A Randomized, Double-Blind, Parallel-Group, Phase I Study to Evaluate the Pharmacokinetics, Safety and Immunogenicity of BIIB800 s.c. Compared to Actemra® in Healthy Male Participants
Phase: PHASE1
Conditions: Healthy Volunteer
Sponsor: Biogen

COVER PAGE 
 
Oﬃcial Title: 
 
 
A Randomized, Double-Blind, Parallel-Group, Phase I Study to 
Evaluate the Pharmacokinetics, Safety and Immunogenicity of 
BIIB800 s.c. Compared to Actemra® in Healthy Male Participants 
 
NCT Number: NCT06262477 
Document Date: 06 December 2023 
 

 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
 
PROTOCOL NUMBER: 
294BS101 
Biogen International GmbH 
Neuhofstrasse 30 6340 Baar 
Switzerland 
 
 
 
 
 
PHASE OF DEVELOPMENT: 
I 
 
Biogen Idec Research Limited, 
Foundation Park, Roxborough 
Way, Maidenhead SL6 3UD 
United Kingdom 
PROTOCOL TITLE: A Randomized, Double-Blind, Parallel-Group, Phase I Study to 
Evaluate the Pharmacokinetics, Safety and Immunogenicity of BIIB800 s.c. compared to 
Actemra® in Healthy Male Participants  
 
 
DATE: 
06 December 2023 
Version 2.0 
 
 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra® 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
SPONSOR INFORMATION 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen International GmbH 
Neuhofstrasse 30 6340 Baar 
Switzerland 
 
 
 
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Study Contact List for complete contact information. 
 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
SPONSOR SIGNATURE PAGE 
 
Protocol 294BS101 was approved by: 
 
 
____
_________________________ 
 
____________________ 
 
Date (DD MMM YYYY) 
 
Biogen Biosimilars 
 
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Protocol 294BS101, Version2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra® 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
TABLE OF CONTENTS 
SPONSOR INFORMATION ..........................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................3 
1. 
KEY STUDY ELEMENTS ..........................................................................................9 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Design Schematic .............................................................................................18 
1.3. 
Schedule of Activities .................................................................................................19 
2. 
LIST OF ABBREVIATIONS.....................................................................................21 
3. 
INTRODUCTION ......................................................................................................23 
3.1. 
Study Rationale ...........................................................................................................23 
3.1.1. 
Rationale for Study Population ...................................................................................23 
3.1.2. 
Rationale for Dose ......................................................................................................23 
3.1.3. 
Study Design Rationale ..............................................................................................24 
3.2. 
Background .................................................................................................................24 
3.2.1. 
Background on Tocilizumab .......................................................................................24 
3.2.2. 
Profile of Previous Experience with BIIB800 ............................................................25 
3.2.2.1. 
Nonclinical Experience ...............................................................................................25 
3.2.2.2. 
Clinical Experience .....................................................................................................25 
3.3. 
Benefit-Risk Assessment ............................................................................................25 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
5. 
STUDY DESIGN .......................................................................................................29 
5.1. 
Study Overview ..........................................................................................................29 
5.2. 
Study Duration for Participants ..................................................................................29 
5.3. 
Study Stopping Rules and Study Termination............................................................30 
5.4. 
Unscheduled Visits .....................................................................................................30 
5.5. 
End of Study ...............................................................................................................30 
6. 
STUDY POPULATION .............................................................................................31 
6.1. 
Inclusion Criteria ........................................................................................................31 
6.2. 
Exclusion Criteria .......................................................................................................32 
6.3. 
Screening, Retesting, Screen Failures, Rescreening, and Randomization .................34 
6.3.1. 
Screening ....................................................................................................................34 
6.3.2. 
Retesting .....................................................................................................................34 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
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5 
6.3.3. 
Screening Failures ......................................................................................................35 
6.3.4. 
Rescreening .................................................................................................................35 
6.3.5. 
Randomization ............................................................................................................35 
7. 
STUDY TREATMENT ..............................................................................................36 
7.1. 
Regimen ......................................................................................................................36 
7.2. 
Study Treatment Management ....................................................................................36 
7.3. 
BIIB800 ......................................................................................................................36 
7.3.1. 
Preparation for Administration ...................................................................................36 
7.3.2. 
Storage ........................................................................................................................37 
7.3.2.1. 
Handling and Disposal ................................................................................................37 
7.3.2.2. 
Accountability .............................................................................................................37 
7.4. 
Reference Product .......................................................................................................37 
7.5. 
Blinding Procedures ....................................................................................................38 
7.6. 
Precautions ..................................................................................................................38 
7.7. 
Concomitant Therapy and Procedures ........................................................................38 
7.7.1. 
Concomitant Therapy .................................................................................................38 
7.7.1.1. 
Allowed Concomitant Therapy ...................................................................................38 
7.7.1.2. 
Prohibited Concomitant Therapy ................................................................................39 
7.7.2. 
Concomitant Procedures .............................................................................................39 
7.8. 
Continuation of Treatment ..........................................................................................39 
7.9. 
Lifestyle Considerations .............................................................................................39 
8. 
RULES FOR WITHDRAWAL FROM STUDY FOR INDIVIDUAL 
PARTICIPANTS ........................................................................................................40 
8.1. 
Lost to Follow-Up.......................................................................................................40 
8.2. 
Withdrawal of Participants from the Study ................................................................40 
9. 
SAFETY ASSESSMENTS ........................................................................................42 
9.1. 
Clinical Assessments ..................................................................................................42 
9.2. 
Laboratory Assessments .............................................................................................42 
9.3. 
Immunogenicity Assessments ....................................................................................43 
10. 
PHARMACOKINETIC ASSESSMENTS .................................................................45 
11. 
PHARMACODYNAMIC ASSESSMENTS ..............................................................46 
12. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................47 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
6 
12.1. 
Definitions ..................................................................................................................47 
12.1.1. 
Adverse Event .............................................................................................................47 
12.1.2. 
Serious Adverse Event ................................................................................................47 
12.2. 
Safety Classifications ..................................................................................................48 
12.2.1. 
Investigator Assessment of Events .............................................................................48 
12.2.2. 
Relationship of Events to Study Treatment ................................................................48 
12.2.3. 
Severity of Events .......................................................................................................48 
12.2.4. 
Expectedness of Events ..............................................................................................49 
12.3. 
Monitoring and Recording Events ..............................................................................49 
12.3.1. 
Adverse Events ...........................................................................................................49 
12.3.2. 
Serious Adverse Events ..............................................................................................49 
12.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................50 
12.3.3.1. 
Deaths .........................................................................................................................51 
12.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................51 
12.4. 
Procedures for Handling Special Situations ...............................................................51 
12.4.1. 
Pregnancy ...................................................................................................................51 
12.4.2. 
Product Complaint ......................................................................................................52 
12.4.3. 
Overdose .....................................................................................................................52 
12.4.4. 
Medical Emergency ....................................................................................................52 
12.4.4.1. 
Unblinding for Medical Emergency ...........................................................................52 
12.5. 
Contraception Requirements ......................................................................................53 
12.6. 
Safety Responsibilities ................................................................................................53 
12.6.1. 
The Investigator ..........................................................................................................53 
12.6.2. 
The Sponsor ................................................................................................................53 
13. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........55 
13.1. 
General Considerations ...............................................................................................55 
13.2. 
Analysis Sets ...............................................................................................................55 
13.3. 
Methods of Analysis ...................................................................................................55 
13.3.1. 
Safety ..........................................................................................................................55 
13.3.1.1. 
Adverse Events ...........................................................................................................55 
13.3.1.2. 
Laboratory Results ......................................................................................................56 
13.3.1.3. 
Vital Signs and 12-lead Electrocardiogram ................................................................56 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
7 
13.3.2. 
Pharmacokinetics ........................................................................................................56 
13.3.3. 
Immunogenicity Data .................................................................................................58 
13.4. 
Interim Analyses .........................................................................................................58 
13.5. 
Sample Size Considerations .......................................................................................58 
13.5.1. 
Initial Sample Size Calculation ..................................................................................58 
13.5.2. 
Blinded Sample Size Recalculation (BSSR) ..............................................................58 
14. 
ETHICAL REQUIREMENTS ...................................................................................60 
14.1. 
Declaration of Helsinki ...............................................................................................60 
14.2. 
Ethics Committee and Institutional Review Boards ...................................................60 
14.3. 
Changes to Final Protocol ...........................................................................................61 
14.4. 
Informed Consent .......................................................................................................61 
14.5. 
Participant Data Protection .........................................................................................61 
14.6. 
Compensation for Injury .............................................................................................62 
14.7. 
Conflict of Interest ......................................................................................................62 
14.8. 
Study Report Signatory...............................................................................................62 
14.9. 
Registration of Study and Disclosure of Study Results ..............................................62 
14.10. 
Retention of Study Data ..............................................................................................62 
15. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES ...............................63 
15.1. 
Vendors .......................................................................................................................63 
15.1.1. 
Contract Research Organization .................................................................................63 
15.1.2. 
Electronic Data Capture ..............................................................................................63 
15.1.3. 
Central Laboratories for Laboratory Assessments .....................................................63 
16. 
ADMINISTRATIVE PROCEDURES .......................................................................64 
16.1. 
Study Site Initiation ....................................................................................................64 
16.2. 
Quality Control and Quality Assurance ......................................................................64 
16.3. 
Monitoring of the Study..............................................................................................64 
16.4. 
Study Funding .............................................................................................................65 
16.5. 
Publications .................................................................................................................65 
17. 
REFERENCES ...........................................................................................................66 
18. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................68 
19. 
APPENDIX 1: GRADING SCALES .........................................................................69 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
8 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................15 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................14 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
9 
1. 
KEY STUDY ELEMENTS 
1.1. 
Synopsis 
Protocol Title 
A Randomized, Double-Blind, Parallel-Group, Phase I Study to 
Evaluate the Pharmacokinetics, Safety, and Immunogenicity of 
BIIB800 s.c. compared to Actemra® in Healthy Male Participants  
Protocol Number 
294BS101 
Version Number 
 2.0 
Name of Study 
Treatment 
Research Name: 
BIIB800 (prefilled autoinjector, 162 mg/0.9 mL, 
for subcutaneous [s.c.] injection) 
 
Actemra® (prefilled autoinjector, 162 mg/0.9 mL, 
for s.c. injection) 
INN: 
Tocilizumab 
Study Phase 
1 
Project Indication 
See Section 3.2.1 for a full list of indications approved for the reference 
Study Rationale 
Tocilizumab (commercial name: RoActemra® in Europe, Actemra in 
the United States [US] and other countries) a biologic disease-
modifying antirheumatic drug, is a recombinant humanized monoclonal 
immunoglobulin G1 (IgG1) antibody against the interleukin 6 receptor 
(IL-6R). BIIB800 (also referred as BAT1806) is being developed as a 
biosimilar tocilizumab product to the reference products RoActemra 
and Actemra. The aim of the current study is to demonstrate 
equivalence in pharmacokinetics (PK) between BIIB800 and Actemra 
and to compare the pharmacodynamics (PD), safety, and 
immunogenicity profiles of BIIB800 and Actemra, administered s.c. to 
healthy adult male participants. 
Rationale for 
Starting Dose and 
Maximum 
Exposure 
In accordance with the approved dosing recommendation for the 
reference product, participants will receive 162 mg BIIB800 or 162 mg 
Actemra, administered s.c. A single dose will be administered at one 
injection location (outer upper arm); this is considered sufficient to 
establish PK equivalence and comparability of immunogenicity and 
safety parameters between BIIB800 and reference tocilizumab. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
10 
Study Objectives and Endpoints 
 
Primary Objective 
Co-Primary Endpoints 
To show equivalence in PK of 
BIIB800 and Actemra following 
s.c. administration of a single dose 
to healthy male participants 
European Medicines Agency (EMA): 
x Maximum tocilizumab serum concentration (Cmax) 
x Tocilizumab area under the concentration-time 
curve from time zero to infinity (AUC0-inf) 
Food and Drug administration (FDA): 
x Tocilizumab Cmax 
x Tocilizumab area under the concentration-time 
curve up to the last measurable concentration 
(AUC0-t) 
Secondary Objectives 
Secondary Endpoints 
To evaluate PK of BIIB800 and 
Actemra over time  
x Time to reach Cmax (Tmax) 
x Apparent total body clearance (CL/F) 
x Apparent terminal half-life (t1/2) 
To evaluate the clinical safety of 
BIIB800 and Actemra  
x Incidence of treatment-emergent adverse events 
(TEAEs) and serious AEs from time of 
administration to end of study (EoS) 
To evaluate PD profiles BIIB800 
and Actemra  
For soluble IL-6R:  
x 
Area under the effect–time curve (AUE)  
x 
Maximum observed effect (Emax) 
x 
Time to Emax (tEmax) 
For high sensitive C-reactive protein (hsCRP): 
x 
AUE 
x 
Minimum observed effect Emin  
x 
Time to Emin (tEmin) 
To evaluate the immunogenicity of 
BIIB800 and Actemra  
x 
Anti-drug antibodies (ADA) and neutralizing 
antibodies (nAbs) 
x 
ADA titers 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
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11 
Study Design: 
Randomized, double-blind, single-dose, 2-treatment arm, parallel-
group study. 
Study Location: 
A maximum of 4 sites across the United Kingdom (1) and the US (3) 
are planned. 
Study Population: 
This study will be conducted in  participants who meet the following 
inclusion criteria:  
x Male, aged 18 to 55 years inclusive at the time of signing 
informed consent 
x Body weight between 60 kg and 90 kg and body mass index 
between 18.5 and 29.9 kg/m², inclusive 
x Good health as determined by the Investigator, based on 
medical history, screening assessments and physical 
examination 
Detailed criteria are described in Section 6. 
Number of 
Planned  
participants: 
Approximately 300 participants are planned to be randomized.  
Treatment Groups: 
Two treatment groups: 
x BIIB800 group, approximately 150 participants 
x Actemra group, approximately 150 participants 
Dosing regimen: a single dose of 162 mg BIIB800 or Actemra 
administered s.c. to the outer upper arm. 
Sample Size 
Determination: 
A sample size of 300 participants (150 per arm) will provide 
approximately 90% power for the bioequivalence testing of each pair of 
co-primary endpoints for each Regulatory Agency: Cmax and AUC0-t for 
FDA, and Cmax and AUC0-inf for EMA. Enrolled participants will be 
randomized 1:1 to receive either BIIB800 or Actemra. An inter-subject 
coefficient of variation (CV) of approximately 0.5 is initially assumed 
and a single injection site is specified. The geometric mean ratio is 
assumed to be 1.05. The PK endpoints are highly correlated; this 
correlation is initially assumed to be 1 and will be revisited during the 
pre-specified blinded sample size reassessment (BSSR), performed to 
recalculate the CV of PK endpoints. Based on the recalculated CV and 
evaluation of the correlation between the coprimary endpoints at the 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
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12 
BSSR timepoint, the sample size will be recalculated, and enrolment 
may be adjusted accordingly to ensure that the targeted study power is 
approximately 90%. Details on the BSSR procedure are described in 
Section 13.5.2. 
Statistical 
Methods: 
Co-primary endpoints and statistical analysis for bioequivalence 
assessment  
The statistical analysis of the PK endpoints, AUC and Cmax, is based 
upon the 90% confidence intervals for the ratio of the population 
geometric means for the parameters under consideration. This method 
is equivalent to two one-sided tests with the null hypothesis of 
bioinequivalence at the 5% significance level. The 90% confidence 
interval (for the average bioequivalence) is derived for the ratio of the 
averages (population geometric means) of the outcomes for BIIB800 or 
Actemra. The data will be transformed prior to analysis using a 
logarithmic transformation and the corresponding confidence interval 
for the difference between products will be obtained from an analysis 
of variance (ANOVA) model (fixed effects for treatment and body 
weight). To establish bioequivalence, the derived 90% confidence 
intervals back-transformed on the original scale should fall within 80-
125% limits. 
Visit Schedule 
Participants will undergo a screening visit and will be admitted to the 
clinical research unit (CRU) from Day -1 to Day 8. After discharge 
participants will attend the CRU for a further 7 scheduled outpatient 
visits.  
Study assessments conducted at each visit are listed in the Schedule of 
Activities (Table 1). 
Duration of Study 
Participation: 
Study duration for each participant will be up to 13 weeks:  
x Screening period up to 5 weeks 
x Treatment period: single dose at Day 1 
x Post-dose period: 8 weeks  
Benefit-Risk 
Analysis 
The study participants (healthy volunteers) will not obtain any clinical 
benefit from the treatment. Possible risks include those associated with 
s.c. injection (e.g. injection site discomfort or reaction). In a Phase I 
study utilizing a single dose of i.v. tocilizumab (4 mg/kg BIIB800, 
RoActemra, or Actemra [1]) approximately 70% of  participants 
experienced treatment-related AEs. The most common treatment-
related AEs were neutrophil count decreased (44%), white blood cell 
count decreased (27%), hypertriglyceridemia (20%), alanine 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
13 
aminotransferase (ALT) increased (18%), and aspartate 
aminotransferase (AST) increased (18%). AEs were transient and no 
serious AEs occurred. 
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Protocol 294BS101, Version2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra® 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
14 
1.2. 
Study Design Schematic 
Figure 1: 
Study Design 
 
CRU=Clinical Research Unit, D=day; EoS=end of study; N=number of  participants; R=randomization. 
 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
15 
1.3. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
 
Screening Admission 
Study period  
 
 
 
In-patient 
Out-patient 
Study Day 
-35 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
11 
15 
22 
29 
36 
43 
57/EoS1 
Hours Post Dose  
(Window) 
 
 
Predose  
 Dosing  
4 (± 10min) 
8 (± 10min) 
12 (± 10min) 
24 (± 1h) 
48 (± 1h) 
60 (± 1h) 
72 (± 1h) 
84 (± 1h) 
96 (± 1h) 
108 (± 1h) 
120 (± 1h)  
144 (± 3h) 
168 (± 3h) 
240 (± 1 day) 
336 (±1 day) 
504 (±1 day) 
672 (± 1 day) 
840 (± 1 day) 
1008 (± 1 day) 
1344 (± 1 day) 
Informed Consent 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
9
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Infor-
mation, Medical and 
Medication History 
9
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cotinine testing 
9
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, BMI 
9
95
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
9
92 
92 
 
 
 
 
92 
92 
 
92 
 
92 
 
92 
92 
92 
92 
92 
92 
92 
92 
92 
92 
Vital Signs 
9 
9 
9 

9 
9 
9 
9 9 

9 

9 

9 9 9 9 
9 
9 
9 
9 
9 
9 
Biochemistry, Hema-
tology, Urinalysis 
9
9





9
 
 
 




9

9 9 
9 
9 9 
9 
9
Coagulation 
9







 
 
 













12-Lead ECG 
9 
9 
 
 
 
 
 
9 
 
 
 

9 




9 
 
 
9 
 
 
9
Tuberculosis Test 
(QuantiFERON Gold) 
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Screen3 
9
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Test 
9
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis4 
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 

 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Dose 


 
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
continued 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
16 
Table 1: 
Schedule of Activities (continued) 
 
Screening Admission 
Study period  
 
 
 
In-patient 
Out-patient 
Study Day 
-35 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
11 
15 
22 
29 
36 
43 
57/EoS1 
Hours Post Dose  
(Window) 
 
 
Predose  
 Dosing  
4 (± 10min) 
8 (± 10min) 
12 (± 10min) 
24 (± 1h) 
48 (± 1h) 
60 (± 1h) 
72 (± 1h) 
84 (± 1h) 
96 (± 1h) 
108 (± 1h) 
120 (± 1h)  
144 (± 3h) 
168 (± 3h) 
240 (± 1 day) 
336 (±1 day) 
504 (±1 day) 
672 (± 1 day) 
840 (± 1 day) 
1008 (± 1 day) 
1344 (± 1 day) 
Blood Sample for PK 


9

9 9 9 9 9 
9 9 
9 9 
9 9 9 9 9 
9 
9 
9 
9 
9 
9 
Blood Sample for 
hsCRP and sIL-R6 


9 

9 
9 
9 
9 9 

9 

9 

9 
9 
9 
9 
9 
9 
9 
 
 
9 
Blood Sample for ADA 
and nAbs 


9















9

9


9
Injection Site Exam. 




9 9 9 9 9

9

9

9 9 9 9 9 9 9 9 9
9
(S)AE Recording6 
9
Concomitant 
medication/procedure 
9
ADA=anti-drug antibodies; AE=adverse event; BMI=body mass index; ECG=electrocardiogram; EoS=end of study; Exam.=examination; HIV=human 
immunodeficiency virus; hsCRP=high sensitive C-reactive protein; IMP=investigational medicinal product; nAbs=neutralizing antibodies; 
PK=pharmacokinetics, SAE=serious adverse event; sIL-R6=soluble interleukin-6-receptor. 
1 Participants who withdraw prior to Day 57 should undergo all assessments specified for the EoS visit.  
2 Full physical examination once during screening:  symptom-directed physical examination at the Investigator’s discretion at other study timings  
3 Blood, breath, or urine testing. 
4 Hepatitis includes: hepatitis C virus antibodies, hepatitis B surface antigen and total hepatitis B core antibody, hepatitis B surface antibody.  
5 Weight and BMI only. 
6 Any AE with onset between consenting and administration of the study treatment must be recorded if related to any study procedures. Between the time of 
administration of study treatment and EoS all AEs regardless of their relationship to study treatment or procedure must be reported. 
Time of study drug administration and all blood draws will be recorded into participant notes and entered into the electronic case report form. 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
17 
2. 
LIST OF ABBREVIATIONS 
ACR20 
American College of Rheumatology 20% 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BSSR 
blinded sample size reassessment 
CRO 
contract research organization 
CRU 
Clinical Research Unit 
CS 
clinically significant 
CV 
coefficient of variation 
D 
day 
DHA 
Dose Handling and Administration  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EoS 
end of study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HbsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
hsCRP 
high sensitive C-reactive protein 
ICH 
International Council for Harmonisation 
ICF 
informed consent form 
Ig 
immunoglobulin 
IL-6(R) 
interleukin-6(-receptor) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
i.v. 
intravenous 
LLN 
lower limit of normal 
N 
number of participants 
nAb 
neutralizing antibody 
NCS 
abnormal not clinically significant 
PD 
pharmacodynamics 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
18 
PK 
pharmacokinetic 
PKAS 
PK analysis set 
PKCS 
PK concentration analysis set 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
RA 
rheumatoid arthritis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAFS 
safety analysis full set 
s.c. 
subcutaneous 
SD 
standard deviation 
sIL-6R 
soluble interleukin-6-receptor 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
ULN 
upper limit of normal 
US 
United States 
USPI 
US prescribing information  
WHO 
World Health Organization 
PK/PD Terms and Definition 
Abbreviation 
Definition 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve up to the last measurable 
concentration 
AUC0-inf 
area under the concentration-time curve from time zero to infinity 
AUE 
area under the effect–time curve 
Cmax 
maximum concentration 
CL/F 
apparent total body clearance 
Emax 
maximum observed effect 
Emin 
minimum observed effect 
t1/2 
apparent terminal half-life 
Tmax 
time to reach Cmax 
tEmax(min) 
time to Emax(min) 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
19 
3. 
INTRODUCTION  
Tocilizumab (commercial name: RoActemra® in Europe, Actemra® in the United States [US] 
and other countries) a biologic disease-modifying antirheumatic drug, is a recombinant 
humanized monoclonal immunoglobulin (Ig) G1 antibody against the interleukin-6 receptor 
(IL-6R). Tocilizumab has been licensed first as an intravenous (i.v.) infusion (2009 in Europe) 
for the management of patients with rheumatoid arthritis (RA) refractory to conventional 
synthetic disease-modifying antirheumatic drugs and tumor necrosis factor inhibitors, followed 
by the approval of a subcutaneous (s.c.) formulation (2014 in Europe) [2]. Both presentations 
show similar effectiveness [2]. The s.c. formulation, however, offers a treatment option that may 
better suit patients’ lifestyle, contributing to improved convenience. Administration time is short 
and the burden on patients due to clinic visits is reduced as the dose can be administered at home 
by self-injection, using a device that requires no pre-injection preparation.  
3.1. 
Study Rationale 
BIIB800 (also referred to BAT1806) is being developed as a biosimilar tocilizumab product to 
the reference product RoActemra (EU brand name)/Actemra (US brand name).  
Bioequivalence of i.v. BIIB800 and the reference products RoActemra and Actemra 
administered to healthy Chinese males was established in a randomized, double-blind, Phase I 
pharmacokinetic (PK) study [1]. In a randomized, double-blind Phase III study in patients with 
moderate to severe RA despite methotrexate treatment, i.v. BIIB800 demonstrated equivalence to 
Actemra in terms of clinical efficacy, as assessed by the American College of Rheumatology 
20% (ACR20) response at 12 and 24 weeks after randomization.  
The aim of the current study is to demonstrate equivalence between BIIB800 and Actemra 
administered s.c. in terms of PK outcomes, and to compare the pharmacodynamics (PD), safety, 
and immunogenicity of BIIB800 and Actemra in healthy adult male participants. 
3.1.1. 
Rationale for Study Population 
This study will be conducted in healthy male volunteers. The study will provide an assessment of 
PK, PD, immunogenicity, and safety of s.c. BIIB800 in a sensitive population i.e., one without 
the confounding effects of comorbidities and concomitant medications which may be prevalent 
in patient populations. 
Enrolling only male participants reduces the potential variability in PK parameters.  
3.1.2. 
Rationale for Dose  
In accordance with the approved dosing recommendation for the reference product, participants 
will receive 162 mg of BIIB800 or Actemra, administered s.c. A single dose will be administered 
at one injection location (outer upper arm). This is considered sufficient to establish PK 
equivalence and comparability of PD, immunogenicity, and safety parameters between BIIB800 
and reference tocilizumab. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
20 
3.1.3. 
Study Design Rationale 
Analytical studies demonstrated a high degree of similarity between BIIB800 and the reference 
product in terms of quality attributes potentially relevant for PK and immunogenicity (Biogen, 
data on file).  
No clinically relevant immunogenicity has been observed for the reference product, regardless of 
administration route [3]. Furthermore, previous studies investigating BIIB800 administered via 
the i.v. route either as a single dose to healthy participants or by repeat dosing to patients with 
RA did not suggest any clinically relevant immunogenicity (Biogen, data on file).  
The study duration (57 days post dose at the participant level) is considered to be adequate, 
based upon the half-life of tocilizumab s.c. in healthy participants (29-43 hours [1,4,5]) and 
immunogenicity data from the Phase I BIIB800 i.v. study, indicating an increased incidence of 
anti-drug antibodies (ADAs) across treatment groups over time up to Day 57 following a single 
i.v. administration of reference or biosimilar tocilizumab [1].  
The final blood draw to measure serum tocilizumab is on Day 57 post dose. This corresponds to 
approximately 31 half-lives of tocilizumab administered s.c., based on calculations according to 
Schwabe et al. [4]. A 57-day follow-up is expected to cover the entirety of the quantifiable 
concentration-time plot for tocilizumab. 
3.2. 
Background 
3.2.1. 
Background on Tocilizumab  
Tocilizumab (commercial name: RoActemra in Europe, Actemra in the US and other countries) 
is a humanized, anti-human monoclonal antibody of the IgG1 subclass that targets soluble and 
membrane-bound IL-6R. It is produced in Chinese hamster ovary cells by recombinant 
deoxyribonucleic acid technology. Tocilizumab was shown to specifically bind to soluble IL-6R 
(sIL-6R) and membrane-bound IL-6R thereby inhibiting both soluble and membrane-bound 
IL-6-mediated signaling. Interleukin 6 (IL-6) is a pleiotropic pro-inflammatory multifunctional 
cytokine produced by a variety of cell types. IL-6 has a local paracrine function and can regulate 
systemic physiological and pathological processes, such as inducing secretion of 
immunoglobulins, activating T cells, inducing secretion of hepatic acute-phase proteins, and 
stimulating erythropoiesis. Elevated tissue and serum levels of IL-6 have been implicated in the 
disease pathology of several inflammatory and autoimmune disorders including RA, systemic 
juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, and 
cytokine-release syndrome. Inhibition of the biological activity of IL-6 or IL-6R has been 
effective in the treatment of these diseases for which tocilizumab has been approved in many 
countries. 
Tocilizumab has i.v. and s.c. formulations. In the US and European Union, both formulations of 
tocilizumab have been approved for many of the indications listed above (including RA, 
systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, systemic 
sclerosis-associated interstitial lung disease, and giant cell arteritis). 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
21 
3.2.2. 
Profile of Previous Experience with BIIB800 
See the Investigator’s Brochure for detailed information on relevant nonclinical and clinical 
studies. In addition, for the nonclinical and clinical profile of the reference products please refer 
to the Prescribing Information of Actemra [6] and the Summary of Product Characteristics for 
RoActemra [7]. 
3.2.2.1. 
Nonclinical Experience 
The nonclinical studies for BIIB800 showed pharmacological effects similar to the reference 
products in vitro and in vivo.  
BIIB800 and Actemra showed similar in vitro binding activity to IL-6R and cellular activity, 
preventing the binding of membrane-bound IL-6R and soluble IL-6R. BIIB800 did not produce 
antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity effects. In 
vivo PD studies showed that BIIB800 can alleviate collagen-induced arthritis in monkeys.  
BIIB800 (i.v.) and the reference products showed similar primary PK characteristics after single 
and multiple dosing in cynomolgus monkeys. No differences between BIIB800 and the reference 
products were observed in toxicology or immunogenicity studies in cynomolgus monkeys. 
The s.c. formulation of BIIB800 also showed similar PK characteristics to the reference products 
(Actemra and RoActemra) in cynomolgus monkeys, with only minor differences. After multiple 
doses, some differences by sex were observed, and the drug exposure was slightly higher in male 
than in female monkeys with both products. The ADA rate of BIIB800 was slightly higher than 
that with RoActemra. Subcutaneous BIIB800 injection did not produce irritation in New Zealand 
rabbits and did not show in vitro hemolytic reactions. 
3.2.2.2. 
Clinical Experience 
BIIB800 is currently in clinical development. Bioequivalence of BIIB800 i.v. versus the 
reference products RoActemra and Actemra was established in a randomized, double-blind, 
Phase I PK study in healthy Chinese males [1]. In a randomized, double-blind Phase 3 study in 
patients with moderate to severe RA despite methotrexate treatment, BIIB800 i.v. demonstrated 
clinical equivalence to Actemra, as assessed by the ACR20 response at 12 and 24 weeks after 
initiation. 
3.3. 
Benefit-Risk Assessment 
The participants participating in this study will not obtain any clinical benefit from the treatment; 
however, the information obtained from this study will contribute to the development of 
additional therapy for immune-mediated inflammatory diseases such as rheumatoid arthritis.  
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of BIIB800 is provided in the Investigator’s Brochure and informed 
consent form (ICF). A high-level summary is provided here. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
22 
In this study, BIIB800 s.c. will be administered to healthy male participants. As discussed in 
Sections 3.1 and 3.2, the extensive nonclinical/physicochemical characterization, and nonclinical 
evaluations of BIIB800 fully support its biosimilarity to Actemra and RoActemra. Based on 
those data, it is expected that BIIB800 s.c. will show a comparable PK and safety profile to its 
reference and thus administration of BIIB800 to healthy participants can be considered to be low 
risk. 
In the Phase I study of a single dose of i.v. tocilizumab (4 mg/kg BIIB800, RoActemra, or 
Actemra [1]) approximately 70% of participants experienced treatment-related AEs. The most 
common treatment-related AEs were neutrophil count decreased (44%), white blood cell count 
decreased (27%), hypertriglyceridemia (20%), alanine aminotransferase (ALT) increased (18%), 
and aspartate aminotransferase (AST) increased (18%) which is in line with the safety profile of 
the reference products. AEs were transient and no serious AEs (SAEs) occurred.  
The participants included in this Phase I study will receive a single dose (162 mg) of study 
treatment s.c. The AE profile is expected to be similar to that observed in the Phase I study of a 
single i.v. dose of tocilizumab. 
Due to the mechanism of action of tocilizumab, as stated in the reference product label, 
recipients may be at an increased risk of infections and serious infections including tuberculosis 
or other opportunistic infections, however these were not observed in the previous Phase I 
healthy volunteer study.  
Neutropenia and thrombocytopenia may occur during tocilizumab treatment. Neutrophil and 
platelet counts will be closely monitored.  
Due to the risk of serious hypersensitivity reactions [6] following study treatment administration, 
all participants will be closely monitored on site, and treatments needed to manage anaphylactic 
reactions must be readily available at the study sites. Injection site reactions including erythema, 
pruritus, pain, and hematoma may occur. In clinical studies these were mild to moderate, and the 
majority resolved without any treatment. Injection site reactions will be closely monitored on site 
[6-8]. 
Due to transient or intermittent mild and moderate elevations of hepatic transaminases and 
observed serious drug-induced liver injury, including acute liver failure, hepatitis, and jaundice, 
with the reference product, bilirubin (total and direct), alkaline phosphatase, ALT, AST, and 
gamma glutamyl transferase will be closely monitored. The ALT, AST, and total bilirubin values 
of eligible participants must be below <1.1 × upper limit of normal (ULN) at Screening.  
Complications of diverticulitis have been reported with the reference product. All participants 
will be closely monitored for signs and symptoms of diverticulitis by the Investigator by means 
of physical examination and laboratory blood tests at the study sites. Development of ADAs was 
observed in some participants with the reference product but there was no correlation of antibody 
development with AEs [6]. 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
23 
4. 
STUDY OBJECTIVES AND ENDPOINTS 
x 
Primary Objective 
x 
Co-Primary Endpoints 
To show equivalence in PK of BIIB800 and 
Actemra following s.c. administration of a single 
dose to healthy male participants 
European Medicines Agency (EMA): 
x 
Maximum tocilizumab serum 
concentration (Cmax) 
x 
Tocilizumab area under the 
concentration-time curve from 
time zero to infinity (AUC0-inf) 
Food and Drug Administration (FDA): 
x 
Tocilizumab Cmax 
x 
Tocilizumab area under the 
concentration-time curve up to the 
last measurable concentration 
(AUC0-t) 
Secondary Objectives 
Secondary Endpoints 
To evaluate PK of BIIB800 and Actemra over time  Time to reach Cmax (Tmax) 
Apparent total body clearance (CL/F) 
Apparent terminal half-life (t1/2) 
To evaluate the clinical safety of BIIB800 and 
Actemra  
Incidence of AEs and SAEs from time 
of administration to end of study (EoS)  
To evaluate PD profiles BIIB800 and Actemra 
For sIL-6R:  
x 
Area under the effect–time curve 
(AUE)  
x 
Maximum observed effect (Emax) 
x 
Time to Emax (tEmax) 
For high sensitive C-reactive protein 
(hsCRP): 
x 
AUE 
x 
Minimum observed effect Emin  
x 
Time to Emin (tEmin) 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
24 
To evaluate the immunogenicity of BIIB800 and 
Actemra  
ADA and neutralizing antibodies (nAbs) 
ADA titers 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
25 
5. 
STUDY DESIGN 
5.1. 
Study Overview 
This is a randomized, double-blind, single-dose, 2-treatment arm, parallel-group study to 
compare the PK, PD, safety, and immunogenicity of BIIB800 with Actemra in healthy male 
participants.  
A total of approximately 300 participants is planned to be enrolled and randomized 1:1 to receive 
a single 162 mg dose of BIIB800 or of Actemra, administered as a s.c. injection in the outer 
upper arm. A blinded sample size reassessment (BSSR) will be performed during the study, to 
assess actual coefficient of variation (CV) to inform whether an adjustment needs to be made to 
the sample size.  
Informed consent will be obtained before performing any study-related procedures. Participants 
will be screened for eligibility between Day -35 and Day -2. On Day -1, eligible participants will 
be admitted to the Phase I unit and will remain resident until after completion of the Day 8 
assessments. On Day 1 participants will be randomized 1:1, stratified according to body weight 
(<75kg, ≥ 75 kg), to 1 of the 2 treatment arms. Outpatient visits will occur on Days 11, 15, 22, 
29, 36, 43, and 57. Safety, PK, PD, and immunogenicity assessments will be performed at 
specified time points throughout the study up to Day 57. 
See Figure 1 for a schematic of the study design and Table 1 for Schedule of Activities. 
5.2. 
Study Duration for Participants  
The total study duration for each participant will be up to 13 weeks:  
x Screening period up to 5 weeks 
x Treatment period: single dose at Day 1 
x Post-dose period: 8 weeks 
Participants will undergo a screening visit, will be admitted on Day –1 and will remain resident 
until Day 8. After discharge participants will have 7 scheduled outpatient visits. All visits and 
assessments must be performed within the time windows from Day 1. Study days are counted 
from Day 1; timing of assessment by hour is relative to time of dosing on Day 1. 
Participants are considered enrolled at admission (Day -1). 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
26 
5.3. 
Study Stopping Rules and Study Termination 
There are no formal stopping rules. 
The Sponsor may terminate this study at any time after informing the Investigator, ethics 
committee, and applicable regulatory agencies. The Sponsor will notify Investigators in the event 
that the study is to be placed on hold, completed, or terminated. 
Conditions that may warrant termination of the study include, but are not limited to, the 
following:  
x Potential health risk for participants deemed unacceptable by an Investigator or the study 
Sponsor 
x High withdrawal rate 
x New scientific knowledge becomes available that makes the objectives of the study no 
longer feasible or valid 
x Insufficient enrolment of participants 
x Request of the Sponsor or regulatory authority, or independent ethics committee 
withdraws its approval 
5.4. 
Unscheduled Visits 
Data collected during unscheduled visits should be recorded on electronic case report forms 
(eCRFs) only if the data support protocol objectives and/or are required for safety monitoring. 
5.5. 
End of Study 
The EoS date for a participant is the date of the last outpatient study visit (Day 57) or the date of 
last contact with the participant in case of early termination, or AE follow-up to Day 57. 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
27 
6. 
STUDY POPULATION 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the timepoint specified for the individual eligibility criterion. 
6.1. 
Inclusion Criteria 
1. Ability to understand the purpose and risks of the study, to provide informed consent, and 
to authorize the use of confidential health information in accordance with national and 
local privacy regulations.  
2. Healthy Male participants aged 18 to 55 years inclusive, at the time of signing the 
informed consent. 
3. Have a body mass index between 18.5 and 29.9 kg/m2, inclusive. 
4. Total body weight between 60.0 and 90.0 kg, inclusive. 
5. Systolic blood pressure <135 mmHg or >85 mmHg at Screening, after being supine for at 
least 5 minutes. 
6. No clinically significant (as determined by the Investigator) 12-lead electrocardiogram 
(ECG) abnormalities, no cardiac pacemaker. 
7. All participants must agree to adhere to the contraception requirements (see Section 
12.5). 
8. Hematology and blood chemistry results at Screening: 
x platelet count t lower limit of normal (LLN) 
x absolute neutrophil count t LLN 
x ALT and AST <1.1 × ULN 
x Total bilirubin <1.1x ULN 
x CRP ≤1.1 x ULN 
x Fasting serum low density lipoprotein-cholesterol ≤190 mg/dL and/or fasting serum 
triglycerides ≤150 mg/dL 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
28 
6.2. 
Exclusion Criteria 
Medical History 
1. History or positive test result at Screening for human immunodeficiency virus (HIV).  
2. History of hepatitis C infection or positive test result at Screening for hepatitis C virus 
antibody. 
3. Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and total hepatitis B core antibody [anti-HBc]). Participants with immunity to hepatitis B 
from previous natural infection (defined as negative HBsAg, positive anti-HBc, and 
positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative 
HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.  
4. Serious infection (as determined by the Investigator) within the 6 months prior to 
Screening. 
5. Any active infection, even if minor, ongoing at the time of Screening or Day -1. 
6. History of systemic hypersensitivity reaction to the active drug substance, the excipients 
contained in the formulation, and if appropriate, any diagnostic agents to be administered 
during the study. 
7. History of any cancer, including carcinoma in situ, lymphoma or leukemia.  
8. History of immunodeficiency or other clinically significant immunological disorders, or 
autoimmune disorders, ongoing or frequent/ recurring infection defined as more than 
3 per year requiring treatment or active herpes zoster (according to the Investigator’s 
discretion, including the post-herpetic neuralgia period if occurring) within one year prior 
to randomization or history of systemic fungal infection at any time. 
9. History of clinically significant (in the opinion of the Investigator) atopic allergy (e.g., 
asthma, urticaria, eczematous dermatitis, allergic rhinitis), hypersensitivity, or allergic 
reactions. 
10. History of angioedema.  
11. History or presence of any clinically relevant nervous system disease including, but not 
restricted to any stroke/Transient Ischemic Attack, demyelinating conditions or of 
seizures other than febrile seizures before the age of 5 years. 
12. Current use of antihyperlipidemic drugs. 
13. Presence of any non-healed wound or bone fracture of a clinically relevant size (in the 
Investigator’s opinion). 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
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Biogen MA Inc. 
29 
14. History of, or current, intestinal ulceration or diverticulitis. 
15. History of any condition that increases the current risk of bleeding, such as hemorrhoids 
with bleeding symptoms, acute gastritis, or gastric and duodenal ulcers, which required 
medical intervention. 
16. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
17. History of alcohol or substance abuse within the past 5 years (as determined by the 
Investigator), a positive urine drug screen or alcohol test at Screening and Day -1, or an 
unwillingness to adhere to visit window alcohol restrictions, or to refrain from illicit 
drugs throughout the study.  
18. History or evidence of habitual use of tobacco- or nicotine-containing products within 
90 days of Screening or a positive urine cotinine test at Screening or at Day -1 and 
unwillingness to abstain throughout the study. 
19. Any history of difficulty in blood sampling or any vasovagal attack during blood 
sampling which in the opinion of the Investigator may interfere with the study sampling.  
20. A positive diagnostic tuberculosis test result within 35 days prior to Day -1, defined as a 
positive QuantiFERON® test result or 2 successive indeterminate QuantiFERON test 
results. 
Medications 
21. Prior use of any biological products within 90 days before Screening. 
22. Any prior exposure to tocilizumab or to any other agent directly acting on IL-6 or on its 
receptors including investigational products (e.g., siltuximab, sarilumab etc.). 
23. Administration of immunoglobulins for anti-tetanus and anti-rabies post-exposure 
prophylaxis within 3 weeks prior to administration of study drug. 
24. Any live or attenuated immunization or vaccination given within 30 days prior to Day -1 
or planned to be given during the study period. 
Other 
25. Blood donation, participation in any study requiring repeated blood sampling, or 
hemorrhage requiring treatment, or any blood/platelet transfusion, where more than one 
unit of blood was taken, in the 3 months prior to Screening. 
26. Clinically significant abnormal laboratory test values, as determined by the Investigator, 
at Screening or Day -1. 
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CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
30 
27. Plans to undergo elective procedures or surgeries at any time after signing the ICF until 
EoS. 
28. Previous participation in this study or previous studies with reference tocilizumab 
(Actemra or RoActemra). 
29. Previous or current enrolment in any other drug, device, or clinical study, or plan to take 
part in other clinical studies during this study, or treatment with an investigational drug or 
approved therapy for investigational use within 90 days prior to Day 1, or 5 half-lives, 
whichever is longer.  
30. Non-suitable skin for dosing or post-dosing evaluations of upper arm for any reasons 
(including presence of tattoos, skin pigmentation disorders, scarring etc., which may 
obscure the injection site).  
31. Inability to comply with study requirements. 
32. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
participant unsuitable for enrolment. 
6.3. 
Screening, Retesting, Screen Failures, Rescreening, and 
Randomization 
6.3.1. 
Screening 
No screening procedures can be carried out prior to participant providing informed consent. 
Participants will have a unique identification number used at Screening. Subjects will be 
assigned a subject number prior to dosing. Assignment of subject numbers will be in ascending 
order and no numbers will be omitted (e.g., Subjects 101, 102, 103). Any identification numbers 
that are assigned will not be reused even if the participant does not continue in the study. 
Replacement subjects will be assigned a subject number corresponding to the number of the 
subject he is replacing plus 1000 (e.g., Subject 1101 replaces Subject 101). 
Participants will be identified on all study documentation only by a screening identification 
number and/or subject number. A list identifying the subjects by subject number will be kept in 
the site master file. Study sites are required to document all screened participants initially 
considered for inclusion in the study. Screening is performed between Day -35 and Day -2. 
6.3.2. 
Retesting 
Laboratory assessments or vital signs assessments not meeting inclusion criteria may be repeated 
once at the Investigator’s discretion, during the screening period. 
Participants who have clinically significant abnormal laboratory test values as determined by the 
Investigator are not eligible for retesting. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
31 
6.3.3. 
Screening Failures 
Screening failures are defined as participants who sign the ICF but are not subsequently 
randomized. If a participant is considered a screen failure, the reasons for exclusion must be 
documented in the participant’s source documents and on the screening log.  
6.3.4. 
Rescreening 
Participants may be re-screened once in the study, only if the reason for screen-fail was not a 
clinically significant out-of-range laboratory evaluation. At the rescreening all eligibility criteria 
must be confirmed and met. 
6.3.5. 
Randomization  
Participants will be randomized pre-dosing at Day 1, only after all screening assessments have 
been completed and after the Investigator has verified that the participants are eligible per criteria 
in 6.1 and 6.2.  
Participants will be randomized, according to the stratification factor body weight (<75kg, ≥ 75 
kg), to receive either BIIB800 or Actemra in a 1:1 ratio based on the study randomization 
scheme provided by the biostatistician.  
The master randomization list is kept at each site pharmacy in a locked location to which only 
the unblinded pharmacists have access. The list is accessed to randomize a patient and dispense 
the corresponding treatment. The randomization is captured on the randomization tracker to 
indicate which subject numbers have been allocated. This is done in a blinded manner and all 
sites have access to the randomization tracker. 
The randomization tracker will document the date, the site and the randomization numbers used. 
Pharmacy staff at each site will be responsible for updating the tracker in order to inform the 
other sites of the data recorded. Study Project Management will ensure that different sites are 
scheduled to randomize participants at different times, taking time zones into consideration and 
allowing sites sufficient time to update the tracker. The CRO’s standard operating procedure 
(SOP) “provides further information about the process. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
32 
7. 
STUDY TREATMENT  
7.1. 
Regimen 
Refer to and follow the Dose Handling and Administration (DHA) document.  
Participants will receive a single dose of 162 mg BIIB800 or Actemra via autoinjector, 
administered s.c. in the outer area of the upper arm. To maintain the blind, participants will be 
blindfolded in the presence of the IMP.  
7.2. 
Study Treatment Management 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practices. 
The IMP will be prepared by the Unblinded pharmacist from supplies of BIIB800 or Actemra, 
based upon the randomization schedule.  
Site staff should follow the DHA document for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  
Study treatment will be administered by qualified site staff only to participants enrolled into the 
study. Autoinjectors are for single-use only and should not be reused. 
7.3. 
BIIB800 
BIIB800 will be provided by the Sponsor as a ready to-use, single-dose 0.9 mL autoinjector that 
delivers 162 mg tocilizumab, 0.112 mg of histidine, 0.605 mg of histidine hydrochloride 
monohydrate, 17.06 mg of arginine hydrochloride, 18.00 mg of sucrose, 0.45 mg polysorbate 80, 
and water for injection. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements. At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law. The study label will be added by the unblinded pharmacist. Study treatment must 
not be used after the expiration date.  
7.3.1. 
Preparation for Administration 
The unblinded study site staff member administering BIIB800 should carefully review the 
instructions provided in the DHA document. 
Check that the autoinjector package is not damaged and that the liquid in the autoinjector is 
clear, not cloudy or discolored, and has no floating particles.  
Do not use the autoinjector if the liquid is cloudy, discolored or has floating particles in it. The 
autoinjector in question should be saved at the study site and the product complaint reported 
immediately to the Sponsor. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
33 
Contact information for reporting a product complaint is provided in the study reference guide. 
7.3.2. 
Storage 
Study treatment must be stored in a secure location.  
BIIB800 is to be stored at 2qC to 8qC (36qF to 46qF), in a locked refrigerator, with limited 
access. For the most up-to-date storage requirements, follow the instructions provided in the 
DHA document. 
7.3.2.1. 
Handling and Disposal 
The Investigator must securely store and then destroy all used and unused autoinjectors of 
BIIB800 unless otherwise instructed by the Sponsor. 
Full drug accountability as described in Section 7.3.2.2 must be completed before any 
destruction may be performed. After such destruction, the Sponsor must be notified, in writing, 
of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction. The documentation will be filed in the Investigator Site 
File (ISF) and the trial master file (TMF). 
7.3.2.2. 
Accountability 
Accountability for study treatment is the responsibility of the Investigator and will be performed 
by unblinded study site staff/unblinded CRAs in order to maintain the blind. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed, and accounts of any study treatment accidentally or deliberately destroyed or lost. 
Appropriate forms to ease study treatment accountability will be provided by the contract 
research organization (CRO). 
By the end of the study, reconciliation must be made between the amount of BIIB800 supplied, 
dispensed, and subsequently destroyed, lost, or returned to the Sponsor. A written explanation 
must be provided for any discrepancies. 
7.4. 
Reference Product 
Actemra (reference product) will be provided by the CRO as a ready to-use, single-dose 0.9 mL 
autoinjector that delivers 162 mg tocilizumab, L-arginine hydrochloride (19 mg), L--histidine 
(1.52 mg), L-histidine hydrochloride monohydrate (1.74 mg), L-methionine (4.03 mg), 
polysorbate 80 (0.18 mg), and water for injection. 
Actemra will be labeled for study use in accordance with all applicable regulatory requirements. 
At a minimum, the label will include a study reference code, study treatment identifier, quantity 
of dosage units, lot number, and other pertinent information in accordance with local law. Study 
treatment must not be used after the expiration date. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
34 
Storage, handling, disposal, and accountability will follow the procedures described above for 
BIIB800. 
The respective reference product labelling (i.e., US Prescribing Information [USPI], Summary of 
Product Characteristics) will be included in the Study Reference Guide. 
7.5. 
Blinding Procedures 
The site staff responsible for administering the dose will be unblinded. The unblinded site staff 
must not participate further with the participant management or reporting. Details regarding 
blinding will be documented in a study specific blinding plan. 
 
In the event of a medical emergency that requires unblinding of a participant’s treatment 
assignment, refer to 12.4.4.1 
7.6. 
Precautions 
Due to the risk of serious hypersensitivity reactions following study treatment administration, 
treatments needed to manage anaphylactic reactions must be readily available at the study sites. For 
other precautions please see the Actemra product labeling. 
 
7.7. 
Concomitant Therapy and Procedures 
7.7.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between Day 1 and Day 57 or EoS. 
Participants should be instructed to contact their Investigators before taking any new 
medications, including nonprescription drugs, dietary supplements, and herbal preparations. 
Subjects are also advised that in the event of a medically urgent indication where delay in taking 
a concomitant medication could place the subject at risk, they should alert the study team as soon 
as possible about concomitant medications taken at the direction of non-study medical 
professionals. 
7.7.1.1. 
Allowed Concomitant Therapy 
x Nonprescription medications for symptomatic relief of mild discomfort are permitted. 
x Therapies that are considered necessary to protect the participant’s welfare in 
emergencies may be given at the Investigator’s discretion. 
The Investigator will record all concomitant medications taken by the participants in the 
participant source data and in the appropriate section of the eCRF. Any AE(s) requiring 
concomitant medication must be reported in the eCRF. 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
35 
7.7.1.2. 
Prohibited Concomitant Therapy 
Prohibited medicines are indicated in the exclusion criteria (Section 6.2).  
7.7.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
time of consent and Day 57 or EoS. 
7.8. 
Continuation of Treatment  
There is no provision to provide study treatment after the study. 
7.9. 
Lifestyle Considerations 
The following will not be allowed: 
x Alcohol  
x 
within 48 hours prior to Screening. 
x 
from 48 hours prior to Day -1 (admission) through discharge from the clinical 
research unit (CRU) on Day 8. 
x 
within 48 hours prior to each outpatient visit until EoS. 
x Nicotine and tobacco-containing products from Screening to Day 57/EoS. 
x Illicit/recreational drugs during the study, or evidence of recent illicit/recreational 
drug use in the screening period. 
x Caffeine- or theophylline-containing food or beverages or dietary supplements 
(including but not limited to coffee, green tea, black tea, cola, energy drinks, and 
cacao) from 36 hours before dosing through discharge from the CRU (Day 8) and 24 
hours prior to each outpatient visit until EoS. 
x Significant changes in diet (at the Investigator discretion) from 2 weeks prior to 
Screening up to Day 1. 
x Foods and beverages containing poppy seeds within 7 days prior to Screening and 
Day -1. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
36 
8. 
RULES FOR WITHDRAWAL FROM STUDY FOR INDIVIDUAL 
PARTICIPANTS  
8.1. 
Lost to Follow-Up 
Participants will be considered ‘lost to follow-up’ if they fail to return for scheduled visits and 
are unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
x In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant. These contact attempts 
should be documented in the subject’s medical record. 
x Should the participant continue to be unreachable, that participant will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
8.2. 
Withdrawal of Participants from the Study 
Participants must be withdrawn from the study for any one of the following reasons: 
x The participant withdraws consent for participation in the study, at their own 
discretion (the participant may or may not give a reason for withdrawal).  
x The participant participates in another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
x The participant is unwilling or unable to comply with the protocol. 
x Any events that endanger the safety of the participant (at the Investigator’s and/or 
Sponsor’s discretion). 
The primary reason for the participant’s withdrawal from the study must be recorded in the 
participant’s eCRF, if provided. 
Participants must undergo an EoS visit and respective assessments, and every attempt must be 
made to complete an EoS visit, except in the event of death, withdrawal of consent, or other 
reasons that feasibly make completion of an EoS visit not possible. 
. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
37 
Participants who withdraw from the study before dosing may be replaced at the discretion of the 
Sponsor. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
38 
9. 
SAFETY ASSESSMENTS 
The timing of assessment of safety events is stated in Table 1 Section 1.3 Schedule of 
Assessments. 
9.1. 
Clinical Assessments 
The following clinical assessments will be performed: 
x AE and SAE recording from dosing throughout the study. 
x Injection site examination including local reactions (pain, tenderness, 
erythema/redness, and induration/swelling) and systemic reactions (fever, 
nausea/vomiting, diarrhea, headache, fatigue, myalgia) according to Appendix 1. 
x A full physical examination (Screening) with subsequent symptom-directed physical 
examination during the study. The full physical examination will include the 
examination of the head, neck, eyes, ears, nose, and throat, cardiovascular system, 
pulmonary system, lymphatic system, endocrine system, muscular and skeletal 
system, general appearance, extremities, abdomen, skin, and neurological system. 
x Vital sign measurements at frequency as per Table 1: temperature, heart rate, systolic 
and diastolic blood pressure (to be assessed on the arm not used for administration of 
study treatment), and respiratory rate. Measurements should be made before blood is 
drawn for laboratory tests, if applicable, and after the participant has been in supine 
position for at least 5 minutes (except for body temperature). All measurements will 
be performed singly and repeated once if outside the relevant reference ranges. 
x Height, weight, and body mass index measurements at Screening and Day -1. 
x 12-lead ECGs will be performed following a minimum of 5 minutes rest in the supine 
position, at frequency as per Table 1. All ECG tracings will be reviewed by the 
Investigator and repeated once, if necessary, at the Investigator’s discretion. The 
Investigator will perform an overall evaluation of the 12-lead ECG for safety 
purposes and recording will be reported as ‘normal’, ‘abnormal clinically significant 
(CS)’, or ‘abnormal not clinically significant (NCS)’. 
x Concomitant therapy and procedure recording throughout the study. 
9.2. 
Laboratory Assessments 
Samples will be analyzed using Good Laboratory Practice validated assays. All samples will be 
clearly identified. Details about the handling and labeling of biological samples are provided in 
the Laboratory Manual. 
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Biogen MA Inc. 
39 
The laboratory reports received from the laboratory will be reviewed, signed, and dated by the 
Investigator or delegate, and filed at the site. Clinically significant abnormal laboratory findings 
as judged by the Investigator must be recorded as AEs in the eCRF.  
The following laboratory assessments will be performed at intervals specified in Table 1: 
x Hematology: red blood cell count, white blood cell count, mean cell volume, mean 
cell hemoglobin, mean cell hemoglobin concentration, hemoglobin and hematocrit, 
platelet count, white blood cell count differential (absolute and %, comprising 
basophils, eosinophils, lymphocytes, monocytes, neutrophils)  
x Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, ALT, AST, gamma glutamyl 
transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, 
low density lipoprotein and triglycerides, C-reactive protein (C-reactive protein only 
at Screening) 
x Urinalysis: blood, glucose, ketones, pH, protein, specific gravity, bilirubin, color, 
nitrites, urobilinogen; microscopy will be done in case of abnormal urinalysis 
findings  
x Coagulation: prothrombin time (PT)/international normalized ratio (INR), partial 
thromboplastin time (PTT) 
x Serology: hepatitis C virus antibodies, hepatitis B surface antigen and total hepatitis B 
core antibody, hepatitis B surface antibody, HIV antigen/antibody, tuberculosis test 
(QuantiFERON Gold) 
x Urine drug screen 
x Alcohol test (urine/breath/blood per site standard) 
x Cotinine 
9.3. 
Immunogenicity Assessments 
The following assessments will be performed to evaluate immunogenicity: 
x ADA 
x nAb 
x ADA titers 
Serum samples for ADA evaluation will be collected and processed according to standard 
procedures as described in the Laboratory Manual. ADA-positive samples will be further 
investigated for determination of nAbs and ADA titers The actual date and time of each sample 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
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Biogen MA Inc. 
40 
collection will be recorded. The serum samples will be stored frozen before shipment to a central 
bioanalytical laboratory for evaluation. Details of ADA blood sample collection, processing, 
storage, and shipping procedures are described in the Laboratory Manual. 
The ADA and nAb levels will be measured using a validated electrochemiluminescence assay. 
Details of the method validation and sample analysis will be described in bioanalytical method 
validation reports and the bioanalytical sample analysis report. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
41 
10. 
PHARMACOKINETIC ASSESSMENTS 
See Section 1.3 for the timing of all assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
clinic to have the evaluations repeated. 
The following parameters will be calculated to assess PK: 
x Cmax 
x AUC0-inf 
x AUC0-t  
x Tmax 
x CL/F 
x t1/2 
The quantification of tocilizumab in serum will be performed using a validated enzyme-linked 
immunosorbent assay. The analytical methods used to measure serum concentrations of 
tocilizumab will be described in a bioanalytical sample analysis report. Details on processes for 
collection and handling (labeling, disposal, storage, and transportation) will be described in the 
Laboratory Manual.  
The exact date and time of sample collection (24-hour clock time) must be recorded in the eCRF 
and will be used to calculate PK parameters. PK parameters will be derived using 
noncompartmental methods with validated software. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
42 
11. 
PHARMACODYNAMIC ASSESSMENTS 
See Section 1.3 for the timing of all assessments. 
PD profiles will be assessed using the following biomarkers: 
x sIL-6R 
x hsCRP 
The quantification of biomarkers will be performed using validated assay methods. Details on 
processes for collection and handling of biomarker samples (labeling, disposal, storage, and 
transportation) will be described in the Laboratory Manual.  
The exact date and time of sample collection (24-hour clock time) must be recorded in the eCRF. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
43 
12. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the participant. If necessary, according 
to Investigator’s clinical judgment, appropriate medical intervention should be provided. 
At the signing of the ICF, each participant must be given the site medical telephone number for 
reporting AEs and medical emergencies. Throughout the protocol, the Sponsor is named, but 
reporting may be done through a CRO. 
12.1. 
Definitions 
12.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation participant (participant) 
who has received a pharmaceutical product, regardless of causal relationship with the product. 
An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease which is temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
Determination of whether an abnormal assessment (e.g., laboratory value, vital sign, 12-lead 
ECG) result meets the definition of an AE will be made by the Investigator. Abnormal results are 
not considered AEs unless the result is considered by the Investigator to be clinically significant. 
12.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that: 
x Results in death. 
x In the view of the Investigator, places the participant at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death. 
x Requires inpatient hospitalization or prolongation of existing hospitalization. 
x Results in persistent or significant disability/incapacity. 
x Results in a congenital anomaly/birth defect. 
x Is a medically important event. 
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
participant or may require intervention to prevent one of the other outcomes listed in the 
definition above. (Examples of such medical events include allergic bronchospasm requiring 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
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Biogen MA Inc. 
44 
intensive treatment in an emergency room or convulsions occurring at home that do not require 
an inpatient hospitalization.) 
12.2. 
Safety Classifications 
12.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
x If the event meets the criteria for an SAE as defined in Section 12.1.2. 
x The relationship of the event to study treatment as defined in Section 12.2.2. 
x The severity of the event as defined in Section 12.2.3. 
12.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment. 
Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational product if there 
is not a reasonable possibility that the event has been caused by the product under 
investigation. Factors pointing toward this assessment include but are not limited to the 
lack of reasonable temporal relationship between administration of the investigational 
product and the AE, the presence of a biologically implausible relationship between the 
product and the AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational product if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation. Factors that point toward this assessment include, but are not limited to a 
positive rechallenge, a reasonable temporal sequence between administration of the 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the product and the AE, or a lack of an alternative explanation for 
the AE. 
12.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to participant or does not make participant uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily needed 
for relief of symptoms. 
Moderate 
Symptoms of sufficient severity to make participant uncomfortable; performance of 
daily activity is influenced; participant is able to continue in study; treatment for 
symptoms may be needed. 
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Biogen MA Inc. 
45 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant 
impact on participant’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptoms may be given and/or participant hospitalized. 
 
12.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by the Sponsor according to the Investigator’s 
Brochure.  
12.3. 
Monitoring and Recording Events 
12.3.1. 
Adverse Events 
Any AE experienced by the participant between the time of consenting and the administration of 
the study treatment is to be recorded on the AE pre-dose page of the eCRF if related to any study 
procedures regardless of the severity or seriousness of the event. Any AE experienced by the 
participant between the time of administration of study treatment and EoS is to be recorded on 
the AE page of the eCRF, regardless of the severity or seriousness of the event or its relationship 
to study treatment. At each study visit, the Investigator will assess the participant for AEs and 
will record any new AEs or updates to previously reported AEs on the eCRF. 
AEs that are ongoing when the participant completes or discontinues the study will not be 
followed by the Investigator. 
12.3.2. 
Serious Adverse Events 
Any SAE experienced by the participant between the time of study drug administration at Day 1 
and Day 57/EoS is to be recorded on the SAE form and the AE page of the eCRF, regardless of 
the severity of the event and/or its relationship to study treatment. After EoS the event should be 
reported to the Sponsor only if the Investigator considers the SAE to be related to study 
treatment. 
SAEs must be reported to the Sponsor’s Global Patient Safety and Pharmacovigilance (GPSP) 
Mailbox within 24 hours of study site staff awareness of the SAE, as described in Section 12.3.3. 
Follow-up information regarding an SAE also must be reported within 24 hours of study site 
staff awareness.  
Any SAE that is ongoing when the participant completes or discontinues the study will not be 
followed by the Investigator.  
 
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46 
12.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor’s GPSP Mailbox within 24 hours of the site staff becoming aware of 
the SAE. It is the Investigator’s responsibility to ensure that the SAE reporting information and 
procedures are used and followed appropriately. 
 
 
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Reporting Information for SAEs 
The SAE Form must be submitted to the Sponsor’s GPSP Mailbox via the email address:  
BBUsafetyreporting@biogen.com 
regardless of the severity of the event or relationship of the event to study treatment. 
To report initial or follow-up information on an SAE, email a completed SAE form; refer to 
the Study Contact List for complete contact information.  
12.3.3.1. Deaths 
Death is an outcome of an event. All causes of death must be reported as SAEs within 24 hours 
of the site becoming aware of the event. The Investigator should make every effort to obtain and 
send death certificates and autopsy reports to the Sponsor. The term ‘Death’ should be reported 
as an SAE only if the cause of death is not known and cannot be determined. 
12.3.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered. 
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs (in blinded or unblinded fashion) to regulatory 
agencies according to local law. The Sponsor will submit SUSARs to Investigators in a blinded 
fashion. 
12.4. 
Procedures for Handling Special Situations 
12.4.1. 
Pregnancy 
Participants should not impregnate their partners during the study and for 90 days after their dose 
of study treatment.  
A pregnancy occurring in a female partner of a study participant within 90 days of administration 
of the study drug to the male participant must be reported by the Investigator on the Pregnancy 
Form to the Sponsor’s GPSP Mailbox BBUsafetyreporting@biogen.com within 24 hours of the 
site staff becoming aware of the pregnancy.  
Refer to the Study Contact List for complete contact information.  
The Investigator or site staff must report the outcome of the pregnancy to the Sponsor. A 
pregnancy is not considered an AE and should not be recorded on the AE eCRF. 
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48 
Congenital abnormalities and birth defects in the offspring of a female partner of the male study 
participants should be reported as an SAE if conception occurred during the study treatment 
period or within 90 days from the dose of study treatment. 
12.4.2. 
Product Complaint    
The Investigator must enter any device malfunction and/or failure into Biogen's Clinical Site 
Support (CSS) portal (https://biogen.service-now.com/csmcss), as a product complaint. 
If the device malfunction and/or failure results in an AE, an AE CRF also needs to be 
completed.  
 
The study site must formally notify the Sponsor’s GPSP Mailbox 
(BBUsafetyreporting@biogen.com) within 24 hours of awareness of any SAE(s) associated with 
the product complaint, by submitting the study-specific SAE Form. 
 
12.4.3. 
Overdose 
An overdose is any dose of study treatment administered to a participant that exceeds the dose 
assigned to the participant according to the protocol. Overdoses are not considered AEs and 
should not be recorded as an AE on the eCRF; however, all overdoses must be recorded on an 
Overdose form and emailed to the Sponsor’s GPSP Mailbox BBUsafetyreporting@biogen.com 
within 24 hours of the site becoming aware of the overdose.  
An overdose must be reported to the Sponsor even if the overdose does not result in an AE. If an 
overdose results in an AE, the AE must be recorded. If an overdose results in an SAE, both the 
SAE and Overdose forms must be completed and emailed to the Sponsor.  
All study treatment-related dosing information must be recorded on the dosing eCRF. 
12.4.4. 
Medical Emergency 
In a medical emergency requiring immediate attention, site Investigator will apply appropriate 
medical intervention, according to current standards of care. The Investigator (or designee) 
should contact the study’s Medical Monitor as soon as possible to discuss the case. Refer to the 
Study Contact List for complete contact information.  
12.4.4.1. Unblinding for Medical Emergency 
In a medical emergency when knowledge of the participant’s treatment assignment may 
influence the participant’s clinical care, the Investigator may access the participant’s assigned 
treatment. The Investigator must document the reasons for unblinding in the participant’s source 
documents. The site will follow their (CRO’s) internal SOPs regarding emergency unblinding. 
The Investigator is strongly advised not to divulge the participant’s treatment assignment to any 
individual not directly involved in managing the medical emergency, or to personnel involved 
with the analysis and conduct of the study. The Investigator must contact the Sponsor or study’s 
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Medical Monitor as soon as possible to inform of such situations. Refer to the Study Contact List 
for complete contact information. 
12.5. 
Contraception Requirements 
All participants must ensure that effective contraception is used during the study and for 90 days 
after their dose of study treatment. This includes barrier methods to prevent exposure to 
participant’s sperm. In addition, participants should not donate sperm for at least 90 days after 
their dose of study treatment. 
Pregnancy reporting is described in Section 12.4.1.  
12.6. 
Safety Responsibilities 
12.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
x Monitor all AEs, including SAEs, and report on the eCRF regardless of the severity 
or relationship to study treatment. 
x Determine the seriousness, relationship, and severity of each event. 
x Determine the onset and resolution dates of each event. 
x Monitor and record any pregnancies and follow up on the outcome of all pregnancies. 
x Complete an SAE form for each SAE and email to the Sponsor within 24 hours of the 
site staff becoming aware of the event. 
x Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to the Sponsor within 24 hours of the site staff becoming aware of 
new information. 
x Ensure all AE and SAE reports are detailed and have supporting documentation in the 
participants’ medical records. 
x Pursue AE follow-up information, if possible, until EoS. Record AE follow-up 
information, including resolution, on the eCRF, as applicable. 
x Report SAEs to Ethics Committees or IRBs in accordance with local requirements. 
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50 
12.6.2. 
The Sponsor  
The Sponsor’s responsibilities include the following: 
x Retention of overall accountability for safety reporting. The study CRO is responsible 
for reviewing with site staff the definitions of AE and SAE, as well as the instructions 
for monitoring, recording, and reporting AEs, SAEs, pregnancies, and product 
complaints. 
x The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames. 
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13. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 4. The details 
of analysis methods will be documented in statistical analysis plan (SAP). 
13.1. 
General Considerations 
Except for the primary endpoint analyses, all analyses will be descriptive with no hypothesis 
testing. No imputation will be applied for missing values except for those specified in the 
protocol. No multiplicity adjustment will be applied in the hypothesis testing for the primary 
analysis. 
13.2. 
Analysis Sets 
PK concentration analysis set (PKCS): includes all study participants with at least one post-
dose assessment. The serum concentration of tocilizumab will be summarized based on the 
PKCS. 
PK analysis set (PKAS): includes all randomized study participants with at least one calculable 
PK parameter. Participants with a major protocol violation that would affect PK evaluation will 
be excluded from the PKAS. Determination of exclusion, with a list of excluded participants , 
will be made prior to the unblinding.  
The PKAS will be used to evaluate the PK equivalence between study treatments. Major 
protocol violations will be specified in the SAP. 
Safety analysis full set (SAFS): all randomized study participants who receive the study 
treatment. Safety analysis will be presented according to treatment received. The SAFS will be 
used for the analysis of safety and immunogenicity. 
13.3. 
Methods of Analysis 
13.3.1. 
Safety 
All safety analyses will be performed descriptively on the SAFS according to treatment received. 
No hypothesis testing will be performed. Previous medication and concomitant medications will 
be coded and summarized according to the World Health Organization (WHO) Anatomical 
Therapeutic Chemical (ATC) classification system.  
13.3.1.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. Treatment-emergent 
adverse events (TEAEs) are defined as AEs that started or worsened in severity from time of 
study drug administration to EoS. The incidence of TEAEs will be summarized by primary 
system organ class (SOC) and preferred term within each SOC. AEs will also be tabulated by 
severity, seriousness, and relationship to study treatment. All data will be presented in summary 
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tables by treatment received group and overall. TEAEs leading to premature study 
discontinuation or death will be listed. 
A listing of non-TEAEs will be provided. 
13.3.1.2. Laboratory Results 
All laboratory assessments will be analyzed descriptively and presented in summary tables. No 
hypothesis testing between treatment groups will be performed. For each variable the summary 
tables will present actual values, and number and proportion of participants with out-of-range 
values by visit.  
13.3.1.3. Vital Signs and 12-lead Electrocardiogram 
Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, respiratory rate) and 
12-lead ECG evaluations will be analyzed descriptively and presented in summary tables by visit. 
13.3.2. 
Pharmacokinetics 
Tocilizumab concentrations will be summarized for the PKCS using descriptive statistics by 
actual time of measurement for each treatment separately. 
Co-primary endpoints and statistical analysis for bioequivalence assessment  
Primary estimand for FDA and EMA 
Population: PKAS including all randomized study participants who receive the study treatment 
and with at least one calculable PK parameter. 
Endpoint: for EMA: Cmax and AUC0-inf calculated on samples collected from Day 1 post-dose to 
EoS;  
 
for FDA: Cmax and AUC0-t calculated on samples collected from Day 1 post-dose to 
EoS. 
Treatment condition: Randomized Actemra (reference product) and BIIB800 (test product). 
Handling intercurrent events: 
x Premature discontinuation of study for any reason with available PK parameters  
x Incomplete or partial dose delivery 
All the intercurrent events will be handled with the Treatment policy strategy. 
 
Contingency measures and missing data handling:  
 
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Considering the safety profile of Actemra as per USPI and EPAR, and the healthy study 
population, fatal events are unexpected. Should such fatal events occur, whether related or 
unrelated to the treatments administered, and/or any other disruptive events such as a pandemic 
occur during the study conduct period, all available data to time of death or  disruptive event will 
be utilised. 
Missing data will be handled through estimation (under estimator assumption), no imputation for 
missing data will be implemented. 
Population-level summary: the ratio of the averages (population geometric means) of the PK 
parameters for the test and reference products. 
The statistical analysis of the PK endpoints, area under the concentration-time curve (AUC0-inf 
for EMA and AUC0-t for FDA [9,10]) and Cmax, is based upon the 90% confidence intervals for 
the ratio of the population geometric means between the test (BIIB800) and reference (Actemra) 
groups. This method is equivalent to two one-sided tests with the null hypothesis of 
bioinequivalence at the 5% significance level. The 90% confidence interval (for the average 
bioequivalence) is derived for the ratio of the averages (population geometric means) of the 
outcomes for BIIB800 and Actemra. The data will be transformed prior to analysis using a 
logarithmic transformation and the corresponding confidence interval for the difference between 
products will be obtained from an analysis of variance (ANOVA) model (fixed effects for 
treatment, site and body weight). If one site has recruited fewer  than 30 participants then  the 
primary analysis of ANOVA analysis will include only treatment and body weight as fixed 
effects. To establish bioequivalence, the derived 90% confidence intervals back-transformed on 
the original scale should fall within 80-125% limits (including 100%) for the ratio of the product 
averages.  
Due to the testing procedure that all null hypotheses of bioinequivalence need to be rejected at 
the 5% significance level, no adjustment for multiplicity will be performed. 
Other PK endpoints 
Except for Tmax, which will be summarized by n, minimum, median, and maximum, all PK 
parameters will be summarized by treatment group using n, mean (arithmetic and geometric), 
standard deviation (SD), percentage of variation coefficient (including geometric variation 
coefficient), minimum, median, and maximum濁 
For PK parameter calculations, concentrations that are below the limit of quantification (BLQ) or 
missing will be set to zero. Further details of the PK parameter analysis will be described in the 
SAP. 
Pharmacodynamics 
All PD measurements (i.e., biomarkers, see Section 11) and the changes from baseline for the 
continues PD endpoints will be summarized by treatment group using n, mean (arithmetic and 
geometric), SD, percentage of variation coefficient (including geometric variation coefficient), 
minimum, median, and maximum. Further details of the PD parameter analysis will be described 
in the SAP. 
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13.3.3. 
Immunogenicity Data 
Incidence of ADAs to BIIB800 and Actemra, their neutralizing potential and ADA titer of 
positive samples will be summarized for the participants in the SAFS dataset by incidence of 
ADA-positive and nAb positive samples for each timepoint and overall for each treatment 
separately. Further details of the analysis will be described in the SAP. 
13.4. 
Interim Analyses 
No formal unblinded interim analysis is planned to be performed. 
13.5. 
Sample Size Considerations 
13.5.1. 
Initial Sample Size Calculation 
A sample size of 300 participants (150 per arm), assuming a non-evaluable rate of 10%, will 
provide approximately 90% power for the bioequivalence testing of each pair of co-primary 
endpoints for each Regulatory Agency: Cmax and AUC0-t for FDA, and Cmax and AUC0inf for 
EMA. Enrolled participants will be randomized (equal allocation ratio 1:1) to receive a single 
dose of either BIIB800 or Actemra. An inter-subject CV of approximately 0.5 is initially 
assumed based on published PK outcome data in healthy participants [4,11,12], and a single 
injection site will be specified (upper arm).The geometric mean ratio is assumed to be 1.05.  
The PK endpoints are known to be highly correlated [13]; this correlation is initially assumed to 
be 1 and will be revisited with the BSSR procedure prespecified to recalculate the CV of PK 
endpoints.  
13.5.2. 
Blinded Sample Size Recalculation (BSSR) 
A BSSR will be performed when the first 100 participants have completed their Day 29 
outpatient visit, to assess the CV and its correlation between co-primary endpoints.  
The first 100 participants in the BSSR are expected to be sufficient to provide a precise estimate 
of the nuisance parameter (CV) for the primary endpoints and correlation between the primary 
endpoints. The BSSR will be conducted on the PK parameters based on the post-dose data up to 
the Day 29 outpatient visit. Previous studies have shown that 29 days post-administration 
represent a sufficient duration in which to measure the evolution of the PK parameters relevant 
to the primary endpoints [5,12].  
The initially targeted sample size (see Section 13.5) corresponds to a CV of approximately 0.5, a 
correlation of 1.0 and a non-evaluable rate of approximately 10%. Based on the recalculated CV 
and evaluation of the correlation between the coprimary endpoints at the BSSR timepoint, the 
sample size will be recalculated, and enrolment may be adjusted accordingly to ensure that the 
targeted study power is approximately 90%. Details will be specified in a separate SAP. 
In principle, a BSSR might lead to a type I error inflation. However, the risk of inflation is 
expected to be small [14,15]. The effect of the BSSR on the type I error rate will be evaluated in 
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a simulation study. Details will be specified in a technical simulation report and the SAP or 
protocol may subsequently be amended.” 
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14. 
ETHICAL REQUIREMENTS 
The Sponsor, any contracted third party, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol and applicable International Council for 
Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines and conduct the study 
according to local regulations. 
The Investigators are responsible for demonstrating timely oversight of all clinical study data 
from their site, including data external to the electronic data capture (EDC) system, such as 
laboratory data. Investigators must e-sign all their data on completed eCRFs, at the participant, 
visit, or casebook level, prior to database lock, as well as before any subsequent re-lock.  
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator must maintain a list of the appropriately 
qualified persons to whom study-related duties have been delegated. The Investigator is 
responsible for oversight of those individuals and for ensuring the integrity of the tasks 
performed and any data generated. 
14.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
14.2. 
Ethics Committee and Institutional Review Boards 
The Investigator must obtain ethics committee or Institutional Review Board (IRB) approval of 
the protocol, ICF, and other required study documents prior to starting the study, as applicable 
according to national and local regulations.  
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee or IRB. A copy of the approved ICF must be 
provided to the Sponsor. After approval, the ICF must not be altered without the agreement of 
the relevant ethics committee or IRB and the Sponsor. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor must receive a letter documenting ethics committee or IRB approval, which 
specifically identifies the protocol, protocol number, and ICF, prior to the initiation of the study. 
Protocol amendments will be participant to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee or IRB at required intervals and not 
less than annually. 
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At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee or IRB and the Sponsor. 
14.3. 
Changes to Final Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect participant safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant. In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 14.4). 
14.4. 
Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, informed consent utilizing the approved ICF must be obtained.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the participant must be explained to the participant. The 
participant must be given sufficient time to consider whether to participate in the study. 
A copy of the signed and dated ICF must be given to the participant. The original signed and 
dated ICF will be retained with the study records. Local regulations must be complied with in 
respect to the final disposition of the original and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the participant’s medical record. 
Should additional information that may affect participants’ willingness to continue in the study 
become available, the Investigators will be notified in a timely manner, according to all local and 
applicable law. An updated ICF may be required. 
14.5. 
Participant Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, participants 
must also provide all authorizations required by applicable national and local privacy regulations 
(e.g., Protected Health Information authorization in North America). 
Study reports will be used for research purposes only. The participant will not be identified by 
name in eCRFs, study-related forms, study reports, or any related publications. The Sponsor, its 
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partners and designees, ethics committees, IRBs, and various government health agencies may 
inspect the records of this study. Every effort will be made to keep the participant’s personal 
medical data confidential. 
14.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
14.7. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or partnering company) with the participant before the participant makes a decision to 
participate in the study. 
14.8. 
Study Report Signatory 
The Sponsor will designate one of the participating Investigators as a signatory for the study 
report. This determination will be made by several factors, including but not limited to the 
Investigator's experience and reputation in the studied indication, the Investigator's contribution 
to the study in terms of design, management, and/or participant enrolment, or by other factors 
determined to be relevant by the Sponsor. 
The Sponsor will follow all applicable local regulations pertaining to study report signatories. 
14.9. 
Registration of Study and Disclosure of Study Results 
The Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
The Sponsor also will notify, when required, the regulatory authorities and ethics committees or 
IRBs about the completion or termination of this study and send a copy of the clinical study 
report in accordance with necessary timelines. 
14.10. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records. 
In addition, the Investigator must notify the Sponsor of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site. 
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Phase I study BIIB800 s.c. vs Actemra 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
59 
15. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES 
15.1. 
Vendors 
The Sponsor will ensure oversight of any study-related duties and functions carried out on its 
behalf and will specify in writing all duties and functions that are transferred.  
15.1.1. 
Contract Research Organization  
A CRO will be responsible for operational aspects of the study including but not limited to study 
initiation, site staff training, monitoring of source data, and data management. 
15.1.2. 
Electronic Data Capture 
Participant information will be captured and managed by study sites via an EDC system. The 
designated study personnel can access the EDC system only upon training and will be 
responsible for entry and update of the raw data in the eCRFs, in a timely manner. To ensure the 
quality of clinical data across all sites, automatic edit checks will be programmed into the 
database, and a data management review will also be performed on data entered into the EDC 
database; data will be checked for consistency and apparent omissions and/or discrepancies. Data 
queries will be raised in the database for resolution by the site. Entry of data into eCRFs and all 
updates made throughout the study will be documented automatically in the software audit trail. 
The site Investigator is responsible for signing off completed, individual participants’ eCRFs. 
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. Biogen retains all data, programs, and 
outputs generated during the study. At study close, data are uploaded from the EDC database and 
stored in accordance with Biogen standard operating procedures. Statistical programming and 
outputs are locked in the analysis environment and no updates are permitted; standard 
programming procedures will apply. 
15.1.3. 
Central Laboratories for Laboratory Assessments 
A central laboratory will perform the PK, ADA, IL-6R and hsCRP analyses. All other blood and 
urine samples will be analyzed locally at the site. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
60 
16. 
ADMINISTRATIVE PROCEDURES 
16.1. 
Study Site Initiation 
The Investigator must not screen any participants prior to completion of a study initiation visit. 
The Investigator and other site staff, as appropriate, will attend the study initiation visit, which 
must include a detailed review of the protocol, study procedures, and study responsibilities, 
including safety reporting. 
16.2. 
Quality Control and Quality Assurance 
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate.   
During and/or after completion of the study, the Sponsor and/or the regulatory authorities may 
wish to perform onsite audits or inspections. The Investigator will be expected to cooperate with 
any audit or inspection and to provide assistance and documentation (including source data) as 
requested. The Investigator must notify the Sponsor immediately if notified of a potential 
inspection by a regulatory authority. 
16.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the participants’ clinic records. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents. 
The CRA will visit the study site at regular intervals during the study and after the study has 
completed, as appropriate. A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review. It also will provide the monitoring strategy, 
with emphasis on participant safety, maintaining the blind, data integrity, and critical data and 
processes. An unblinded CRA will be responsible for monitoring randomization and medication 
records. 
During these visits, eCRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. Documentation of 
results will be provided to the Sponsor or designee in a timely fashion to allow follow-up and 
verification of compliance with the monitoring plan. Remote evaluation of data (centralized 
monitoring) may also be conducted and reported as defined in the monitoring plan. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of participant rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
61 
16.4. 
Study Funding 
The Sponsor is responsible for study funding. All financial details are provided in the separate 
contracts between the institution, Investigator, and the Sponsor organization. 
16.5. 
Publications 
Authorship of any publications resulting from this study will be determined on the basis of the 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals 2018, which 
states: 
Authorship credit should be based on (1) substantial contributions to conception and design, 
acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it 
critically for important intellectual content; (3) final approval of the version to be published and 
(4) agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. Authors should meet conditions 1, 2, 3, and 4. 
Acquisition of funding, collection of data, or general supervision of the research alone does not 
justify authorship. 
All persons designated as authors should qualify for authorship, and all those who qualify should 
be listed. 
Each author should have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content. 
All publications (e.g., manuscripts, abstracts, oral/slide presentations, book chapters) based on 
this study must be submitted to Biogen for review.  
 
 
 
 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
62 
17. 
REFERENCES 
1. 
Zhang H, Wang H, Wei H, Chen H, Liu J, Li C, et al. A Phase I Clinical Study 
Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed 
Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men. Front 
Pharmacol 2020;11:609522. 
2. 
Lauper K, Mongin D, Iannone F, Klami Kristianslund E, Kvien TK, Nordström D, et al. 
Comparative effectiveness of subcutaneous tocilizumab versus intravenous tocilizumab 
in a pan-European collaboration of registries. RMD Open 2018;4(2):e000809. 
3. 
Burmester GR, Choy E, Kivitz A, Ogata A, Bao M, Nomura A, et al. Low 
immunogenicity of tocilizumab in patients with rheumatoid arthritis. Ann Rheum Dis 
2017;76(6):1078-85. 
4. 
Schwabe C, Illes A, Ullmann M, Ghori V, Vincent E, Petit-Frere C, et al. 
Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar 
MSB11456 versus both the US-licensed and EU-approved products: a randomized, 
double-blind trial. Expert review of clinical immunology 2022;18(5):533-43. 
5. 
Yu KS, Kim B, Shin D, Park MK, Hwang JG, Kim MG, et al. Pharmacokinetics and 
safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a 
randomized, double-blind, single-dose phase I study. Expert Opin Investig Drugs 
2023;32(5):429-39. 
6. 
Actemra - drug label information (last updated Dec 2022). Available at: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-
e35c6bf2de13. 
7. 
EMA. RoActemra - summary of product characteristics Available at: 
https://www.ema.europa.eu/en/documents/product-information/roactemra-epar-product-
information_en.pdf. 
8. 
Kivitz A, Olech E, Borofsky M, Zazueta BM, Navarro-Sarabia F, Radominski SC, et al. 
Subcutaneous tocilizumab versus placebo in combination with disease-modifying 
antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 
2014;66(11):1653-61. 
9. 
EMA. Guideline on the invesigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 
1/ Corr ). Published 2010. Available at: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-
bioequivalence-rev1_en.pdf. 
10. 
FDA. Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted 
Under an ANDA Guidance for Industry. Published 2023. Available at: 
https://www.fda.gov/media/87219/download. 
11. 
Celtrion. A Phase 1, Randomized, Double-blind, Two-arm, Parallel Group, Single-dose 
Study to Compare the Pharmacokinetics and Safety of Two Subcutaneous Injection 
Formulations of Tocilizumab (CT-P47 and EU-approved RoActemra) in Healthy 
Subjects [Internet]. clinicaltrials.gov; 2021 Dec [cited 2022 Oct 6]. Report No.: 
NCT05188378.Available from: https://clinicaltrials.gov/ct2/show/NCT05188378. 
12. 
Fettner S, Mela C, Wildenhahn F, Tavanti M, Wells C, Douglass W, et al. Evidence of 
bioequivalence and positive patient user handling of a tocilizumab autoinjector. Expert 
opinion on drug delivery 2019;16(5):551-61. 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
63 
13. 
Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption 
rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 
1991;29(10):394-9. 
14. 
 Kieser, Meinhard. (2020). Methods and Applications of Sample Size Calculation and 
Recalculation in Clinical Trials. 10.1007/978-3-030-49528-2.    
15. 
Friede T., Kieser M Blinded sample size reassessment in non-inferiority and equivalence 
trials. Stat Med 2003; 22(6):995-1007.   
16. 
FDA. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. Published 2007. Available at: 
https://www.fda.gov/media/73679/download. 
 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
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Biogen MA Inc. 
64 
18. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Randomized, Double-Blind, Parallel-Group, Phase I 
Study to Evaluate the Pharmacokinetics, Safety, and Immunogenicity of BIIB800 s.c. compared 
to  Actemra® in Healthy Male Participants,” and agree to conduct the study according to the 
protocol and the applicable ICH guidelines and GCP regulations, and to inform all who assist me 
in the conduct of this study of their responsibilities and obligations. 
 
 
 
_______________________________________________________________ 
Investigator’s Signature 
 
 
 
Date (DD MMM YYYY) 
 
 
_______________________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 
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Protocol 294BS101, Version 2.0, 06 December 2023 
 
Phase I study BIIB800 s.c. vs Actemra 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
65 
19. 
APPENDIX 1: GRADING SCALES 
A-Table 1: 
Local and systemic reaction grading scale 
 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially life 
threatening  
(Grade 4) 
Local 
Pain 
Does not interfere with 
activity 
Repeated use of 
nonnarcotic pain 
reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room (ER) 
visit or hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
ER visit or 
hospitalization 
Erythema/ 
Redness 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/ 
Swellinga 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or 
interferes with activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Systemic 
Feverb 
38.0 - 38.4 °C 
38.5 - 38.9 °C 
39.0 - 40.0 °C 
> 40.0 °C 
Nausea/ 
vomiting  
No interference with 
activity or 1 - 
2 episodes/24 hours  
Some interference with 
activity or 
>2 episodes/24 hours  
Prevents daily activity, 
requires outpatient IV 
hydration  
ER visit or 
hospitalization for 
hypotensive shock  
Diarrhea  
2 - 3 loose stools in 
24 hours 
4 - 5 loose stools in 
24 hours  
6 or more loose stools 
in 24 hours or requires 
outpatient IV hydration 
ER visit or 
hospitalization  
Headache  
No interference with 
activity  
Repeated use of non- 
narcotic pain reliever 
>24 hours or some 
interference with 
activity  
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity  
ER visit or 
hospitalization  
Fatigue  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents 
daily activity  
ER visit or 
hospitalization  
Myalgia 
No interference with 
activity  
Some interference with 
activity  
Significant; prevents 
daily activity  
ER visit or 
hospitalization  
a 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
b 
Oral temperature; no recent hot or cold beverages or smoking. 
ER=emergency room. 
From [16] (slightly adapted). 
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