Clinical trial NCT04680637
Conditions: Active Systemic Lupus Erythematosus
Sponsor: Amgen
Start date: 2021-05-06; Completion date: 2023-05-22
Enrollment: 168 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to evaluate the efficacy and safety of efavaleukin alfa in subjects with active systemic lupus erythematosus.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Efavaleukin Alfa intervention 2: Placebo intervention 3: Standard of Care
Intervention descriptions: intervention 1: Administered as a subcutaneous (SC) injection. intervention 2: Administered as a subcutaneous (SC) injection. intervention 3: Standard of care procedures and therapies for managing active systemic lupus erythematosus will be carried out according to each investigator's standard procedures.

Protocol documents:
Prot_000.pdf: 
Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
Page 1 of 118 
CONFIDENTIAL  
FORM-495569, v.26, 29 May 2020 
 
Title Page 
Protocol Title: 
A Phase 2b Dose Ranging Study to Evaluate 
the Efficacy and Safety of Efavaleukin Alfa in 
Subjects with Active Systemic Lupus 
Erythematosus With Inadequate Response to 
Standard of Care Therapy (VIOLET) 
Short Protocol Title: 
Efficacy and Safety of Efavaleukin Alfa in 
Subjects with Active Systemic Lupus 
Erythematosus 
Protocol Number: 
20200234 
Investigational Product: 
Efavaleukin Alfa 
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
, MD 
Function: 
Vice President Global Development 
Key 
Sponsor 
Contact 
Name: 
, MD 
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
Telephone Number: 
Email Address: 
EudraCT Number: 
2020‐003509‐72 
NCT Number: 
NCT04680637 
Protocol Version Date: 
Document Version 
Date 
Original 
09 October 2020 
Superseding Original 
Protocol 
30 November 2020 
Amendment 1 
25 August 2021 
Amendment 2 
01 September 2022 
Amendment 3 
21 October 2022 
Amendment 4 
06 March 2023 
Data Elements Standards Version: 
7.0 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
Page 2 of 118 
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Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000.   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
Page 3 of 118 
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Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 2b Dose Ranging Study to Evaluate 
the Efficacy and Safety of Efavaleukin Alfa in Subjects with Active Systemic Lupus 
Erythematosus With Inadequate Response to Standard of Care Therapy (VIOLET), 
dated 06 March 2023, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary .................................................................................................. 9 
1.1 
Synopsis ..................................................................................................... 9 
1.2 
Study Schema ........................................................................................... 18 
1.3 
Schedule of Activities ................................................................................ 19 
2. 
Introduction ........................................................................................................... 26 
2.1 
Study Rationale ......................................................................................... 26 
2.2 
Background ............................................................................................... 26 
2.2.1 
Disease ..................................................................................... 26 
2.2.1.1 
Interleukin 2 and T Regulatory Cells in 
Systemic Lupus Erythematosus .............................. 26 
2.2.1.2 
Low Dose Interleukin 2 in Inflammatory 
Disease ................................................................... 27 
2.2.1.3 
Clinical experience with Low Dose IL-2 in 
Systemic Lupus Erythematosus .............................. 28 
2.2.2 
Amgen Investigational Product Background:  
Efavaleukin Alfa ........................................................................ 29 
2.2.2.1 
Toxicology ............................................................... 29 
2.2.2.2 
Human Exposure .................................................... 29 
2.3 
Benefit/Risk Assessment ........................................................................... 30 
2.3.1 
COVID-19 .................................................................................. 31 
3. 
Objectives and Endpoints/Estimands .................................................................... 32 
4. 
Study Design ........................................................................................................ 36 
4.1 
Overall Design .......................................................................................... 36 
4.1.1 
Adaptive Design Elements ......................................................... 37 
4.2 
Patient Input into the Study Design ........................................................... 38 
4.3 
Justification for Investigational Product Dose ............................................ 38 
4.4 
End of Study ............................................................................................. 39 
5. 
Study Population .................................................................................................. 40 
5.1 
Inclusion Criteria ....................................................................................... 41 
5.2 
Exclusion Criteria ...................................................................................... 43 
5.3 
Lifestyle Considerations ............................................................................ 46 
5.4 
Subject Enrollment .................................................................................... 46 
5.5 
Screen Failures ......................................................................................... 47 
6. 
Study Intervention ................................................................................................. 47 
6.1 
Study Interventions Administered .............................................................. 47 
6.1.1 
Investigational Products ............................................................ 47 
6.1.1.1 
Dose Administration and Schedule .......................... 48 
6.1.2 
Medical Devices ........................................................................ 48 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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6.1.3 
Other Protocol-permitted Therapies ........................................... 49 
6.1.3.1 
Immunosuppressants/Immunomodulators ............... 49 
6.1.3.2 
Oral Corticosteroids................................................. 49 
6.1.3.3 
Topical Corticosteroids and Topical 
Calcineurin Inhibitors ............................................... 49 
6.1.3.4 
Non-steroidal Anti-inflammatory Drugs 
(NSAIDS) and Other Analgesic Therapies ............... 49 
6.1.3.5 
Anti-proteinuria Agents ............................................ 50 
6.1.4 
Other Treatment Procedures ..................................................... 50 
6.1.4.1 
Home Health Care Visits ......................................... 50 
6.1.5 
Product Complaints ................................................................... 50 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 51 
6.2 
Dose Modification ...................................................................................... 51 
6.2.1 
Dose Treatment Group Study Escalation/De-
escalation and Stopping Rules .................................................. 51 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 51 
6.2.2.1 
Amgen Investigational Product:  
Efavaleukin Alfa ...................................................... 51 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 52 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 52 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 52 
6.4.1 
Method of Treatment Assignment .............................................. 52 
6.4.2 
Blinding ..................................................................................... 53 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 53 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 53 
6.5 
Treatment Compliance .............................................................................. 53 
6.6 
Treatment of Overdose ............................................................................. 53 
6.7 
Prior and Concomitant Treatment ............................................................. 53 
6.7.1 
Prior Treatment ......................................................................... 53 
6.7.2 
Concomitant Treatment ............................................................. 53 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 54 
7.1 
Discontinuation of Study Treatment........................................................... 54 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 55 
7.2.1 
Reasons for Removal From Study ............................................. 55 
7.3 
Lost to Follow-up ....................................................................................... 56 
8. 
Study Assessments and Procedures .................................................................... 56 
8.1 
General Study Periods .............................................................................. 56 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 56 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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8.1.2 
Treatment Period ....................................................................... 57 
8.1.3 
Safety Follow-up Period ............................................................ 58 
8.1.4 
End of Study .............................................................................. 58 
8.2 
General Assessments ............................................................................... 58 
8.2.1 
Informed Consent ...................................................................... 58 
8.2.2 
Demographics ........................................................................... 58 
8.2.3 
Medical History .......................................................................... 58 
8.2.4 
Lupus Narrative ......................................................................... 59 
8.2.5 
Physical Examination ................................................................ 59 
8.2.6 
Physical Measurements ............................................................ 59 
8.2.7 
Substance Use History .............................................................. 59 
8.2.8 
Lupus Nephritis History ............................................................. 59 
8.2.9 
Efficacy Assessments ................................................................ 59 
8.2.9.1 
Hybrid Systemic Lupus Erythematosus 
Disease Activity Index ............................................. 59 
8.2.9.2 
British-Isles Lupus Assessment Group 
Index ....................................................................... 60 
8.2.9.3 
Cutaneous Lupus Erythematosus Disease 
Area and Severity Index .......................................... 60 
8.2.9.5 
Swollen and Tender Joint Count ............................. 61 
8.2.9.6 
Physician Global Assessment – Visual 
Analog Scale ........................................................... 61 
8.2.9.7 
Physician Global Assessment – 4-Point 
Verbal Rating Scale................................................. 62 
8.2.9.8 
SRI-4 ....................................................................... 62 
8.2.9.10 
Lupus Low disease Activity State (LLDAS) .............. 62 
8.2.9.11 
BILAG-based Combined Lupus 
Assessment (BICLA) ............................................... 62 
8.2.9.12 
Patient Reported Outcomes .................................... 63 
8.3 
Safety Assessments .................................................................................. 64 
8.3.1 
Vital Signs ................................................................................. 65 
8.3.2 
Electrocardiograms (ECGs) ....................................................... 65 
8.3.3 
Clinical Laboratory Assessments ............................................... 65 
8.3.3.1 
Serum Complement, Anti-dsDNA, and 
Anti-phospholipid Antibody Testing ......................... 66 
8.3.3.2 
Tuberculosis Testing ............................................... 66 
8.3.3.3 
HIV Antibodies, Hepatitis B, and Hepatitis 
C Testing ................................................................. 66 
8.3.4 
Adverse Events and Serious Adverse Events ............................ 66 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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8.3.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 67 
8.3.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 68 
8.3.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 68 
8.3.4.4 
Regulatory Reporting Requirements for 
Safety Information ................................................... 68 
8.3.4.5 
Safety Monitoring Plan ............................................ 69 
8.3.4.6 
Pregnancy and Lactation ......................................... 69 
8.4 
Pharmacokinetic Assessments .................................................................. 70 
8.5 
Pharmacodynamic Assessments .............................................................. 71 
8.6 
Pharmacogenetic Assessments ................................................................ 71 
8.7 
Antibody Testing Procedures .................................................................... 71 
8.8 
Biomarkers ................................................................................................ 72 
8.8.1 
Biomarker Assessment During the Study .................................. 72 
8.8.2 
Biomarker Development ............................................................ 72 
8.8.3 
Biomarker Future Research ....................................................... 73 
9. 
Statistical Considerations ...................................................................................... 74 
9.1 
Statistical Hypotheses ............................................................................... 74 
9.2 
Sample Size Determination ....................................................................... 74 
9.2.1 
Populations for Analysis ............................................................ 75 
9.2.2 
Covariates ................................................................................. 75 
9.2.3 
Subgroups ................................................................................. 75 
9.3 
Statistical Analyses ................................................................................... 76 
9.3.1 
Planned Analyses ...................................................................... 76 
9.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 76 
9.3.1.2 
Final Analysis .......................................................... 77 
9.3.2 
Methods of Analyses ................................................................. 77 
9.3.2.1 
General Considerations ........................................... 77 
9.3.2.2 
Efficacy Analyses .................................................... 77 
9.3.2.3 
Safety Analyses ...................................................... 77 
9.3.2.4 
Other Analyses ........................................................ 79 
10. 
References ........................................................................................................... 80 
11. 
Appendices ........................................................................................................... 84 
11.1 
Appendix 1.  List of Abbreviations ............................................................. 85 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 88 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 91 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 100 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 108 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 113 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 115 
 
List of Tables 
Table 1-1.  Analyses Schedule ...................................................................................... 17 
Table 1-2.  Schedule of Activities – Screening and Baseline ......................................... 19 
Table 1-3.  Schedule of Activities – Treatment Period ................................................... 22 
Table 1-4.  Schedule of Activities – Safety Follow-up/week 56 Visit ............................... 25 
Table 2-1.  Steady-state Median (IQR) of Efavaleukin Alfa Pharmacokinetic 
Parameter Prediction Following Q2W Subcutaneous Doses in 
Subjects with SLE ................................................................................... 30 
Table 4-1. 
Median (IQR) Peak Blood Treg Count and Fold Expansion 
Predicted at Planned Doses in Subjects with SLE .................................. 39 
Table 11-1.  Analyte Listinga .......................................................................................... 89 
Table 11-2.  DILI Potential Analyte Listing ..................................................................... 90 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 116 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 18 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 105 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 111 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and Safety of 
Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy (VIOLET) 
Short Protocol Title:  Efficacy and Safety of Efavaleukin Alfa in Subjects with Active 
Systemic Lupus Erythematosus 
Study Phase:  2b 
Indication:  Systemic lupus erythematosus (SLE) 
Study Rationale 
This is a phase 2b dose-ranging study to assess the efficacy and safety of efavaleukin 
alfa (AMG 592) in subjects with active SLE.  Efavaleukin alfa may be a viable treatment 
option for SLE patients who are not responding to current standard of care (SOC). 
Benefit/Risk Assessment 
Based upon the totality of currently available safety data, the benefit/risk profile of 
efavaleukin alfa is favorable.  Efavaleukin alfa has been well tolerated in clinical 
studies and has an acceptable safety profile.  Adverse drug reactions reported 
with efavaleukin alfa in clinical studies include erythema, pruritus, exacerbation in 
subjects with rheumatoid arthritis (RA), hypersensitivity, rash, and injection site 
reaction.  Potential risks include cardiovascular, respiratory, hematopoietic, 
changes in leukocyte population, immunomodulation, immunogenicity, and 
cytokine release syndrome.  


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Objectives and Endpoints/Estimands 
Objectives 
Endpoints 
Primary 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by the 
SRI-4 response 
 
SRI-4 response at week 52 
Primary Estimand 
The primary estimand is the difference in SRI-4 response rates between each 
efavaleukin alfa dose group and placebo at week 52 for all subjects with SLE with 
inadequate response to SOC therapy who are randomized, regardless of 
investigational product compliance; subjects will be considered nonresponders for 
using more than protocol-permitted therapies as follows: 
 
Subjects requiring a dose of systemic corticosteroids for SLE above their 
baseline dose after week 16 
 
Subjects requiring either dose increases of the current 
immunosuppressants/immunomodulators or initiation of new 
immunosuppressant/immunomodulator(s) 
Secondary 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by the 
BICLA index responses 
 
BICLA response at week 52 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by 
LLDAS response 
 
LLDAS response at week 52 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by OCS 
tapering 
 
Reduction of OCS to ≤ 7.5 mg/day by 
week 44 and sustained through 
week 52 in subjects with a baseline 
OCS dose ≥ 10 mg/day 
 
Evaluate the efficacy of efavaleukin 
alfa at week 24, as measured by 
SRI-4 response 
 
SRI-4 response at week 24 
 
Evaluate the efficacy of efavaleukin 
alfa at week 24, as measured by the 
BICLA index responses 
 
BICLA response at week 24 
 
Evaluate the efficacy of efavaleukin 
alfa at weeks 24 and 52, as measured 
by hSLEDAI 
 
hSLEDAI response (ie, reduction 
≥ 4 points from baseline) at week 24  
 
hSLEDAI response (ie, reduction 
≥ 4 points from baseline) at week 52 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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 
Evaluate the efficacy of efavaleukin 
alfa on joints and skin 
 
Improvement from baseline in tender 
and swollen joint count ≥ 50% at 
weeks 8, 12, 24, 36, and 52 in 
subjects with  6 tender and swollen 
joints in hands and wrists 
 
Improvement from baseline in CLASI 
activity score  50% at weeks 8, 12, 
24, 36, and 52 in subjects with a 
CLASI activity score  8 at baseline 
 
Evaluate the efficacy of efavaleukin 
alfa using BILAG score 
 
Annualized flare rate (as measured by 
BILAG score designation of “worse” or 
“new” resulting in a B score in 
≥ 2 organs or an A score in ≥ 1 organ) 
over 52 weeks 
 
Evaluate the efficacy of efavaleukin 
alfa using patient reported outcomes 
 
Change from baseline in fatigue 
standardized score using the PROMIS 
Fatigue SF 7a at weeks 12, 24, 36, 
and 52 
 
Change from baseline in the physical 
component score, mental component 
score and individual domains of the 
SF 36 v2 at weeks 12, 24, 36, and 52 
 
Change from baseline in the domain 
scores on the Lupus QoL at 
weeks 12, 24, 36, and 52 
 
Characterize the safety of efavaleukin 
alfa 
 
Treatment-emergent adverse events 
 
Serious adverse events 
 
Clinically significant changes in 
laboratory values and vital signs 
 
Characterize the PK of efavaleukin 
alfa 
 
Trough and sparse postdose serum 
concentrations of efavaleukin alfa 
BICLA = British Isles Lupus Assessment Group Based Composite Lupus Assessment; BILAG = British-Isles 
Lupus Assessment Group; CLASI = Cutaneous Lupus Erythematosus Area and Severity Index ; 
hSLEDAI = Hybrid Systemic Lupus Erythematosus Disease Activity Index; IL-2 = interleukin-2; 
LLDAS = Lupus Low Disease Activity State; OCS = oral corticosteroid; PGA = Physician Global 
Assessment; PK = pharmacokinetic(s); PROMIS Fatigue SF7A = Patient-Reported Outcome Measurement 
Information System Fatigue Short Form 7a Instrument; QoL = quality of life; SLE= systemic lupus 
erythematosus; SF36v2 = Medical Outcomes Short Form 36 version 2 Questionnaire; SOC = standard of 
care; SRI-4 = Systemic Lupus Erythematosus Responder Index;


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Overall Design 
This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, 
placebo-controlled dose ranging study in subjects with active SLE and inadequate 
response to SOC therapies, including oral corticosteroids (OCS), immunosuppressants, 
and immunomodulators.  Previous biologic use is allowed with an adequate washout 
period.  
The study design includes 3 active efavaleukin alfa treatment groups 
every 
2 weeks [Q2W],
Q2W, and
Q2W) and a placebo group, SRI-4 response 
at week 52 as the primary endpoint, and an approximate sample size of 320 subjects.   
Subjects will be randomized to receive either placebo or 1 of 3 doses of efavaleukin alfa 
for a duration of 52 weeks.  The randomization ratio will start as 1:1:1:1, and then may 
be adapted at planned interim analyses (IAs) based on the clinical efficacy, as measured 
by SRI-4 response, using Response Adaptive Randomization (RAR) for the purpose of 
allocating more subjects to more efficacious doses and fewer subjects to less efficacious 
doses, with a fixed 25% of subjects allocated to placebo throughout the study.  The RAR 
will be implemented with a computerized system that assigns a treatment to subjects 
without unblinding any study personnel or Amgen study team members, including the 
investigators or subjects, to the subject’s randomized treatment assignment or the 
current allocation ratio.  
Study duration for a single subject will be 56 weeks (including the safety follow-up 
period) plus the screening period.  Treatment will be administered every 2 weeks with 
the final dose at week 50.  All subjects will be followed for safety for at least 6 weeks 
after the last dose of investigational product.   
Subjects will undergo a screening visit to confirm eligibility requirements.  At day 1 
(baseline), prior to randomization, disease activity (clinical hybrid SLEDAI score  4) and 
stability and compliance of OCS and other immunosuppressant/immunomodulator 
doses, must be present and confirmed by the investigator.  The maximum time between 
screening and randomization is 33 days.  Subjects who do not meet all the eligibility 
requirements prior to randomization on day 1 will be considered screen failures.  
Subjects may be allowed to rescreen up to 3 times. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Immunosuppressant/immunomodulator dose(s) should remain stable through week 52.  
For OCS, initiation or temporary increases in OCS are allowed between weeks 0 to 10, 
provided that return to baseline dose occurs within the subsequent 2 weeks.  Oral 
corticosteroids may be tapered after week 12 at the investigator’s discretion but should 
not be changed during the last 8 weeks (week 44 to 52) of the 52-week treatment period.  
Subjects that use more than protocol-permitted therapies will be allowed to continue the 
study but will be considered as experiencing treatment failure for the primary efficacy 
endpoint analyses as specified in the primary estimand. 
Interim analyses will be conducted to allow for adaption of the randomization ratio for 
newly enrolled subjects to the 3 efavaleukin alfa treatment groups, holding the allocation 
to placebo constant at 25%, and assessing efficacy for early futility or administrative 
success decisions: 
 
The study team, investigators, and subjects will remain blinded to the results of the 
IAs unless futility is determined.   
 
The first IA will be executed after the first 40 subjects are randomized and have had 
the opportunity to complete the week 24 assessment.  Subsequent IAs are 
scheduled after every additional 32 subjects are randomized and have had the 
opportunity to complete the week 24 assessment until full enrollment or until futility is 
determined for all doses at an IA.  The last IA will occur when all 320 subjects are 
randomized and have had the opportunity to complete the week 24 assessment.  
This IA will be referred to as the ‘all-subjects-week-24 IA’.  Analyses planned at each 
IA are listed in Table 1-1.   
 
Efficacy analyses will be performed at the IAs to assess the likelihood of each 
efavaleukin alfa treatment group being superior to placebo by a clinically meaningful 
difference.   
 
From the second IA until before the last IA, if this likelihood is unacceptably low 
for all dose levels, the trial is recommended to stop for futility.   
 
At the ‘all-subjects-week-24 IA’, if this likelihood is sufficiently high with at least 
1 efavaleukin alfa dose level, this IA will trigger an administrative success signal.  
This would not alter the ongoing or planned activities of this phase 2b study, but 
downstream planning for subsequent trials (eg, a phase 3 study) may 
commence.   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Adaptive Design Elements: 
The prospectively defined adaptive features include RAR, early decision for futility and 
an early administrative trigger for success.  Adaptations are based on the results of IAs: 
 
Adaptive randomization begins after a fixed allocation period.  After each IA before 
the full enrollment, the randomization probability for each of the 3 active doses may 
be changed based on clinical efficacy, while the randomization probability for 
placebo is kept constant, ie, 25%.   
 
Efficacy is assessed against predefined early stopping rules for futility at the second 
and subsequent IAs.  If futility is triggered, the study may be terminated, eg, 
continued enrollment and follow-up activities for previously enrolled subjects could 
be stopped.  
 
Efficacy is assessed against predefined rules for administrative success only at the 
last IA (ie, all-subjects-week-24 IA).  If administrative success is determined, 
downstream activities may be planned/initiated (eg, a phase 3 study), but the 
execution of this phase 2b trial would not be stopped or altered.   
 
All adaptive decisions will be based on the SRI-4 response at week 52 with 
longitudinal modeling of SRI-4 response data.  For a subject who has not yet 
completed through week 52, their 52-week value will be imputed using a longitudinal 
model based on their week 16, 20, or 24 SRI-4 response data, whichever is the 
latest. 
Modeling and simulations are used to design this Bayesian adaptive trial and refine 
study design features to achieve optimal operating characteristics. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of 
Activities (see Section 1.3).   
Number of Subjects 
Approximately 320 subjects will be enrolled.  Because enrollment may be stopped if 
early stopping rules for futility are met, the actual sample size may be smaller. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
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Summary of Subject Eligibility Criteria 
Eligible subjects must be between the ages of 18 to 75 years of age, inclusive, and be 
able to provide informed consent.  Subjects must fulfill the classification criteria for SLE 
according to the 2019 European League Against Rheumatism (EULAR)/American 
College of Rheumatology (ACR) classification criteria for SLE, with antinuclear 
antibody  1:80 by immunofluorescence on Hep-2 cells or positive anti-double 
stranded DNA (anti-dsDNA) antibodies or positive anti-Smith at screening per 
central laboratory assessment.  In addition, at screening, subjects must have a Hybrid 
Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) ≥ 6 points and a 
clinical hSLEDAI  4 points.  Subjects must be taking  1 of the following SLE treatments 
(or regional equivalent):  mycophenolate mofetil, azathioprine, methotrexate, 
hydroxychloroquine, chloroquine, dapsone, quinacrine, oral calcineurin inhibitors, or 
OCS.  A subject may enter the study on OCS alone (prednisone  10 mg/day or 
equivalent) only if the subject has previously documented trial of anti-malarial or 
immunosuppressant treatment for SLE.  Subjects must be on a stable dose for ≥ 8 
weeks prior to screening for all antimalarials and immunosuppressants, with the 
exception of OCS doses which must be stable for  2 weeks prior to screening.   
Subjects requiring induction therapy for lupus nephritis currently or within 1 year prior to 
screening or active central nervous system (CNS) lupus within the past year are not 
eligible for enrollment.  Subjects with any disease other than SLE requiring treatment 
with oral or parenteral corticosteroids for  2 weeks within 4 months of the screening visit 
or any clinically significant concurrent medical conditions and/or significant laboratory 
abnormalities will not be eligible for enrollment (Section 5.2).  Female subjects must not 
be pregnant or breastfeeding or plan to become pregnant or breastfeeding during 
treatment or for an additional 6 weeks after the last dose of investigational product.  
Female subjects of reproductive potential must agree not to donate eggs during 
the study and for 6 weeks after receiving the last dose of investigational product. 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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Treatments 
Efavaleukin alfa and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  Both are liquid 
formulations presented in highly similar glass vials and stored in the same manner.  
Efavaleukin alfa or placebo will be administered by subcutaneous (SC) injection Q2W.   
Three efavaleukin alfa dose levels are planned 
Q2W,
Q2W, and
Q2W). 
Statistical Considerations 
The Efficacy Analysis Set including all randomized subjects will be used to perform the 
efficacy analysis based on subjects’ randomized treatment assignment.  For safety 
endpoints, all randomized subjects who received at least 1 dose of investigational 
product will be analyzed according to the actual treatment received. 
At IAs: 
 
As in Table 1-1, beginning with the second IA until before the last IA, enrollment to 
the study may be stopped for futility if the posterior probability of achieving a clinically 
meaningful difference in SRI-4 response rates of at least 15% between each active 
treatment group and placebo is below 2.5% for all 3 efavaleukin alfa doses. 
 
Once all subjects have had the opportunity to complete the week 24 visit, the primary 
efficacy analysis model, a Bayesian Hierarchical Model will be fitted to the 
week 52 SRI-4 response data with longitudinal modeling of earlier visits week 16, 
20 and 24 to compute the predictive probability of success in a hypothetical, future 
phase 3 study.  If the predictive probability of success in this hypothetical future 
phase 3 study is larger than 80% for any efavaleukin alfa dose, planning for a 
phase 3 study may be initiated.  Regardless of the result of this IA, the conduct of the 
current study will not be impacted; the current study will continue until all subjects 
have had the opportunity to complete the week 52 visit and safety follow-up. 
At the final analysis,  
 
The efficacy goal of the study is to demonstrate the superiority of treatment relative 
to placebo control. 
 
The null hypothesis will be rejected (ie, study will be claimed successful) if the 
posterior probability of superiority of any active treatment group is above 0.981.  This 
threshold was chosen to ensure the simulated overall one-sided type I error rate is 
less than 2.5% (one-sided).   
 
The analysis of the primary endpoint, SRI-4 at week 52, will be based on a Bayesian 
Hierarchical Model which borrows information dynamically in order to share 
information across the 3 active efavaleukin alfa treatment groups while controlling 
the overall type I error at the 1-sided 2.5% level across multiple comparisons.   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234  
Date:  06 March 2023 
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All categorical variables will be summarized using the number and percent of subjects 
falling into each category, and all continuous variables will be summarized using mean, 
standard error or standard deviation, median, minimum, maximum, and number of 
subjects with observations.  Safety endpoints will be summarized descriptively, 
including incidence of treatment-emergent adverse events and serious adverse events, 
clinically significant changes in laboratory values and vital signs, and incidence of 
antidrug antibodies. 
Table 1-1.  Analyses Schedule 
Decisions at Each Interim Analysis and Final Analysis 
Time point 
Adaptive Decision 
Number of subjects with 
opportunity to complete week 24 
1st IA  
RAR 
40 
2nd IA 
Futility, RAR 
72 
3rd IA 
Futility, RAR 
104 
4th IA 
Futility, RAR 
136 
5th IA 
Futility, RAR 
168 
6th IA 
Futility, RAR 
200 
7th IAa 
Futility, RAR 
232 
Last IAb 
Administrative success 
320 
Final Analysis 
Not applicable 
All subjects reach EOS 
IA = interim analysis; RAR = response adaptive randomization; EOS = end of study 
a Interim analyses are planned after every 32 subjects are randomized and have had the opportunity to 
complete the week 24 assessment until full enrollment or until futility is determined for all doses at an IA.  
Number of IAs will depend on the observed enrollment rate.   
b Last IA is the all-subjects-week-24 IA.  The administrative success analysis at the last IA will not result in 
any adaptive decision for the ongoing study. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
At least 1 efavaleukin alfa dose will have greater efficacy than placebo as measured by 
the SRI-4 response rate at week 52 in subjects with active SLE with inadequate 
response to SOC therapy who are randomized, regardless of investigational product 
compliance; subjects using more than protocol-permitted therapies will be considered as 
nonresponders as specified in the primary estimand. 
Sponsor Name:  Amgen Inc. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
 
 
Q2W = every 2 weeks 
 


Product:  Efavaleukin Alfa 
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1.3 
Schedule of Activities 
Table 1-2.  Schedule of Activities – Screening and Baseline 
DAY 
Screening 
Baseline 
Start of Treatment Period 
-33 to -1 
1 
3 to 5 
 
 
Pre-
randomization 
Predose 
Dose 
6 to 24 hr  
postdose 
48 to 96 hr 
postdose 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Physical examination  
X 
 
X 
 
 
 
2019 EULAR/ACR classification criteria for SLE 
X 
 
 
 
 
 
Lupus narrative 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
Medical history 
X 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
Lupus nephritis historya 
X 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
Adverse events 
 
 
 
X 
 
 
Serious adverse eventsb 
X 
 
 
 
 
 
Concomitant therapies review 
X 
 
 
 
 
 
Randomizationc 
 
 
X 
 
 
 
Home health visitd 
 
 
 
 
X 
X 
LABORATORY ASSESSMENTS 
Pregnancy teste 
X 
X 
 
 
 
 
Tuberculosis screeningf 
X 
 
 
 
 
 
HIV, Hepatitis B and C screeningg 
X 
 
 
 
 
 
Antinuclear antibody (Hep-2 cells) 
X 
 
 
 
 
 
Anti-dsDNAh  
X 
 
X 
 
 
 
Anti-phospholipid antibodies 
X 
 
X 
 
 
 
C3 and C4 complements 
X 
 
X 
 
 
 
anti-Smith, anti-RNP, anti-SSA/Ro/anti-SSB/La, 
anti-CCP and rheumatoid factor 
X 
 
 
 
 
 
Footnotes are presented on last page 
Page 1 of 3 


Product:  Efavaleukin Alfa 
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Table 1-2.  Schedule of Activities – Screening and Baseline  
DAY 
Screening 
Baseline 
Start of Treatment Period 
-33 to -1 
1 
3 to 5 
 
 
Pre- 
randomization 
Predose 
Dose 
6 to 24 hr  
postdose 
48 to 96 hr 
postdose 
Coagulation 
X 
 
 
 
 
 
Thyroid panel 
X 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
Chemistry 
X 
 
X 
 
 
 
Urinalysisi (clean catch) 
X 
 
X 
 
 
 
EFFICACY ASSESSMENTS 
Tender/swollen joint count 
X 
 
X 
 
 
 
PGA VASj 
X 
 
X 
 
 
 
PGA 4-Point Verbal Rating Scalej 
X 
 
X 
 
 
 
hSLEDAI 
X 
 
X 
 
 
 
Clinical hSLEDAI 
X 
X 
 
 
 
 
Prior history of BILAG domains 
X 
 
 
 
 
 
BILAG 
X 
 
X 
 
 
 
CLASI activity and damage 
X 
 
X 
 
 
 
CLINICAL OUTCOME ASSESSMENTS 
SF-36v2 
 
 
X 
 
 
 
PROMIS-Fatigue SF 7a 
 
 
X 
 
 
 
LupusQoL 
 
 
X 
 
 
 
Symptom Questionnaire 
 
 
X 
 
 
 
IMMUNOGENICITY 
BIOMARKER ASSESSMENTS 
PHARMACOGENETIC ASSESSMENTS 
PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic blood sample 
 
 
X 
 
Xd 
Xd 
Footnotes are presented on last page 
Page 2 of 3 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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Table 1-2.  Schedule of Activities – Screening and Baseline  
DAY 
Screening 
Baseline 
Start of Treatment Period 
-33 to -1 
1 
3 to 5 
 
 
Pre- 
randomization 
Predose 
Dose 
6 to 24 hr  
postdose 
48 to 96 hr 
postdose 
STUDY TREATMENT 
Investigational product administrationl 
 
 
 
X 
 
 
 
Page 3 of 3 
ACR = American College of Rheumatology; anti-CCP = anti-cyclic citrullinated peptide; anti-dsDNA = anti-double stranded DNA; anti-RNP = anti-ribonucleoprotein; 
anti-SSA/Ro = anti-Sjögren’s-syndrome related antigen A; anti-SSB/La = anti-Sjögren’s-syndrome related antigen B;; BILAG = British-Isles Lupus Assessment Group; 
CLASI = Cutaneous Lupus Erythematosus Disease and Severity Index; Clinical hSLEDAI = hybrid SLEDAI assessment score without the inclusion of points 
attributable to any laboratory parameter, including urine and immunologic parameters; ECG = electrocardiogram; eCRF = electronic case report form; ET = early 
termination visit; EULAR = European League Against Rheumatism; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HIV = Human 
Immunodeficiency Virus; hSLEDAI = Hybrid Systemic Lupus Erythematosus Disease Activity Index; PGA = Physician Global Assessment;
 
; PROMIS = Patient Reported Outcomes Measures Information System;
 
; SF36v2 = Medical Outcomes Short Form 36 version 2 questionnaire; SLE = systemic lupus erythematosus; SOC = standard 
of care; VAS = visual analog scale;
 
a Only for subjects with a history of lupus nephritis.   
b After end of study, serious adverse events suspected to be related to investigational product will be reported to Amgen.  Please refer to Section 8.3.4.1.3 for 
additional details.   
c Randomization may occur at any time after confirmation of all eligibility criteria, but the maximum time between initiation of screening and randomization is 
33 calendar days.   
d Visit may be performed as a home health visit.  In addition to collection of pharmacokinetic and 
, adverse events, serious adverse events, 
and concomitant medications review will be conducted.   
e For women of childbearing potential only:  serum pregnancy test is to be performed at screening (central laboratory) and urine pregnancy test is to be performed prior 
to randomization (local laboratory).  To determine if follicle-stimulating hormone (FSH) level should be assessed, refer to the definition of postmenopausal female 
provided in Section 11.5.   
f Either a centrally performed QuantiFERON®-TB or locally performed purified protein derivative (PPD) or T-spot test will be done during screening.  For subjects with a 
positive tuberculosis test (ie, positive PPD or positive or indeterminate QuantiFERON®-TB or T-spot test) a chest X-ray will be performed.   
g HIV screening will be performed where allowed by local regulations.   
h A subject’s anti-dsDNA will be tested with a consistent assay throughout the study.   
i Clean catch urine specimen required and urine protein/creatinine ratio will be calculated.   
j Must be completed by a health care provider before assessing the hSLEDAI and BILAG scores.   
 
At visits on which investigational product is administered, all assessments are to be completed in advance of investigational product administration unless otherwise 
noted.  The dose of investigational product must be given within ± 5 days of the scheduled time point.  If that window is missed, that dose will not be administered, 
and the next dose will be administered at the next scheduled dosing date.  Any 2 consecutive doses of investigational product must be at least 7 days apart.   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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Table 1-3.  Schedule of Activities – Treatment Period 
WEEK 
Treatment Period (Weeks) 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52/ETa 
STUDY DAY 
 VISIT WINDOW 
15 
 
29 
 
43 
 
45 
to 
47 
57 
 
71 
 
85 
 
99 
 
113 
 
127 
 
141 
 
155 
 
169 
 
183 
 
197 
 
211 
 
225 
 
239 
 
253 
 
267 
 
281 
 
295 
 
309 
 
323 
 
337 
 
351 
 
365 
 
GENERAL AND SAFETY ASSESSMENTS 
Physical examinationb 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious adverse eventsc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies 
review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Home health visit 
 
 
Xd 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Pregnancy teste 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Anti-dsDNAf  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Anti-phospholipid 
antibodies 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C3 and C4 complements 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Thyroid panel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Urinalysisg (clean catch) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
EFFICACY ASSESSMENTS 
Tender/swollen joint count 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PGA VASh 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PGA 4-Point Verbal Rating 
Scaleh 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
hSLEDAI 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
BILAG 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CLASI activity and damage 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Footnotes are presented on last page 
Page 1 of 2 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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Table 1-3.  Schedule of Activities – Treatment Period  
WEEK 
Treatment Period (Weeks) 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52/ETa 
STUDY DAY 
 VISIT WINDOW 
15 
 
29 
 
43 
 
45 
to 
47 
57 
 
71 
 
85 
 
99 
 
113 
 
127 
 
141 
 
155 
 
169 
 
183 
 
197 
 
211 
 
225 
 
239 
 
253 
 
267 
 
281 
 
295 
 
309 
 
323 
 
337 
 
351 
 
365 
 
CLINICAL OUTCOME ASSESSMENTS 
SF-36v2 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PROMIS-Fatigue SF 7a 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
LupusQoL 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Symptom Questionnaire 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMMUNOGENICITY 
BIOMARKER ASSESSMENTSi 
PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic blood 
sample 
 
Xi 
Xj 
Xj 
 
 
Xi 
 
 
 
 
 
Xi 
 
 
 
 
 
Xi 
 
 
 
Xi 
 
 
 
X 
STUDY TREATMENT 
Investigational productk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Page 2 of 2 
Anti-dsDNA = anti-double stranded DNA; BILAG = British-Isles Lupus Assessment Group; CLASI = Cutaneous Lupus Erythematosus Disease and Severity Index; 
Clinical hSLEDAI = hybrid SLEDAI assessment score without the inclusion of points attributable to any laboratory parameter, including urine and immunologic 
parameters; eCRF = electronic case report form; ET = early termination visit ; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HIV = Human 
Immunodeficiency Virus; hSLEDAI = Hybrid Systemic Lupus Erythematosus Disease Activity Index; PGA = Physician Global Assessment;
 PROMIS = Patient Reported Outcomes Measures Information System;
SF36v2 = Medical Outcomes Short Form 36 version 2 questionnaire; 
SLE = systemic lupus erythematosus; SOC = standard of care; VAS = visual analog scale;
a An ET is required for all subjects who discontinue the study completely prior to week 52.  Please refer to Section 8.1.2. 
b After initiation of treatment, physical examination is required for all elements relevant to lupus endpoints and/or adverse events. 
c After end of study, serious adverse events suspected to be related to investigational product will be reported to Amgen.  Please refer to Section 8.3.4.1.3 for 
additional details.   
d On day 43, investigational product administration and assessments which are to be completed prior to investigational product administration, will be completed at the 
study site.  Visit for pharmacokinetic blood sample collection may be performed as a home health visit.  In addition to collection of pharmacokinetic blood samples, 
adverse events, serious adverse events, and concomitant medications review will be conducted. 


Product:  Efavaleukin Alfa 
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e For women of childbearing potential only:  serum pregnancy test is to be performed at screening (central laboratory) and urine pregnancy test is to be performed at all 
other indicated time points (local laboratory).  To determine if follicle-stimulating hormone (FSH) level should be assessed, refer to the definition of postmenopausal 
female provided in Section 11.5. 
f A subject’s anti-dsDNA will be tested with a consistent assay throughout the study. 
g Clean catch urine specimen required and urine protein/creatinine ratio will be calculated.  
h Must be completed by a health care provider before assessing the hSLEDAI and BILAG scores. 
i To be taken predose. 
j A single pharmacokinetic blood sample will be collected between 6 and 24 hours postdose week 6 and another pharmacokinetic sample will be collected between 
48 and 96 hours postdose week 6.  These samples may be collected as part of a home health visit. 
k At visits on which investigational product is administered, all assessments are to be completed in advance of investigational product administration unless otherwise 
noted.  The dose of investigational product must be given within ± 5 days of the scheduled time point.  If that window is missed, that dose will not be administered, 
and the next dose will be administered at the next scheduled dosing date.  Any 2 consecutive doses of investigational product must be at least 7 days apart. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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Table 1-4.  Schedule of Activities – Safety Follow-up/week 56 Visit 
Safety Follow-up Visit (Weeks) 
Week ± Visit Window (days) 
56 weeks 5 daysa 
Vital signs 
X 
Adverse events 
X 
Serious adverse eventsb 
X 
Concomitant medications review 
X 
LABORATORY ASSESSMENTS  
Urine pregnancy test 
X 
Hematology  
X 
IMMUNOGENICITY 
a This separate safety follow-up/week 56 visit only applies to subjects who require an additional visit 
following the planned 52-week period to ensure at least 6 weeks follow-up for safety data collection after 
last dose of investigational product.   
b After end of study, serious adverse events suspected to be related to investigational product will be 
reported to Amgen.  Please refer to Section 8.3.4.1.3 for additional details.   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
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2. 
Introduction 
2.1 
Study Rationale 
This is a phase 2b dose-ranging study to assess the efficacy and safety of efavaleukin 
alfa (AMG 592) in subjects with active systemic lupus erythematosus (SLE). 
2.2 
Background 
2.2.1 
Disease 
Systemic lupus erythematosus is a multisystem autoimmune disease of unknown cause 
with diverse clinical manifestations that disproportionately affects minorities (eg, in the 
United States, blacks and Hispanics) and women of childbearing potential 
(Rhaman and Isenberg, 2008; Kotzin, 1996).  In the United States (US), moderate to 
severe SLE is estimated to affect one-third of the more than the 250 000 patients 
diagnosed with lupus.  The progression of SLE may vary from mild episodes to severe, 
even fatal outcomes with symptoms varying widely in individuals over time and 
characterized by periods of remission and flare.  Systemic lupus erythematosus can 
affect the skin, musculoskeletal system, nervous system, lungs, cardiovascular system, 
kidneys, and the blood.  In addition, approximately 65% of patients will develop lupus 
nephritis, which is an inflammation of the kidney that can range from mild 
glomerulonephritis to severe diffuse proliferative glomerulonephritis 
(Adams et al, 2006). 
Currently, corticosteroids, immunosuppressants, immunomodulators, and cytotoxic 
agents are frequently used to control active disease, but significant need exists for more 
effective therapies with fewer short- and long-term toxicities.  Although the clinical 
heterogeneity of SLE presents challenges in the diagnosis, antibodies to nuclear 
components represent almost a prerequisite for the disease.  The presence of 
class-switched immunoglobulin G (IgG) autoantibodies implicate immune dysregulation 
as a driving force for disease pathogenesis, with T cells appearing to play a role in the 
development of autoantibody production by B cells. 
2.2.1.1 
Interleukin 2 and T Regulatory Cells in Systemic Lupus 
Erythematosus 
T regulatory cells (Tregs) are a subset of T cells that maintain self- tolerance by 
suppressing the activation and expansion of autoreactive lymphocytes.  Defects in Treg 
numbers or function have been described in SLE patients and are thought to contribute 
to SLE pathogenesis (Zhang et al, 2018; Bonelli et al, 2009; Myara et al, 2005; 
Suen et al 2008; von Spee-Mayer et al 2015).  Interleukin-2 (IL-2), a multi-functional 


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cytokine produced predominantly by activated cluster of differentiation 4+ (CD4+) 
T cells, is a key growth factor for Tregs and is essential for Treg maintenance, survival 
and metabolism (Malek and Castro, 2010; Boyman and Sprent, 2012).  Impaired 
IL-2 production has been reported in patients with SLE (Linker-Israeli et al, 1983; 
Alcocer-Varela and Alarcon Segovia, 1982; von Spee-Mayer et al, 2015).  Moreover, 
reduced levels of circulating IL-2 have been associated with Treg dysfunction in SLE 
patients (Lieberman and Tsokos, 2010; von Spee-Mayer et al, 2015).  These data 
suggest that immune homeostasis in SLE patients may be restored by correction of 
Treg dysfunction and numerical deficiency through treatment with low dose IL-2.   
2.2.1.2 
Low Dose Interleukin 2 in Inflammatory Disease 
Low dose IL-2 (aldesleukin) has been shown to increase Treg numbers in multiple 
inflammatory diseases such as Type 1 Diabetes (Yu et al, 2015), chronic graft versus 
host disease (GVHD) (Koreth et al, 2011), hepatitis C virus induced vasculitis 
(Sadoun et al, 2011) and alopecia areata (Castela et al, 2014); as well as to correct 
defects in Treg function in SLE (von Spee-Mayer et al, 2015), Type 1 Diabetes 
(Long et al, 2010; Long et al, 2012) and GVHD (Matsuoka et al, 2013).  Genetic variants 
of the IL-2 receptor have been associated with the severity of rheumatoid arthritis (RA) 
joint destruction and persistence (van Steenbergen et al, 2015). 
The therapeutic efficacy of low dose IL-2 has also been studied in chronic GVHD 
(cGVHD) (Koreth et al, 2011; Koreth et al, 2016), hepatitis C induced vasculitis 
(Sadoun et al, 2011), and alopecia areata (Castela et al, 2014).  The clinical response 
to low dose IL-2 has been promising in these small early phase studies in multiple 
diverse inflammatory conditions, with efficacy reported in various indications.  In these 
conditions, the overall safety and tolerability profile of low-dose IL-2 has been 
acceptable with mild to moderate constitutional symptoms associated with higher 
levels of exposure.  However, the therapeutic window between adequate Treg 
enrichment and stimulation of effector cells is narrow and may limit achievement of 
optimal Treg expansion.  For instance, in a recent phase 1b clinical trial of cGVHD 
(ClinicalTrials.gov NCT00529035), aldesleukin, a human recombinant IL-2, given at 
the dose of 3 x 106 IU/m2 daily induced persistent National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) grade 1 constitutional symptoms 
(fever, malaise, and arthralgia) necessitating a 50% dose reduction 
(Koreth et al, 2011).  In addition, aldesleukin can activate pro-inflammatory/effector 
lymphocytes such as CD4+ T effector cells (Teff) and natural killer (NK) cells, which 


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may compromise efficacy and safety.  These data suggest the potential for a 
therapeutic agent with greater Treg selectivity and a prolonged pharmacodynamic 
(PD) effect compared with recombinant IL-2.   
2.2.1.3 
Clinical experience with Low Dose IL-2 in Systemic Lupus 
Erythematosus 
Treatment with low dose IL-2 has been associated with clinical efficacy in small clinical 
trials.  In 1 placebo-controlled study of 60 patients (30 IL-2; 30 placebo) on standard 
treatment with active SLE, after 12 weeks of treatment the SRI-4 response rates were 
55.17% for the IL-2 group compared to 30.00% for the placebo group (p = 0.052).  At 
week 24 (12 weeks post last dose) the SRI-4 response rate for the IL-2 group was 
65.52% compared with 36.67% for the placebo group (p = 0.027).  Low-dose 
IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus 
nephritis compared with 16.67% (2/12) in the placebo group (p = 0.036) (He et al, 2020). 
In a study of 12 patients with moderate to severe SLE (Systemic Lupus Erythematosus 
Disease Activity Index [SLEDAI] score  6 points despite treatment with 2 different 
immunosuppressive therapies), 10/12 subjects (83.3%) achieved a reduction in 
SELENA SLEDAI score and 8/12 (66.7%) achieved a clinical response after receiving 
four 5-day cycles of low dose IL-2 therapy separated by washout periods of 9 and 
16 days.  Clinical responses included complete resolution of SLE manifestations 
including rash, arthralgias, myositis and alopecia.  Complement levels increased but 
no change in anti-double stranded DNA (anti-dsDNA) antibodies was observed.  
Regulatory T cells numbers increased in all treated subjects (Humrich et al, 2019; 
Humrich et al, 2016; Humrich et al, 2015).   
In another study of 38 SLE patients who completed three 2-week cycles of low dose 
IL-2 over 12 weeks, 34/38 subjects (89.5%) achieved a Systemic Lupus Erythematosus 
Responder Index 4 (SRI-4) response at the end of 12 weeks, with concomitant 
decreases in anti-dsDNA antibodies and increase in complement levels.  Regulatory 
T cells numbers increased in most treated subjects (He et al, 2016).  In these studies, 
low dose IL-2 was generally well- tolerated, though constitutional symptoms (eg, fever, 
myalgias, arthralgias, flu-like symptoms) were reported at the higher dose levels.  
Overall, these studies provide compelling support for further investigation of IL-2 for the 
treatment of SLE. 


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2.2.2 
Amgen Investigational Product Background:  Efavaleukin Alfa 
Efavaleukin alfa is an IL-2 mutein Fc fusion protein with increased Treg selectivity 
compared to recombinant IL-2, which has been developed to preferentially expand 
Tregs in subjects with inflammatory diseases (refer to the Efavaleukin Alfa 
Investigator’s Brochure for more details).  Interleukin-2 is a key growth factor for Tregs 
and is essential for Treg development, homeostasis and function.  At low doses 
IL-2 binds preferentially to the -subunit (CD25) of the high-affinity IL-2 receptor which 
is expressed constitutively by Tregs and is absent on naive T-cells and inactivated 
T memory cells.  This results in selective activation of Tregs.  However, at higher doses 
IL-2 also activates other immune cells such as CD4+ and CD8+ Teff, NK cells and 
natural killer T cells  cells via the dimeric low affinity IL-2 receptor.  Compared with 
aldesleukin, efavaleukin alfa exhibits greatly improved selectivity for Tregs over Teff 
and NK cells both in vitro and in vivo, potentially resulting in an improved therapeutic 
margin.  In addition, the Fc domain of efavaleukin alfa provides a prolonged half-life 
compared with aldesleukin, thus reducing dosing frequency to maintain Treg 
enrichment (Tchao, 2019). 
2.2.2.1 
Toxicology 
In the 6-month repeat-dose toxicology studies in the cynomolgus monkey (dose levels 
0.03 and 0.1 mg/kg, weekly subcutaneous [SC] injections for 6 months), the no 
observed adverse effect level (NOAEL) dose was 0.03 mg/kg based on the observation 
of 2 efavaleukin alfa-related unscheduled euthanasia at 0.1 mg/kg associated with 
moribund condition and markedly decreased RBC mass.  The NOAEL of 0.03 mg/kg 
corresponded to a mean efavaleukin alfa maximum observed concentration (Cmax) of 
130 ng/mL (day 176) and an area under the concentration-time curve from time 0 to 
168 hours (AUClast) of 10 300 hr•ng/mL (day 176) in animals that maintained exposure.  
For further details regarding efavaleukin alfa toxicology studies, please refer to the 
Investigator’s Brochure. 
2.2.2.2 
Human Exposure 
The observed efavaleukin alfa human exposures from single ascending doses of 
efavaleukin alfa ranging from
in the first in human (FIH) study 20140324 
in healthy subjects and all available pharmacokinetic (PK) data up to 
from 3 
phase 1b studies (20170103 in subjects with SLE; 20170149 in subjects with RA; and 
20160283 in subjects with cGvHD) were used to predict efavaleukin alfa exposures at 
the selected dose levels for the current study in subjects with SLE (Table 2-1).  The 


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geometric mean Cmax and AUCinf increase approximately dose proportionally over the 
dose range of 
The estimated terminal phase half-life ranges from 
about 10.6 to 30.4 hours.  Given the estimated half-life, minor accumulation of 
efavaleukin alfa is expected at the selected dose levels with Q2W dosing regimens in 
patients with SLE.   
Table 2-1.  Steady-state Median (IQR) of Efavaleukin Alfa Pharmacokinetic 
Parameter Prediction Following Q2W Subcutaneous Doses in Subjects with SLE 
Dose 
AUCss 
(day•ng/mL) 
Cmax 
(ng/mL) 
Q2W 
11.75 
(8.18 - 16.20) 
9.30 
(7.55 - 11.47) 
Q2W 
22.88 
(15.87 - 32.27) 
18.91 
(14.96 - 23.16) 
Q2W 
43.10 
(29.92 - 60.31) 
34.84 
(27.81 - 43.10) 
AUCss = area under the serum concentration curve at steady state; Cmax = maximum observed 
concentration; IQR = interquartile range; Q2W = every 2 weeks; SLE= systemic lupus erythematosus 
A detailed description of the chemistry, pharmacology, and safety of efavaleukin alfa is 
provided in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
The safety of efavaleukin alfa has been evaluated in healthy subjects and 
phase 1 studies of subjects with RA, cGvHD, and SLE.  Cumulative data from completed 
and ongoing phase 1 clinical studies conducted since the beginning of the development 
program through 26 April 2022 include 167 subjects who have been exposed to at least 
1 dose of efavaleukin alfa.  Single doses of up to 
 g have been studied in healthy 
subjects (82 subjects).  Repeated doses of up to
Q2W have been evaluated in 
subjects with RA over the course of a 12-week period (28 subjects).  Repeated doses of 
up to
Q2W have been evaluated in subjects with cGvHD over a 52-week period 
(32 subjects).  Repeated doses of up to
Q2W have been evaluated in subjects 
with SLE over a 12-week treatment period (25 subjects).   
Based upon the totality of currently available safety data, the benefit/risk profile of 
efavaleukin alfa is favorable.  Efavaleukin alfa has been well tolerated in clinical studies 
and has an acceptable safety profile.  Adverse drug reactions reported with efavaleukin 
alfa in clinical studies include erythema, pruritus, exacerbation in subjects with RA, 
hypersensitivity, rash, and injection site reaction.  Potential risks include cardiovascular, 
respiratory, hematopoietic, changes in leukocyte population, immunomodulation, 
immunogenicity, and cytokine release syndrome.  The most frequent adverse events 


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have been mild or moderate (grade 1 or 2) injection site reactions, erythema, pruritis, 
and rash.  More information about the safety profile of efavaleukin alfa may be found in 
the latest version of the Investigator’s Brochure. 
2.3.1 
COVID-19 
Amgen closely monitors the coronavirus disease 2019 (COVID-19) pandemic around the 
world.  As part of this effort, Amgen performs a rigorous assessment, considering the 
study design, patient safety, public health risk, benefit-risk assessment, as well as the 
burden on country healthcare systems.  Decisions are made on a study-by-study and 
country-by-country basis to minimize risk to subjects and avoid undue burden on 
healthcare facilities. 
Subjects who display symptoms consistent with COVID-19 infections or who have tested 
positive for COVID-19 should contact the investigator to ensure appropriate care as well 
as documentation and management of study activities.  Amgen considers that it is 
important to continue the proposed development of efavaleukin alfa in this study in order 
to advance potential therapy options for patients as rapidly as possible, while balancing 
this with appropriate measures to monitor and mitigate the potential impact of 
COVID-19.  Subjects enrolled in this study are permitted to receive vaccinations for 
COVID-19 except as described in exclusion criterion 220 and Section 6.1.6. 


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3. 
Objectives and Endpoints/Estimands 
Objectives 
Endpoints 
Primary 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by the 
SRI-4 response 
 
SRI-4 response at week 52 
Primary Estimand 
The primary estimand is the difference in SRI-4 response rates between each 
efavaleukin alfa dose group and placebo at week 52 for all subjects with SLE with 
inadequate response to SOC therapy who are randomized, regardless of 
investigational product compliance; subjects will be considered nonresponders for 
using more than protocol-permitted therapies as follows: 
 
Subjects requiring a dose of systemic corticosteroids for SLE above their 
baseline dose after week 16 
 
Subjects requiring either dose increases of the current 
immunosuppressants/immunomodulators or initiation of new 
immunosuppressant/immunomodulator(s) 
Secondary 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by the 
BICLA index responses 
 
BICLA response at week 52 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by 
LLDAS response 
 
LLDAS response at week 52 
 
Evaluate the efficacy of efavaleukin 
alfa at week 52, as measured by OCS 
tapering 
 
Reduction of OCS to ≤ 7.5 mg/day by 
week 44 and sustained through 
week 52 in subjects with a baseline 
OCS dose ≥ 10 mg/day 
 
Evaluate the efficacy of efavaleukin 
alfa at week 24, as measured by 
SRI-4 response 
 
SRI-4 response at week 24 
 
Evaluate the efficacy of efavaleukin 
alfa at week 24, as measured by the 
BICLA index responses 
 
BICLA response at week 24 
 
Evaluate the efficacy of efavaleukin 
alfa at weeks 24 and 52, as measured 
by hSLEDAI 
 
hSLEDAI response (ie, reduction 
≥ 4 points from baseline) at week 24  
 
hSLEDAI response (ie, reduction 
≥ 4 points from baseline) at week 52 


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 
Evaluate the efficacy of efavaleukin 
alfa on joints and skin 
 
Improvement from baseline in tender 
and swollen joint count ≥ 50% at 
weeks 8, 12, 24, 36, and 52 in 
subjects with  6 tender and swollen 
joints in hands and wrists 
 
Improvement from baseline in CLASI 
activity score  50% at weeks 8, 12, 
24, 36, and 52 in subjects with a 
CLASI activity score  8 at baseline 
 
Evaluate the efficacy of efavaleukin 
alfa using BILAG score 
 
Annualized flare rate (as measured by 
BILAG score designation of “worse” or 
“new” resulting in a B score in 
≥ 2 organs or an A score in ≥ 1 organ) 
over 52 weeks 
 
Evaluate the efficacy of efavaleukin 
alfa using patient reported outcomes 
 
Change from baseline in fatigue 
standardized score using the PROMIS 
Fatigue SF 7a at weeks 12, 24, 36, 
and 52 
 
Change from baseline in the physical 
component score, mental component 
score and individual domains of the 
SF 36 v2 at weeks 12, 24, 36, and 52 
 
Change from baseline in the domain 
scores on the Lupus QoL at 
weeks 12, 24, 36, and 52 
 
Characterize the safety of efavaleukin 
alfa 
 
Treatment-emergent adverse events 
 
Serious adverse events 
 
Clinically significant changes in 
laboratory values and vital signs 
 
Characterize the PK of efavaleukin 
alfa 
 
Trough and sparse postdose serum 
concentrations of efavaleukin alfa 
BICLA = British Isles Lupus Assessment Group Based Composite Lupus Assessment; BILAG = British-Isles 
Lupus Assessment Group; CLASI = Cutaneous Lupus Erythematosus Area and Severity Index ; 
hSLEDAI = Hybrid Systemic Lupus Erythematosus Disease Activity Index; IL-2 = interleukin-2; 
LLDAS = Lupus Low Disease Activity State; OCS = oral corticosteroid; PGA = Physician Global 
Assessment; PK = pharmacokinetic(s); PROMIS Fatigue SF7A = Patient-Reported Outcome Measurement 
Information System Fatigue Short Form 7a Instrument; QoL = quality of life; SLE= systemic lupus 
erythematosus; SF36v2 = Medical Outcomes Short Form 36 version 2 Questionnaire; SOC = standard of 
care; SRI-4 = Systemic Lupus Erythematosus Responder Index;


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Exploratory 


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4. 
Study Design 
4.1 
Overall Design 
This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, 
placebo-controlled dose ranging study in subjects with active SLE and inadequate 
response to SOC therapies, including oral corticosteroids (OCS), immunosuppressants, 
and immunomodulators.  Previous biologic use is allowed with an adequate washout 
period.  
The study design includes 3 active efavaleukin alfa treatment groups 
Q2W, 
Q2W, and
 Q2W) and a placebo Q2W group, SRI-4 response at 
week 52 as the primary endpoint, and an approximate sample size of 320 subjects.   
Subjects will be randomized to receive either placebo or 1 of 3 doses of efavaleukin alfa 
for a duration of 52 weeks.  The randomization ratio will start as 1:1:1:1, and then may 
be adapted at planned interim analyses (IAs) based on the clinical efficacy, as 
measured by SRI-4 response, using Response Adaptive Randomization (RAR) for the 
purpose of allocating more subjects to more efficacious doses and fewer patients to 
less efficacious doses.  The RAR will be implemented with a computerized system that 
assigns a treatment to subsequent subjects without unblinding any study personnel or 
Amgen study team members including the investigators or subjects, the subject’s 
randomized treatment assignment or the current allocation ratio.  
Study duration for a single subject will be 56 weeks (including safety follow-up) plus the 
screening period.  Treatment will be administered every 2 weeks with the final dose at 
week 50.  All subjects will be followed for safety for at least 6 weeks after the last dose of 
investigational product.   
Subjects will undergo a screening visit to confirm eligibility requirements.  At day 1 
(baseline), prior to randomization, disease activity (defined by clinical hybrid SLEDAI 
score  4) and stability and compliance of OCS and other 
immunosuppressant/immunomodulator doses, must be present and confirmed by the 
investigator.  Subjects may be randomized at any time after confirmation of all eligibility 
criteria, but the maximum time between screening and randomization is 33 days.  
Subjects who do not meet all the eligibility requirements at day 1 will be considered 
screen failures.  Subjects may be allowed to rescreen up to 3 times.   


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Immunosuppressant/immunomodulator doses should remain stable through week 52.  
For OCS, initiation or temporary increases in OCS are allowed between weeks 0 to 10, 
provided that return to baseline dose occurs within the subsequent 2 weeks.  Oral 
corticosteroids may be tapered after week 12 at the investigator’s discretion but should 
not be changed during the last 8 weeks (week 44 to 52) of the 52-week treatment period.  
Subjects that use more than protocol-permitted therapies will be allowed to continue the 
study but will be considered as experiencing treatment failure for the primary efficacy 
endpoint analyses as specified in the primary estimand.   
Interim analyses will be conducted to allow for adaption of the randomization ratio for 
newly enrolled subjects to the 3 efavaleukin alfa treatment groups, holding the allocation 
to placebo constant at 25%, and assessing efficacy for early futility or administrative 
success decisions: 
 
The study team, investigators, and subjects will remain blinded to the results of the 
IAs unless futility is determined. 
 
The first IA will be executed after the first 40 subjects are randomized and have had 
the opportunity to complete the week 24 assessment.  Subsequent IAs are 
scheduled after every additional 32 subjects are randomized and have had the 
opportunity to complete the week 24 assessment until full enrollment or until futility is 
determined for all doses at an IA.  The last IA, referred to as ‘all-subjects-week-24 IA’ 
will occur when all 320 subjects are randomized and have had the opportunity to 
complete the week 24 assessment.  Analyses planned at each IA are listed in 
Table 1-1.  
 
Efficacy analyses will be performed at the IAs to assess the likelihood of efavaleukin 
alfa treatment group being superior to placebo by a clinically meaningful difference.  
 
From the second IA until before the last IA, if this likelihood is unacceptably low 
for all dose levels, the trial is recommended to stop for futility.   
 
At the ‘all-subjects-week-24 IA’, if this likelihood is sufficiently high with 
at least 1 efavaleukin alfa dose level, IA triggers an administrative success 
signal.  This would not alter ongoing or planned activities of this phase 2b study, 
but downstream planning for subsequent trials (eg, a phase 3 study) may 
commence. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.1.1 
Adaptive Design Elements 
The prospectively defined adaptive features include RAR, early decision for futility and 
an early trigger for administrative success.  Adaptations are based on the results of IAs: 
 
Adaptive randomization begins after a fixed allocation period.  After each IA before 
the full enrollment, the randomization probability for each of the 3 active doses may 


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be changed based on clinical efficacy, while the randomization probability for 
placebo is kept constant, ie, 25%.   
 
Efficacy is assessed against predefined early stopping rules for futility (see 
Section 9.3.1.1) at the second and subsequent IAs.  If futility is triggered, the study 
may be terminated, eg, continued enrollment and follow-up activities for previously 
enrolled subjects could be stopped.   
 
Efficacy is assessed against predefined rules for administrative success (see 
Section 9.3.1.1) only at the last IA (ie, all-subjects-week-24 IA).  If administrative 
success is determined, downstream activities may be planned/initiated (eg, a 
phase 3 study), but the execution of this phase 2b trial would not be stopped or 
altered.   
 
All adaptive decisions will be based on the SRI-4 response at week 52 with 
longitudinal modeling SRI-4 response data.  For a subject who has not yet 
completed through 52 weeks, their 52-week value will be imputed using a 
longitudinal model based on their week 16, 20, or 24 SRI-4 response data, 
whichever is the latest. 
Modeling and simulations are used to design this Bayesian adaptive trial and refine 
study design features to achieve optimal operating characteristics. 
4.2 
Patient Input into the Study Design 
Patient input was not obtained for design of this study. 
4.3 
Justification for Investigational Product Dose 
Efavaleukin alfa has demonstrated an acceptable safety and tolerability profile as well 
as pharmacodynamic selectivity (
 
) in subjects with SLE at doses up to 
 
Q2W for 12 weeks.  A higher dose of 
 Q2W was also safe and well-tolerated 
although results suggest a plateau in Treg expansion with low-level increases in other 
IL-2-responsive cells.  Interpretation of these data is limited due to small subject 
numbers.   
Three doses of
 Q2W were selected for this phase 2b study 
with a predicted upper range of Treg expansion close to 5-, 7-, and 10- fold 
respectively.  These doses provide an opportunity to test a wide range of Treg 
expansion to help select an efficacious dose.  
The low dose of 
 Q2W was selected because the mean Treg expansion at this 
dose level was statistically different from the placebo group in the phase 1b study of 
efavaleukin alfa in SLE subjects.  Also, Treg expansion at the 
Q2W dose 
appears comparable to Treg expansion associated with clinical efficacy in studies of low 
dose IL-2 in SLE patients, as reported by Humrich et al, 2019 and He et al, 2020.  


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However, this comparison may not be accurate due to the methodological differences 
between studies in efavaleukin alfa and these publications.   
A high dose of 
Q2W was selected for the phase 2 study based on predicted 
Treg expansion with sustained pharmacodynamic selectivity that is substantially higher 
than the
Q2W dose and on average higher than
Q2W dose, thus 
providing wide range of Treg expansion.  In addition, the
Q2W dose has been 
tested in subjects with cGVHD for up to 52 weeks with, acceptable safety, sustained 
pharmacodynamic selectivity, and increased mean Treg expansion compared to other 
doses.   
The middle dose of 
Q2W was selected to minimize the overlap in predicted Treg 
expansion between the low and high doses. 
The predicted Treg expansion was determined by integrated PK/Treg modeling using all 
available PK and Treg data from phase 1 studies in both healthy subjects and subjects 
with RA, cGvHD and SLE.  Simulations from the PK/Treg model predicted meaningful 
Treg expansion in subjects with SLE at all selected doses with an expected difference in 
median Treg cell count between doses (Table 4-1). 
Table 4-1. 
Median (IQR) Peak Blood Treg Count and Fold Expansion Predicted 
at Planned Doses in Subjects with SLE 
Dose 
Peak Treg expansion 
Peak Treg expansion 
Cell Count  
(Cells/µL) 
Fold-Change from Baseline 
Q2W) 
196.66 
(126.55 – 283.67) 
3.92  
(2.97 – 5.21) 
Q2W) 
272.43 
(180.79 – 355.27) 
5.14 
(3.92 – 6.92) 
(Q2W) 
349.13 
(264.91 – 427.55) 
6.81  
(5.23 – 9.28) 
Treg = regulatory T cells; Q2W = every other week; IQR = interquartile range 
4.4 
End of Study 
An individual subject is considered to have completed the study if they have remained 
on study for the entire treatment period (ie, through the week 52 visit) and completed the 
safety follow-up/week 56 visit (if applicable, see Table 1-4).  
The end of study date for the entire study is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), including any additional parts in the study (eg, safety follow-up, 
additional antibody testing), as applicable. 


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5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Response 
Technology (IRT) system.  Eligibility criteria will be evaluated at the screening visit and 
at the baseline/day 1 visit, prior to randomization. 
The screening visit will confirm all eligibility requirements described in Inclusion 
Criteria 101 through 110.  For France, affiliation to a social security scheme is required 
(criterion 111).  All SLE-related screening criteria will be reviewed by the adjudication 
team.   
Eligibility Adjudication 
Adjudication committee description:  An Adjudication Committee composed of 
medically-qualified SLE experts will be utilized to confirm eligibility during screening and 
will be utilized throughout the study to confirm Hybrid Systemic Lupus Erythematosus 
Disease Activity Index (hSLEDAI), BILAG-2004, Cutaneous Lupus Erythematosus Area 
and Severity Index (CLASI), joint count, 
, Physician Global 
Assessment (PGA), and Systemic Lupus International Collaborating Clinics (SLICC) 
damage index.  The Adjudication Committee will also ensure that the completion of 
efficacy assessments by investigators is of proper quality and consistency.  
The Adjudication Committee will adjudicate eligibility for this trial.  During screening, the 
Adjudication Committee will confirm eligibility criteria are met based on review of the 
data captured in the electronic data capture (EDC) system and from the central 
laboratory.  The Adjudication Committee will review all data necessary to characterize 
subject's SLE including past medical history, concomitant medications, 2019 European 
League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 
criteria, lupus narrative, hSLEDAI, BILAG-2004, 28-joint count, CLASI, and central 
laboratory results.  Sites will be notified of the external SLE Adjudication Committee's 
decision on whether the subject can proceed to baseline/day 1 visit or to screen fail the 
subject. 
The site will be notified by electronic communication of the results of this review and 
baseline/visit 1 should not occur prior to this notification.  Subjects who do not meet the 
eligibility criteria will be considered screen fails but may be eligible for rescreening as 
described in Section 8.1.1. 


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The baseline/day 1 visit will occur within 33 calendar days following the screening visit.  
At the baseline/day 1 visit subjects will be assessed for Inclusion Criteria 108 and 109 
prior to randomization.  Subjects who meet all eligibility criteria may proceed to 
randomization and dosing. 
Before any study-specific activities/procedures, the appropriate written informed 
consent must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be allowed. 
Post-randomization Adjudication 
The Adjudication Committee will assist in the ongoing review of data and adjudication of 
this trial including all clinical reported outcome assessments.  The group will remain 
blinded for the duration of the study.  
If there is inconsistency between assessments, additional clarification and training on 
these assessments will be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Inclusion Criteria - Screening Visit 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Age ≥ 18 years to 75 years at screening. 
103 
Fulfills classification criteria for SLE according to the 2019 EULAR/ACR 
classification criteria for SLE (Aringer et al, 2019), with antinuclear 
antibody  1:80 by immunofluorescence on Hep-2 cells or positive anti-dsDNA 
antibodies or positive anti-Smith at screening per central laboratory 
assessment.  
110 
Hybrid SLEDAI score ≥ 6 points with a "Clinical" hSLEDAI score ≥ 4 points.  The 
"Clinical" hSLEDAI is the hSLEDAI assessment score without the inclusion of 
points attributable to laboratory results, including urine and immunologic 
parameters.  Including the following protocol specific rules: 
 
Arthritis:  for hSLEDAI scoring purposes, a minimum of 3 joints with pain and 
signs of inflammation (ie, tenderness with swelling or effusion) must involve 
small joints in the hands, wrists, or a combination of joints in hands and 
wrists. 
 
Alopecia:  subjects should have active hair loss without scarring; should 
neither have alopecia areata nor androgenic alopecia; and should have a 
CLASI activity score for alopecia  2. 
 
Oral ulcers:  ulcers location and appearance must be documented by the 
investigator. 


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 
Scleritis and episcleritis:  the presence of stable SLE-related scleritis and 
episcleritis (ie, that will likely not require initiation/increase in 
immunosuppressants/immunomodulators as outlined in the 
inclusion/exclusion criteria) must be documented by an ophthalmologist and 
other causes excluded. 
 
Renal:  subjects with urine protein/creatinine ratio < 2000 mg/g (or 
equivalent) in a clean catch spot urine sample can enroll and be scored in the 
hSLEDAI, provided the subject has a clinical hSLEDAI ≥ 4. 
 
Pleurisy and Pericarditis:  symptoms of pleurisy and pericarditis must be 
accompanied by objective findings to be scored in the hSLEDAI.
105 
BILAG index score (BILAG 2004) of  1 A item or  2 B items. 
106 
Must be taking  1 of the following SLE treatments (or regional equivalent):  
hydroxychloroquine, chloroquine, quinacrine, mycophenolate mofetil, 
azathioprine, methotrexate, dapsone, or oral calcineurin inhibitors, or OCS.  A 
subject may enter the study on OCS alone (prednisone  10 mg/day or 
equivalent) only if the subject has previously documented trial of anti-malarial or 
immunosuppressant treatment for SLE.  Subjects must be on a stable dose for 
≥ 8 weeks prior to screening for all antimalarials and immunosuppressants, with 
the exception of OCS doses which must be stable for  2 weeks prior to 
screening. 
107 
For subjects taking OCS, the dose must be  20 mg/day of prednisone or OCS 
equivalent, and the dose must be stable for  2 weeks prior to screening visit. 
111 
For France, affiliation to a social security scheme is required.   
Inclusion Criteria - Day 1 (Baseline) 
The baseline/day 1 visit should occur after confirmation of eligibility by the adjudication 
team within 33 days after the screening visit.  At the baseline/day 1 visit, the following 
2 criteria should be assessed prior to randomization: 
108 
Stability of SLE treatments:  OCS and other 
immunosuppressants/immunomodulator agents and doses must be stable since 
screening visit. 
109 
Disease activity:  active disease as indicated by clinical hSLEDAI score ≥ 4 must 
be observed (clinical hSLEDAI score is the hSLEDAI assessment score without 
the inclusion of points attributable to laboratory results including urine and 
immunologic parameters). 


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5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
231 
Lupus nephritis if any of the following are present: 
 
urine protein creatinine ratio  2000 mg/g (or equivalent) at screening, OR  
 
requiring induction therapy currently or within 1 year prior to screening, OR 
 
histological evidence (if available) of diffuse proliferative glomerulonephritis 
within 12 weeks prior to screening. 
202 
Active central nervous system (CNS) lupus within 1 year prior to screening 
including, but not limited to, aseptic meningitis, ataxia, CNS vasculitis, cranial 
neuropathy, demyelinating syndrome, optic neuritis, psychosis, seizures, or 
transverse myelitis. 
Other Medical Conditions 
232 
Currently present or within 1 year prior to screening a diagnosis of any chronic 
inflammatory disease other than SLE (eg, presence of anti-cyclic citrullinated 
peptide [anti-CCP] and rheumatoid factor OR current history of RA OR 
presence of erosive arthritis on imaging) which would interfere with SLE 
disease assessment. 
204 
History of any disease other than SLE that has required treatment with oral or 
parenteral corticosteroids for > 2 weeks within 4 months prior to screening. 
205 
Active infection (including chronic or localized infections) currently or within 
2 weeks prior to screening visit OR presence of serious infection, defined as 
requiring hospitalization or intravenous anti-infectives within 8 weeks prior to 
screening visit. 
206 
Active tuberculosis (TB) or latent TB with no documented past history of 
adequate treatment per local standard of care. 
207 
Positive test for TB during screening defined as:  either a positive or 
indeterminate QuantiFERON®-TB or T-spot test OR positive purified protein 
derivative (PPD) ( 5 mm of induration at 48 to 72 hours after test is placed). 
 
Subjects with a positive PPD and a history of Bacillus Calmette-Guérin 
vaccination are allowed to enroll with a negative QuantiFERON®-TB or 
T Spot test and negative chest X-ray. 
 
Indeterminate QuantiFERON®-TB or T-spot test can be repeated once, based 
on investigator judgment.  Subjects can enroll if second result is negative.  
Subjects with persistent indeterminate or positive test results should proceed 
as below. 
 
Subjects with a positive PPD test (without a history of Bacillus 
Calmette-Guérin vaccination) or a positive or indeterminate 
QuantiFERON®-TB or T Spot test (including repeated results when 
performed) are allowed to enroll if they meet ALL the following criteria at 
screening: 
 
no symptoms per TB worksheet provided by Amgen. 


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 
documented history of adequate TB treatment or prophylactic treatment 
for latent TB (completed per local standard of care prior to the start of 
investigational product). 
 
no known exposure to a case of active TB after most recent 
treatment/prophylaxis. 
 
chest X-ray with no new radiographic findings suggestive of active TB (to 
be read by local facility). 
Note:  For criterion 207, these tests do not need to be repeated at the time of 
rescreening, unless rescreening occurs  12 months from screening visit or subject’s 
medical/exposure history suggests newly acquired infection or recent contact with TB 
cases and repeat testing of an indeterminate QuantiFERON®-TB test using the T spot 
test may be performed. 
233 
Positive for hepatitis B surface antigen (HBsAg); or positive for hepatitis B core 
antibody (HBcAb).  A positive hepatitis B surface antibody (HBsAb) without 
history of hepatitis B infection (ie, positive HBsAb, negative HBsAg and negative 
HBcAb) is allowed. 
234 
Positive for hepatitis C antibody. 
210 
Known history of HIV or positive HIV test at screening. 
Note:  For criteria 233, 234, and 210, these tests do not need to be repeated at the time 
of rescreening, unless re-screening occurs  12 months from screening or there is 
evidence or suspicion of recent infection. 
235 
Presence of 1 or more significant concurrent medical conditions, including but not 
limited to the following: 
 
Poorly controlled diabetes (hemoglobin A1C  7) or hypertension.  
 
symptomatic heart failure (New York Heart Association class III or IV). 
 
myocardial infarction or unstable angina pectoris within the past 12 months 
prior to screening. 
 
severe chronic pulmonary disease requiring oxygen therapy. 
 
multiple sclerosis or any other demyelinating disease. 
Note:  For criterion 235, subjects with positive antiphospholipid antibodies or diagnosis 
of antiphospholipid antibody syndrome according to the revised Sapporo classification 
criteria (Miyakis et al, 2006) can enroll in the study provided they have no current or 
past history of thrombotic events and meet all the other eligibility criteria. 
212 
Any history of malignancy with the following exceptions: 
 
resolved non-melanoma skin cancers  5 years prior to screening. 
 
resolved cervical carcinoma  5 years prior to screening. 
 
resolved breast ductal carcinoma in situ  5 years of screening. 


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Prior/Concomitant Therapy 
213 
Currently receiving or had treatment with:  cyclophosphamide, chlorambucil, 
nitrogen mustard, or any other alkylating agent within 6 months prior to screening 
or sirolimus within 4 weeks prior to screening.
237 
Currently receiving or had treatment with a Janus kinase (JAK) inhibitor or 
tyrosine kinase (TYK) inhibitor within less than 5 drug half-lives prior to 
screening.
215 
Currently receiving or had treatment with an immune checkpoint inhibitor (eg, 
PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor). 
Note:  Abatacept is not considered a CTLA-4 inhibitor and is referred to below.  
216 
Currently receiving or had treatment within 12 months prior to screening with 
T-cell depleting agents (eg, antithymocyte globulin, Campath).  
217 
Currently receiving or had treatment with an IL-2 based therapy (eg, Proleukin).
238 
Current or previous treatment with a biologic agent with 
immunosuppressive/immunomodulatory activity as follows:  rituximab within 
6 months prior to screening; abatacept, belimumab, and anifrolumab within the 
past 3 months prior to screening; other biologics within  5 drug half-lives prior to 
screening. 
219 
Subjects who have received intraarticular, intralesional, or intramuscular 
corticosteroids within 2 weeks prior to screening or intravenous corticosteroids 
within 6 weeks prior to screening. 
220 
Subjects who have received live vaccines within 5 weeks prior to screening, or 
plan to receive live vaccines during the treatment period and up to 6 weeks after 
the end of treatment period in the study. 
Prior/Concurrent Clinical Study Experience 
221 
Currently receiving treatment in another investigational device or drug study. 
222 
Ending a treatment with an investigational drug or investigational device less 
than 3 months or 5 half-lives from the last dose of the investigational drug 
(whichever is longer) at screening. 
Diagnostic Assessments 
236 
Presence of laboratory abnormalities at screening including the following: 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)  2 x 
upper limit of normal (ULN). 
 
Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 mol/L) except for 
Gilbert’s Syndrome. 
 
Hemoglobin < 8 g/dL (< 80 g/L). 
 
Platelet count < 75,000/mm3 (75 x 109/L). 
 
White blood cell count < 2000 cells/mm3 (2 x 109/L). 
 
Absolute neutrophil count (ANC) < 1,000/mm3 (1 x 109/L). 
 
Calculated glomerular filtration rate of  50 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) formula. 


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224 
Any other laboratory abnormality, which in the opinion of the investigator, poses 
a safety risk, will prevent the subject from completing the study or will interfere 
with the interpretation of the study results, or might cause the study to be 
detrimental to the subject. 
Other Exclusions 
225 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during the study and for an additional 6 weeks after the last dose of 
investigational product.  
239 
Female subjects of reproductive potential must agree not to donate eggs 
during the study and for 6 weeks after receiving the last dose of 
investigational product.
226 
Female of childbearing potential with a positive pregnancy test (assessed by a 
serum pregnancy test at screening and a urine pregnancy test prior to 
randomization).   
227 
Female subject of childbearing potential unwilling to use 1 highly effective 
method of contraception (see Section 11.5) during treatment and for an 
additional 6 weeks after the last dose of investigational product. 
228 
Subject has known sensitivity to any products to be administered during dosing. 
229 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
230 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that would pose a risk to 
subject safety or interfere with the study evaluation, procedures or completion. 
5.3 
Lifestyle Considerations 
Subjects who are taking methotrexate should be advised to limit alcohol consumption to 
no more than 4 ounces per week.   
5.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, as applicable (see Section 11.3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the subject has met all eligibility criteria (including 
criteria at the screening visit and the baseline/day 1 visit) and has subsequently been 
randomized.  The investigator is to document this decision and date, in the subject’s 
medical record and in/on the enrollment case report form (CRF).  At the baseline/day 1 
visit, if the subject meets all eligibility criteria, they will subsequently be randomized to a 


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treatment regimen and enrolled.  Subjects who meet screening visit eligibility but do not 
meet the baseline/day 1 visit eligibility criteria are considered screen failures.  Screen 
failures may be eligible for rescreening up to 3 times, as described in Section 8.1.1. 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by the IRT system.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization 
number assigned for the study. 
5.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened up to 3 times.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), or medical device(s) intended to be 
administered to a study subject according to the study protocol. 
Note that according to local regulations in several countries, investigational product(s) 
are referred to as investigational medicinal product(s) and non-investigational product(s) 
and other protocol-required therapies are referred to as non-investigational 
medicinal product(s)/auxiliary medicinal product(s). 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 
Efavaleukin alfa and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures. 


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Both are liquid formulations presented in highly similar glass vials and stored in the 
same manner.  Detailed information regarding the storage, preparation, and 
administration of investigational product will be provided separately. 
6.1.1.1 
Dose Administration and Schedule 
Efavaleukin alfa or placebo will be administered by SC injection Q2W starting on day 1.  
The following treatment groups are planned: 
 
efavaleukin alfa
2W 
 
efavaleukin alfa
2W  
 
efavaleukin alfa
 Q2W  
 
placebo Q2W 
Investigational product will be administered by SC injection in the abdomen, upper thigh 
or upper arm by authorized site personnel.  A physician must be available at the time of 
the first dose of the investigational product administration.  
The dose of investigational product must be given within  5 days of the scheduled time 
point (see Schedule of Activities Table 1-2 and Table 1-3).  If that window is missed, that 
dose will not be administered, and the next dose will be administered at the next 
scheduled dosing date.  Any 2 consecutive doses of investigational product must be at 
least 7 days apart. 
Subjects will remain at the site for at least 1 hour following the first and second doses of 
investigational product and for at least 30 minutes following subsequent doses.   
Total volume of preparation, quantity administered, start date, start time, and box 
number of efavaleukin alfa/placebo are to be recorded on each subject’s electronic 
case report form (eCRF). 
6.1.2 
Medical Devices 
No investigational medical devices will be used in this study. 
Non-investigational medical devices may be used in the conduct of this study as part of 
standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 


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6.1.3 
Other Protocol-permitted Therapies 
6.1.3.1 
Immunosuppressants/Immunomodulators 
Immunosuppressants/immunomodulator agents and doses should remain stable from 
 8 weeks prior to screening through week 52.  Investigators may reduce dosage of 
immunomodulators and/or immunosuppressants if the subject develops unacceptable 
side effects or abnormal laboratory values attributable to these medications. 
6.1.3.2 
Oral Corticosteroids 
Subjects who are taking OCS prior to screening should remain on a stable dose of OCS 
between  2 weeks prior to screening through week 12, with some exceptions as 
defined below.  Initiation or temporary increases in the OCS dosage is not encouraged 
but are allowed if initiated at any time between day 1 and week 10 with a return to 
baseline dose within the subsequent 2 weeks.  In such cases, initiation or temporary 
increase of OCS is limited to a dose  5 mg/day of prednisone (or equivalent).   
Subjects may begin tapering OCS after the week 12 assessment up to the 
week 44 assessment with initiation of tapering based upon clinical judgement of the 
treating physician.  The tapering schedule should be directed at the discretion of the 
investigator but should generally not be tapered more than 20% of the prior dose per 
week.  Tapering OCS before week 12 is not encouraged but may be allowed based 
upon investigator’s judgement.  Between weeks 44 and 52, the OCS dosing must again 
remain stable. 
6.1.3.3 
Topical Corticosteroids and Topical Calcineurin Inhibitors 
Subjects who are using topical corticosteroids or topical calcineurin inhibitors should 
remain on a stable regimen during the study but may discontinue topical corticosteroids 
or calcineurin inhibitors at any time if clinically indicated.   
6.1.3.4 
Non-steroidal Anti-inflammatory Drugs (NSAIDS) and Other 
Analgesic Therapies 
Subjects taking non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesic 
therapies should remain on a stable dose from day 1 through week 52.  No initiation or 
increases in NSAIDs are allowed within 2 weeks of the week 52 visit.  NSAIDs used for 
SLE disease activity should be held for 24 hours prior to scheduled visits.  Subjects can 
return to their regular doses immediately after the clinical visit is 
complete.  Discontinuation or reduction in frequency or dose of NSAIDs or other 
analgesic therapy dose during the study is allowed based on the investigator’s 
judgment.  Initiation or increases in NSAIDs or other analgesic therapy doses during the 


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study are allowed if:  1) subject is on baseline dose within 24 hours of scheduled 
efficacy assessments and 2) the subject returns to baseline dose within the subsequent 
2 weeks of initiation or increase and 3) it is not within 2 weeks prior to the week 52 visit. 
6.1.3.5 
Anti-proteinuria Agents 
Subjects with proteinuria due to SLE and taking anti-proteinuria agents (eg, angiotensin 
II receptor blockers, angiotensin-converting enzyme inhibitors), should remain on stable 
doses from day 1 through week 52.  Discontinuation or dose reduction of 
anti-proteinuria agents during the study is allowed in case of intolerance or toxicity.  
Initiation or dose increase of anti-proteinuria agents (eg, angiotensin II receptor 
blockers, angiotensin-converting enzyme inhibitors) during the study should be avoided. 
6.1.4 
Other Treatment Procedures 
6.1.4.1 
Home Health Care Visits 
If permitted by local regulations, the investigator may utilize a qualified home health care 
service provider, approved by sponsor, for collection of PK and biomarker samples 
(investigational product will not be administered at these visits).  In addition to PK and 
biomarker sample collection, safety assessments including adverse events, serious 
adverse events, and concomitant medications review will be collected. 
Home health care staff must be included on the study delegation log (authorized by the 
investigator) before any study-related tasks to be conducted by each home health care 
provider are started.  In addition, study-specific training including requirements for 
recording source documentation for the home health care provider, must be completed 
before they conduct any study-related tasks. 
Following home health care visits, all the information collected will be documented on 
the home health care services visit worksheet and provided to the investigator.   
A comprehensive list of all home health care services, as well as mandatory procedural 
and data collection requirements, will be separately provided in a home health care 
manual. 
6.1.5 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors and partners for whom Amgen 


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manufactures the material.  This includes all components distributed with the drug such 
as packaging drug containers, delivery systems, labelling, and inserts. 
This includes efavaleukin alfa/placebo provisioned and/or repackaged/modified by 
Amgen. 
Any product complaint(s) associated with an investigational product(s) 
(efavaleukin alfa/placebo), non-investigational products supplied by Amgen are to be 
reported. 
6.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications are not allowed at any time during the study: 
 
investigational therapies or commercially available biologic agents with 
immunosuppressive/immunomodulatory activity (eg, rituximab, abatacept, 
belimumab, or anifrolumab) 
 
cytotoxic agents including:  chlorambucil, cyclophosphamide, nitrogen mustard, or 
other alkylating agents 
 
live vaccines 
 
T cell depleting agents (eg, antithymocyte globulin, Campath) 
 
IL-2 based therapies (eg, Proleukin) 
 
Intravenous, intra-articular, intramuscular, or intralesional corticosteroids, including 
adrenocorticotropic hormone 
 
intra-articular hyaluronic acid injections 
 
JAK inhibitors and TYK inhibitors  
 
immune checkpoint inhibitors 
6.2 
Dose Modification 
6.2.1 
Dose Treatment Group Study Escalation/De-escalation and Stopping 
Rules 
All subjects will receive a fixed dose of the investigational product 
(efavaleukin alfa/placebo) according to the randomization assignment.  No dose 
adjustments will be allowed. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  Efavaleukin Alfa 
No dosage adjustments will be allowed. 
The investigational product must be withheld if the following occur: 
 
any serious and/or clinically significant grade  3 adverse event deemed possibly 
related to investigational product until the adverse event resolves to  grade 2. 


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Investigational product must be permanently discontinued if the following occur: 
 
any anaphylactic reactions or  grade 3 acute allergic reactions deemed possibly 
related to investigational product by either the investigator and/or the sponsor that 
requires immediate treatment. 
 
any grade 4 life-threatening treatment-emergent adverse events deemed possibly 
related to investigational product. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study will be provide to the site.   
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet all eligibility criteria will be randomized to receive efavaleukin alfa at 
Q2W,
Q2W,
Q2W, or placebo Q2W in a double-blind manner.  
The randomization will be stratified by geographic region (North America + West Europe 
+ Asia Pacific versus Rest of the World) and screening hSLEDAI score ( 10 versus 
 10, with  10 screening hSLEDAI capped at 80% of the study population).  The 
randomization ratio starts as 1:1:1:1, and then may be adapted at planned IAs based on 
the clinical efficacy, as measured by SRI-4 response, based on RAR for the purpose of 
allocating more subjects to more efficacious doses and fewer subjects to less efficacious 
doses.  The RAR will be implemented with a computerized system that assigns a 
treatment to subsequent subjects without unblinding any study personnel including the 
investigators or subjects. 
The randomization will be performed via an IRT system.  Each randomized subject will 
receive a single, unique randomization number via an IRT system at randomization.  
The randomization date is to be documented in the subject’s medical record as 
registered in the IRT system and on the enrollment eCRF. 


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6.4.2 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
6.4.2.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on 
this study or may potentially impact the safety of the subject.  Unblinding at the study 
site for any other reason will be considered a protocol deviation.  It is encouraged that 
the Amgen Trial Manager be notified before the blind is broken unless the investigator 
believes that identification of the study treatment is required for a medical emergency.  
If this is not possible, the Amgen Trial Manager must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation. 
6.4.2.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information is not to be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded except as specified (eg, Section 6.4.2.1). 
6.5 
Treatment Compliance 
When subjects are dosed, they will receive investigational product directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered will be recorded in the source documents and recorded in the eCRF. 
6.6 
Treatment of Overdose 
The effects of overdose of this product are not known. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior therapies for SLE that were being taken/used from time of initial diagnosis with 
SLE through the date of randomization will be collected.  For prior therapies, collect 
therapy name, indication, dose, unit, frequency, start date, and stop date. 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Sections 6.1.3 and 6.1.6. 


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Concomitant therapies (including vaccines) are to be collected from randomization 
through the end of the safety follow-up period.  For concomitant therapies, collect 
therapy name, indication, dose, unit, frequency, start date, and stop date.  Guidelines for 
immunomodulators, immunosuppressants, and OCS are provided in Section 6.1.3. 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Section 7. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/or procedures at 
any time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 1-2, 
Table 1-3, Table 1-4, and Section 8.1.3) including different options of follow-up (eg, in 
person, by phone/mail, through family/friends, in correspondence/communication with 
other treating physicians, from the review of medical records) and collection of data, 
including endpoints, adverse events, and must document this decision in the subject’s 
medical records.  Subjects who have discontinued investigational product and/or other 
protocol-required therapies and/or procedures and subjects who require a dose of OCS 
for SLE above their baseline dose after week 16 and patients requiring either dose 
increases of the current immunosuppressants/new 
immunosuppressant/immunomodulator(s) should not be automatically removed from 
the study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 


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Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Pregnancy 
 
Disease flare 
7.2 
Subject Discontinuation/Withdrawal From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.  Subjects who are 
withdrawn or removed from treatment or the study will not be replaced. 
If a subject withdraws from the study, they may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor* 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
* Study discontinuation of ‘decision by sponsor’ will only be used in the event that the 
study is terminated, for any reason, including due to futility.  Subjects who are still on 
study at the time of that decision may be terminated per sponsor decision. 


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7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, they will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.   
 
For subjects who are lost to follow-up, the investigator should search publicly 
available records where permitted to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedules of Activities 
(see Table 1-2, Table 1-3, and Table 1-4).   
If an enrolled subject is subsequently determined to be ineligible for the study, this must 
be discussed with the sponsor immediately upon occurrence or awareness to determine 
if the subject is to continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
Informed consent must be obtained before completing any screening procedure.  After 
the subject has signed the informed consent form, the site will register the subject in the 
IRT system and screen the subject in order to assess eligibility for participation.  The 
screening window is up to 33 calendar days. 
All eligibility evaluations (conducted at the screening and baseline/day 1 visits prior to 
randomization) must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria.  The investigator will maintain a screening log to record details of all 


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subjects screened and to confirm eligibility or record reasons for screening failure, (see 
Section 5.5) as applicable.  If a lab retest is required during screening, the sponsor 
should approve prior to being retested.   
A subject is considered enrolled when all eligibility criteria (from screening visit and 
baseline/day 1 visit) have been met and subject is subsequently randomized.  The 
investigator is to document this decision and date, in the subject’s medical record and 
in/on the enrollment case report form (CRF).  At baseline/day 1 visit, if the subject 
meets all eligibility criteria they are subsequently enrolled and randomized to a 
treatment regimen. 
If a subject has not met all eligibility criteria at the end of the screening period and/or at 
the baseline/day 1 visit, the subject will be registered in IRT as a screen failure.  Screen 
failures may be rescreened up to 3 times as follows: 
 
Subjects who do not meet the hSLEDAI criteria (clinical hSLEDAI score  4 at 
baseline/day 1 visit) must wait at least 2 weeks before rescreening.   
 
Subjects who have not maintained stable OCS dosing will be required to wait at 
least 2 weeks prior to rescreening.   
 
Subjects who have not maintained stable immunosuppressant/immunomodulatory 
dosing will be required to wait at least 8 weeks prior to rescreening.   
 
Subjects who met eligibility criteria but were not able to enroll within the screening 
period (within the 33 days), can rescreen immediately. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 33 day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  All procedures noted in Section 8, including the 
informed consent and all laboratory parameters (Section 8.3.3) must be repeated with 
the following exception:  
 
Tuberculosis screening tests (QuantiFERON®-TB, T-spot test OR positive PPD), 
serologies for hepatitis B virus, hepatitis C virus and HIV do not need to be repeated, 
provided that rescreening occurs  12 months of screening visit and there is no 
patient’s medical/epidemiological history suggestive of infection or recent exposure 
to cases of infection.   
8.1.2 
Treatment Period 
Visits will occur per the Schedules of Activities (Table 1-2 and Table 1-3).  The date of 
the first dose of investigational product is defined as day 1.  All subsequent doses and 
study visits will be scheduled based on the day 1 date.  The investigational product is to 


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be administered following the completion of all other study required procedures for that 
visit. 
If a subject discontinues investigational product prior to week 52, the subject will be 
encouraged to maintain the planned scheduled assessments through week 52 
(Table 1-3).  If the subject discontinues the study completely prior to week 52, the 
subject should complete an early termination (ET) visit (ie, week 52 visit procedures) 
which must be scheduled to allow for at least 6 weeks for safety data collection after last 
dose of investigational product.   
8.1.3 
Safety Follow-up Period 
The safety follow-up period consists of a single safety follow-up visit which may be 
required at week 56 5 days per the Schedule of Activities (Table 1-4).  This visit only 
applies to subjects who require an additional visit following week 52 to ensure 6 weeks 
of safety data collection after last dose of investigational product (Section 8.1.2).   
8.1.4 
End of Study 
Refer to Section 4.4 for End of Study definition.   
All end of study procedures (ie, week 52/ET visit) should be performed at the final visit 
for subjects who discontinue study before week 52.   
8.2 
General Assessments  
8.2.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, the correlation between specific demographic data and PK, PD, and 
biomarkers may be explored. 
8.2.3 
Medical History 
The investigator or designee will collect a relevant medical, psychiatric, and surgical 
history that started within 5 years of enrollment or as necessary to describe chronic or 
co-morbid conditions prior to enrollment through the start of the adverse event reporting 
period.  Medical history will include information on the subject's concurrent medical 
conditions.  Findings are to be recorded on the medical history eCRF.  In addition to the 


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medical history above, SLE history must date back to the original diagnosis.  The 
current severity will be collected for each condition that has not resolved. 
8.2.4 
Lupus Narrative 
The screening lupus narrative form provides relevant information related to the subject’s 
lupus.  This form is to be used to provide a more holistic view of the subject’s lupus 
history and current disease activity and aids in eligibility adjudication of the subject. 
8.2.5 
Physical Examination  
Physical examinations will be performed as per the Schedules of Activities.  Physical 
examination findings should be recorded on the appropriate eCRF (eg, medical history, 
Events). 
8.2.6 
Physical Measurements 
Height in centimeters and weight in kilograms should be measured without shoes. 
8.2.7 
Substance Use History  
Obtain a detailed history of prior and/or concurrent use of alcohol and tobacco.   
Note:  Subjects who are taking methotrexate should be advised to limit alcohol 
consumption to no more than 4 ounces per week. 
8.2.8 
Lupus Nephritis History 
Obtain details regarding history of lupus nephritis as per Lupus Nephritis History Form. 
8.2.9 
Efficacy Assessments 
Efficacy assessments are recommended to be performed prior to obtaining any blood 
samples and administration of investigational product.  Assessments will be captured 
on a paper source then transcribed into the study database.  It is highly recommended 
that the same assessor performs efficacy assessments at every timepoint for a given 
subject. 
8.2.9.1 
Hybrid Systemic Lupus Erythematosus Disease Activity Index  
The hybrid SLEDAI (hSLEDAI) is a global index that evaluates disease activity and 
includes both laboratory and clinical parameters and consists of 24 items.  The 
maximum score is 105.  Hybrid SLEDAI is the index score used during the validation of 
the SLE Responder Index (SRI) (Navarra et al, 2011; Furie et al, 2011).  The hSLEDAI 
includes scleritis and episcleritis in visual disturbance assessments.  Scleritis and 
episcleritis should be confirmed by ophthalmologist and clinically stable if used for 
scoring purposes.  Additionally, arthritis should be scored when > 2 joints manifest 
signs of inflammation strictly defined as the presence of tenderness plus 1 of the 


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following:  swelling, effusion, warmth or erythema.  The presence of tenderness alone is 
not sufficient and at least 3 joints, and not only 2, must be affected.  In this study, for 
arthritis to be scored it is required to involve the small joints in the hands, wrists, or a 
combination of joints in the hands and wrists.  
A total hSLEDAI  6 points is required for eligibility purposes, together with the presence 
of a clinical hSLEDAI  4 points.  A clinical hSLEDAI score is a hSLEDAI score without 
the inclusion of points attributable to laboratory results including urine and immunologic 
parameters.   
Findings should reflect activity during the 30 calendar days prior to the current visit.   
8.2.9.2 
British-Isles Lupus Assessment Group Index 
The BILAG index (BILAG 2004) evaluates disease activity in 9 separate organ systems 
and comprises a total of 97 items.  Each item is measured qualitatively by review of 
medical history and physical examination (yes/no, improving/same/worse/new) or 
quantitatively by measuring laboratory values.  Based on these items, each of the 
9 organ systems allocated an alphabetical score of A (most active), B (moderate 
activity), C (minor activity), D (stable) or E (never present).  The BILAG index can be 
converted into a numerical score (A grade = 12 points, B = 8, C = 1, D = 0, E = 0) 
(Yee et al, 2010).  Findings should reflect activity during the 4-week period prior to the 
current visit and attributable to the subject’s SLE.  
8.2.9.3 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
The CLASI consists of 2 scores, the first summarizes the activity of the disease while 
the second is a measure of the damage done by the disease.  Activity is scored based 
on erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss 
and non-scarring alopecia.  Damage is scored in terms of dyspigmentation and 
scarring, including scarring alopecia.  Subjects are asked whether dyspigmentation due 
to cutaneous lupus lesion usually remains visible for more than 12 months, which is 
considered permanent.  If so, the dyspigmentation score is doubled.  The scores are 
calculated by simple addition based on the extent of the symptoms.  The CLASI is 
designed as a table where the rows denote anatomical areas, while the columns score 
major clinical symptoms.  The extent of involvement for each of the skin symptoms is 
documented according to specific anatomic areas that are scored according to the 
worst affected lesion within that area for each symptom.  


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8.2.9.5 
Swollen and Tender Joint Count 
Swollen and tender joint counts will be performed as noted in the Schedule of Activities 
(Table 1-2 and Table 1-3). 
The swollen and tender joint count assessments will be performed at the site by an 
experienced independent and blinded joint evaluator and must be identified on the 
delegation of authority for this responsibility.  It is highly recommended that the same 
joint evaluator performs the assessments throughout the study for a given subject.  The 
score for each joint will be recorded on a paper source then transcribed into the study 
database.   
Joints that have been replaced are considered non-evaluable throughout the study.  
Swollen Joint Count Assessments:  A total of 28 joints will be scored for presence or 
absence of swelling.  A separated score for joints in the hands and wrists will be 
calculated. 
Tender Joint Count Assessments:  A total 28 joints will be scored for presence or 
absence of tenderness.  A separate score for joints in the hands and wrists will be 
calculated. 
Swollen and Tender Joint Count Assessments:  joints in hands and wrists will be scored 
for the simultaneous presence or absence of swelling and tenderness.   
8.2.9.6 
Physician Global Assessment – Visual Analog Scale 
The PGA is a visual analog scale (VAS) using 4 descriptive anchors for assessing 
disease activity over the last 4 weeks.  When scoring the PGA VAS, the previous visit 
score should be noted, and the current score should be relative to that previous visit.  
The score ranges from 0 to 3 with 3 indicating severe disease.  This refers to the most 
severe possible disease and does not reflect the most severe ever seen in a particular 
subject, but the most severe disease ever seen in all SLE patients.  Therefore, a score 
of 3 should rarely be seen.  Any disease rated greater than 2.5 is very severe.  The 
range of moderate disease covers approximately 1.5 to 2.4.  Mild disease falls 
below 1.5.   


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This is a global assessment, factoring in all aspects of the subject’s lupus disease 
activity.  It should not reflect non-lupus medical conditions.  An increase of ≥ 0.3 points 
(> 10% on the 3 point-VAS) from baseline is considered clinically significant worsening 
of disease.  This assessment will be completed by a health care provider  and must be 
done before assessing the hSLEDAI and BILAG.   
8.2.9.7 
Physician Global Assessment – 4-Point Verbal Rating Scale 
The PGA 4-Point Verbal Rating Scale uses 4 verbal descriptors for assessing the 
severity of disease since the last visit.  The options for disease severity are none, mild, 
moderate, and severe.   
This is a global assessment, factoring in all aspects of the subject’s lupus disease 
activity.  It should not reflect non-lupus medical conditions.  This assessment will be 
completed by a health care provider and must be done before assessing the hSLEDAI 
and BILAG.   
8.2.9.8 
SRI-4 
SRI-4 will be calculated as detailed in Luijten et al, 2012.  A subject achieves 
SRI-4 response if all of the following criteria are met:   4-point reduction from baseline 
in hSLEDAI score, AND no new BILAG A score and no  1 new BILAG B organ domain 
scores compared with baseline, AND  0.3-points deterioration from baseline in PGA 
VAS score (scale 0 to 3).   
8.2.9.10 
Lupus Low disease Activity State (LLDAS) 
The LLDAS will be calculated as detailed in Golder et al, 2019. 
8.2.9.11 
BILAG-based Combined Lupus Assessment (BICLA) 
BICLA response is defined as at least 1 gradation of improvement in baseline BILAG 
domain scores in all body systems with moderate or severe disease activity at entry (eg, 
all A [severe disease] domain scores falling to B [moderate], C [mild], or D [no activity], 
and all B domain scores falling to C or D); no new BILAG 2004 A domain score and no 
> 1 new BILAG 2004 B domain scores compared with baseline; no worsening of the 
hSLEDAI score from baseline; < 0.3-points deterioration from baseline in PGA VAS 
(scale 0 to 3); and no initiation of non-protocol treatment (Wallace et al, 2011; 
Wallace et al, 2014).  


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8.2.9.12 
Patient Reported Outcomes 
Patient reported outcomes should be completed prior to any assessments and before 
being clinically evaluated by the investigator or designee. 
The assessments will be recorded directly into the electronic tablet which will serve as 
the source documentation and will not be transposed to an eCRF. 
8.2.9.12.1 
Medical Outcomes Short Form-36 Questionnaire Version 2 
The SF-36v2 (acute version) Health Survey (Ware et al, 2000) contains 36 items and is 
a revised version of the SF-36 Health Survey.  The SF-36v2 acute version is a 
patient-reported generic measure of health status.  This survey yields assessments of 
8 domains of health-related quality of life:  1) limitations in physical activities because of 
health problems; 2) limitations in social activities because of physical or emotional 
problems; 3) limitations in usual role activities because of physical health problems; 
4) bodily pain; 5) general mental health (psychological distress and well-being); 
6) limitations in usual role activities because of emotional problems; 7) vitality (energy 
and fatigue); and 8) general health perceptions.  The scores from the 8 domains will be 
evaluated independently and aggregated into 2 norm-based summary component 
measures of physical and mental health.  The recall period is the past 7 days.   
This survey takes approximately 10 to 15 minutes to complete. 
8.2.9.12.2 
Patient-Reported Outcome Measurement Information System 
Fatigue Short Form 7a Instrument (PROMIS Fatigue SF 7A) 
The PROMIS Fatigue Short Form 7a is a 7-item instrument originally constructed by the 
PROMIS Fatigue team to represent the range of the fatigue traits (PROMIS Fatigue 
Scoring Manual).  It assesses the experience of fatigue as well as its impact on 
physical, mental, and social activities.  Both psychometric properties and clinical input 
were used in the development of the short form from the PROMIS item bank.  
Estimates of responsiveness and minimally important differences have been reported 
for the 4 item PROMIS Fatigue instrument in SLE patients (Katz et al, 2020).  The 
PROMIS Fatigue has also been able to differentiate disease activity in other 
rheumatologic diseases (Wohlfahrt et al, 2019). 
The PROMIS Fatigue Short Form 7a takes 1 to 2 minutes to complete. 
8.2.9.12.3 
LupusQoL 
The LupusQoL is the US version of the 34-item LupusQol originally developed in the 
United Kingdom (Jolly et al, 2010; McElhone et al, 2007).  This is a SLE-specific 


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health-related quality of life instrument.  The LupusQoL consists of 8 domains:  physical 
health (8 items), pain (3 items), planning (3 items), intimate relationships (2 items), 
burden to others (3 items), emotional health (6 items), body image (5 items), and 
fatigue (4 items).  The final instrument has demonstrated good internal reliability 
(Cronbach's 0.88 to 0.95), good test-retest reliability (r 0.72 to 0.93), good concurrent 
validity with the comparable domains of the SF-36 (r 0.71 to 0.79) and good 
discriminant validity for different levels of disease activity, measured by BILAG index, 
and damage (Systemic Lupus International Collaborating Clinics/ACR damage index) 
but not for all domains.  The instrument also has acceptable ceiling effects and minimal 
floor effects. 
Subjects typically complete the LupusQoL in less than 10 minutes.  The scoring and the 
transformation of the scores takes approximately 5 minutes per subject. 
8.2.9.12.4 
Symptom Questionnaire 
The Symptom Questionnaire is a new patient reported outcome instrument to evaluate 
inflammatory symptoms, non-inflammatory symptoms, and flare (Pisetsky et al, 2019).  
The items are based on a 11-point numerical rating scale, with 1 item being a choice of 
yes or no, all with a 7-day recall.  Response to therapy and psychometric properties of 
the questionnaire will be evaluated with data derived from this study. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedules of Activities 
see (Table 1-2, Table 1-3, and Table 1-4). 


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8.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, 
heart rate, respiratory rate, and temperature.  Subject must be in a supine or seated 
position in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital signs eCRF.  The 
temperature location should be oral, forehead, or tympanic (with oral preferred).  Once 
a location for temperature assessment is selected for a subject, the location should be 
the same throughout the study and documented on the vital signs eCRF.  Record all 
measurements on the vital signs eCRF. 
8.3.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements:  heart rate, QRS, QT, QTc, and PR intervals.  The 
investigator or designee will review all ECGs.  Once signed, the original ECG tracing will 
be retained with the subject's source documents.  At the request of the sponsor, a copy 
of the original ECG will be made available to Amgen.   
8.3.3 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-2, Table 1-3, and Table 1-4) for the timing and frequency.   
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Events eCRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event.   
Abnormal laboratory values that are considered to be clinically significant by the 
investigator must be repeated as soon as possible to rule out laboratory error.  
Persistent abnormal laboratory values should be followed-up until they return to normal 
or until an etiology of the persistent abnormality is determined.   


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All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-2, Table 1-3, and Table 1-4).   
After baseline, PK/PD parameters and lymphocyte value that could unblind the study will 
not be reported to investigative sites or other blinded personnel until the study has been 
unblinded.   
8.3.3.1 
Serum Complement, Anti-dsDNA, and Anti-phospholipid Antibody 
Testing 
All subjects will have samples for C3, C4, anti-dsDNA and anti-phospholipid antibody 
collected as outlined in the Schedule of Activities (Table 1-2 and Table 1-3).  
Anti-dsDNA will be done for hSLEDAI determination throughout the study and will be 
collected as outlined in the Schedule of Activities (Table 1-2 and Table 1-3). 
8.3.3.2 
Tuberculosis Testing 
All subjects must receive either a PPD, QuantiFERON®-TB, or T-Spot test at screening.  
A chest X-ray will be performed for subjects with a positive TB test (ie, positive PPD or 
positive or indeterminate QuantiFERON®-TB or T-spot test). 
8.3.3.2.1 
Purified Protein Derivative 
The PPD test must be read by a trained health care professional 48 to 72 hours after 
the test is placed.  The PPD reader must be identified on the delegation of authority for 
this responsibility.  PPD test kits will not be provided by the sponsor and must be 
procured locally.  
8.3.3.2.2 
QuantiFERON®-TB or T-Spot Testing 
If a QuantiFERON®-TB test is performed for eligibility, the test will be performed centrally 
with test kits provided.  If a T-spot test is performed for eligibility, the test will be 
performed locally with test kits procured locally.  
8.3.3.3 
HIV Antibodies, Hepatitis B, and Hepatitis C Testing 
Hepatitis B surface antibody (HBsAb), hepatitis B surface antigen (HBsAg), hepatitis B 
core antibody (HBcAb), hepatitis C (HCAb), and HIV antibodies (where permitted by 
local regulations) will be assessed at screening. 
8.3.4 
Adverse Events and Serious Adverse Events  
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4.   


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8.3.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.3.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE 
version 5 and is described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
product (efavaleukin alfa/placebo) through the EOS are reported using the Events 
eCRF. 
8.3.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 6 weeks (5 days) after the last dose of the investigational product/end 
of study/safety follow-up visit, whichever occurs later, are reported using the Events 
eCRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee immediately and no later than 24 hours of the investigator’s awareness of the 
event, as indicated in Section 11.4.  The investigator will submit any updated serious 
adverse event data to the sponsor immediately and no later than 24 hours of it being 
available. 
Since the criteria in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life-threatening status), it will be left to the investigator’s judgment to 
also report these abnormalities as serious adverse events.  For any adverse event that 
applies to this situation, comprehensive documentation of the event’s severity must be 
recorded in the subject medical records. 
8.3.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After end of study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  However, if 
the investigator becomes aware of serious adverse events suspected to be related to 
investigational product, then these serious adverse events will be reported to Amgen 


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immediately and no later than 24 hours following the investigator’s awareness of the 
event. 
Serious adverse events reported after the end of the study will be captured within the 
safety database as clinical trial cases and handled accordingly based on relationship to 
investigational product.  
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records if the subject ends the study. 
8.3.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence.  In the event that a local 
reaction occurs at the site of the investigational product administration, the adverse 
event is to be reported in the Events eCRF as “injection site reaction” and the specific 
location and symptoms associated with the injection site reaction should also be 
provided.  If there are multiple signs or symptoms at an injection site, each symptom of 
the event should be reported individually.  
8.3.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required 
to proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen immediately and no later than 24 hours following awareness of the new 
information.  If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or extracts from 
the medical records.  Information provided about the serious adverse event must be 
consistent with that recorded on the Events eCRF. 
8.3.4.4 
Regulatory Reporting Requirements for Safety Information 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 


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Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
For studies in which the treatment assignment is blinded, to comply with worldwide 
reporting regulations for serious adverse events, the treatment assignment of subjects 
who develop serious, unexpected, and related adverse events may be unblinded by 
Amgen before submission to regulatory authorities.  Aggregate analyses may also be 
unblinded by the Safety Assessment Team, as appropriate.  Investigators will receive 
notification of related serious adverse events reports sent to regulatory authorities in 
accordance with local requirements. 
Amgen will prepare a single Development Safety Update Report (DSUR) (also referred 
to as Annual Safety Report [ASR] in the European Union) for the Amgen Investigational 
Product.  In order to ensure that consolidated safety information for the trial is provided, 
this single DSUR will also include appropriate information on any other investigational 
products used in the clinical trial, if applicable.   
8.3.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes.   
8.3.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and through 6 weeks 
after the last dose of protocol-required therapies.   


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If a pregnancy is reported, the investigator is to inform Amgen immediately and no later 
than 24 hours of learning of the pregnancy and/or lactation and is to follow the 
procedures outlined in Section 11.5.  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested.   
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.   
Further details regarding pregnancy and lactation are provided in Section 11.5.   
Pregnancy Testing 
A high sensitivity serum pregnancy test should be completed at screening and a high 
sensitivity urine pregnancy test should be completed prior to randomization for females 
of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Section 11.5.  Refer to Section 11.5 for contraceptive requirements.    
Additional pregnancy testing using a high sensitivity urine pregnancy test should be 
performed at monthly intervals during treatment with the investigational product and at 
the follow-up safety assessment.   
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations.   
8.4 
Pharmacokinetic Assessments 
All subjects randomized to efavaleukin alfa will have PK samples assessed.   
Blood samples will be collected for measurement of serum concentrations of efavaleukin 
alfa as specified in the Schedule of Activities (Table 1-2 and Table 1-3).   
Instructions for the collection and handling of biological samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded.   
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.   


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8.5 
Pharmacodynamic Assessments 
Lymphocyte subsets:  Blood samples will be collected for all subjects at the time points 
indicated in the Schedule of Activities (Table 1-2 and Table 1-3) 
 
Detailed instructions on sample collection, processing, and shipping will be provided in a 
separate manual. 
8.6 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of inflammatory conditions 
and/or to identify subjects who may have positive or negative response to efavaleukin 
alfa.  Additional samples are not collected for this part of the study.  For subjects who 
consent to these analyses, DNA may be extracted. 
The final disposition of samples will be described in Section 11.6.  


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8.8 
Biomarkers  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.8.1 
Biomarker Assessment During the Study 
8.8.2 
Biomarker Development 
Samples will also be collected to develop or address biomarker hypotheses related 
to efavaleukin alfa activity, eg, to evaluate potential biomarkers that may correlate with 
treatment response. 
Blood will be collected for biomarker development at the time points specified in the 
Schedule of Activities (Table 1-2 and Table 1-3).  


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8.8.3 
Biomarker Future Research 
Future research can be useful in developing markers to identify disease subtypes, 
guide therapy, and/or predict disease severity.   
If consent is provided by subjects, any remaining samples collected per the Schedule of 
Activities, including samples collected for biomarker assessments may be used for 
future research as described in Appendix 6 (Section 11.6).  No additional samples will 
be collected for future research. 
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to efavaleukin alfa to 
investigate and further understand inflammatory conditions. 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
At least 1 efavaleukin alfa dose will have greater efficacy than placebo as measured by 
the SRI-4 response rate at week 52 in subjects with active SLE with inadequate 
response to SOC therapy who are randomized, regardless of investigational product 
compliance; subjects using more than protocol-permitted therapies will be considered as 
nonresponders as specified in the primary estimand. 
9.2 
Sample Size Determination 
The approximate sample size of 320 subjects is chosen to provide approximately 80% 
power to detect ≥ 25% absolute improvement for at least 1 efavaleukin alfa dose group 
relative to placebo in the primary endpoint of SRI-4 response rate at week 52 at a 
significance level of 0.025 (1-sided) using a Bayesian Hierarchical Model, assuming a 
40% response rate in placebo group. 
Because enrollment can be stopped once early stopping rules for futility are met at an 
IA, the actual sample size could be smaller and cannot be pre-specified.  The 
approximate sample size of 320 subjects ensures if there is no interim signal for ET 
based on futility of all efavaleukin alfa doses, the trial will have adequate power to 
achieve the primary objective once all subjects have had the opportunity to complete the 
study. 


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9.2.1 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
Full Analysis Set 
All subjects randomized in the study, with treatment assignment 
based on subjects’ randomized treatment assignment. 
Efficacy Analysis Set 
All subjects randomized in the study.  Data will be analysed 
based on subjects’ randomized treatment assignment. 
Safety Analysis Set 
All randomized subjects who received at least 1 dose of 
investigational product.  Data will be analysed according to 
actual treatment received. 
PK Concentration Analysis 
Set 
The PK Concentration Analysis Set is defined as the subset of 
subjects in the Safety Analysis Set who had at least 1 evaluable 
serum concentration (including results below the level of 
detection) of investigational product.  PK concentration data will 
be analysed according to the actual treatment received. 
PK Parameter Analysis Set 
The PK parameter analysis set is defined as the subset of 
subjects in the Safety Analysis Set who had at least 1 PK 
parameter adequately derived.  PK parameter will be analysed 
according to the actual treatment received. 
9.2.2 
Covariates 
The impact of the baseline covariates on the treatment effect may be explored and 
adjusted in the model for the primary and secondary endpoints as deemed necessary.  
The baseline covariates may include but are not limited to:  
 
Age, region, race, sex 
 
Baseline SLE disease activity 
 
Baseline OCS dose 
 
Baseline biomarkers 
Stratification factors will be included as covariates in the model.  If included as 
covariates in the model for treatment comparisons, the IRT value will be used to be 
consistent with the randomization scheme. 
9.2.3 
Subgroups 
In addition to stratification factors, some covariates, not limited to those mentioned 
above, may be used for further exploration in subgroups.  For subgroup analyses, the 
value collected from source-verified eCRF will be used to reflect the true clinical 
relevance of the covariate. 


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9.3 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock 
for the final analysis.  Below is a summary of the timing and methods for the planned 
statistical analyses.  To preserve study integrity, the final analysis will be conducted and 
reported following the end of study, as defined in Section 4.4. 
9.3.1 
Planned Analyses 
9.3.1.1 
Interim Analysis and Early Stopping Guidelines 
Interim analyses will be conducted to allow for adaption of the randomization ratio for 
newly enrolled subjects to the 3 efavaleukin alfa treatment groups, holding the allocation 
to placebo constant at 25%, and assessing efficacy for early futility or administrative 
success decisions: 
 
The study team, investigators, and subjects will remain blinded to the results of the 
IAs. 
 
The first IA will be executed after the first 40 subjects are randomized and have had 
the opportunity to complete the week 24 assessment.  Subsequent IAs are 
scheduled after every additional 32 subjects are randomized and have had the 
opportunity to complete the week 24 assessment until full enrollment.  The last IA will 
occur when all 320 subjects are randomized and have had the opportunity to 
complete the week 24 assessment.  This IA will be referred to as the 
‘all-subjects-week-24 IA.   
 
Efficacy analyses will be performed at the IAs to assess the likelihood of efavaleukin 
alfa treatment group being superior to placebo by a clinically meaningful difference.   
 
From the second IA until before the last IA, if this likelihood is unacceptably low 
for all dose levels, the trial is recommended to stop for futility.   
 
At the ‘all-subjects-week-24 IA’, if this likelihood is sufficiently high with at least 
1 efavaleukin alfa dose level, the IA triggers an administrative success signal.  This 
would not alter ongoing or planned activities of this phase 2b study, but downstream 
planning for subsequent trials (eg, a phase 3 study) may commence.  Analysis 
planned at each IA are listed in Table 1-1. 
At IAs:   
 
From the second IA until before the last IA, enrollment to the study may be stopped 
for futility if the posterior probability of achieving a clinically meaningful difference in 
SRI-4 response rates of at least 15% between each active treatment group and 
placebo is below 2.5% for all 3 efavaleukin alfa doses. 
 
Once all subjects have had the opportunity to complete the week 24 visit, the primary 
efficacy analysis model, a Bayesian Hierarchical Model will be fitted to the 
week 52 SRI-4 response data with longitudinal modeling of earlier visits week 16, 
20 and 24 to compute the predictive probability of success in a hypothetical, future 
phase 3 study.  If the predictive probability of success in this hypothetical future 
phase 3 study is larger than 80% for any efavaleukin alfa dose, planning for a 
phase 3 study may be initiated.  Regardless of the result of this IA, the conduct of the 
current study will not be impacted; the current study will continue until all subjects 
have had the opportunity to complete the week 52 visit and safety follow-up. 


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9.3.1.2 
Final Analysis 
9.3.2 
Methods of Analyses 
9.3.2.1 
General Considerations 
All categorical variables will be summarized using the number and percent of subjects 
falling into each category and all continuous variable will be summarized using mean, 
standard error or standard deviation, median, minimum, maximum, and number of 
subjects with observations.  Safety endpoints will be summarized descriptively, including 
treatment-emergent adverse events and serious adverse events, clinically significant 
changes in laboratory values and vital signs, and incidence of antidrug antibodies. 
9.3.2.2 
Efficacy Analyses 
Endpoint/Estimand 
Statistical Analysis Methods 
Primary 
Bayesian Hierarchical Model will be used to evaluate primary 
efficacy estimand.   
Secondary 
Bayesian Hierarchical Model/Generalized Linear Model will be used 
to evaluate secondary efficacy estimands.  Details will be described 
in the SAP.   
Exploratory 
9.3.2.3 
Safety Analyses 
Endpoint 
Statistical Analysis Methods 
Secondary 
All safety analyses will be performed using the Safety Analysis Set 
based on subject’s actual treatment received.  Safety analysis will 
include analyses of adverse events, clinical laboratory tests, and 
vital signs. 
Exploratory 


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9.3.2.3.1 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to discontinuation from investigational product or other 
protocol-required therapies, and significant treatment emergent adverse events will also 
be provided. 
9.3.2.3.2 
Laboratory Test Results 
Clinical laboratory test results and change from baseline will be summarized over time 
by each treatment group.  In addition, shift tables, from baseline to the worst on-study 
laboratory toxicity based on the latest version of CTCAE grading, will be presented. 
9.3.2.3.3 
Vital Signs 
Vital sign data (observed and change from baseline) will be summarized using 
descriptive statistics by each treatment group. 
9.3.2.3.4 
Physical Measurements 
Clinically significant findings from physical examinations will be listed by subject and 
assessed for clinical significance which will be included in the adverse event listings and 
summaries. 
9.3.2.3.6 
Exposure to Investigational Product 
Summary statistics will be provided for the total number of doses administered, total 
dose received, and total duration of investigational product exposure by treatment. 
9.3.2.3.7 
Exposure to Other Protocol-required Therapy 
Descriptive statistics of total dose (mg), dosage categories, duration of usage, number 
and percentage of subjects with dose modifications, and reasons for modification will be 
produced to describe the exposure by treatment group from baseline to end of study. 
9.3.2.3.8 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
system organ class, preferred term, or category for each treatment group as coded by 
latest version of the World Health Organization Drug dictionary. 


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9.3.2.4 
Other Analyses 
Serum concentrations will be summarized descriptively by treatment for each PK 
sampling time point using PK Concentration Analysis Set.  PK parameters (if deemed 
necessary) will be summarized with PK parameter analysis set.  
 
.  Medical history will be 
summarized by system organ class and preferred term and tabulated by treatment group 
and total using the Safety Analysis Set according to the actual treatment received. 


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1 and 2a clinical trial.  Lancet.  2019;1(1):E44-E54. 
Jolly M, Pickard AS, Wilke C et al.  Lupus-specific health outcome measure for US 
patients:  the LupusQoL-US version.  Ann Rheum Dis.  2010;69:29-33. 
Katz P, Pedro S, Alemao E, et al.  Estimates of responsiveness, minimally import 
differences and patient acceptable symptom state in five patient-reported outcomes 
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activity assessments of systemic lupus erythematosus:  results from the lupus activity 
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Abstract number 714. 
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Graft-versus-Host Disease.  N Engl J Med.  2011;365:2055-2066. 
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low-dose interleukin-2 therapy for chronic graft-versus-host disease.  Blood.  
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1983;130:2651-2655. 
Long A, Cerosaletti K, Bollyky P, et al.  Defects in IL-2R signaling contribute to 
diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-Cells of 
type 1 diabetic subjects.  Diabetes.  2010;59:407-415. 


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T cell homeostasis in patients with chronic graft-versus-host disease.  Sci Transl Med.  
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11. 
Appendices 
 


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11.1 
Appendix 1.  List of Abbreviations 
Abbreviation 
Explanation 
ACR 
American College of Rheumatology 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
Anti-CCP 
anti-cyclic citrullinated peptide 
Anti-dsDNA 
anti-double stranded DNA 
ASR 
Annual Safety Report 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BICLA 
BILAG based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
CD4+ 
cluster of differentiation 4+ 
CFR 
US Code of Federal Regulations 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Clinical hybrid SLEDAI 
hybrid SLEDAI assessment score without the inclusion of points 
attributable to any urine or laboratory results including immunologic 
parameters.   
Cmax 
maximum observed concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury 
DMC 
data monitoring committee 
DSUR 
Development Safety Update Report  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
early termination 
EULAR 
European League Against Rheumatism 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 
hSLEDAI 
Hybrid Systemic Lupus Erythematosus Disease Activity Index  
IA 
interim analysis 


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Abbreviation 
Explanation 
IBG 
Independent Biostatistics Group 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IL-2 
Interleukin 2 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
JAK 
Janus kinase  
LLDAS 
Lupus Low Disease Activity State 
NCT 
National Clinical Trials 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
non-steroidal anti-inflammatory drugs 
OCS 
oral corticosteroids 
PD 
pharmacodynamic 
PGA 
Physician Global Assessment 
PK 
pharmacokinetic 
PPD 
purified protein derivative 
PROMIS 
Patient-Reported Outcome Measurement Information System 
PT  
prothrombin time 
Q2W 
every 2 weeks 
QLT 
quality tolerance limit parameter 
RA 
rheumatoid arthritis 
RAR 
Response Adaptive Randomization  
RBC 
red blood cell 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SF36v2 
Medical Outcomes Short Form 36 version 2 questionnaire 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 


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Abbreviation 
Explanation 
SLICC 
Systemic Lupus International Collaborating Clinics 
SOC 
standard of care 
SRI 
Systemic Lupus Erythematosus Responder Index 
TB 
tuberculosis 
TBL 
total bilirubin 
Treg 
regulatory T cells 
TYK 
Tyrosine kinase  
TMF 
trial master file 
ULN 
upper limit of normal 
VAS 
visual analog scale 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and/or 
by the local laboratory.  Additional tests may be performed at any time during the study 
as determined necessary by the investigator or required by local regulations.  Additional 
analyte test results may be reported by the local or central laboratory, in accordance with 
standard laboratory procedures (eg, components of a hematology panel). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 


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Table 11-1.  Analyte Listinga 
Central Laboratory:  
Chemistry 
Central Laboratory:  
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarb 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
GGT 
Creatinine clearance by 
MDRD 
C-reactive protein 
CK 
 
Central Laboratory: 
Coagulation 
PT/INR 
aPTT 
 
Central Laboratory: 
Thyroid Panel 
TSH 
free T4 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Total neutrophils 
• Segmented neutrophils 
 
Central Laboratory:  
Urinalysis 
Protein/creatinine ratio 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Central Laboratory:  
Hep B surface antigen 
Hep B surface antibody 
Hep B core antibody 
Hep C antibody 
Antinuclear antibody  
Anti-dsDNA  
C3 and C4 
HIV antibody  
Lymphocyte subsets 
Serum pregnancy test 
PK samplesb 
PGx samples 
QuantiFERON®-TB 
Antiphospholipid Ab (lupus 
anticoagulant, anticardiolipin 
Ab [IgG and IgM], Anti-2 
glycoprotein1 Ab [IgG and 
IgM]) 
anti-Smith 
anti-RNP 
anti-SSA/Ro/anti-SSB/La 
Rheumatoid factor 
anti-CCP  
Local Laboratory: 
Urine Pregnancy 
PPD or T-spot 
FSH 
Coombs’ testc 
Ab = antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; anti-CCP = anti-cyclic 
citrullinated peptide; anti-dsDNA = anti-double stranded DNA; anti-RNP = anti-ribonucleoprotein; 
anti-SSA/Ro = anti-Sjögren’s-syndrome related antigen A; anti-SSB/La = anti-Sjögren’s-syndrome related 
antigen B; aPPT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CK = creatinine kinase; FSH = follicle stimulating hormone; GGT = gamma glutamyl 
transferase; HDL = high density lipoprotein; Hep = hepatitis; HIV = Human Immunodeficiency Virus; 
INR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; MDRD = Modification of Diet in Renal Disease; PD = pharmacodynamic; 
PGx = pharmacogenetics; PK = pharmacokinetic; PPT = purified protein derivative; PT = prothrombin 
time; RBC = red blood cell count; RDW = Red cell distribution width; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; T3 = triiodothyronine; T4 = thyroxine; 
TSH = thyroid-stimulating hormone; WBC = white blood cell count 
a. Approval for applicable local lab testing may be granted by sponsor as needed in the event that central lab 
testing is unavailable.   
b. After baseline, PK/PD parameters that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.   
c. Although Coombs’ test is part of the BILAG 2004 disease activity index, this test is required only, when in 
the opinion of the investigator, there is a clinical justification to conduct direct Coombs’ test.  In such cases, 
the test needs to be performed.  Sites will be reimbursed by Amgen for Coombs’ tests and this will be 
reflected in sites’ contracts.   


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If the subject is being followed for possible drug induced liver injury (DILI), the analytes 
included in Table 11-2 may be tested at the local laboratory depending on the clinical 
situation (see Section 11.7). 
 
Table 11-2.  DILI Potential Analyte Listing 
Chemistry 
Total bilirubin, direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT), 
creatine kinase, ferritin, gamma-glutamyl transferase, haptoglobin 
Hematology 
Hemoglobin, Platelets, RBC Morphology, WBC Count, WBC Differential 
Coagulation 
PT, INR 
Immunology 
5 Prime Nucleotidase, Alpha-1 Antitrypsin, Antinuclear Antibodies, 
Anti-Smooth Muscle Antibody, Anti-Soluble Liver Ag/Liver-Pancreas Ag, 
Cytomegalovirus IgG Antibody, Cytomegalovirus IgM Antibody, Endomysial 
IgA Antibody, Epstein-Barr Virus EDA IgG Antibody, Epstein-Barr Virus NA 
IgG Antibody, Epstein-Barr Virus VCA IgG Antibody, Epstein-Barr Virus 
VCA IgM Antibody, Hepatitis A Virus IgG Antibody, Hepatitis A Virus IgM 
Antibody, Hepatitis B Core Antibodies, Hepatitis B Core IgM Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Virus DNA Genotyping, Hepatitis B 
Virus Surface Antibody, Hepatitis C Antibodies, Hepatitis C Virus RNA 
Genotyping, Hepatitis D Virus Antibody, Hepatitis E IgG Antibody, Hepatitis 
E IgM Antibody, Herpes Simplex Virus Type 1_2 IgG AB, Herpes Simplex 
Virus Type 1_2 IgM AB, Human Herpes Virus 6 DNA, Human Herpes Virus 
7 DNA, Human Herpes Virus 8 DNA, IgG, Liver Kidney AB 1, Parvovirus 
IgM/IgG Antibody, Serum Caeruloplasmin, Tissue Transglutaminase IgA 
Antibody, Toxoplasma IgM/IgG, Varicella Zoster Virus Antibody 
Toxicology 
Acetaminophen 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
Ig = immunoglobulin; INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin 
time; PTT = partial thromboplastin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white blood cell 


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11.3 
Appendix 3.  Study Governance Considerations 
Independent Data Monitoring Committee 
An Independent Biostatistics Group (IBG) will perform the interim analysis (IA) and 
provide the interim report to an independent unblinded Data Monitoring Committee 
(DMC).  The first DMC meeting for safety will occur after first 20 subjects complete 
week 12 visit, and approximately every 12 weeks thereafter.  The DMC will review all 
available safety and efficacy data periodically (Table 1-1).  The IBG and DMC will have 
access to subjects’ individual treatment assignments.  To minimize the potential 
introduction of bias to the conduct of the study, members of the DMC and Data 
Monitoring Group will not have any direct contact with study site personnel or subjects.  
The DMC will communicate major safety concerns and recommendations regarding 
study modification or termination based on the safety and efficacy parameters to Amgen 
in accordance with the DMC charter. 
Records of all meetings will be maintained by the DMC for the duration of the study.  
Records of all meetings will be transferred and stored in the trial master folder (TMF) at 
the conclusion of the study.  Further details are provided in the DMC charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all protocol amendments and changes 
to the informed consent document that Amgen distributes to the site.  The investigator 
must send a copy of the approval letter from the IRB/IEC and amended protocol 


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Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen. 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures. 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations. 
Recruitment Procedures 
Site staff will identify potential subjects from their existing patient population or may seek 
referral patients through existing professional networks or other community sources such 
as patient advocacy groups.  All patient facing materials must be reviewed/approved by 
the sponsor (Amgen Inc.) and the local IRB/IEC. 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative will then be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 


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Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 7. 
If important new information becomes available that may be relevant to the 
subject’s consent during their participation in the study, subjects will be reconsented.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 33 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 


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specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
The subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the sponsor’s systems.  The 
sponsor uses access-controlled systems to house, review and analyze subject data.  


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These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book 
chapters) based on this study must be prepared in accordance with Amgen’s 
publications policy and submitted to Amgen for review.  Authorship of any 
publications resulting from this study will be determined on the basis of the Uniform 
Requirement for Manuscripts Submitted to Biomedical Journals International Committee 
of Medical Journal Editors Recommendations for the Conduct of Reporting, Editing, and 
Publications of Scholarly Work in Medical Journals, which states:  Authorship credit is to 
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 need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 


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persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.   Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered on the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
The sponsor or designee will perform ongoing source data verification to confirm that 
data entered on the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements per the sponsor’s monitoring plan.  


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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance and Audit function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Quality tolerance limit parameters (QTLs) will be pre-defined in the QTL definitions table 
to identify possible systematic issues that can impact participant safety and/or reliability 
of the study results.  These pre-defined parameters will be monitored during the study.  
Important deviations from the QTL threshold limits for these parameters and remedial 
actions taken will be summarized in the clinical study report. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom they 
have delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 


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and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT 
system (if used, such as subject ID and randomization number) and eCRF entries if the 
eCRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment or certain 
demographic information). 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
 
Subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable] 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 


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Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the SAP. 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.   
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 


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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 


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Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Events case report form (CRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product; 
 
Assessment of seriousness; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product (efavaleukin 
alfa/placebo), other protocol-required therapies, devices, and/or 
study-required activity and/or procedures; 
 
Action taken; and 
 
Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Events eCRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor/responsible contact research organization  in lieu of completion 
of the Events eCRF. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on the Common Terminology Criteria for Adverse Events, version 5 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product(s), protocol-required therapies, device(s), and/or study-required activity 
and/or procedure(s) and each occurrence of each adverse event/serious adverse 
event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that they have reviewed the adverse event/serious adverse 
event and has provided an assessment of causality.  For sites reporting serious 
adverse events via electronic data capture (EDC), the investigator or 
sub-investigator must confirm causality in EDC within 72 hours of the serious 
adverse event being entered on the Events CRF. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment.  In this case, for sites reporting serious adverse events via 
EDC, the investigator or sub-investigator must reconfirm causality in the EDC 
system within 72 hours of the serious adverse event being entered on the Events 
CRF. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 


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Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any postmortem findings 
including histopathology. 
 
New or updated information will be recorded in the originally completed Events 
eCRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
immediately and no later than 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the EDC 
system. 
 
If the EDC system is unavailable, then the site will report the information to Amgen 
using a paper-based Serious Adverse Event Contingency Report Form (also 
referred to as the electronic Serious Adverse Event [eSAE] Contingency Report 
Form) (see Figure 11-1) immediately and no later than 24 hours of the 
investigator’s awareness of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes 
aware of a serious adverse event.  The investigator should use the paper-based 
Serious Adverse Event Contingency Report Form to report the event. 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form  
 
 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for females of childbearing potential are 
outlined in Section 5.2.  Contraceptive use and methods should be consistent with local 
regulations for subjects participating in clinical studies. 
Female subjects of childbearing potential should be advised of the pregnancy prevention 
requirements and the potential risk to the fetus if they become pregnant during treatment 
and for 6 weeks after the last dose of investigational product. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR   
 
A woman age < 55 years with no menses for at least 12 months and with a follicle-
stimulating hormone (FSH) level within the definition of “postmenopausal range” for 
the laboratory involved.  In the absence of 12 months of amenorrhea, confirmation 
with more than 1 FSH measurement is required.  
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  


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 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 weeks after the last dose 
of investigational product. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety immediately and no 
later than 24 hours of the site’s awareness of a subject’s pregnancy.  (Note:  Sites 
are not required to provide any information on the Pregnancy Notification Form that 
violates the country or regions local privacy laws). 
 
After obtaining the female subject’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 6 weeks after the 
last dose of investigational product.  This information will be forwarded to Amgen 
Global Patient Safety.  Generally, infant follow-up will be conducted up to 12 months 
after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an adverse event or serious adverse event.  Abnormal 
pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, congenital 
anomalies) will be reported as an adverse event or serious adverse event.  Note that 
an elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must be 
reported to Amgen as a pregnancy exposure case. 
 
Any serious adverse event occurring as a result of a poststudy pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue 
investigational product while pregnant (see Section 7.1 for details). 


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Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
6 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety immediately and no later than 24 hours of 
the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
The investigator will attempt to obtain a signed consent for release of pregnancy and 
infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed consent for release of pregnancy and 
infant health information, the investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks after the last dose of 
investigational product. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety immediately and no later than 24 hours of 
the investigator’s awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in the exclusion criteria (see Section 5.2). 
 
With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 6 weeks after discontinuing 
protocol-required therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms 
 
 


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FORM-495569, v.26, 29 May 2020 
 
 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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11.6 
Appendix 6.  Sample Storage and Destruction 
When permitted by local regulations, any blood (eg, biomarker, PK) or skin-biopsy 
sample collected according to the Schedules of Activities (Table 1-2, Table 1-3, 
Table 1-4, Table 1-5, and Table 1-6) can be analyzed for any of the tests outlined in the 
protocol and for any tests necessary to minimize risks to study subjects.  This includes 
testing to ensure analytical methods produce reliable and valid data throughout the 
course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
When permitted by local regulations and if informed consent is provided by the 
subject, Amgen can do additional testing on remaining samples (ie, residual and 
back-up) to investigate and better understand the Inflammatory conditions, the dose 
response and/or prediction of response to efavaleukin alfa, characterize antibody 
response, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis are to be documented and maintained, but are 
not necessarily reported as part of this study.  Samples can be retained for up to 
20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or skin samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 


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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
> 3x ULN (when baseline was < ULN), 
in the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then efavaleukin alfa is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 11-3) are never to be rechallenged. 


Product:  Efavaleukin Alfa 
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Date:  06 March 2023 
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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event immediately and 
no later than 24 hours of discovery or notification of the event (ie, before additional 
etiologic investigations have been concluded) 
 
The appropriate case report form (CRF) (eg, Events eCRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-3 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours   
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve  
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic.   
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-
type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for PK analysis if this has not already been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding eCRFs. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
Page 1 of 25 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and 
Safety of Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus 
With Inadequate Response to Standard of Care Therapy (VIOLET) 
 
Amgen Protocol Number Efavaleukin Alfa 20200234 
EudraCT Number:  2020‐003509‐72 
NCT Number:  NCT04680637 
 
Amendment Date: 
06 March 2023 
 
Rationale: 
This protocol is being amended to remove the specific reference to anti-dsDNA assay 
(Phadia) in order to allow for regional difference in assay being performed.  Additional 
updates to exclusion for active infection and general updates for clarity have been 
incorporated in various sections of the protocol which represent minor modifications, 
clarifications, and grammatical corrections.  Updates to the protocol have been made to 
align with the most recent protocol template to ensure compliance with current regulatory 
requirements.  The following changes have been implemented to:  
 
Include summaries for Benefit/Risk Assessment and Study Assessments and 
Procedures to the protocol Synopsis section, in accordance with European Union 
Clinical Trials Regulation (EU-CTR) (Section 1.1). 
 
 
Update pregnancy test assessment to clarify that urine pregnancy test is to be 
performed prior to randomization (Section 1.3 [Table 1-2] and exclusion 
criterion no. 226) 
 
Remove specific reference to Phadia assay in order to allow for regional 
differences in the assay for anti-double stranded DNA (Section 1.3, Section 5.1 
[criterion no. 103], and Section 8.3.3.1). 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  06 March 2023 
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 
Update exploratory endpoints (Section 3) to: 
o 
o 
 
Update inclusion criterion no. 103 to include anti-Smith test. 
 
Update exclusion criteria (Section 5.2) to:  
o Update exclusion criteria for active infection prior to screening (from 
4 weeks to 2 weeks) (criterion no. 205). 
o Include “presence of anti-cyclic citrullinated peptide [anti-CCP] and 
rheumatoid factor OR current history of RA (rheumatoid arthritis) OR 
presence of erosive arthritis on imaging” as example of diagnosis of any 
chronic inflammatory disease other than systemic lupus erythematosus 
(criterion no. 232). 
o Include tyrosine kinase inhibitor as prohibited medication during the study 
(criterion no. 237). 
o Add a new criteria to state that female subjects of reproductive potential 
must agree not to donate eggs during the study and for 6 weeks after 
receiving the last dose of investigational product (new criterion no. 239). 
 
Refer to auxiliary medicinal product, in accordance with EU-CTR (Section 6).  
 
Clarify that samples testing positive for anti-efavaleukin antibodies will also be 
tested for neutralizing antibodies (Section 8.7). 
 
Include minor language updates in Biomarker Development and Future Research 
sections to align with current protocol template version 29.0, effective date 
25 May 2022 (Section 8.8.2 and Section 8.8.3).  
 
Minor updates in the list of references (Section 10). 
 
Minor updates in the list of abbreviations (Section 11.1). 
 
Make administrative and editorial changes throughout the protocol for 
clarification. 


Product:  Efavaleukin alfa 
Protocol Number:  20200234 
Date:  21 October 2022 
Page 1 of 3 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and Safety of 
Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy (VIOLET) 
 
Amgen Protocol Number Efavaluekin alfa (AMG 592) 20200234 
NCT04680637 
Amendment Date: 
21 October 2022 
 
Rationale: 
This protocol has been amended to:   
 
Add back the requirement for an independent blinded joint evaluator to conduct joint 
count assessments (number of tender and swollen joints).  In the recently approved 
protocol amendment 2, this requirement was removed, and it needs to be re-
incorporated to ensure consistency of the evaluation of this parameter in the trial.  
 
Incorporate administrative and editorial changes (including document version date, 
grammatical, typographical, abbreviations, and formatting) throughout the protocol. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
Page 1 of 6 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and Safety of 
Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus With Inadequate 
Response to Standard of Care Therapy (VIOLET) 
 
Amgen Protocol Number Efavaleukin Alfa 20200234 
NCT04680637 
 
Amendment Date:  
01 September 2022 
 
Rationale:   
The main reason to conduct this protocol amendment is to remove the requirement for an 
independent blind joint assessor to conduct joint count assessments (number of tender and 
swollen joints).  There is no need to have a separate blinded assessor to perform joint count, 
since for the primary endpoint and other main efficacy endpoints this assessment is performed 
by the investigator from each site, who have the required training and are performing all efficacy 
assessments.  Important clarifications and grammatical corrections were also made.  Based on 
this, the following changes were included:  
 
Efficacy Assessments: 
o Remove requirement for a separate blinded joint assessor (Section 8.2.9).   
o Clarify that the same assessor must perform efficacy assessments at every 
time point for a given subject (Sections 8.2.9 and 8.2.9.5).   
o Improve clarity of the definition of Systemic Lupus Erythematosus Responder 
Index (SRI-4) response and British Isles Lupus Assessment Group 
(BILAG)-based Combined Lupus Assessment (BICLA) response 
(Sections 8.2.9.8 and 8.2.9.11).  


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
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o Clarify that for arthritis to be scored in this study, affected joints must involve 
small joints in hands, wrists, or a combination of joints in hands and wrists 
(Section 8.2.9.1).  
 
Endpoint for secondary objective aiming to evaluate efficacy of efavaleukin alfa on 
joint count was updated to clarify that the combined tenderness and swelling of joint 
count will be conducted for joints in hands and wrists, as it is described in 
Section 8.2.9.5 (Sections 1.1 and 3).  
 
New exploratory objective and endpoint were added to evaluate the efficacy of 
efavaleukin alfa on 
 
 
 
Primary estimand language was revised to remove specific details as they are 
specified in the statistical analysis plan.  The principles of how intercurrent events of 
protocol-prohibited rescue therapies are handled remains unchanged (ie, subjects 
will be considered as non-responders) (Sections 1.1 and 3)  
 
Table 1-3 Schedule of Activities – Treatment Period was updated to clarify that an 
early termination visit is required for all subjects who discontinue the study 
completely prior to week 52 (Table 1-3 and Section 8.1.4).   
 
Table 1-4 Schedule of Activities – Safety Follow-up/Week 56 Visit was updated to 
clarify that this table describes a separate safety follow-up visit which only applies to 
subjects who require an additional visit following completion of the entire planned 
52-week treatment period to ensure at least 6 weeks follow-up data collection after 
last dose of investigational product (Table 1-4). 
 
 
Statistical hypothesis was updated to align it with updates made to the primary 
estimand language (Sections 1.1 and 9.1).   


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
Page 3 of 6 
Amgen Proprietary - Confidential 
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 
Human Exposure and Risk Assessment were updated to include data from 
completed and ongoing clinical studies that evaluate the safety profile of the 
investigational product including adverse drug reactions and potential risks 
(Sections 2.2.2.2. and 2.3).  
 
Clarify that at day 1, prior to randomization, the investigator must confirm disease 
activity and compliance and stability of Systemic Lupus Erythematosus (SLE) 
treatment (Sections 1.1 and 4.1). 
 
Justification for Investigational Product Dose was updated to include information 
regarding doses and recently collected data (Section 4.3). 
 
Information pertaining to eligibility assessment, which includes all the events that 
must occur before randomization and dosing, was re-organized to improve 
readability and clarity (Section 5).   
 
Update end of study definition for individual subjects to clarify that an individual 
subject is considered to have completed the study if they have remained on study for 
the entire treatment period and completed the safety follow-up, if applicable 
(Sections 4.4 and 8.1.4). 
 
Clarifications were provided on Safety Follow-up for subjects that complete the 
planned 52-week treatment period and for subjects that discontinue investigational 
product early to ensure safety follow-up is complete (Sections 1.1, 4.1, 4.4, 8.1.3, 
and Table 1-4).   
 
To ensure adequate safety surveillance for subjects who discontinue the study 
completely, instructions for scheduling the early termination visit were revised to 
state that this visit must be scheduled to allow for at least 6 weeks of safety follow-up 
after last dose of investigational product (Section 8.1.2).   
 
Interim analysis language was updated to remove details related to the 
administrative success as they do not impact the conduct of this study and will be 
pre-specified in the study data monitoring committee charter, statistical analysis plan, 
and simulation report, as appropriate (Sections 1.1 and 9.3.1.1). 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
Page 4 of 6 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Clarify within the table for Analyses Schedule that after the 7th interim analysis, 
additional interim analyses are planned after every 32 subjects are randomized and 
have had the opportunity to complete the week 24 assessment until full enrollment.  
Additionally, it was clarified that the number of interim analyses will depend on the 
observed enrollment rate (Table 1-1).   
 
Add Biomarker Discovery section to describe collection of biomarker samples during 
the study, specify the type of sample to be collected, and include a description of the 
use of these samples (Sections 8.8.1, 8.8.2, 8.8.3, and 8.9.2).  
o To maintain consistency between the Schedule of Activities (Tables 1-2, 1-3, 
1-5, and 1-6) and Biomarker Discovery section, the name of the Biomarker 
Assessment for sample collection was changed to Biomarker discovery.  
 
Inclusion criteria was updated to (Section 5.1):  
o Criterion 103:  clarify that results of the Phadia method will be used for the 
purposes of Hybrid Systemic Lupus Erythematosus Disease Activity Index 
(hSLEDAI) scoring during screening and throughout the study and not for 
SLE classification criteria.   
o Criterion 110:  clarifications on protocol specific rules for arthritis hSLEDAI 
and alopecia scoring. 
o New criterion (code 111):  add affiliation to social security scheme as a 
requirement for France. 
 
Exclusion criteria was updated to (Section 5.2): 
o Criterion 205:  clarify that current use, in addition to within 4 weeks prior to 
screening, of anti-infectives will also be considered as an exclusion criterion. 
o Criterion 214:  revise washout period for Janus kinase (JAK) inhibitor by 
removing the 3-month window prior to screening requirement and retaining 
the less than 5 drug half-lives requirement (new code 237).  


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
Page 5 of 6 
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o Criterion 218:  specify that prior or concomitant treatment with a biological 
agent must have immunosuppressive/immunomodulatory activity and provide 
additional examples of such treatment (new code 238).  This update was also 
made to Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period (Section 6.1.6).   
o Criterion 231:  clarify for lupus nephritis that current, in addition to within 
1 year prior to screening, requirement of induction therapy will also be 
considered an exclusion criterion. 
o Criterion 233:  updated to clarify exclusion conditions for hepatitis B. 
o Criterion 236:  include Gilbert’s Syndrome as an exception for presence of 
laboratory abnormalities during screening in serum total bilirubin.   
 
Information collected for screen failure was updated to remove medical history and 
prior therapies as these are not considered required forms for screen failure per 
electronic case report form standard instructions (Section 5.5).   
 
Add intravenous corticosteroids, antifrolumab, and tyrosine kinase inhibitors to the 
list of excluded medications or treatments in the study (Section 6.1.6).  
 
Include a footnote in Analyte Listing table to provide the option for conduction of local 
lab testing if central lab testing is unavailable (Table 11-1 footnote a) 
 
For consistency, multiple sections of the protocol were updated to describe that 
individual who do not meet the criteria for participation in the study may be 
rescreened up to 3 times (Sections 1.1, 4.1, and 8.1.1).    
 
Clarify that lab retests required specifically during screening should be approved by 
the sponsor prior to conduction to avoid having delays of other study assessments 
that do not require sponsor pre-approval (Section 8.1.1).    
 
Remove instruction that subjects who screen fail within the screening period must 
wait until end of the screening period before being considered for rescreen 
(Section 8.1.1) 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  01 September 2022 
Page 6 of 6 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Clarify that small joints in hands and wrists or a combination of joints in hands and 
wrists are required to score arthritis (Section 8.2.9.1). 
 
Provide specific instructions for capturing location and associated symptoms of 
reaction at the site of study drug administration (injection site reaction) as an adverse 
event (Section 8.3.4.2).    
 
For simplicity, Antibody Testing Procedures were updated to remove a redundant 
statement and to clarify that in the event of safety-related concerns more testing may 
be requested (Section 8.7). 
 
Incorporate updated language for safety collection and reporting of serious adverse 
events to align with current procedures (Table 1-2, Table 1-3, Table 1-4, Sections 
6.1.5, 8.3.4, 8.3.4.1.2, 8.3.4.1.3, 8.3.4.3, 8.3.4.4, 8.3.4.6, Appendix 11-4, Appendix 
11-5, and Appendix 11-7). 
 
Remove organ involvement as a baseline covariate on the treatment effect 
(Section 9.2.2). 
 
Incorporate an abbreviated study name, VIOLET, to have a short and concise name 
that can be used to refer to the study (Title page, Investigator’s Agreement, 
Section 1.1). 
 
Administrative and editorial changes (including document version date, grammatical, 
typographical, abbreviations, and formatting) have been made throughout the 
protocol. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  25 August 2021 
Page 1 of 2 
Amendment 1 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and 
Safety of Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus 
With Inadequate Response to Standard of Care Therapy 
 
Amgen Protocol Number Efavaleukin Alfa 20200234 
 
Amendment Date: 
25 August 2021 
 
Rationale: 
The following changes were made to the protocol to incorporate regulatory authority 
recommendations and to clarify/correct other items in the protocol: 
 
The efficacy analysis set has been updated to include all subjects randomized in the 
study and not those who have received at least 1 dose of investigation product. 
 
To add the 2019 European League Against Rheumatism (EULAR)/American College 
of Rheumatology (ACR) criteria, lupus narrative and prior history of British Isles 
Lupus Assessment Group (BILAG) domains to the Schedule of Activities (SoA) 
 
To update BILAG reference and scoring. 
 
To add exploratory endpoint as below: 
 
Add blinded samples to protocol (lymphocyte subset) 
 
To add study adjudication language. 
 
To update the first data monitoring committee (DMC) meeting for safety to occur 
after the first 20 subjects complete the week 12 visit. 
 
Added a subsection to Section 2.3 (Risk Assessment) to include guidance to sites 
regarding coronavirus disease 2019 (COVID-19). 
 
Updated the following eligibility criteria: 
 
104 (now 110):  changed upper limit of urine protein/creatinine ratio to 
2000 mg/g 
 
201 (now 231):  changed upper limit of urine protein creatinine ratio to 
2000 mg/g and to exclude subjects with histological evidence of diffuse 
proliferative glomerulonephritis within 12 weeks prior to screening. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  25 August 2021 
Page 2 of 2 
 
203 (now 232):  updated to indicate subjects with chronic inflammatory disease 
other than systemic lupus erythematosus (SLE) (eg, rheumatoid arthritis) are 
excluded; additionally, removed the use of “confirmed by investigator” and 
“based on investigator judgement” 
 
208 and 209 (now 233 and 234):  removed reference to presence of viral DNA 
assessed by polymerase chain reaction (PCR) (Sections 1.3, 8.3.3.3, and 11.2 
updated accordingly) 
 
211 (now 235):  removed “per investigator judgement” and clarify that poorly 
controlled diabetes is hemoglobin A1C  7. 
 
217 and 230:  minor clarification of wording 
 
222 (now 236):  changed lower limit of glomerular filtration rate from 30 to 
50 mL/min/1.73 m2 
 
Sections 5.4, 5.5, and 8.1.1 updated to change numbering of rescreening attempts 
from 2 to 3. 
 
Section 6.2.2.1 updated to included guidance on which adverse events lead to 
withholding or permanently discontinuing efavaleukin alfa 
 
To update vital signs section of the protocol (Section 8.3.1) to include “forehead” as a 
temperature location. 
 
Section 7.2.1 updated to provide clarification for “decision by sponsor” as a reason to 
remove subject from study 
 
Section 8.3.3 updated to include guidance for the investigator to repeat any labs that 
are considered to be clinically significant to rule out laboratory error. 
 
Section 8.3.3.1 updated to remove the Phadia assay being used on anti-double 
stranded DNA (anti-dsDNA) to determine eligibility. 
 
Several sections of the protocol have been updated to include required alignments 
with current Amgen protocol template (Sections 6.1.6, 8.3.4.1.2, 8.3.4.1.3, 11.2, 
11.3, and 11.4). 
 
Administrative and editorial changes (including grammatical, typographical, and 
formatting) have been made throughout the protocol. 


Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
Date:  30 November 2020 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Superseding Amendment 
Protocol Title:  A Phase 2b Dose Ranging Study to Evaluate the Efficacy and 
Safety of Efavaleukin Alfa in Subjects with Active Systemic Lupus Erythematosus 
With Inadequate Response to Standard of Care Therapy 
 
Amgen Protocol Number AMG 592 20200234 
 
Original Date: 
09 October 2020 
Superseding Original Date: 
30 November 2020 
 
Superseding Original Summary of Changes: 
 
Incorporate changes to align with the Data Monitoring Committee (DMC) Charter: 
 
Clarify efficacy analyses language around interim analyses. 
 
Change ‘Futility’ to ‘Administrative Success’ in Table 1-1. 
 
Clarify efficacy assessment data will be captured on a paper source then 
transcribed or entered into the study database. 
 
Clarify language around primary estimand nonresponders. 
 
Remove unnecessary clarification around medication history. 
 
Clarify role of adjudication team.  Central Review Team removed from protocol as 
routine data monitoring is not included in protocol. 
 
Clarify language around immunomodulator agents. 
 
Clarify timing of pharmacokinetic assessments. 
 
Clarify language around joint replacement. 
 
Clarify language around hepatitis B core antibody testing 
 
Added hepatitis B surface antibody to Table 11-1. 
 
Administrative, typographical, and formatting changes were made throughout the 
protocol. 

SAP_001.pdf: 
Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 1 of 64 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 2b Dose Ranging Study to Evaluate the 
Efficacy and Safety of Efavaleukin Alfa in Subjects 
with Active Systemic Lupus Erythematosus With 
Inadequate Response to Standard of Care Therapy 
(VIOLET) 
Short Protocol Title: 
Efficacy and Safety of Efavaleukin Alfa in Subjects 
with Active Systemic Lupus Erythematosus 
Protocol Number: 
20200234 
NCT Number: 
NCT04680637 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, 
Thousand Oaks, CA 91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
26 October 2021 
Amendment 1 
29 November 2022 
Amendment 2 
25 September 2023 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
26OCT2021 
 
Amendment 1 
29NOV2022 
Incorporate changes in protocol 
amendment 3: 
 
Added tender and swollen joint 
counts not limited to the hands 
and wrist as exploratory endpoint. 
 
Updated estimand definition. 
 
Updated the imputation rules for 
missing data. 
 
 
Updated the analyses of adverse 
events. 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 2 of 64 
CONFIDENTIAL  
 
 
 
Administrative, typographical and 
formatting changes throughout. 
Amendment 2 
25SEP2023 
Incorporate changes in the scope of 
planned analyses due to early 
termination of the study: 
 
Removed subsequent IAs 
following study early 
termination 
 
Removed some exploratory 
endpoints 
 
Removed statistical 
comparisons of treatment 
groups; descriptive statistics by 
treatment groups will be 
generated instead 
 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 3 of 64 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints/Estimands .......................................................... 8 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 11 
3.1 
Study Design ............................................................................................. 11 
3.2 
Sample Size .............................................................................................. 13 
3.3 
Adaptive Design ........................................................................................ 14 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates ................................................................................... 15 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 15 
5.1 
Basic Definition ......................................................................................... 15 
5.2 
Study Points of Reference ......................................................................... 17 
5.3 
Study Dates .............................................................................................. 18 
5.4 
Study Time Intervals ................................................................................. 18 
5.5 
Arithmetic Calculations .............................................................................. 18 
5.6 
Efficacy Assessments ............................................................................... 19 
5.7 
Patient-reported Outcome (PRO) Assessments ........................................ 24 
6. 
Analysis Sets ........................................................................................................ 26 
6.1 
Full Analysis Set........................................................................................ 26 
6.2 
Safety Analysis Set ................................................................................... 26 
6.3 
Interim Analyses Set(s) ............................................................................. 26 
7. 
Planned Analyses ................................................................................................. 26 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 26 
7.2 
Final Analysis ............................................................................................ 28 
8. 
Data Screening and Acceptance ........................................................................... 29 
8.1 
General Principles ..................................................................................... 29 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 29 
8.3 
Handling of Missing and Incomplete Data ................................................. 29 
8.4 
Detection of Bias ....................................................................................... 32 
8.5 
Outliers ..................................................................................................... 32 
8.6 
Distributional Characteristics ..................................................................... 32 
8.7 
Validation of Statistical Analyses ............................................................... 32 
9. 
Statistical Methods of Analysis.............................................................................. 33 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 4 of 64 
CONFIDENTIAL  
 
 
9.1 
General Considerations ............................................................................. 33 
9.2 
Subject Accountability ............................................................................... 33 
9.3 
Important Protocol Deviations ................................................................... 33 
9.4 
Demographic and Baseline Characteristics ............................................... 33 
9.5 
Efficacy Analyses ...................................................................................... 36 
9.6 
Safety Analyses ........................................................................................ 39 
9.6.1 
Adverse Events ......................................................................... 39 
9.6.2 
Laboratory Test Results ............................................................ 40 
9.6.3 
Vital Signs ................................................................................. 40 
9.6.4 
Electrocardiogram ..................................................................... 40 
9.6.6 
Exposure to Investigational Product .......................................... 41 
9.6.7 
Exposure to Other Protocol-permitted Therapy .......................... 41 
9.6.8 
Exposure to Concomitant Medication ........................................ 41 
9.7 
Other Analyses ......................................................................................... 41 
9.7.1 
Analyses of Pharmacokinetic Endpoints .................................... 41 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 42 
9.7.3 
Analyses of Biomarker Endpoints .............................................. 42 
10. 
Changes From Protocol-specified Analyses.......................................................... 42 
11. 
Literature Citations / References ........................................................................... 42 
12. 
Appendices ........................................................................................................... 44 
Appendix A.  Reference Values/Toxicity Grades ................................................... 44 
Appendix B.  SLE Assessment Forms/Instruments ............................................... 45 
Appendix C.  Patient-reported Outcome Forms/Instruments ................................. 56 
Appendix D.  Analytical Windows .......................................................................... 59 
Appendix E.  Handling of Dates, Incomplete Dates and Missing Dates ................. 64 
 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 5 of 64 
CONFIDENTIAL  
 
 
List of Tables 
Table 3-1 Analyses Schedule ........................................................................................ 16 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 40 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 42 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 44 
Table 9-4 Selected Safety Laboratory Tests .................................................................. 51 
 
List of Figures 
No table of figures entries found. 
 
 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 6 of 64 
CONFIDENTIAL  
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
Anti-dsDNA 
anti-double stranded DNA 
AST 
aspartate aminotransferase 
BHM 
Bayesian Hierarchical Model 
BICLA 
BILAG based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity 
Index 
Clinical SLEDAI-2K 
SLEDAI-2K assessment score without the inclusion of 
points attributable to any urine or laboratory results 
including immunologic parameters.   
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
end of study 
ET 
early termination 
FAS 
Full Analysis Set 
GLM 
Generalized linear model 
hSLEDAI 
Hybrid Systemic Lupus Erythematosus Disease Activity 
Index  
IA 
interim analysis 
IBG 
Independent Biostatistics Group 
Ig 
immunoglobulin 
IL-2 
interleukin 2 
IP 
Investigational product 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 7 of 64 
CONFIDENTIAL  
 
 
IPD 
Important protocol deviation 
IRT 
interactive response technology 
LLDAS 
Lupus Low Disease Activity State 
NSAID 
non-steroidal anti-inflammatory drugs 
OCS 
oral corticosteroids 
PD 
pharmacodynamic 
PGA 
Physician Global Assessment 
PK 
pharmacokinetic 
PROMIS 
Patient-Reported Outcome Measurement Information 
System 
Q2W 
every 2 weeks 
RAR 
Response Adaptive Randomization  
SAP 
statistical analysis plan 
SF36v2 
Medical Outcomes Short Form 36 version 2 questionnaire 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 
2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
SOC 
standard of care 
SRI 
Systemic Lupus Erythematosus Responder Index 
Treg 
regulatory T cells 
VAS 
visual analog scale 
 
 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 8 of 64 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for study 20200234, 
Efavaleukin Alfa  dated 21 October 2022.  The scope of this plan is reduced from 
those outlined in the protocol due to determination of futility at a preplanned 
interim analysis and subsequent study early termination. It includes the final 
analysis that is planned and will be executed by the Amgen Global Biostatistical Science 
department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
Evaluate the efficacy of 
efavaleukin alfa at week 52, as 
measured by the SRI-4 response 
 
SRI-4 response at week 52 
Primary Estimand 
The primary estimand is the difference in SRI-4 response rates between each 
efavaleukin alfa dose group and placebo at week 52 for all subjects with SLE with 
inadequate response to SOC therapy who are randomized, regardless of 
investigational product compliance; subjects will be considered non-responders for 
using more than protocol-permitted therapies including: 
 
Subjects requiring a dose of systemic corticosteroids for SLE above their baseline 
dose after week 16 
 
Subjects requiring either dose increases of the current 
immunosuppressants/immunomodulators or initiation of new 
immunosuppressant/immunomodulator(s) 
Secondary 
 
Evaluate the efficacy of 
efavaleukin alfa at week 52, as 
measured by the BICLA index 
responses 
 
BICLA response at week 52 
 
Evaluate the efficacy of 
efavaleukin alfa at week 52, as 
measured by LLDAS response 
 
LLDAS response at week 52 
 
Evaluate the efficacy of 
efavaleukin alfa at week 52, as 
measured by OCS tapering 
 
Reduction of OCS to ≤ 7.5 mg/day 
by week 44 and sustained through 
week 52 in subjects with a 
baseline OCS dose ≥ 10 mg/day 
 
Evaluate the efficacy of 
efavaleukin alfa at week 24, as 
measured by SRI-4 response 
 
SRI-4 response at week 24 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 9 of 64 
CONFIDENTIAL  
 
 
 
Evaluate the efficacy of 
efavaleukin alfa at week 24, as 
measured by the BICLA index 
responses 
 
BICLA response at week 24 
 
Evaluate the efficacy of 
efavaleukin alfa at weeks 24 and 
52, as measured by hSLEDAI 
 
hSLEDAI response (i.e., reduction 
≥ 4 points from baseline) at 
week 24  
 
hSLEDAI response (i.e., reduction 
≥ 4 points from baseline) at 
week 52 
 
Evaluate the efficacy of 
efavaleukin alfa on joints and skin 
 
Improvement from baseline in 
tender and swollen joint count 
≥ 50% at weeks 8, 12, 24, 36, and 
52 in subjects with  6 tender and 
swollen joints involving hands and 
wrists at baseline 
 
Improvement from baseline in 
CLASI activity score  50% at 
week 8, 12, 24, 36, and 52 in 
subjects with a CLASI activity 
score  8 at baseline 
 
Evaluate the efficacy of 
efavaleukin alfa using BILAG 
score 
 
Annualized flare rate (as 
measured by BILAG score 
designation of “worse” or “new” 
resulting in a B score in 
≥ 2 organs or an A score in 
≥ 1 organ) over 52 weeks 
 
Evaluate the efficacy of 
efavaleukin alfa using patient 
reported outcomes 
 
Change from baseline in fatigue 
standardized score using the 
PROMIS Fatigue SF 7a at week 
12, 24, 36, and 52 
 
Change from baseline in the 
physical component score, mental 
component score and individual 
domains of the SF 36 v2 at week 
12, 24, 36, and 52 
 
Change from baseline in the 
domain scores on the Lupus QoL 
at weeks 12, 24, 36, and 52 
 
Characterize the safety of 
efavaleukin alfa 
 
Treatment-emergent adverse 
events 
 
Serious adverse events 
 
Clinically significant changes in 
laboratory values and vital signs 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 10 of 64 
CONFIDENTIAL  
 
 
 
Characterize the PK of 
efavaleukin alfa 
 
Trough and sparse postdose 
serum concentrations of 
efavaleukin alfa 
BICLA = British Isles Lupus Assessment Group Based Composite Lupus Assessment; CLASI = Cutaneous 
Lupus Erythematosus Area and Severity Index ; hSLEDAI = Hybrid Systemic Lupus Erythematosus 
Disease Activity Index; IL-2 = interleukin-2; LLDAS = Lupus Low Disease Activity State; OCS = oral 
corticosteroid; PGA = Physician Global Assessment; 
 
 PK = pharmacokinetic(s); PROMIS Fatigue SF7A = Patient-
Reported Outcome Measurement Information System Fatigue Short Form 7a Instrument; QoL = quality of 
life; SLE= systemic lupus erythematosus; SF36v2 = Medical Outcomes Short Form 36 version 2 
Questionnaire; SOC = standard of care; SRI-4 = Systemic Lupus Erythematosus Responder Index; 
  
 
   
 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 11 of 64 
CONFIDENTIAL  
 
 
Exploratory 
2.2 
Hypotheses and/or Estimations 
At least 1 efavaleukin alfa dose will have greater efficacy than placebo as measured by 
the SRI-4 response rate at week 52 in subjects with active SLE with inadequate 
response to SOC therapy who are randomized, regardless of investigational product 
compliance; subjects using more than protocol-permitted therapies will be considered as 
non-responders: 
 
Subjects requiring a dose of systemic corticosteroids for SLE above their baseline 
dose after week 16 
 
Subjects requiring either dose increases of the current 
immunosuppressants/immunomodulators or initiation of new 
immunosuppressant/immunomodulator(s). 
3. 
Study Overview 
3.1 
Study Design 
This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, placebo-
controlled dose ranging study in subjects with active SLE and inadequate response to 
SOC therapies, including OCS, immunosuppressants, and immunomodulators.  
Previous biologic use is allowed with an adequate washout period.  
The study design includes 3 active efavaleukin alfa treatment groups 
 every 
2 weeks [Q2W],
Q2W, and
Q2W) and a placebo group, SRI-4 response 
at week 52 as the primary endpoint, and an approximate sample size of 320 subjects.   
Subjects will be randomized to receive either placebo or 1 of 3 doses of efavaleukin alfa 
for a duration of 52 weeks.  The randomization ratio will start as 1:1:1:1, and then may 
be adapted at planned interim analyses (IAs) based on the clinical efficacy, as measured 
by SRI-4 response, using Response Adaptive Randomization (RAR) for the purpose of 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 12 of 64 
CONFIDENTIAL  
 
 
allocating more subjects to more efficacious doses and fewer subjects to less efficacious 
doses, with a fixed 25% of subjects allocated to placebo throughout the study.  The RAR 
will be implemented with a computerized system that assigns a treatment to subjects 
without unblinding any study personnel or Amgen study team members, including the 
investigators or subjects, to the subject’s randomized treatment assignment or the 
current allocation ratio.  
Study duration for a single subject will be 56 weeks (including the safety follow-up 
period) plus the screening period.  Treatment will be administered every 2 weeks with 
the final dose at week 50.  All subjects will be followed for safety for 6 weeks after the 
last dose of investigational product.   
Subjects will undergo a screening visit to confirm eligibility requirements.  At day 1 
(baseline), prior to randomization, disease activity (clinical hybrid SLEDAI score  4) and 
stability and compliance of OCS and other immunosuppressant/immunomodulator 
doses, must be present.  The maximum time between screening and randomization is 
33 days.  Subjects who do not meet all the eligibility requirements prior to randomization 
on day 1 will be considered screen failures.  Subjects may be allowed to rescreen three 
times.   
Immunosuppressant/immunomodulator dose(s) should remain stable through week 52.  
For OCS, initiation or temporary increases in OCS are allowed between weeks 0 to 10, 
provided that return to baseline dose occurs within the subsequent 2 weeks.  OCS may 
be tapered after week 12 at the investigator’s discretion but should not be changed 
during the last 8 weeks (week 44 to 52) of the 52-week treatment period.  
Subjects who meet the criteria listed below will be allowed to continue the study but will 
be considered as experiencing treatment failure for the primary efficacy endpoint 
analyses: 
 
Subjects requiring a dose of systemic corticosteroids for SLE above their baseline 
dose after week 16 
 
Subjects requiring either dose increases of the current immunosuppressants/ 
immunomodulators or initiation of new immunosuppressant/ immunomodulator(s) 
IAs will be conducted to allow for adaption of the randomization ratio for newly enrolled 
subjects to the 3 efavaleukin alfa treatment groups, holding the allocation to placebo 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 13 of 64 
CONFIDENTIAL  
 
 
constant at 25%, and assessing efficacy for early futility or administrative success 
decisions: 
 
The study team, investigators, and subjects will remain blinded to the results of the 
IAs unless futility is determined. 
 
The first IA will be executed after the first 40 subjects are randomized and have had 
the opportunity to complete the week 24 assessment.  Subsequent IAs are 
scheduled after every additional 32 subjects are randomized and have had the 
opportunity to complete the week 24 assessment until full enrollment or until futility is 
determined for all doses at an IA.  The last IA will occur when all 320 subjects are 
randomized and have had the opportunity to complete the week 24 assessment.  
This IA will be referred to as the ‘all-subjects-week-24 IA’.  Analyses planned at each 
IA are listed in Table 3-1.  
 
Efficacy analyses will be performed at the IAs to assess the likelihood of each 
efavaleukin alfa treatment group being superior to placebo by a clinically meaningful 
difference.  
o From the second IA until before the last IA, if this likelihood is unacceptably low 
for all dose levels, the trial is recommended to stop for futility.  
o At the ‘all-subjects-week-24 IA’, if this likelihood is sufficiently high with at 
least one efavaleukin alfa dose level, this IA will trigger an administrative success 
signal.  This would not alter the ongoing or planned activities of this phase 2b 
study, but downstream planning for subsequent trials (e.g., a phase 3 study) may 
commence. 
 
Based on the Data Monitoring Committee’s recommendation following review 
of the results from the 3rd IA and subsequent decision by the Data Access Plan 
Team, the study was terminated due to futility and further enrollment in the 
study was stopped. Previously enrolled subjects were discontinued from IP 
and terminated the study after being followed for an additional 6 weeks 
following last dose of IP. The remaining planned IAs, including the 4th to the 
last IA (‘all-subjects-week-24-IA’) were not conducted.  
3.2 
Sample Size 
The approximate sample size of 320 subjects is chosen to provide approximately 80% 
power to detect ≥ 25% absolute improvement for at least 1 efavaleukin alfa dose group 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 14 of 64 
CONFIDENTIAL  
 
 
relative to placebo in the primary endpoint of SRI-4 response rate at week 52 at a 
significance level of 0.025 (1-sided) using a Bayesian Hierarchical Model, assuming a 
40% response rate in placebo group. 
Because enrollment was stopped early, the actual sample size is smaller. 
3.3 
Adaptive Design 
The prospectively defined adaptive features include RAR, early decision for futility and 
an early trigger for administrative success. The following adaptations are based on the 
planned IA results:  
 
Adaptive randomization begins after a fixed allocation period. After each IA (if 
before full enrolment), the randomization probability for each of the 3 active 
doses may be changed based on clinical efficacy after an IA, while the 
randomization allocation for placebo is kept constant at 25%.   
 
Efficacy is assessed against predefined early stopping rules for futility from the 
second IA until before the last IA. If futility is triggered, the study could be 
terminated, e.g., continued enrollment and IP dosing for previously enrolled 
subjects would be stopped, etc.  
 
Efficacy is assessed against predefined rules for early administrative success 
only at the last planned IA. If administrative success is determined, downstream 
activities may be planned/initiated, but the execution of the trial would not be 
stopped or altered. 
 
All adaptive decisions will be based on the SRI-4 response at week 52 with 
longitudinal modeling of SRI-4 response data.  For a subject who has not yet 
completed through week 52, their 52-week value will be imputed using a 
longitudinal model based on their week 16, 20, or 24 SRI-4 response data, 
whichever is the latest. 
Modeling and simulations were used to design this Bayesian adaptive trial and refine 
study design features to achieve optimal operating characteristics, including but not 
limited to type I error, power and estimation bias. 
The IAs will be conducted by an Independent Biostatistics Group (IBG) and will be 
reviewed by a Data Monitoring Committee (DMC), both external to Amgen. The study 
team, investigators and subjects will remain blinded to the results of the IAs unless 
futility is determined. 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 15 of 64 
CONFIDENTIAL  
 
 
Table 3-1 Planned Analyses Schedule 
Decisions at Each Interim Analysis and Final Analysis 
Timepoint 
Adaptive Decision 
Number of subjects with opportunity to 
complete week 24 
1st IA  
RAR 
40 
2nd IA 
Futility, RAR 
72 
3rd IA 
Futility, RAR 
104 
4th IA ac 
Futility, RAR 
136 
5th IAac 
Futility, RAR 
168 
6th IAac 
Futility, RAR 
200 
7th IAac 
Futility, RAR 
232 
Last IAbc 
Administrative success 
320 
Final Analysis 
Not applicable 
All subjects reach EOS 
IA = interim analysis; RAR = response adaptive randomization; EOS = end of study 
a Interim analyses are planned after every 32 subjects are randomized and have had the opportunity to 
complete the week 24 assessment until full enrollment or until futility is determined for all doses at an IA. 
Number of IAs will depend on the observed enrollment rate.  
b Last IA is the all-subjects-week-24 IA.  The administrative success analysis at the last IA will not result in 
any adaptive decision for the ongoing study. 
c  Canceled due to study early termination. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable. 
4.2 
Subgroups 
The primary endpoint will be summarized within each of the subgroups listed below. If 
the subgroup sample size is less than 10% of the population, this subgroup may not be 
evaluated. The subgroups of interest include the following:  
 
baseline hSLEDAI (< 10, ≥ 10) 
 
region (North America + Western Europe + Asia Pacific, ROW) 
5. 
Definitions 
5.1 
Basic Definition 
Investigational Product (IP) 
Efavaleukin alfa and placebo. 
Enrollment/Randomization Date 


Product: Efavaleukin Alfa  
Protocol Number:  20200234 
Date:  25 September 2023 
Page 16 of 64 
CONFIDENTIAL  
 
 
The enrollment/randomization date is the date on which a subject is assigned to a 
treatment group by the IRT system.  
First Dose Date 
The first dose date is the date of administration of the first dose of IP; this may or may 
not be the same as randomization date.  
Actual Treatment Received 
The actual treatment received is the IP the subject actually received, regardless of what 
the subject was randomized to. In cases where a subject received both efavaleukin alfa 
and placebo, the actual treatment received will be the efavaleukin alfa dose.  In cases 
where a subject received multiple different efavaleukin alfa doses, the actual treatment 
received will be based on the highest efavaleukin alfa dose received. In cases where 
the subject received more than
 efavaleukin alfa dose, the subject will be 
assigned to
 efavaleukin alfa dose. 
Duration of IP exposure 
The duration of IP exposure will be derived as the date of the last IP administration plus 
13 days (14-day window-1), end of study date or data cutoff date, whichever occurs first, 
minus the date of first IP administration plus 1 day. 
Flare Exposure Time 
The flare exposure time is the time from study day 1 up to the last flare assessment 
date. 
Treatment-emergent adverse event 
Treatment-emergent adverse events are defined as events categorized as Adverse 
Events (AEs) starting on or after first dose of IP as determined by “Did event start before 
first dose of investigational product?” equal to “No” or missing on the Events eCRF and 
up to the end of study date. 
Baseline medication 
Baseline medication is defined as any medication with start date on or before study day 
1 and ongoing while on study. 
Concomitant medication 


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Concomitant medication is defined as any medication with start date prior to study day 1 
and ongoing while on study or any medication with start date on or after study day 1 and 
up to the end of study. 
Prednisone-equivalent dose 
The prednisone-equivalent dose of OCS will be computed based on the table below. 
Additionally, a multiplier will be applied depending on the dosing frequency: 2 for ‘twice 
daily’ or ‘every 12 hours’ and 0.5 for every other day. For example, cortisone 25 mg is 
equivalent to prednisone 5 mg and a cortisone 25 mg twice daily is equivalent to 
prednisone 10 mg/day. 
Corticosteroids 
Equivalent dose  
Prednisone 
5 mg 
Betamethasone 
0.75 mg 
Cortisone 
25 mg 
Deflazacort 
6 mg 
Dexamethasone 
0.75 mg 
Hydrocortisone 
20 mg 
Methylprednisolone/Meprednisone/ 
Methylprednisolone Acetate 
4 mg 
Prednisolone 
5 mg 
Triamcinolone 
4 mg 
5.2 
Study Points of Reference 
Baseline 
Baseline is the last measurement for the endpoint of interest taken before the first dose 
of IP. If the measurement is taken on the same day as the first dose and the exact 
measurement time relative to the first dose is unknown, it will be assumed to have been 
taken prior to the first dose of IP. If a subject did not receive IP, baseline is the closest 
recorded measurement on or prior to the randomization date. 
Study Day 1 
Study day 1 for each subject is the first day of IP administration or the day of 
randomization for subjects who did not receive IP. 
Study Day 


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Study day for each subject is defined as (day of interest – study day 1) + 1 for dates on 
or after study day 1, or (day of interest – study day 1) for dates prior to study day 1. 
5.3 
Study Dates 
End of 52-Week Treatment Period Date 
End of 52-week treatment period date for each subject is defined as the date of the last 
assessment for the week 52 visit, the end of study date in case of subject early 
termination, study day 394 or 
 (date of study early termination), 
whichever occurs first.  
End of Study Date 
End of study for each subject is the date recorded on the End of Study CRF page. 
5.4 
Study Time Intervals  
Treatment Period 
The time period from study day 1 to the end of treatment period date inclusive. 
Final Analysis Period 
The time period from study day 1 to the end of study date, inclusive.  
5.5 
Arithmetic Calculations 
Change from baseline 
The arithmetic difference between a post-baseline value and baseline for a given 
timepoint: 
(post-baseline value – baseline value). 
Percent change from baseline  
The change from baseline divided by baseline value and multiplied by 100:  
(change from baseline / baseline) * 100. 
If the change from baseline is not equal to zero and the baseline value is zero then 
percent change from baseline is not defined. If the change from baseline is equal 
to zero and the baseline value is also zero then percent change from baseline is 
100. 
Fold change from baseline or ratio from baseline 
Fold change from Baseline equals the post-baseline value divided by the baseline value. 
If the change from baseline is not equal to 0 and the baseline value is 0 then fold change 


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is not defined. If the change from baseline is equal to 0 and the baseline value is also 0 
then fold change is 1. 
5.6 
Efficacy Assessments 
Hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) 
The hSLEDAI is a global index that evaluates disease activity and includes both 
laboratory and clinical parameters and consists of 24 items. The maximum score is 105. 
Hybrid SLEDAI is the index score used during the validation of the SLE Responder 
Index (SRI) (Navarra et al, 2011; Furie et al, 2011). The hSLEDAI includes scleritis and 
episcleritis in visual disturbance assessments. Scleritis and episcleritis should be 
confirmed by ophthalmologist and clinically stable if used for scoring purposes. 
Additionally, arthritis should be scored when > 2 joints manifest signs of inflammation 
strictly defined as the presence of tenderness plus one of the following: swelling, 
effusion, warmth or erythema. The presence of tenderness alone is not sufficient and at 
least 3 joints, and not only 2, must be affected. In this study, for arthritis to be scored it is 
required to involve the small joints of hands and/or wrists. 
Findings should reflect activity during the 30 calendar days prior to the current visit. 
Details of hSLEDAI descriptors and the scoring algorithm are described in Appendix B.  
British-Isles Lupus Assessment Group (BILAG) 
The BILAG index (BILAG 2004) evaluates disease activity in 9 separate organ systems 
and comprises a total of 97 items. Each item is measured qualitatively by review of 
medical history and physical examination (yes/no, improving/same/worse/new) or 
quantitatively by measuring laboratory values. Based on these items, each of the 9 
organ systems allocated an alphabetical score of A (most active), B (moderate activity), 
C (minor activity), D (stable) or E (never present). The BILAG index can be converted 
into a numerical score (A grade = 12 points, B = 8, C = 1, D = 0, E = 0). Findings should 
reflect activity during the 4-week period prior to the current visit and should be related to 
the subject’s SLE. Details of BILAG descriptors and the scoring algorithm are described 
in Appendix B. 
Physician Global Assessment (PGA) – Visual Analog Scale 
The PGA is a visual analog scale (VAS) using 4 descriptive anchors for assessing 
disease activity over the last 4 weeks. When scoring the PGA VAS, the previous visit 
score should be noted, and the current score should be relative to that previous visit. 
The score ranges from 0 to 3 with 3 indicating severe disease. This refers to the most 


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severe possible disease and does not reflect the most severe ever seen in a particular 
subject, but the most severe disease ever seen in all SLE patients.  
This is a global assessment, factoring in all aspects of the subject’s lupus disease 
activity. It should not reflect non-lupus medical conditions. An increase of ≥ 0.3 points (> 
10% on the 3 point-VAS) from baseline is considered clinically significant worsening of 
disease.  
Systemic Lupus Erythematosus Responder Index (SRI-4)  
A subject achieves SRI-4 response if all of the following criteria are met: 
1. ≥ 4-point reduction from baseline in hSLEDAI score 
2. no new BILAG 2004 A and no > 1 new BILAG 2004 B domain scores compared 
with baseline (e.g. no B, C, D or E scores at baseline becomes an A or no more 
than 1 C, D or E score at baseline becomes a B) 
3. < 0.3-point deterioration from baseline in PGA VAS (scale 0 to 3). 
4. no use of more than protocol-permitted therapies (i.e. requiring a dose of 
systemic steroid [for e.g., OCS or intravenous [IV] or intramuscular [IM] 
corticosteroid] above their baseline dose after week 16; requiring either dose 
increases of the current immunosuppressants/immunomodulators or initiation of 
new immunosuppressant/immunomodulatory(s)).   
The latest visit date among hSLEDAI, BILAG and PGA VAS will be considered the SRI-4 
visit date. In the case when all three visit dates are missing, the upper limit of the 
analytic window of this visit will be the SRI-4 visit date. 
BILAG-based Composite Lupus Assessment (BICLA) 
A subject achieves BICLA response if all of the following criteria are met: 
1. at least one gradation of improvement in baseline BILAG domain scores in all 
body systems with moderate or severe disease activity at entry (e.g., all A 
(severe disease) domain scores at baseline falling to B (moderate), C (mild), or D 
(no activity), and all B domain scores at baseline falling to C or D)  
2. no new BILAG 2004 A domain score and no > 1 new BILAG 2004 B domain 
scores compared with baseline 
3. no worsening of the hSLEDAI score from baseline 
4. < 0.3-point deterioration from baseline in PGA VAS (scale 0 to 3) 


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5. no use of more than protocol-permitted therapies (i.e. requiring a dose of 
systemic steroid [for e.g., OCS or IV or IM corticosteroid] above their baseline 
dose after week 16; requiring either dose increases of the current 
immunosuppressants/immunomodulators or initiation of new 
immunosuppressant/immunomodulatory(s)).   
PGA – 4-Point Verbal Rating Scale 
The PGA 4-Point Verbal Rating Scale uses 4 verbal descriptors for assessing the 
severity of disease since the last visit. The options for disease severity are none, mild, 
moderate, and severe. 
This is a global assessment, factoring in all aspects of the subject’s lupus disease 
activity. It should not reflect non-lupus medical conditions. This assessment will be 
completed by a health care provider (HCP) and must be done before assessing the 
hSLEDAI and BILAG. 
Swollen and Tender Joint Count 
Joints that have been replaced during the study, or have trauma or received intra-
articular injections are considered non-evaluable throughout the study.  
Swollen Joint Count Assessments – A total 28 joints will be scored for presence or 
absence of swelling. A separated score for joints in the hands and wrists will be 
calculated.  
Tender Joint Count Assessments – A total 28 joints will be scored for presence or 
absence of tenderness. A separated score for joints in the hands and wrists will be 
calculated.  
Swollen and Tender Joint Count Assessments: joints in hands and wrists will be scored 
for the simultaneous presence or absence of swelling and tenderness.  
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
The CLASI consists of 2 scores, the first summarizes the activity of the disease while the 
second is a measure of the damage done by the disease. Activity is scored based on 
erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss and 
non-scarring alopecia. Damage is scored in terms of dyspigmentation and scarring, 
including scarring alopecia. Subjects are asked whether dyspigmentation due to 
cutaneous lupus lesion usually remains visible for more than 12 months, which is taken 
to be permanent. If so, the dyspigmentation score is doubled. The scores are calculated 


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by simple addition based on the extent of the symptoms. The CLASI is designed as a 
table where the rows denote anatomical areas, while the columns score major clinical 
symptoms. The extent of involvement for each of the skin symptoms is documented 
according to specific anatomic areas that are scored according to the worst affected 
lesion within that area for each symptom. 
A CLASI response is defined as ≥ 50% improvement of CLASI activity score from 
baseline. 
Lupus Low Disease Activity State (LLDAS)  
A subject achieves LLDAS response if all of the following criteria are met:  
1. hSLEDAI ≤ 4 with no activity in major organ systems (renal [proteinuria, 
haematuria, pyuria, urinary casts], central nervous system (CNS) [seizure, 
psychosis, organic brain syndrome, cranial nerve disorder, CVA], 
cardiopulmonary [pericarditis, pleurisy], vasculitis, fever) 
2. no new lupus disease activity (i.e. no new descriptor scores in hSLEDAI) 
compared with the previous assessment  
3.   PGA VAS (scale 0-3) ≤1 
4.  Current prednisolone (or equivalent) dose ≤ 7.5 mg/day 
5.  Standard maintenance doses of immunosuppressive drugs and approved 
biological agents (i.e. no increase or initiation of immunosuppressive drugs).  
BILAG Flare Index 
The BILAG flare index will be derived from BILAG 2004, as measured by BILAG score 
designation of “worse” or “new” resulting in a B score in ≥ 2 organs or an A score in ≥1 
organ at one visit (Gordon et al, 2003) compared with the previous available 
assessment. 


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Anti-dsDNA 
Anti-dsDNA is categorized as negative, indeterminate or positive as follows: 
Positive:  > 15 IU/mL for subjects in Asia (Japan, Hong Kong, Taiwan and South 
Korea) and > 75 IU/mL for all other subjects. 
Indeterminate:  10 - 15 IU/mL for subjects in Asia (Japan, Hong Kong, Taiwan 
and South Korea) and 30 - 75 IU/mL for all other subjects. 
Negative: < 10 IU/mL for subjects in Asia and < 30 IU/mL for all other subjects. 
5.7 
Patient-reported Outcome (PRO) Assessments 
Medical Outcomes Short Form-36 Questionnaire Version 2 (SF36v2) 
The SF-36v2 (acute version) Health Survey (Ware et al, 2000) contains 36 items and is 
a revised version of the SF-36 Health Survey. The SF-36v2 acute version is a patient 
reported generic measure of health status. This survey yields assessments of 8 domains 
of health-related quality of life: 1) limitations in physical activities because of health 
problems; 2) limitations in social activities because of physical or emotional problems; 3) 
limitations in usual role activities because of physical health problems; 4) bodily pain; 5) 
general mental health (psychological distress and well-being); 6) limitations in usual role 
activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general 
health perceptions. The scores from the 8 domains will be evaluated independently and 
aggregated into 2 norm-based summary component measures of physical and mental 
health. The recall period is the past 7 days. The scoring of SF-36v2 will be processed by 
QualityMetric’s PRO CoRE Software. 
Patient-Reported Outcome Measurement Information System Fatigue Short Form 
7a Instrument (PROMIS Fatigue SF 7A v1.0) 
The PROMIS Fatigue Short Form 7a is a 7-item instrument originally constructed by the 
PROMIS Fatigue team to represent the range of the fatigue trait (PROMIS Fatigue 
Scoring Manual).  It assesses the experience of fatigue as well as its impact on physical, 
mental and social activities.  Both psychometric properties and clinical input were used 
in the development of the short form from the PROMIS item bank.  Estimates of 
responsiveness and minimally important differences have been reported for the 4 item 
PROMIS Fatigue instrument in SLE patients (Katz et al, 2019).  The PROMIS Fatigue 


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has also been able to differentiate disease activity in other rheumatologic diseases.  
(Wohlfahrt et al, 2019), 
Details of the scoring algorithm are described in Appendix C. 
LupusQoL Score 
The LupusQoL is the US version of the 34-item PRO originally developed in the United 
Kingdom (McElhone et al, 2007) for use in adults. This is a SLE-specific health-related 
quality of life instrument. The LupusQoL consists of 8 domains: physical health (8 items), 
pain (3 items), planning (3 items), intimate relationships (2 items), burden to others (3 
items), emotional health (6 items), body image (5 items), and fatigue (4 items). The final 
instrument has demonstrated good internal reliability (Cronbach’s 0.88 to 0.95), good 
test-retest reliability (r 0.72 to 0.93), good concurrent validity with the comparable 
domains of the SF-36 (r 0.71 to 0.79) and good discriminant validity for different levels of 
disease activity, measured by BILAG index, and damage (Systemic Lupus International 
Collaborating Clinics/ACR damage index) but not for all domains. The instrument also 
has acceptable ceiling effects and minimal floor effects. 
Details of the scoring algorithm are described in Appendix C.  
Symptom Questionnaire 
The Symptom Questionnaire is a new patient reported outcome instrument to evaluate 
inflammatory symptoms, non-inflammatory symptoms, and flare (Pisetsky et al, 2019).  
The items are based on a 11-point numerical rating scale, with 1 item being a choice of 
yes or no, all with a 7-day recall.  Response to therapy and psychometric properties of 
the questionnaire will be evaluated with data derived from this study. 


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6. 
Analysis Sets 
6.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects. Data will be analyzed 
based on randomized treatment assignment. 
6.2 
Safety Analysis Set 
The Safety Analysis set includes all randomized subjects who received at least 1 dose of 
investigational product.  Data will be analyzed according to actual treatment received. 
6.3 
Interim Analyses Set(s) 
The Interim Analyses Sets include all subjects randomized on or before the interim 
analyses cutoff dates, and had the opportunity to complete week 16 (actual week 16 visit 
date ≤ the cutoff date, or randomization date + 126 -1 < the cutoff date). The interim data 
cutoff dates are based on the number of subjects having the opportunity to complete 
week 24 visit presented in Table 3-1. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Interim analyses will be conducted to inform adaption of the randomization ratio to enroll 
future subjects to the 3 efavaleukin alfa treatment groups, holding the allocation to 
placebo constant at 25%, and to assess efficacy for early futility or administrative 
success decisions: 


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 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that outstanding 
data issues are resolved ahead of the snapshot to the extent possible. All available 
data up to and including the data cut-off date will be included in the analysis based 
on an “as-is” snapshot of the database without data locking. 
 
The study team, investigators, and subjects will remain blinded to the results of the 
IAs unless futility is determined. 
 
The first IA will be executed after the first 40 subjects are randomized and have had 
the opportunity to complete the week 24 assessment.  Subsequent IAs are 
scheduled after every additional 32 subjects are randomized and have had the 
opportunity to complete the week 24 assessment until full enrollment.  The last IA will 
occur when all 320 subjects are randomized and have had the opportunity to 
complete the week 24 assessment.  This IA will be referred to as the ‘all-subjects-
week-24 IA'.   
 
Efficacy analyses will be performed at the IAs to assess the likelihood of each 
efavaleukin alfa treatment group being superior to placebo by a clinically meaningful 
difference.   
o From the second IA until before the last IA, if this likelihood is unacceptably low 
for all dose levels, the trial is recommended to stop for futility.   
o At the ‘all-subjects-week-24 IA’, if this likelihood is sufficiently high with at least 1 
efavaleukin alfa dose level, the IA triggers an administrative success signal.  This 
would not alter ongoing or planned activities of this phase 2b study, but 
downstream planning for subsequent trials (e.g., a phase 3 study) may 
commence. Analysis planned each IA are listed in Table 3-1. This interim 
analysis was cancelled due to the study being terminated for futility prior to 
the enrollment trigger for this analysis. 
At IAs:   
 
For all IAs before full enrollment, the randomization ratio to each active treatment 
group is proportional to the posterior probability that each group has the highest 
response rate among the three active treatment groups with power scale of 2.  
𝐴𝑙𝑙𝑜𝑐𝑎𝑡𝑖𝑜𝑛𝑑∝Pr ( 𝑝𝑑,52 = max
𝑐
𝑝𝑐,52 ∣∣∣Interim Data ), 𝑐, 𝑑∈{𝑙𝑜𝑤, 𝑚𝑒𝑑𝑖𝑢𝑚, ℎ𝑖𝑔ℎ} 
where 𝑝𝑑,52 is the posterior probability of achieving SRI-4 response for group d, 
calculated using a Bayesian independent logistic model with non-informative priors. 


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 
From the second IA until before the last IA, interim futility analysis will be performed 
based on the Bayesian Hierarchical Model (BHM) as described in the primary 
efficacy analysis. Enrollment to the study may be stopped for futility if the posterior 
probability of achieving a clinically meaningful difference in SRI-4 response rates of 
at least 15% between each active treatment group and placebo is below 2.5% for all 
3 efavaleukin alfa doses. 
max Pr( 𝑝𝑑,52 −𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜,52 > 𝛿∣∣Interim Data ) < 0.025, 𝑑∈{𝑙𝑜𝑤, 𝑚𝑒𝑑𝑖𝑢𝑚, ℎ𝑖𝑔ℎ}  
where 𝛿= 0.15 and 𝑝𝑑,52 is the posterior probability of achieving SRI-4 response for 
group d, calculated using a BHM. 
 
The futility rule and the administrative success trigger are made using estimates of 
the response rate 𝑝𝑑,52 for each dose. However, due to the covariate adjustment, the 
Bayesian models provide estimates of 𝑝𝑑∣𝑍, the response rate in each dose 
conditional on the stratification factor 𝑍. The population level estimate for each dose 
is obtained using a weighted average of the response rate in each stratification 
group. 
𝑝𝑑= ∑𝑤𝑧⋅
𝑍∈𝒵
𝑝𝑑∣𝑍    for  𝑑∈{𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 𝑙𝑜𝑤, 𝑚𝑒𝑑𝑖𝑢𝑚, ℎ𝑖𝑔ℎ} 
The set 𝑍 indicates the four possible stratification combinations (hSLEDAI 
stratification [≥10, <10] and region [North America + Western Europe + Asia Pacific 
vs ROW]). The weights 𝑤𝑧 will be set equal to the observed proportion of patients in 
each stratification group at the time of the analysis. 
 
To address the challenge of the lag time between randomization and the week 52 
outcome in the adaptive design, a longitudinal model is used to impute week 52 
outcome for subjects not yet complete week 52 using their week 16, week 20, or 
week 24 response data. 
7.2 
Final Analysis 
The final analysis will occur after all subjects reach the end of study. 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that outstanding data 
issues are resolved ahead of the lock. The data supporting the final analysis will be 
locked to prevent further changes. 


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8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. All laboratory, PK, 
 and biomarker data from the 
central laboratory or vendor will be transferred to GSO-DM. SLE efficacy assessment 
and PRO data from the central vendor will be transferred to GSO-DM. All other data will 
be captured on the eCRF. 
8.3 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of reasons. In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or non-
evaluability of a specific clinical or laboratory measurement at its planned clinical visit. 
Additionally, as the study was terminated before the planned completion, subjects 
may have missed clinical visits including not completing the week 52 visit. For 
efficacy and PRO outcomes, subjects who terminated early due to sponsor 
decision will be excluded from analyses of data from visits for which they did not 
have the opportunity to participate in by the date of study termination decision 
being communicated to sites, i.e. April 5, 2023.  Efficacy data collected after this 
date will be censored and excluded from analyses for that particular visit. Unless 
specified, no imputation will be used. The general procedures outlined below describe 
what will be done when a data point is missing. 
Hybrid SLEDAI 
In case of completely missing hSLEDAI assessment (e.g. missed visit) or partially 
missing (e.g. laboratory measurements not available), the missing post-baseline 
hSLEDAI total score will be imputed using last observation carried forward (LOCF) if the 
previous analysis visit is not missing. Baseline hSLEDAI will not be carried forward to 
post-baseline.  
The hSLEDAI total score will then be computed based on the non-missing and imputed 
data. If the hSLEDAI total score cannot be evaluated after imputation, the hSLEDAI 
score ≥ 4 points reduction from baseline will be considered not met. 


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CLASI 
In case of completely missing CLASI assessment (e.g. missed visit) or partially 
missing, the missing post-baseline CLASI items will be imputed using LOCF if the 
previous analysis visit is not missing. Baseline CLASI will not be carried forward 
to post-baseline.  
The CLASI activity score will then be computed based on the non-missing and 
imputed data. If the CLASI activity score cannot be evaluated after imputation, the 
CLASI activity score ≥ 50% improvement endpoint will be considered not met. 
BILAG 
In case of completely missing BILAG assessment (e.g. missed visit), the missing post 
baseline BILAG item scores will be imputed using LOCF if the previous analysis visit is 
not missing.  
In case of partially missing, missing laboratory items (e.g. UPCR, creatinine, etc.) will be 
imputed using LOCF if the previous visit is not missing; other missing items (e.g. active 
nephritis, Coombs' test positive, etc.) will be imputed as ‘No’ or ‘Not Present’.  
Baseline BILAG will not be carried forward to missing post-baseline BILAG. 
The BILAG organ domain scores will be calculated based on the non-missing and 
imputed components. If the non-missing and imputed components are not sufficient to 
identify the organ domain score, worst scenario approach will be used to determine the 
BILAG organ domain scores.  
PGA VAS 
Missing post-baseline PGA score will be imputed using LOCF if the score at the previous 
analysis visit is not missing. Baseline PGA will not be carried forward to missing post-
baseline PGA. 
SRI-4, BICLA and LLDAS 
The criteria for SRI-4, BICLA and LLDAS responses will be evaluated based on the non-
missing and imputed PGA, hSLEDAI and BILAG data. If any criteria based on the non-
missing and imputed PGA, hSLEDAI and BILAG data cannot be evaluated, then the 
subject will be considered as a non-responder. 
BILAG Flare index 


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BILAG flare index will be evaluated based on BILAG scores. In case of partially 
missing BILAG assessment, imputed BILAG scores will be used. In case of 
completely missing BILAG assessment, BILAG flare index will remain missing. 
Tender and Swollen Joint Counts 
If a joint is excluded (non-evaluable or missing), the joint counts will be prorated based 
on the algorithm described below.  
Prorated Joint Counts: If at least half but not all joints are evaluable (at least 14 joints for 
the total 28 joint count, at least 11 joints for the 22 hands and wrists joint count) then the 
observed prorated tender or swollen joint count will be calculated. The prorated scores 
will be adjusted based upon the number of evaluable joints: the counted score will be 
multiplied by 28 (for total) or 22 (for hands and wrists) as applicable and divided by the 
number of joints evaluated. If less than half of the joints are evaluable, the number of 
tender or swollen joints is missing. For example, if only 25 of the 28 joints are assessed 
at a visit and 10 of those 25 are tender/painful and 8 of those 25 are swollen, the 
prorated total joint counts are:  
Tender: (10/25)*28 = 11.20,  
Swollen: (8/25)*28 = 8.96.  
That is, the values of 11.20 and 8.96 will be used in calculating the % reductions in total 
joint counts, not the values of 10 and 8. Similar proration will be conducted for hands 
and wrists joint count.  
If the tender and swollen joint counts cannot be evaluated after proration, the 
tender and swollen joint count ≥ 50% improvement from baseline endpoint will be 
considered not met. 
Lupus anticoagulant 
Lupus anticoagulant results will be derived as follows: 
 
When activated partial thromboplastin time (aPTT) ≤ 29.4 seconds, then 
lupus anticoagulant is ‘negative’. 
 
When aPTT ≥ 29.4 seconds and hexagonal phospholipid < 11 seconds, then 
lupus anticoagulant is ‘negative’. 
 
When aPTT ≥ 29.4 seconds and hexagonal phospholipid ≥ 11 seconds, then 
lupus anticoagulant is ‘positive’. 


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Lupus anticoagulant results will only be derived for baseline, week 24 and week 
52 visits. 
Dates 
Missing and incomplete dates will be imputed as outlined in Appendix E. 
Laboratory Toxicity Grading 
In cases when supplemental information for laboratory toxicity grading is missing 
or the result is ambiguous, the worse toxicity grade possible will be assigned. 
Laboratory Measurements 
Laboratory measurements that are below the lower quantification limits will be 
considered equal to the lower limit of quantification for all analyses unless 
explicitly noted otherwise. 
8.4 
Detection of Bias 
Important protocol deviations and early withdrawal from treatment and from study may 
bias the results of the study. The incidence of these factors will be assessed and reason 
for early withdrawals will be tabulated. 
8.5 
Outliers 
Scatter plots will be examined to identify potential outliers in any of the continuous 
variables and frequencies of the categorical data will be examined to identify 
questionable values. The validity of any questionable values will be verified, and 
observations found to be due to data entry errors will be queried. Potential outliers that 
are not due to data entry error will be included in the analysis. 
8.6 
Distributional Characteristics 
Not applicable. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
All categorical variables will be summarized using the number and percent of subjects 
falling into each category and all continuous variable will be summarized using mean, 
standard error (SE), standard deviation (SD), median, first quartile (Q1), third quartile 
(Q3), minimum, maximum, and number of subjects with observations.  Safety endpoints 
will be summarized descriptively, including treatment-emergent adverse events and 
serious adverse events, clinically significant changes in laboratory values and vital signs, 
and incidence of antidrug antibodies.  All safety analyses will be performed using the 
Safety Analysis Set based on subject’s actual treatment received. 
9.2 
Subject Accountability 
The study dates for the first subject enrolled, last subject enrolled, last subject’s end of 
IP and last subject’s end of study will be presented. 
The number and percent of subjects who were randomized, received investigational 
product, completed investigational product, discontinued investigational product and 
reasons for discontinuing, completed study, discontinued study and reasons for 
discontinuing study will be summarized overall and by randomized treatment group. 
Summary of subjects who discontinue investigational product/study due to COVID-19 
control measures will be included. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. The final IPD list will be used to produce the summary of IPDs table and 
the list of subjects with IPDs. IPDs related to COVID-19 control measures will be 
summarized separately. 
9.4 
Demographic and Baseline Characteristics 
The following demographic, baseline characteristics, baseline disease characteristics 
and baseline therapies of interest will be summarized descriptively by randomized 
treatment group.   
Demographics: 
 
sex (female, male) 


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 
age (years) 
 
age groups (≥ 18 to < 50, ≥ 50 and 18 – 64, 65 – 74,75 – 84) 
 
race (American Indian or Alaska Native, Asian, Black or African-American, Native 
Hawaiian or Other Pacific Islander, White, Other) 
 
ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
geographic region (North America [Canada and United States] + Western Europe 
[Austria, France, Switzerland] + Asia Pacific [Hong Kong, Japan, South Korea 
and Taiwan], ROW [Bulgaria, Chile, Colombia, Greece, Italy, Mexico, Poland, 
Russia, Spain and Turkey]) 
Baseline characteristics: 
 
height (cm) 
 
weight (kg) 
 
body mass index (BMI) (kg/m2) 
Baseline disease characteristics: 
 
years since SLE diagnosis 
 
hSLEDAI score (continuous, < 10 or ≥ 10) 
 
baseline hSLEDAI organ involvement (CNS [seizure, psychosis, organic brain 
syndrome, visual disturbance, cranial nerve disorder, lupus headache, 
cerebrovascular accident], vascular [vasculitis], renal [urinary casts, hematuria, 
proteinuria, pyuria], musculoskeletal [arthritis, myositis], serosal [pleurisy, 
pericarditis], dermal [rash, alopecia, mucosal ulcers], immunologic [low 
complement, increased DNA binding], constitutional [fever], hematologic 
[thrombocytopenia, leukopenia])  
 
baseline BILAG domain score (A, B, C, D, E) 
o constitutional 
o mucocutaneous 
o neuropsychiatric 
o musculoskeletal 
o cardiorespiratory 
o gastrointestinal 


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o ophthalmic 
o renal 
o haematological 
 
CLASI activity score (continuous, 0, > 0 to < 8, ≥ 8)  
 
total swollen and tender joint counts 
 
hand and wrist swollen and tender joint counts 
 
PGA VAS score 
 
baseline biomarkers 
o antinuclear antibody (≥ 1:80 vs. negative or < 1:40) 
o anti-dsDNA (continuous, positive, indeterminate or negative) 
o C3, C4 complement (continuous, low or normal/high, low C3 or C4 vs. 
normal/high C3 and C4) 
o anti-dsDNA and complement  
o anti-dsDNA positive and low complement 
o anti-dsDNA positive and normal/high complement 
o anti-dsDNA indeterminate and low complement 
o anti-dsDNA indeterminate and normal/high complement 
o anti-dsDNA negative and low complement 
o anti-dsDNA negative and normal/high complement 
Baseline medications  
 
immunosuppressant/immunomodulator (yes, no) 
o mycophenolate mofetil 
o azathioprine 
o methotrexate 
o anti-malarial (hydroxychloroquine, chloroquine, quinacrine) 
o dapsone 
o other 
 
daily OCS dose (prednisone-equivalent mg/day; continuous, 0 mg/day, > 0 to < 
10 mg/day, ≥ 10 mg/day) 


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9.5 
Efficacy Analyses 
Unless stated otherwise, the Full Analysis Set (FAS) will be used for analysis of efficacy 
endpoints. The efficacy analyses are summarized in Table 9-1, Table 9-2 and Table 9-3. 
The SLE efficacy assessment data (BILAG, hSLEDAI, PGA, CLASI, swollen and tender 
joint counts, and 
) will be submitted to an external 
independent committee comprised of clinicians with expertise in managing and 
assessing SLE disease and clinical trials for adjudication. The committee will adjudicate 
the data and determine whether the efficacy assessments are scored correctly and 
consistently based on the instruments’ specifications. 
Unless stated otherwise, the analysis of the SLE efficacy assessment data and their 
derived endpoints (SRI-4, BICLA, LLDAS and BILAG flare index) will be based on the 
data resulting from the adjudication. Additionally, to assess the concordance between 
the investigators and adjudicators, the SRI-4 responses at week 16, 20, 24 and 52 
based on the two sources will be cross-tabulated and the concordance rate will be 
computed as the frequency of cases where the data based on the investigator's 
assessment and the data resulting from adjudication agree on classification of a subject 
as an SRI-4 responder/non-responder.  If the concordance rate at week 52 is < 0.95, the 
primary endpoint may be summarized using SRI-4 responses derived based on the 
investigator-reported data as a sensitivity analysis. 
 


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Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and 
Analysis Method 
Sensitivity and 
Supplementary Analysis 
SRI-4 response at week 52 
Within each treatment arm, 
the number and percentage 
of subjects achieving SRI-4 
will be computed.     
 
 
To assess different data 
sources: 
The primary analysis may be 
repeated using SRI-4 
responses based on the 
investigator data, if the 
concordance rate is <0.95. 
 
  
Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
 
BICLA response at week 52 
 
LLDAS response at week 52 
 
Reduction of OCS to ≤ 7.5 mg/day 
by week 44 and sustained through 
week 52 in subjects with a baseline 
OCS dose ≥ 10 mg/day 
 
SRI-4 response at week 24 
 
BICLA response at week 24 
 
HSLEDAI reduction ≥ 4 points from 
baseline at week 24  
 
HSLEDAI reduction ≥ 4 points from 
baseline at week 52 
Number and percentage of subjects 
achieving response of interest will be 
summarized by randomized treatment arm. 
 
Improvement from baseline in 
tender and swollen joint count 
≥ 50% at weeks 8, 12, 24, 36, and 
52 in subjects with ≥ 6 tender and 
swollen joints involving the hands 
and wrists at baseline 
 
CLASI activity score  50% 
improvement from baseline at week 
12, 24, 36, and 52 in subjects with a 
CLASI activity score  8 at baseline 
Number and percentage of subjects 
achieving response of interest will be 
summarized by randomized treatment arm. 
 
Annualized flare rate (as measured 
by BILAG score designation of 
“worse” or “new” resulting in a B 
score in ≥ 2 organs or an A score in 
≥ 1 organ) over 52 weeks 
Descriptive statistics will be summarized 
by randomized treatment arm. 
 
Change from baseline in fatigue 
standardized score using the 
PROMIS Fatigue SF 7a at week 12, 
24, 36, and 52 
 
Change from baseline in the 
physical component score, mental 
Descriptive statistics will be summarized 
by randomized treatment arm. 


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Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
 
component score and individual 
domains of the SF 36 v2 at week 
12, 24, 36, and 52 
 
Change from baseline in the domain 
scores on the Lupus QoL at weeks 
12, 24, 36, and 52 


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9.6 
Safety Analyses 
In the safety analysis, data up to the end of study will be summarized in the final 
analysis. 
9.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 26.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. The severity of each event will be graded using Common Terminology 
Criteria for Adverse Events (CTCAE) version 5. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to discontinuation of 
investigational product, fatal adverse events, treatment-related adverse events, 
treatment-related serious adverse events, treatment-related adverse events leading to 
withdrawal of IP, treatment-related fatal adverse events, and adverse events of interest. 
Subject incidence of treatment-emergent adverse events identified by COVID-19 
standardized MedDRA queries and serious adverse events occurring on or after the 
COVID-19 infection will also be summarized.   
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to discontinuation of investigational product, and fatal adverse 
events will be tabulated by system organ class in alphabetical order and preferred term 
in descending order of frequency.   
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
Medical Queries) will also be summarized according to their categories and preferred 
term. Events of interest could include but are not limited to hypersensitivity, 
tachyarrhythmias, tachypnea, hematopoietic cytopenia, eosinophilic disorder, leucocyte 
changes, infection and infestation, cytokine release syndrome injection site reaction and 
drug related hepatic disorder. Number of episodes and duration of treatment-
emergent injection site reactions will be further summarized by treatment group. 
Overall summary of subject incidence of treatment-emergent adverse events and by 
preferred term and worst severity grade will be provided by anti-AMG592 and Anti-IL-2 
antibody status. 


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Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade. An overall summary of adverse events 
by severity grade will be provided.  
Summary of exposure-adjusted subject rates of treatment-emergent adverse 
events will be tabulated overall and by system organ class and preferred term. 
9.6.2 
Laboratory Test Results 
Selected clinical laboratory test results, presented in Table 9-4, change and percent 
change from baseline will be summarized over time by each treatment group.  In 
addition, shift tables, from baseline to the worst on-study laboratory toxicity based on the 
CTCAE version 5, will be presented. 
Subject incidence of worst post-baseline of eosinophils counts and percentages by the 
laboratory normal range will be tabulated by treatment group. 
Table 9-4 Selected Safety Laboratory Tests 
Central Laboratory: 
Chemistry 
Central Laboratory: 
Hematology 
Central Laboratory: Urinalysis 
Creatinine 
Total bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
GGT 
Creatinine clearance by 
MDRD 
C-reactive protein 
CK 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
Reticulocytes 
WBC 
Differential 
• Eosinophils 
• Lymphocytes 
• Total neutrophils 
  
Protein/creatinine ratio 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = 
creatinine kinase; GGT = gamma glutamyl transferase; MDRD = Modification of Diet in Renal Disease; 
RBC = red blood cell count; WBC = white blood cell count 
9.6.3 
Vital Signs 
The actual value, change and percent change from baseline in vital signs will be 
summarized over time by treatment arm for diastolic blood pressure and, heart rate. 
9.6.4 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 


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provided, and these data would not be expected to be useful for meta-analysis with data 
from other trials. 
9.6.6 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to IP by treatment arm. 
Summary statistics will be provided for the total dose received and total duration of IP 
exposure by treatment arm. 
9.6.7 
Exposure to Other Protocol-permitted Therapy 
Other protocol-required therapies for this study are 
immunomodulators/immunosuppressants, OCS,  NSAIDs, topical corticosteroids and 
topical calcineurin inhibitors and anti-proteinuria agents. 
The baseline exposure to OCS and immunomodulators/immunosuppressants will 
be summarized using descriptive statistics (number and percentages). 
9.6.8 
Exposure to Concomitant Medication 
Not applicable. 
9.7 
Other Analyses 
Medical history will be summarized by SOC and PT and tabulated by treatment group 
and total using the Safety Analysis Set according to the actual treatment received. 
9.7.1 
Analyses of Pharmacokinetic Endpoints 
Amgen Clinical Pharmacology Modeling and Simulation (CPMS) group will 
conduct PK analysis. Serum concentration data will be summarized by treatment 
for each PK sampling time point. PK parameters may be summarized if adequately 
estimated.  
The descriptive statistics for absolute change from baseline, percentage change 
from baseline and ratio to baseline will be provided by treatment arms at specified 
time-points for the endpoints C3, C4, anti-dsDNA antibody and antiphospholipid 


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antibody (anticardiolipin antibody IgG and IgM, beta-2 glycoprotein IgG and IgM 
and lupus anticoagulant). 
9.7.2 
Analyses of Clinical Outcome Assessments 
The PRO endpoints include fatigue standardized score using PROMIS Fatigue SF 7, 
physical and mental component score and individual domains of the SF 36 v2. 
9.7.3 
Analyses of Biomarker Endpoints 
Exploratory biomarker analyses beyond those mentioned in this SAP may be conducted 
by Amgen Clinical Biomarker group. 
10. 
Changes From Protocol-specified Analyses 
Based on the Data Monitoring Committee’s recommendation after interim analysis 
3 and subsequent decision by the Data Access Plan Team, enrollment in the study 
was stopped and the study terminated as the study met the pre-specified futility 
criteria.  As such, some analyses that were initially planned in the protocol will not 
be performed. Key changes from protocol-specified analyses are as follows:  
 
Removal of subsequent IAs following study early termination. 
 
Removal of some exploratory endpoints. 
 
Removal of statistical comparison of treatment groups at the final analysis; 
descriptive statistics by treatment groups will be generated instead. 
11. 
Literature Citations / References 
Agresti A. Categorical Data Analysis, New York: John Wiley & Sons, Inc, 1990. 
Buyon JP, Petri MA, Kim MY, et. al. The effect of combined estrogen and progesterone 
hormone replacement therapy on disease activity in systemic lupus erythematosus: A 
randomized trial. Ann Intern Med. 2005;142:953. 
Efavaleukin Alfa Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low 
Disease Activity State (LLDAS). Ann Rheum Dis. 2016 Sep;75(9):1615-1621. 
Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus 
erythematosus responder index. Arthritis & Rheum. 2009;61(9):1143-1151. 
Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the 
systemic lupus international collaborating clinics/American College of Rheumatology 
Damage Index for Systemic Lupus Erythematosus. Arthritis Rheum. 1996; 39(3):363-
369. 
Golder V, Kandane-Rathnayake R, Huq M, et al.  Lupus low disease activity state as a 
treatment endpoint for systemic lupus erythematosus: a prospective validation study.  
Lancet Rheum.  2019;1(2):e95-e102. 
Gordon C, Sutcliffe N, Skan J, et al. Definition and treatment of lupus flares measured by 
the BILAG index. Rheumatology. 2003;42(11):1372-9. 


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Jolly M, Pickard AS, Wilke C et al. Lupus-specific health outcome measure for US 
patients: the LupusQoL-US version. Ann Rheum Dis. 2010;69:29-33. 
Katz P, Pedro S, Alemao E, et al.  Estimates of responsiveness, minimally import 
differences and patient acceptable symptom state in five patient-reported outcomes 
measurement information system short forms in systemic lupus erythematosus.  ACR 
Open. 2019: 1-8.  Doi 10.1002/acr2.11100 
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997; 53: 983-997 
Khraishi M, Aslanov R, Dixit S, et al 2014. The validity of patient and physician global 
disease activity assessments of systemic lupus erythematosus: results from the lupus 
activity coring tool (LAST) as compared to the Selena Sledai (SS) modification 
multicentre study. ACR 2014.  
Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for 
the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis 
Rheum. 1989;32(9):1107-18. 
Longford NT. Random Coefficient Models, New York: Oxford University Press, Inc, 1993 
McElhone K, Abbott J, Shelmerdine J et al. Development and validation of a disease 
specific health-related quality of life measure, the LupusQol, for adults with systemic 
lupus erythematosus. Arthritis Rheum. 2007;57:972-979.  
Navarra SV, Guzmán RM, Gallacher AE, et al.  Efficacy and safety of belimumab in 
patients with active systemic lupus erythematosus: a randomised, placebo-controlled, 
phase 3 trial. Lancet. 2011 Feb 26;377(9767):721-731. 
Pisetsky DS, Clowse MEB, Criscione-Schreiber LG, et al.  A Novel System to Categorize 
the Symptoms of Systemic Lupus Erythematosus.  Arth Care Res.  2019;71(6):735-741. 
PROMIS Fatigue Scoring Manual. Accessed at 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_M
anual.pdf on 29 Jan 2020  
Ware JE. SF-36 Health Survey Update. SPINE. 2000; 25:3130-3139. 
Wohlfahrt A, Bingham CO, Marder W, et al. Responsiveness of patient-reported 
outcomes measurement information system measures in rheumatoid arthritis patients 
starting or switching a disease-modifying antirheumatic drug. Arth Car Res 2019: (4): 
521-529. 
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage 1997; 13: 63-74. 


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12. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
Assessment of severity for each adverse event and serious adverse event reported 
during the study will be based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 5 which is 
available at the following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 


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Appendix B.  SLE Assessment Forms/Instruments 
The hSLEDAI score is computed as sum of the score across the descriptors. 
Weight 
Score Descriptor 
Definition  
8 
 
Seizure 
Recent onset, exclude metabolic, infectious or 
drug causes 
8 
 
Psychosis 
Altered ability to function in normal activity due 
to severe disturbance in the perception of 
reality. Include hallucinations, incoherence, 
marked loose associations, impoverished 
thought content, marked illogical thinking, 
bizarre, disorganized or catatonic behavior. 
Exclude uremia and drug causes 
8 
 
Organic brain 
syndrome 
Altered mental function with impaired 
orientation, memory, or other intellectual 
function, with rapid onset and fluctuating clinical 
features, inability to sustain attention to 
environment, plus at least two of the following: 
perceptual disturbance, incoherent speech, 
insomnia or daytime drowsiness, or increased 
or decreased psychomotor activity. Exclude 
metabolic, infection, or drug causes 
8 
 
Visual 
disturbance 
Retinal changes of SLE. Include cystoid bodies, 
retinal hemorrhages, serous exudate or 
hemorrhages in the choroid, optic neuritis, 
scleritis or episcleritis. Exclude hypertension, 
infection, or drug causes 
8 
 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy 
involving cranial nerves 
8 
 
Lupus 
headache 
Severe, persistent headache; may be 
migrainous, but must be non-responsive to 
narcotic analgesia.  
8 
 
CVA 
New onset of cerebrovascular accident(s). 
Exclude arterisclerosis 
8 
 
Vasculitis 
Ulceration, gangrene, tender finder nodules, 
periungual infarction, splinter hemorrhages, or 
biopsy or angiogram proof of vasculitis 
4 
 
Arthritis 
>2 joints of hands and wrists with signs of 
inflammation (i.e., tenderness with swelling or 
effusion) 


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4 
 
Myositis 
Proximal muscle aching/weakness, associated 
with elevated creatinine phosphokinase 
(CK)/aldolase or EMG changes or a biopsy 
showing myositis 
4 
 
Urinary casts 
Heme-granular or RBC casts 
4 
 
Hematuria 
> 5 RBC/high power field. Exclude stone, 
infection, or other cause 
4 
 
Proteinuria 
More than 0.5 gram/24 hours.  
4 
 
Pyuria 
> 5 WBC/high power field. Exclude infection 
2 
 
Rash 
Inflammatory type rash. 
2 
 
Alopecia 
Abnormal, patchy or diffuse loss of hair 
2 
 
Mucosal ulcers 
Oral or nasal ulcerations 
2 
 
Pleurisy 
Pleuritic chest pain or pleural rub with effusion 
or pleural thickening . 
2 
 
Pericarditis 
Classic pericardial pain and/or rub effusion with 
ECG confirmation 
2 
 
Low 
complement 
Decrease in CH50, C3, or C4 < lower limit of nl 
for testing laboratory 
2 
 
Increased DNA 
binding 
Increased DNA binding above normal range for 
testing laboratory 
1 
 
Fever 
> 38 °C. Exclude infectious cause 
1 
 
Thrombocytope
nia 
< 100 x 109 platelets / L, exclude drug causes. 
1 
 
Leukopenia 
< 3 x 109 WBC/L, exclude drug causes 
 
 
BILAG-2004 Index Form 


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BILAG-2004 INDEX SCORING 
 
    
 scoring based on the principle of physician’s intention to treat 
 
Category 
 
 
Definition 
 
 
A 
Severe disease activity requiring any of the following treatment: 
1. systemic high dose oral glucocorticoids (equivalent to 
prednisolone > 20 mg/day) 


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2. intravenous pulse glucocorticoids (equivalent to pulse 
methylprednisolone ≥ 500 mg) 
3. systemic immunomodulators (include biologicals, 
immunoglobulins and plasmapheresis) 
4. therapeutic high dose anticoagulation in the presence of high 
dose steroids or immunomodulators  
e.g.: warfarin with target INR 3 - 4 
 
B 
 
Moderate disease activity requiring any of the following treatment: 
1. systemic low dose oral glucocorticoids (equivalent to 
prednisolone ≤ 20 mg/day) 
2. intramuscular or intra-articular or soft tissue glucocorticoids 
injection (equivalent to methylprednisolone < 500mg) 
3. topical glucocorticoids 
4. topical immunomodulators 
5. antimalarials or thalidomide or prasterone or acitretin 
6. symptomatic therapy 
      e.g.: NSAIDs for inflammatory arthritis 
 
C 
 
Mild disease 
 
D 
 
 
Inactive disease but previously affected 
 
 
E 
 
System never involved 
BILAG Constitutional Scoring Algorithm 
Grade 
Criteria 
A 
1. Pyrexia recorded as 2 (same), 3 (worse) or 4 (new) AND  
2. Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 
(new): 
a) Weight loss 
b) Lymphadenopathy/splenomegaly 
c) Anorexia 
 
B 
1. Pyrexia recorded as 2 (same), 3 (worse) or 4 (new) OR  
2. Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 
(new): 
a) Weight loss 
b) Lymphadenopathy/splenomegaly 
c) Anorexia 
3. BUT do not fulfil criteria for Category A 
 
C 
1. Pyrexia recorded as 1 (improving) OR 
2. One or more of the following recorded as > 0:  
a) Weight loss 
b) Lymphadenopathy/Splenomegaly 
c) Anorexia 


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3. BUT does not fulfil criteria for category A or B 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
BILAG Mucocutaneous Scoring Algorithm 
Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Skin eruption - severe  
b) Angio-oedema - severe 
c) Mucosal ulceration - severe 
d) Panniculitis/Bullous lupus - severe 
e) Major cutaneous vasculitis/thrombosis 
B 
1. Any Category A features recorded as 1 (improving) OR  
2. Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
1. Skin eruption - mild 
2. Panniculitis/Bullous lupus - mild 
3. Digital infarcts or nodular vasculitis 
4. Alopecia - severe 
C 
a) Any Category B features recorded as 1 (improving) OR 
b) Any of the following recorded as > 0: 
a) Angio-oedema - mild 
b) Mucosal ulceration - mild 
c) Alopecia - mild 
d) Periungual erythema/chilblains 
e) Splinter haemorrhages 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
BILAG Neuropsychiatric Scoring Algorithm 
Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
1. Aseptic meningitis 
2. Cerebral vasculitis 
3. Demyelinating syndrome 
4. Myelopathy 
5. Acute confusional state 
6. Psychosis 
7. Acute inflammatory demyelinating polyradiculoneuropathy 
8. Mononeuropathy (single/multiplex) 
9. Cranial neuropathy 
10. Plexopathy 


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11. Polyneuropathy 
12. Status epilepticus 
13. Cerebellar ataxia 
B 
a) Any Category A features recorded as 1 (improving) OR 
b) Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Seizure disorder  
b) Cerebrovascular disease (not due to vasculitis) 
c) Cognitive dysfunction 
d) Movement disorder 
e) Autonomic disorder  
f) Lupus headache - severe unremitting 
g) Headache due to raised intracranial hypertension 
C 
Any Category B features recorded as 1 (improving) 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
 
BILAG Musculoskeletal Scoring Algorithm 
Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Severe Myositis 
b) Severe Arthritis 
B 
1. Any Category A features recorded as 1 (improving) OR 
2. Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Mild Myositis 
b) Moderate Arthritis/Tendonitis/Tenosynovitis 
C 
1. Any Category B features recorded as 1 (improving) OR  
2. Any of the following recorded as > 0: 
a) Mild Arthritis/Arthralgia/Myalgia 
 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes)  
E 
No previous involvement 
Missing 
 
 
BILAG Cardiorespiratory Scoring Algorithm 
Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Myocarditis/Endocarditis + Cardiac failure 
b) Arrhythmia 
c) New valvular dysfunction 


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d) Cardiac tamponade 
e) Pleural effusion with dyspnoea 
f) Pulmonary haemorrhage/vasculitis  
g) Interstitial alveolitis/pneumonitis  
h) Shrinking lung syndrome 
i) 
Aortitis 
j) 
Coronary vasculitis 
B 
1. Any Category A features recorded as 1 (improving) OR  
2. Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Pleurisy/Pericarditis 
b) Myocarditis - mild 
C 
Any Category B features recorded as 1 (improving) 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
 
BILAG Gastrointestinal Scoring Algorithm 
Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Peritonitis 
b) Lupus enteritis/colitis 
c) Intestinal pseudo-obstruction  
d) Acute lupus cholecystitis 
e) Acute lupus pancreatitis 
 
B 
1. Any Category A feature recorded as 1 (improving) OR 
2. Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Abdominal serositis and/or ascites  
b) Malabsorption 
c) Protein losing enteropathy 
d) Lupus hepatitis 
 
C 
Any Category B features recorded as 1 (improving)  
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
 
BILAG Ophthalmic Scoring Algorithm 


Product:  Efavaleukin Alfa 
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Grade 
Criteria 
A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Orbital inflammation/myositis/proptosis 
b) Keratitis - severe 
c) Posterior uveitis/retinal vasculitis - severe 
d) Scleritis - severe 
e) Retinal/choroidal vaso-occlusive disease 
f) Optic neuritis 
g) Anterior ischaemic optic neuropathy  
B 
1. Any Category A features recorded as 1 (improving) OR  
2. Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
a) Keratitis - mild 
b) Anterior uveitis 
c) Posterior uveitis/retinal vasculitis - mild 
d) Scleritis - mild 
C 
1. Any Category B features recorded as 1 (improving) OR  
2. Any of the following recorded as > 0: 
a) Episcleritis 
b) Isolated cotton-wool spots (cystoid bodies) 
 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
 
BILAG Renal Scoring Algorithm 
Grade 
Criteria 
A 
Two or more of the following providing 1, 4 or 5 is included: 
1. Deteriorating proteinuria (severe) defined as   
a) urine dipstick increased by ≥ 2 levels (used only if other methods of 
urine protein estimation not available); or  
b) 24-hour urine protein > 1 g that has not decreased (improved) by  
25%; or 
c) urine protein-creatinine ratio > 100 mg/mmol that has not decreased 
(improved) by  25%; or 
d) urine albumin-creatinine ratio > 100 mg/mmol that has not 
decreased (improved) by  25% 
2. Accelerated hypertension  
3. Deteriorating renal function (severe) defined as  
a) plasma creatinine > 130 mol/l and having risen to > 130% of 
previous value; or  
b) GFR < 80 ml/min per 1.73 m2 and having fallen to < 67% of 
previous value; or  
c) GFR < 50 ml/min per 1.73 m2, and last time was > 50 ml/min per 
1.73 m2 or was not measured. 


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4. Active urinary sediment 
5. Histological evidence of active nephritis within last 3 months  
6. Nephrotic syndrome 
B 
One of the following: 
1. One of the Category A feature 
2. Proteinuria (that has not fulfilled Category A criteria) 
a) urine dipstick which has risen by 1 level to at least 2+ (used only if 
other methods of urine protein estimation not available); or 
b) 24-hour urine protein ≥ 0.5 g that has not decreased (improved) by 
 25%; or 
c) urine protein-creatinine ratio ≥ 50 mg/mmol that has not decreased 
(improved) by  25%; or 
d) urine albumin-creatinine ratio ≥ 50 mg/mmol that has not decreased 
(improved) by  25% 
3. Plasma creatinine > 130 mol/l and having risen to ≥ 115% but ≤ 130% 
of previous value 
C 
One of the following: 
1. Mild/Stable proteinuria defined as 
a) urine dipstick ≥ 1+ but has not fulfilled criteria for Category A & B 
(used only if other methods of urine protein estimation not 
available); or 
b) 24 hour urine protein > 0.25 g but has not fulfilled criteria for 
Category A & B; or 
c) urine protein-creatinine ratio > 25 mg/mmol but has not fulfilled 
criteria for Category A & B; or  
d) urine albumin-creatinine ratio > 25 mg/mmol but has not fulfilled 
criteria for Category A & B 
2. Rising blood pressure (providing the recorded values are > 140/90 mm 
Hg) which has not fulfilled criteria for Category A & B, defined as 
a) systolic rise of ≥ 30 mm Hg; and  
b) diastolic rise of ≥ 15mm Hg 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous involvement 
Missing 
 
Since the urine albumin-creatinine ratio and 24-hour urine protein are not collected in 
this study, the criteria for BILAG proteinuria will be based on urine dipstick and urine 
protein-creatinine ratio only. 
 
BILAG Hematological Scoring Algorithm 
Grade 
Criteria 
A 
1. TTP recorded as 2 (same), 3 (worse) or 4 (new) or 
2. Any of the following: 
a) Evidence of haemolysis and Haemoglobin < 8 g/dl 


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b) Platelet count < 25 x 109/l 
B 
1. TTP recorded as 1 (improving) or 
2. Any of the following:  
a) Evidence of haemolysis and Haemoglobin 8 - 9.9 g/dl 
b) Haemoglobin  < 8 g/dl (without haemolysis) 
c) White cell count < 1.0 x 109/l 
d) Neutrophil count < 0.5 x 109/l 
e) Platelet count  25 - 49 x 109/l 
C 
Any of the following: 
a) Evidence of haemolysis and Haemoglobin ≥ 10g/dl 
b) Haemoglobin   8 - 10.9 g/dl (without haemolysis) 
c) White cell count  
1 - 3.9 x 109/l 
d) Neutrophil count  
0.5 - 1.9 x 109/l 
e) Lymphocyte count  
< 1.0 x 109/L 
f) Platelet count  
50 - 149 x 109/l 
g) Isolated Coombs’ test positive 
D 
Previous involvement (i.e. A, B, C or D domain grade at any previous visits 
or domain previous involvement is yes) 
E 
No previous Involvement. 
Missing 
 
 
LLDAS 
Criteria 
Derivation 
HSLEDAI ≤ 4 with no activity in major 
organ systems (renal, CNS, 
cardiopulmonary, vasculitis, fever) 
HSLEDAI score ≤ 4 
proteinuria, haematuria, pyuria, urinary 
casts, seizure, psychosis, organic brain 
syndrome, cranial nerve disorder, CVA, 
pericarditis, pleurisy, vasculitis and fever 
in hSLEDAI are marked ‘not present'  
 
No new lupus activity compared with the 
previous assessment 
No new ‘present’ hSLEDAI descriptors 
compared to previous visit 
PGA ≤ 1 
PGA ≤ 1 


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Current prednisolone (or equivalent) 
dose ≤ 7.5 mg/day 
Prednisone equivalent is ≤ 7.5 mg/day at 
the visit 
Standard maintenance doses of 
immunosuppressive drugs and 
approved biological agents (i.e. no 
increase or initiation of 
immunosuppressive drugs.) 
No new or increase in 
immunosuppressant at the visit 
 
 
 


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Appendix C.  Patient-reported Outcome Forms/Instruments 
C1. SF-36 Version 2 
SF-36 items will be scored using the SF-36 version 2.0 Quality Metric Health Outcome 
Scoring Software (Ware et al, 2007). 
C2. Scoring algorithm for PROMIS Fatigue SF 7A 
PROMIS SF v1.0 – Fatigue 7A will be scored according to the PROMIS Fatigue Brief 
Guide including the scoring in the Instrument Section downloaded from  
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_M
anual.pdf on 28 Feb 2019. 
To calculate the score for PROMIS Fatigue SF 7A, sum the values of the 
responses to each of the 7 questions. The lowest and highest possible sum is 7 
and 35, respectively. Then, use the table below to rescale the score into a 
standardize score with a mean of 50 and a standard deviation of 10. 
Conversion Table 
Raw score 
T-score 
7 
29.4 
8 
33.4 
9 
36.9 
10 
39.6 
11 
41.9 
12 
43.9 
13 
45.8 
14 
47.6 
15 
49.2 
16 
50.8 
17 
52.2 
18 
53.7 
19 
55.1 
20 
56.4 
21 
57.8 
22 
59.2 
23 
60.6 
24 
62.0 
25 
63.4 


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26 
64.8 
27 
66.3 
28 
67.8 
29 
69.4 
30 
71.1 
31 
72.9 
32 
74.8 
33 
77.1 
34 
79.8 
35 
83.2 
 
C3. Scoring algorithm for Modified LupusQoL 
The LupusQoL will be scored using the scoring algorithm from the RWS Life Science 
website accessed 10 April 2020. http://www.corptransinc.com/sites/lupusqol/instrument-
information/instrument-scoring 
To compute the LupusQOL raw domain score, sum the values of the responses to 
each question by domain based on the tables below and divide by the number of 
items. Then, transform the raw domain score by dividing by 4 and multiplying by 
100. 
Item 
Respons
All the 
time 
Most of the 
time 
A good bit 
of the time 
Occasionally 
Never 
Not 
applicable 
Score 
0 
1 
2 
3 
4 
Do not 
score 
 
Domain 
Number of Items 
Item Numbers 
Physical Health 
8 
1-8 
Pain 
3 
9-11 
Planning 
3 
12-14 
Intimate Relationship 
2 
15, 16 
Burden to Others 
3 
17-19 
Emotional Health 
6 
20-25 
Body Image 
5 
36-30 
Fatigue 
4 
31-34 
 


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C4. Scoring algorithm for Patient Global Assessment 
The Patient Global Assessment is a 10 cm visual analog scale with 0 being very well 
and 10 very poor. The score on this instrument is taken directly from the mark made by 
the patient on the VAS. 
 
 


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Appendix D.  Analytical Windows 
The last measurement for the endpoint of interest taken prior to or on the first dose of IP 
in this study, unless stated otherwise, will be defined as a baseline visit and the analysis 
visit name will be 'Baseline'. For any visit up to Day 1 pre-dose which is not a baseline 
visit, the analysis visit will be 'Pre-analysis'. 
Since the actual visit for a subject may not exactly coincide with their scheduled visit 
date, to allow for variations in scheduling, the following visit windows will be used to 
assign evaluations to a most appropriate nominal visit for analysis and summarization. 
Furthermore, there will be no gaps between visit windows in order to include as many 
data points as possible for summarization.  
If more than one actual visit (including the unscheduled visits) falls within the same 
defined window, the visit closest to the target day with non-missing data will be 
considered for analysis. If two actual visit dates are at the same distance from the target 
day, the latest visit with non-missing data will be considered for analysis.  
The rules above for selecting a visit from multiple ones within the same visit window are 
not applicable to retest values of lab data. If the lab measurement is a retest, the retest 
value will be used.  
Efficacy assessment (tender/swollen joint count, hSLEDAI, BILAG, 
, PGA VAS, PGA 4-Point Verbal Rating Scale, CLASI), weight, 
and laboratory assessment (anti-dsDNA, C3 and C4 complement, chemistry, 
urinalysis) 
Study Visit 
Target Day 
Study Day 
Baseline 
1 
Last evaluation prior to or on Study Day 1 
Week 4 
29 
2 - 42 
Week 8 
57 
43 - 70 
Week 12 
85 
71 - 98 
Week 16 
113 
99 - 126 
Week 20 
141 
127 - 154 
Week 24 
169 
155 - 182 
Week 28 
197 
183 - 210 


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Week 32 
225 
211 - 238 
Week 36 
253 
239 - 266 
Week 40 
281 
267 - 294 
Week 44 
309 
295 - 322 
Week 48 
337 
323 - 350 
Week 52 
365 
351 - 394 
Hematology 
Study Visit 
Target Day 
Study Day 
Baseline 
1 
Last evaluation prior to or on Study Day 1 
Week 4 
29 
2 - 42 
Week 8 
57 
43 - 70 
Week 12 
85 
71 - 98 
Week 16 
113 
99 - 126 
Week 20 
141 
127 - 154 
Week 24 
169 
155 - 182 
Week 28 
197 
183 - 210 
Week 32 
225 
211 - 238 
Week 36 
253 
239 - 266 
Week 40 
281 
267 - 294 
Week 44 
309 
295 - 322 
Week 48 
337 
323 - 350 
Week 52 
365 
351 - 378 
Week 56 
393 
≥ 379 
Vital sign 
Study Visit 
Target Day 
Study Day 


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Baseline 
1 
Last evaluation prior to or on Study Day 1 
Week 2 
15 
2 - 21 
Week 4 
29 
22 - 35 
Week 6 
43 
36 - 49 
Week 8 
57 
50 - 63 
Week 10 
71 
64 - 77 
Week 12 
85 
78 - 91 
Week 14 
99 
92 - 105 
Week 16 
113 
106 - 119 
Week 18 
127 
120 - 133 
Week 20 
141 
134 - 147 
Week 22 
155 
148 - 161 
Week 24 
169 
162 - 175 
Week 26 
183 
176 - 189 
Week 28 
197 
190 - 203 
Week 30 
211 
204 - 217 
Week 32 
225 
218 - 231 
Week 34 
239 
232 - 245 
Week 36 
253 
246 - 259 
Week 38 
267 
260 - 273 
Week 40 
281 
274 - 287 
Week 42 
295 
288 - 301 
Week 44 
309 
302 - 315 
Week 46 
323 
316 - 329 
Week 48 
337 
330 - 343 
Week 50 
351 
344 - 357 


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Week 52 
365 
358 - 378 
Week 56 
393 
≥ 379 
Anti-phospholipid antibodies 
Study Visit 
Target Day 
Study Day 
Baseline 
1 
Last evaluation prior to or on Study Day 1 
Week 24 
169 
2 - 266 
Week 52 
365 
267 - 378 
SF-36v2, PROMIS Fatigue SF 7A, LupusQoL 
Study Visit 
Target Day 
Study Day 
Baseline 
1 
Last evaluation prior to or on Study Day 1 
Week 4 
29 
2 - 56 
Week 12 
85 
57 - 98 
Week 24 
169 
99 - 210 
Week 36 
253 
211 - 308 
Week 52 
365 
309 - 394 


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Protocol Number:  20200234 
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Product:  Efavaleukin Alfa 
Protocol Number:  20200234 
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Appendix E.  Handling of Dates, Incomplete Dates and Missing Dates 
The reference date for the following rules is the date of first dose efavaleukin alfa. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose or the randomization date if not treated; 2=Impute the first of the month; 
3=Impute January 1 of the year; 4=Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date.