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)
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Fresenius Kabi SwissBioSim GmbH

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 
 
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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 
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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. 
 
 
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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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