study drug due to a study drug-related TEAE 
o Patients discontinuing the study due to a TEAE 
o Patients discontinuing the study due to a study drug-related TEAE  
o Patients with any TEAE leading to death 
o Patients with any study drug-related TEAE leading to death 
o Patients with at least 1 serious injection site reaction (ISR) or ISR leading to 
treatment interruption or discontinuation.  
o Non-Serious TEAEs Experienced by ≥ 5% of Patients by Preferred Term 
o TEAEs Experienced by ≥ 2% of Patients by Preferred Term 
 
• TEAE incidence rate with corresponding 95% confidence intervals (calculated as LnRate= 
log(Rate), and SE of LNRate=1/sqrt(number of events); 95%CI Rate =  exp(LnRate +/- 
1.96*SE)) per patient year for all TEAE categories above 
Incidence rate per patient year is calculated as follows: 
 
𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦=
∑
(𝑙𝑎𝑠𝑡 𝑑𝑎𝑦−𝑑𝑎𝑦 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛+ 7)
𝑎𝑙𝑙 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑖𝑛 𝑆𝐴 𝑆𝑒𝑡
 
𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑟𝑎𝑡𝑒 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟= 𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒∗365,25
𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦
 


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where last day is the 28th day after the day of treatment discontinuation if applicable and the date 
of data extraction for those patients that have not yet ended the study. 
TEAEs are defined as occurring or worsening (in severity or relationship to study drug) with an 
onset at the time of or following dosing time at Visit 2 (initial injection at Day 1). In reality, all 
AEs which change in severity or relationship to study drug are assigned a new start date and 
captured as a new record.  
 
The start of TEAEs (or worsening of an existing AE) that start on a patient’s re-randomization day 
and for which dosing and/or start time of the AE are not available will be assigned to the Extended 
Period. In case dosing and TEAE start time are both available they should be considered for 
allocating the TEAE start to a study period.  
In case the end day of an AE falls on the re-randomization day and dosing and AE stop time do 
not clearly prove that the AE has ended before the W24 dosing the AE stop falls in the Extended 
Period. All AE summaries are presented by SOC and PT unless otherwise specified. 
The following displays of TEAE related information will be provided: 
• A breakdown of the number and percentage of patients reporting each TEAE, categorized 
by body system and PT. Note: Counting will be by patient, not by event and patients are 
only counted once within each body system or PT.  
• A further tabulation of these data categorized by relationship to study drug. Patients with 
multiple events within a particular body system or PT will be counted under the category of 
their most drug-related event within that body system or PT. Relationship to study drug is 
categorized as related and not related 
• A summary of TEAEs reported, categorized by NCI-CTCAE Toxicity Grades 1 to 5. 
Patients with multiple events within a particular body system or PT will be counted under 
the category of their most severe event within that body system or PT 
• A summary of study drug-related TEAEs reported, categorized by NCI-CTCAE Toxicity 
Grades 1 to 5. 
• A summary of TEAEs leading to withdrawal of study drug 
• A summary of TEAEs leading to discontinuation of the study 
• A summary of TEAEs of special interest (TEAEs of special interest will be defined 
according to the protocol and will be identified via the tick box on the CRF) 
• A summary of non-serious TEAEs that exceed a frequency threshold of 5 % within any 
treatment group. (The frequency threshold is to be calculated as number of patients in a 
treatment group who had this TEAE at least once divided by number of patients in this 
treatment group.) In case the 5 % threshold is only exceeded for less than 5 TEAE terms 
the threshold will be reduced to 2 % 
• A further tabulation presenting the PTs for the events in descending order of frequency for 
the MSB11456 patients (all data from MSB11456 only patients and Extended Period data 
for the switchers) will also be presented 
• TEAEs by SOC and PT and by ADA Status  
• TEAEs by SOC and PT and by NAb Status (if sufficient data available)  
• MedDRA (version 23.0) SMQ defined Hypersensitivity and Anaphylaxis reactions 
tabulated by ADA status 


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• TEAEs of special interest and SAEs presented by ADA and NAb status (if sufficient data 
available)  
All AEs (including non-treatment-emergent events) recorded on the CRF will be listed. 
12.7.2 Deaths and Serious Adverse Events  
The following displays of SAE and death related information will be provided: 
• A breakdown of the number and percentage of patients reporting each SAE, categorized by 
body system and PT coded according to the MedDRA dictionary. Note: Counting will be 
by patient, not by event and patients are only counted once within each body system or PT.  
• A further tabulation of these data categorized by relationship to study drug. Patients with 
multiple events within a particular body system or PT will be counted under the category of 
their most drug-related event within that body system or PT. Relationship to study drug is 
categorized as related and not related 
• Any TEAE leading to death 
• Any study drug related TEAE leading to death 
Tables will be sorted by decreasing order of frequency in the SOCs and PTs within SOCs in the 
total across all treatment groups. 
A listing of SAEs and a listing of deaths will be provided in the Safety Tables section. 


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12.7.3 Laboratory Data 
Laboratory test results are reported in International System of Units (SI) units. However, due to 
the Covid-19 situation usage of the central laboratory may be limited. If this is the case, certain 
safety assessments may be performed at a local laboratory. Local lab results for all parameters 
except ESR and urinalysis (dipstick) will be included in data listings and shift tables but not in 
summaries of continuous values. 
Summary statistics on observed values and changes from baseline will be provided for continuous 
laboratory variables for the Core Period, Extended Period, and Overall Period by treatment group 
and visit. For the Extended Period summaries of change from baseline tables will be provided for 
change from Core Period baseline. Shift tables for the Core, Extended and Overall Period will be 
used to present changes in categorical laboratory variables by visit. Core and Overall Period shift 
tables will use the Core Period baseline, Extended Period shift tables will be provided for Core 
Period and Extended Period baseline. Categories should be low, normal, high and missing.  
Further a summary and shift tables of worst post-baseline value by categories (low, normal, high, 
missing) will be provided for Core, Extended and Overall Period. For the shift tables, Core Period 
and Overall Period will use Core Period baseline, Extended Period will use Core Period and 
Extended Period baseline.   
Where applicable, hematology and clinical chemistry laboratory results will be graded 
programmatically using version 5.0 of the NCI-CTCAE criteria (see Section 15.11 of the 
appendix). These laboratory NCI-CTCAE toxicity grades will be summarized by worst grade and 
by shift tables from baseline to worst NCI-CTCAE toxicity grade. These summaries will all use 
the Core Period baseline for the core, extended and overall period and the worst value. An 
additional shift table for the extended period which utilizes the extended period baseline line will 
be presented. 
Abnormal values will be displayed in a listing. This listing will additionally present the rest of the 
respective patient’s values for the laboratory parameter in question in order to display the 
conspicuous values in a chronological context.  
Laboratory data will be displayed in a pyramid table for the Core Period, Extended Period and for 
the Overall Treatment Period (see Section 15.4.4 of the Appendix).  
The laboratory data will be displayed in a box and whisker plot for the Core Period and Extended 
Periods together in one graph. 
Completion status and results of QuantiFERON-TB Gold tests will be summarized by visit and 
treatment group for the Overall Period.  
Anti-double-stranded DNA data will be listed only. 
12.7.4 Vital Signs 
The following vital sign data (observed values and changes from baseline) will be summarized 
using descriptive statistics over time for the Core Period, Extended Period, and Overall Period: 
• Respiratory rate 
• Heart rate after a 5-minute rest, and  
• Arterial blood pressure after a 5-minute rest 




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12.7.5.3 Local Tolerability 
Injection site reactions (ISRs) will be summarized for the Core Period and Extended Period by 
treatment group and in total. Frequency will be provided by term provided on eCRF (including 
“Other”), then by severity and by relationship to treatment.  
The event rate will be analyzed by number of injections. The total number of ISR for a patient will 
be divided by the number of injections the patient has received during the period. These normalized 
event rates will be summarized as described above. ISRs will be presented by ADA and NAb status 
(if enough patients with Nab positive status) to assess the impact of ADA and NAb results on 
safety. 
Action taken with study treatment and outcome will be presented in a listing only.  
An additional listing will be provided that only contains those cases of ISRs of CTCAE grade 3 
and above. 
 References 
Burmester, GR et al. A randomized, double-blind, parallel-group study of the safety and efficacy 
of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional 
disease-modifying anti-rheumatic drugs in patients with moderate to severe RA (SUMMACTA) 
study. Ann Rheum Dis 2014;73:69-74. 
Genovese, MC et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity 
in RA with inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 
2008;58:2968-80. 
Smolen, JS et al. Effect of interleukin -6 receptor inhibition with tocilizumab in patients with RA 
(OPTION study): a double-blind, placebo controlled, randomized trial. Lancet 2008;371:987-97. 
Kremer, JM et al. Tocilizumab inhibits structural joint damage in RA patients with inadequate 
responses to methotrexate. Arthritis Rheum 2011;63:609-21. 
Emery, P et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in 
patients with RA refractory to anti-tumor necrosis factor biologicals: results from a 24-week 
multicenter randomized placebo controlled trial. Ann Rheum Dis 2008;67:1516-23. 
Cro S et al. Sensitivity analysis for clinical trials with missing continuous outcome data using 
controlled multiple imputation: A practical guide. Statistics in Medicine. 2020;39: 2815–2842. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a two-arm 
randomized clinical trial. Statistics in Medicine. 2014 October 30; 33(24): 4170–4185. 
Siddiqui O. MMRM versus MI in dealing with missing data--a comparison based on 25 NDA 
data sets. J Biopharm Stat. 2011 May;21(3):423-36. doi: 10.1080/10543401003777995. PMID: 
21442517. 
 




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SBP 
Systolic Blood Pressure 
SDAI 
Simple Disease Activity Index 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event