Clinical trial NCT05540665
Conditions: Lupus Nephritis
Sponsor: Amgen
Start date: 2023-04-26; Completion date: 2024-01-04
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of daxdilimab in patients with active, proliferative lupus nephritis (LN).

Detailed description:
Approximately 210 participants will be randomized to receive daxdilimab or placebo administered subcutaneously through Week 52 in addition to their standard of care background therapy (mycophenolate mofetil (MMF) and corticosteroids). At Week 64, all participants will be assigned to a quarterly dosing maintenance regimen of either daxdilimab or placebo based upon pre-defined renal response observed by Week 52. The maximum trial duration per participant is approximately 116 weeks including a 4-week screening period, the 104 weeks for the treatment period where participants will receive daxdilimab or placebo, and approximately 8 weeks for the follow-up period. Safety evaluations will be performed regularly throughout the course of the study.

Acquired from Horizon in 2024.

Arms: arm 1: Daxdilimab injections over a total of 104 weeks arm 2: Daxdilimab injections over a total of 104 weeks arm 3: Placebo injections over a total of 104 weeks
Interventions: intervention 1: Daxdilimab intervention 2: Daxdilimab intervention 3: Placebo (Normal Saline)
Intervention descriptions: intervention 1: Daxdilimab will be administered subcutaneously as two injections for each dose.

Other Names: HZN-7734 intervention 2: Daxdilimab will be administered subcutaneously as two injections for each dose.

Other Names: HZN-7734 intervention 3: Placebo will be administered subcutaneously as two injections for each dose.

Protocol documents:
Prot_000.pdf: 
Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
Page 1 of 118 
TITLE PAGE 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE 2 STUDY EVALUATING THE 
EFFICACY AND SAFETY OF DAXDILIMAB IN ADULT PARTICIPANTS 
WITH ACTIVE PROLIFERATIVE LUPUS NEPHRITIS 
PROTOCOL HZNP-DAX-203 
Investigational New Drug (IND) Number: 127898 
EudraCT Number: 2022-001377-31 
VERSION 2.0 
17 MAY 2022 
Sponsor: 
Horizon Therapeutics Ireland DAC 
70 St. Stephen’s Green  
Dublin 2, Ireland  
D02 E2X4 
Sponsor Medical Expert: 
, MD, MSc  
, Clinical Development  
Horizon Therapeutics  
2400 Research Blvd  
Rockville, MD 20850  
Telephone: 857-498-0977  
    
Sponsor Signatory: 
, PhD  
, Biostatistics, Biometrics  
Horizon Therapeutics  
2400 Research Blvd  
Rockville, MD 20850  
Telephone: 240-972-6134   
  
Clinical Research Organization: 
PPD Development, LP 
929 North Front Street 
Wilmington, NC 28401 
 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
Page 2 of 118 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................... 14 
1.1. 
Synopsis ........................................................................................................................ 14 
1.2. 
Schema .......................................................................................................................... 29 
1.3. 
Schedule of Activities (SoA) ........................................................................................ 30 
2. 
INTRODUCTION ........................................................................................................... 38 
2.1. 
Background ................................................................................................................... 38 
2.1.1. 
Trial Rationale ........................................................................................................... 40 
2.2. 
Risk/Benefit Assessment .............................................................................................. 41 
2.2.1. 
Known Potential Risks ............................................................................................... 41 
2.2.2. 
Known Potential Benefits .......................................................................................... 42 
2.2.3. 
Overall Benefit Risk Conclusion ............................................................................... 42 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................. 43 
4. 
STUDY DESIGN............................................................................................................. 48 
4.1. 
Overall Design .............................................................................................................. 48 
4.2. 
Scientific Rationale for Study Design........................................................................... 50 
4.3. 
Justification for Dose .................................................................................................... 50 
4.4. 
End-of-Study Definition ............................................................................................... 51 
5. 
STUDY POPULATION .................................................................................................. 52 
5.1. 
Inclusion Criteria .......................................................................................................... 52 
5.2. 
Exclusion Criteria ......................................................................................................... 54 
5.3. 
Restrictions ................................................................................................................... 58 
5.3.1. 
Fasting Lipid Profile .................................................................................................. 58 
5.3.2. 
Perioperative Management of Investigational Product .............................................. 58 
5.3.3. 
Major Surgeries .......................................................................................................... 58 
5.3.4. 
Non-Major Surgeries ................................................................................................. 59 
5.3.5. 
Blood Donation .......................................................................................................... 59 
5.4. 
Screen Failures .............................................................................................................. 59 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ............................. 60 
6.1. 
Study Interventions Administered ................................................................................ 60 
6.2. 
Preparation, Handling, Storage, and Accountability .................................................... 61 
6.2.1. 
Preparation and Administration ................................................................................. 61 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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6.2.2. 
Labeling ..................................................................................................................... 61 
6.2.3. 
Storage ....................................................................................................................... 62 
6.2.4. 
Drug Accountability................................................................................................... 62 
6.3. 
Assignment to Study Intervention ................................................................................ 62 
6.4. 
Blinding/Masking ......................................................................................................... 63 
6.5. 
Treatment Compliance .................................................................................................. 63 
6.6. 
Treatment of Overdose ................................................................................................. 63 
6.7. 
Prior and Concomitant Therapy .................................................................................... 64 
6.7.1. 
Concomitant Medications .......................................................................................... 64 
6.7.2. 
Prohibited Medications .............................................................................................. 64 
6.7.3. 
Restricted Medications............................................................................................... 65 
6.7.4. 
Permitted Therapies ................................................................................................... 65 
6.7.5. 
Other Concomitant Medications ................................................................................ 70 
6.7.6. 
Rescue Medicine ........................................................................................................ 72 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................................ 73 
7.1. 
Discontinuation ............................................................................................................. 73 
7.1.1. 
Discontinuation of Study Intervention ....................................................................... 73 
7.1.2. 
Discontinuation from the Trial ................................................................................... 75 
7.1.3. 
Withdrawal of Consent from the Trial ....................................................................... 75 
7.2. 
Lost to Follow-Up ......................................................................................................... 76 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 77 
8.1. 
Efficacy Assessments.................................................................................................... 77 
8.1.1. 
Training and Certification for Systemic Lupus Erythematosus Assessments ........... 79 
 
 
 
 
8.1.4. 
Renal Biopsy .............................................................................................................. 82 
8.2. 
Safety Assessments ....................................................................................................... 83 
8.2.1. 
Physical Examinations ............................................................................................... 83 
8.2.2. 
Vital Signs .................................................................................................................. 83 
8.2.3. 
Electrocardiograms .................................................................................................... 84 
 
 
8.2.5. 
Local Injection Site Assessment ................................................................................ 85 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ...................................................................................................................... 85 
8.3.1. 
Definitions.................................................................................................................. 85 
8.3.2. 
Classification of an Adverse Event ............................................................................ 87 
8.3.3. 
Time Period and Frequency for Event Assessment and Follow-Up .......................... 88 
8.3.4. 
Adverse Event Reporting ........................................................................................... 89 
8.3.5. 
Serious Adverse Event Reporting .............................................................................. 89 
8.3.6. 
Pregnancy Reporting .................................................................................................. 89 
8.3.7. 
Overdose .................................................................................................................... 90 
8.4. 
Pharmacokinetics .......................................................................................................... 90 
 
 
 
 
 
 
8.8. 
Immunogenicity Assessments ....................................................................................... 92 
9. 
STATISTICAL CONSIDERATIONS............................................................................. 93 
9.1. 
Statistical Hypotheses ................................................................................................... 93 
9.2. 
Sample Size Determination........................................................................................... 93 
9.3. 
Analysis Sets ................................................................................................................. 93 
9.4. 
Statistical Analyses ....................................................................................................... 93 
9.4.1. 
General Considerations .............................................................................................. 93 
9.4.2. 
Primary Endpoint Analysis ........................................................................................ 94 
9.4.3. 
Secondary Endpoints Analysis .................................................................................. 94 
9.4.4. 
 
9.4.5. 
Handling Plan for Missing Data: ............................................................................... 96 
9.4.6. 
Safety Analyses .......................................................................................................... 96 
9.4.7. 
Pharmacokinetic Analyses ......................................................................................... 96 
9.4.8. 
/Immunogenicity Analyses........................................................... 96 
9.4.9. 
Planned Analyses ....................................................................................................... 97 
10. 
REGULATORY, ETHICAL, AND TRIAL OVERSIGHT CONSIDERATIONS......... 98 
10.1. 
Local Regulations/Declaration of Helsinki ................................................................... 98 
10.2. 
Ethical Review .............................................................................................................. 98 
10.3. 
Informed Consent Process ............................................................................................ 98 
10.4. 
Trial Discontinuation and Closure ................................................................................ 99 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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10.5. 
Confidentiality and Privacy .......................................................................................... 99 
10.6. 
Clinical Monitoring ..................................................................................................... 100 
10.7. 
Quality Assurance and Quality Control ...................................................................... 100 
10.8. 
Data Handling and Record Keeping ........................................................................... 100 
10.9. 
Biological Specimens and Data .................................................................................. 101 
10.10. 
Protocol Deviations ..................................................................................................... 101 
10.11. 
Publication Policy ....................................................................................................... 102 
11. 
REFERENCES .............................................................................................................. 103 
12. 
APPENDIX .................................................................................................................... 108 




Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), and applicable local regulations. The 
Principal Investigator will assure that no planned deviation from, or changes to the protocol will 
take place without prior agreement from the Sponsor and documented approval from the 
institutional review board (IRB)/research ethics board (REB), except where necessary to eliminate 
an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed ICH GCP training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/REB for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the protocol 
will require review and approval by the IRB/REB before the changes are implemented to the study. 
All changes to the consent form will be IRB/REB approved. 
 
 




Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
Investigator Name: 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
(DD-MMM-YYYY) 
 
Institution Name: 
 
 
 
 
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with the protocol, informed consent, institutional 
review board/independent ethics committee procedures, instructions from Sponsor’s 
representatives, ICH GCP guidelines, and applicable local regulations governing the conduct 
of clinical studies. 
 
 
 










Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Protocol Title:  
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Evaluating the Efficacy and 
Safety of Daxdilimab in Adult Participants with Active Proliferative Lupus Nephritis 
Phase of Development:  
Phase 2 
Trial Center(s):  
This multicenter trial will be conducted at approximately 105 trial centers internationally.  
Target Population:  
Adults aged ≥ 18 to ≤ 80 years who have documented active, proliferative lupus nephritis (LN). 
Number of Participants (planned):  
The trial is planned to enroll approximately 210 participants. Participants will be randomized to 3 treatment 
groups, with approximately 70 participants to each treatment group. 
Duration of Trial: 
 
The maximum trial duration per participant is approximately 116 weeks, as follows: 
 
Screening Period: approximately 4 weeks (Days -28 to -1) 
 
Treatment Period: 104 weeks 
 
Safety Follow-Up (SFU) Period: 8 weeks (12 weeks after the last study intervention 
administration at Week 100) 
Investigational Product [IP], Dosage, and Mode of Administration:  
Randomized participants will receive either daxdilimab 
 mg or 
mg administered subcutaneously 
(SC) as 
 
 
At 
, all participants will be assigned to a 
 based upon the 
renal response observed at 
 All participants, regardless of treatment assignment, who are 
unable to achieve at least a 
 
 
 in addition to SOC therapy. Participants who achieve at 
least a 
 and were randomized to 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
daxdilimab treatment with either 
 
 
 in addition to SOC therapy. 
Further guidance and information for the packaging, labeling, preparation, and administration of the 
Investigational Product are provided in the Pharmacy Manual. 
Reference therapy, dosage, and mode of administration:  
Placebo will be procured as commercially available Normal Saline and will be administered SC to 
randomized participants at baseline, 
 
in addition to SOC therapy. 
At 
 participants who were originally assigned to treatment with placebo and achieved at least a 
 
 in addition to SOC therapy. 
Further guidance and information for the packaging, labeling, preparation, and administration of the placebo 
are provided in the Pharmacy Manual. 
Stratification: 
Randomization will be stratified by: 
 
Pre-randomization urine protein to creatinine ratio (UPCR) < 3.0 mg/mg vs. ≥ 3.0 mg/mg 
 
Screening estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 vs. 
≥ 60 mL/min/1.73m2  
Objectives and Endpoints: 
Primary Objective and Endpoint 
Primary Objective 
Primary Endpoint 
To evaluate the efficacy of 
daxdilimab in combination 
with SOC compared to 
placebo in combination with 
SOC in participants with 
active, proliferative LN. 
Proportion of participants achieving CRR at 
 
 
CRR is defined as meeting all of the following: 
 
eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below 
baseline 
 
24-hour UPCR ≤ 0.5 mg/mg  
 
No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
 
Secondary Objectives and Endpoints 
 Secondary Objectives 
Secondary Endpoints 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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To assess ORR (defined as 
CRR plus PRR) with 
daxdilimab versus placebo in 
participants with active, 
proliferative LN. 
 
 
Proportion of participants achieving ORR at 
 
 
See above for definition of CRR. PRR is defined as meeting all of 
the following: 
 
eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below 
baseline 
 
Improvement in 24-hour UPCR:  
 
For participants with a baseline UPCR ≤ 3.0 mg/mg: < 1.0 
mg/mg 
 
For participants with a baseline UPCR > 3.0 mg/mg: > 50% 
improvement from baseline and ≤ 3.0 mg/mg 
 
No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
To assess the change from 
baseline in eGFR with 
daxdilimab versus placebo in 
participants with active, 
proliferative LN. 
 
Change from baseline in eGFR at Week 52. 
To evaluate the ability to 
improve dose requirements 
of oral corticosteroids (OCS) 
with daxdilimab versus 
placebo in participants with 
active, proliferative LN. 
Proportion of participants able to taper OCS to ≤ 2.5 mg/day 
prednisone-equivalent by Week 24 and maintain this dose through 
Week 52. 
Sustained reduction of OCS dose: 
 
Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and not 
exceeding this dose through Week 52, and 
 
No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
To characterize the 
pharmacokinetics (PK) and 
immunogenicity of 
daxdilimab in participants 
with active, proliferative LN. 
 
Serum concentration of daxdilimab.  
 
Rate of anti-drug antibodies (ADA) directed against 
daxdilimab and ADA titer for the duration of the study. 
To evaluate the safety and 
tolerability of daxdilimab in 
combination with SOC in 
participants with active, 
proliferative LN. 
 
Incidence of treatment-emergent adverse events (TEAEs). 
 
Incidence of treatment-emergent serious adverse events 
(TESAEs). 
 
Incidence of treatment-emergent AEs of special interest 
(TEAESIs): hypersensitivity reaction, including anaphylaxis, 
severe (Grade 3 or higher) viral infection/reactivation, herpes 
zoster, opportunistic infection, and malignancy (except 
non-melanoma skin cancer). 
 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Adjudication Committees and Data Monitoring Committee: 
Adjudication Committee 
An external Renal Pathology Adjudication Committee will evaluate 
the qualifying renal biopsies post-randomization and post-treatment 
biopsies to confirm the validity of local readings for the major 
classes of LN (ie, III, IV, and V) and to provide uniform, 
high-quality readings of more detailed assessments of the biopsies 
to better understand the relationship between histological findings 
and renal response in the study. 
Data Monitoring Committee 
An external, independent Data Safety Monitoring Board (DSMB) 
will evaluate safety data at regular intervals throughout the study 
and make recommendations to the Sponsor as needed. 
 
 
 
 
 This futility analysis is designed to be non-binding, so 
the DSMB may elect not to recommend terminating the trial after 
considering all of the data, even if the pre-specified futility criteria 
is met. 
Trial Design 
This trial is a Phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial to 
assess the efficacy and safety of daxdilimab in patients with active, proliferative LN despite standard of 
care. An overview of the trial design is presented in the schematic provided in Section 1.2 and details of 
trial activities are provided in Section 1.3. 
Approximately 210 participants will be randomized in a ratio of 1:1:1 (70 participants per group) to 
receive either daxdilimab SC or placebo SC in addition to SOC background therapy as described below: 
Group Treatment 
1 
2 
3 
At 
 participants from all three Treatment Groups (above) will be assigned to a 
 
regimen based upon the renal response observed at 
 described below: 
Group Treatment 
1 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Participants may enter the study taking daily OCS at a maximum dose of 0.5 mg/kg/day of prednisone-
equivalent, not to exceed 40 mg/day, and must be on a stable dose for at least 10 days prior to 
Randomization. In addition, participants will receive IV methylprednisolone pulse 500 mg on the day of 
Randomization, prior to receiving the study intervention, unless they received a methylprednisolone pulse 
of ≥ 500 mg within 10 days prior to Randomization followed by a reducing taper of OCS for participants 
already taking OCS prior to entry. For participants who are not already taking prescribed mycophenolate 
mofetil (MMF) prior to Randomization, the dosing of MMF will start at 500 mg twice a day (BID) for a 
total daily dose of 1 gm/day for the first week, increasing to 1 gm BID for a total daily dose of 2 gm/day 
for the second and subsequent weeks (ie, beginning on Day 8). An equivalent dose of mycophenolic acid 
(MPA) may be used as an alternative to MMF. 
The trial will comprise a Screening Period of approximately 4 weeks (Days -28 to -1), a Treatment Period 
with Randomization on Day 1 followed by treatment through 
 (
 
 totaling 19 administrations for all Treatment Groups with assignment of a 
 
maintenance regimen at 
 based upon the 
 and a SFU 
Period of 8 weeks (through Week 112). Under exceptional circumstances such as delayed laboratory 
results, drug washout, or the impact of Coronavirus Disease 2019 (COVID-19), the Screening Period may 
be increased by 2 weeks, upon approval by the Medical Monitor. In general, re-screening of participants 
may occur only in consultation with and approval by the Medical Monitor. The trial will be conducted on 
an outpatient basis. For all administrations, study intervention will be administered by site staff in the 
clinic and the participant will be observed for at least 60 minutes after the first three doses as well as at 
 Participants who prematurely 
 will be followed for regularly 
scheduled visits through 
 after the last study intervention 
administration, whichever is longer, unless participants withdraw consent of trial participation or are lost 
to follow-up. Participants should be followed to assess AE/SAEs for at least 12 weeks after the last study 
intervention administration, approximately 4, 8, and 12 weeks after the last study intervention dose, unless 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
the participant withdraws consent. Participants who prematurely stop dosing after
 but remain in 
the study will be complete the End-of-Treatment (EOT) Visit and the SFU Period, unless the participant 
withdraws consent. Participants will not automatically be removed from the trial if any administration of 
study intervention is missed.  
Rescue therapy for worsening LN may be administered at the discretion of Investigators as clinically 
indicated. Rescue therapy includes the initiation of any new treatment for lupus or LN or an increase from 
baseline in the SOC background therapy (MMF/MPA or corticosteroids). For any rescue medications, 
study intervention may be continued after discussion with and approval by the Horizon Medical Monitor. 
However, if the participant receives a prohibited medication as a rescue, study intervention will be 
discontinued (See Section 6.7.2). Participants who receive rescue therapy will be considered treatment 
failures for subsequent endpoint analyses (such as CRR). 
The primary assessment of the efficacy endpoints will be performed at 
. The final 
evaluation of the double-blind Treatment Period will occur at 
. The SFU Period will begin after 
completion of the
 EOT Visit and will last for 8 weeks. All participants will continue to receive 
SOC immunosuppressive background therapy with MMF/MPA and OCS, unless the participant has 
successfully discontinued OCS. Participants will continue to follow all trial requirements and will return 
to the clinical site for the Week 112 End-of-Study Visit for final safety assessments, as described in the 
Schedule of Activities, and return all remaining trial-related supplies not previously returned. 
Safety assessments, including monitoring and recording of all AEs, whether or not drug-related, 
measurement of vital signs, physical examinations, and monitoring of hematology and blood chemistry, 
will be performed. 
Inclusion/Exclusion Criteria: 
All participants must meet/provide all of the following criteria to be eligible for trial participation: 
1. Written informed consent and any locally required authorization (eg, Health Insurance Portability 
and Accountability Act [HIPAA] in the United States) obtained from the participant prior to 
performing any protocol-related procedures, including screening evaluations. 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 
3. Adult men or women ≥ 18 and ≤ 80 years of age. 
4. Fulfill the 2019 European League Against Rheumatism/American College of Rheumatology 
Classification Criteria for systemic lupus erythematosus (SLE) (Aringer et al, 2019). 
5. Have at least one of the following at Screening per central lab: 
 
Antinuclear antibodies (ANA) ≥ 1:80. 
 
Anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies elevated to above 
normal range as established by the central laboratory (ie, positive results). 
 
Anti-Smith antibodies elevated to above normal (ie, positive results). 


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6. Diagnosis of proliferative LN based on a renal biopsy obtained within 6 months prior to signing 
the informed consent form (ICF) or during the Screening Period: 
 
Class III (± class V) or class IV (± class V) LN according to the World Health 
Organization (WHO) or 2003 ISN/RPS classification (based on local evaluation of renal 
biopsy). 
 
Note: the local biopsy report will be used to confirm participant eligibility. The 
submission of the Screening biopsy sample (archived or fresh tissue block, slides, or 
digital pathology images) for adjudication is required to participate in the study. 
7. Urine protein to creatinine ratio ≥1.5 mg/mg (113.17 mg/mmol), obtained via a 24-hour urine 
collection at both: 
 
The start of Screening and 
 
Within 14 days of expected date of Randomization. Without the results of the second 
sample, which will be used for stratification, participants cannot be randomized. The 
second sample may be collected after a minimum of 10 days after the Screening sample 
was obtained. The second sample may be repeated once, upon approval by the Medical 
Monitor (this will not be considered a re-screen). Typical turn-around time for results 
from central laboratory is up to 7 days. On rare occasion, an extension of the 28-day 
screening window is allowed if re-collection of the sample is necessary or the results 
needed for Randomization are delayed. 
8. Estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease 
[MDRD] formula, with screening laboratory results for serum creatinine value) ≥ 35 mL/min/1.73 
m2. 
9. Negative serum β human chorionic gonadotropin (β-hCG) test at Screening (females of 
childbearing potential only).  
Note: if the result of the serum β-hCG test is borderline or thought to be false positive, the test may be 
repeated during the Screening Period. The participant may continue if the repeat test is negative.  
 
Women of childbearing potential (WOCBP)(including those with an onset of menopause < 
2 years prior to Screening, non-therapy-induced amenorrhea for < 12 months prior to 
Screening, or not surgically sterile [absence of ovaries and/or uterus]) must have negative 
serum and urine pregnancy tests during Screening and Randomization, respectively. 
 
WOCBP who are sexually active with a non-sterilized male partner must agree to use a highly 
effective method of contraception (Table 1) from signing of the informed consent, and must 
agree to continue using such precautions through the end of the study follow-up or 6 months 
(approximately 5 half-lives) following the last dose of IP in the case of early withdrawal from 
the study, and refrain from egg retrieval/egg donation during this period. A decision 
about contraception after this point should be made by the participant and her regular 
healthcare providers.  
 
Sustained abstinence is an acceptable practice; however periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Table 1 
Highly Effective Methods of Contraception 
Physical Methods  
Hormonal Methods a  
Intrauterine device   
Intrauterine hormone-releasing system b  
Combined (estrogen and progestogen-containing 
hormonal contraception)  
PO (combined pill)  


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Bilateral tubal occlusion  
Vasectomized partner c  
Sexual abstinence d  
Injectable  
Transdermal (patch)  
Progestogen-only hormonal contraception associated 
with inhibition of ovulation e  
Injectable  
Implantable  
Intravaginal  
NOTE: because mycophenolate affects the metabolism 
of hormonal contraceptives and may reduce their 
effectiveness in women receiving MMF or MPA who 
are using hormonal contraceptives for birth control, 
the participant must employ an additional contraceptive 
method (eg, barrier method) 
PO: oral(ly).  
a Any change in hormonal birth control during the study requires use of at least two methods of highly effective contraception 
for at least two months.   
b This is also considered to be a hormonal method.  
c A vasectomized partner is a highly effective method of birth control provided that partner is the sole sexual partner of 
the woman of childbearing potential study participant and that the vasectomized partner has received medical assessment 
of the surgical success.  
d Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of the study and if it is the preferred and usual lifestyle of the participant.  
e Progestogen-only hormonal contraception where inhibition of ovulation is not the primary mode of action (minipill) is not 
accepted as a highly effective method.  
10. Men who are not vasectomized must agree to use appropriate contraception so as to not 
impregnate a female partner of reproductive potential during the trial and continuing for at least 
3 months (approximately 5 half-lives) after receipt of the last dose of daxdilimab and refrain from 
donating sperm during this period. 
Exclusion Criteria: 
Participants will be ineligible for trial participation if they meet any of the following criteria at the Screening 
and/or Day 1 Visits, as applicable: 
General Exclusion Criteria 
1. Individuals involved in the conduct of the study, their employees, or immediate family members of 
such individuals. 
2. Any condition that, in the opinion of the Investigator or the Sponsor/Central Review Committee, 
would interfere with evaluation of the IP or interpretation of participant safety or study results. 
3. Weight > 160 kg (352 pounds) at Screening. 
4. History of allergy, hypersensitivity reaction, or anaphylaxis to any component of the IP or to a 
previous monoclonal antibody (mAb) or human immunoglobulin (Ig) therapy. 
5. Known intolerance to ≤1.0 gm/day of MMF or equivalent dose of MPA. 
6. Participation in another clinical study with an investigational drug within 4 weeks prior to Day 1 or 
within 5 published half-lives, whichever is longer. 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
7. Breastfeeding or pregnant women or women who intend to become pregnant anytime from signing 
the ICF through 6 months after receiving the last dose of IP. 
8. History of drug or alcohol abuse that, in the opinion of the Investigator, might affect participant 
safety or compliance with visits, or interfere with other study assessments. 
9. Major surgery within 8 weeks prior to Screening or elective surgery planned from Screening 
through the end of the trial. 
10. Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to Screening 
through Randomization. 
11. A diagnosis of pure Class V membranous LN based on a renal biopsy obtained within 6 months 
prior to signing ICF or during the Screening Period. 
12. History of dialysis within 12 months prior to signing the ICF or expected need for renal 
replacement therapy (dialysis or renal transplant) within a 12-month period after enrollment. 
13. History of, or current renal diseases (other than LN) that in the opinion of the Investigator could 
interfere with the LN assessment and confound the disease activity assessment (eg, diabetic 
nephropathy). 
14. Known history of a primary immunodeficiency or an underlying condition such as known human 
immunodeficiency virus (HIV) infection, a positive result for HIV infection per central laboratory, 
splenectomy, or any underlying condition that in the opinion of the Investigator significantly 
predisposes the participant to infection. 
15. During Screening, any of the following per central laboratory (tests may be repeated once within 
the same Screening Period to confirm results prior to Randomization):  
 
Aspartate aminotransferase > 2.5× upper limit of normal (ULN) 
 
Alanine aminotransferase > 2.5× ULN 
 
Total bilirubin > 1.5× ULN (unless due to Gilbert’s syndrome) 
 
Serum IgG < 600 mg/dL (or < 6 g/L) or < 400 mg/dL (<4 g/L) if due to active 
SLE/LN 
 
Neutrophil count < 1000/μL (or < 1.0×109/L) or < 500/μL (< 0.5×109/L) if due to   
active SLE 
 
Platelet count < 50,000/μL (or < 50×109/L) or < 25,000/μL (< 25×109/L) if due to 
active SLE 
 
Hemoglobin < 8 g/dL (or < 80 g/L) or < 7 g/dL (< 70 g/L) if due to active SLE 
 
Glycosylated hemoglobin > 8% (or > 0.08) 
 
Total lymphocyte count < 200 cells/mm3 
16. Confirmed positive test for hepatitis B serology defined as: 
 
Hepatitis B surface antigen, or  
 
Hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA detected above 
the lower limit of quantitation (LLOQ) by reflex testing by the central laboratory at 
Screening. 
Note that participants who are HBcAb positive at Screening will be tested every 3 months for HBV 
DNA. IP will be discontinued if the participant’s HBV DNA levels are confirmed to exceed the 
LLOQ as per the central laboratory. 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
17. Positive test for hepatitis C virus antibody unless documented as having had successful treatment 
of active hepatitis C infection. 
18. Active tuberculosis (TB), or a positive IFN-gamma release assay (IGRA) test at Screening, unless 
documented history of appropriate treatment for active or latent TB. Note that participants with an 
indeterminate IGRA test result with well-documented previous treatment do not need to repeat 
testing and are eligible for randomization. Participants with an indeterminate IGRA test result can 
repeat the test, but if the repeat test is also indeterminate, they are excluded. 
19. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus [CMV]) 
at any time prior to Randomization, including, but not limited to, disseminated herpes, herpes 
encephalitis, recent recurrent herpes zoster (defined as 2 episodes within the last 2 years), or 
ophthalmic herpes. 
20. Any herpes zoster, CMV, or Epstein-Barr virus infection that was not completely resolved 
12 weeks prior to Randomization. 
21. Any of the following within 30 days prior to signing the ICF and through Randomization: 
 
Clinically significant active infection in the opinion of the Investigator, including ongoing, 
and chronic infection requiring antibiotics or antiviral medication (chronic nail infections are 
allowed). 
 
Any infection requiring hospitalization or treatment with intravenous anti-infectives. 
 
A participant with a documented positive severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) test may be rescreened: 
o At least 2 weeks after a positive test if the participant is asymptomatic (no negative 
test result is required) OR 
o At least 3 weeks after symptomatic COVID-19 illness (no negative test result is 
required). 
22. Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 
2 years prior to Randomization. 
23. Any acute illness or evidence of clinically significant active infection on Day 1. 
24. Clinically significant cardiac disease including unstable angina, myocardial infarction, congestive 
heart failure within 6 months prior to Randomization. Any cardiac condition including, but not 
limited to the following, if in the opinion of the Investigator or Medical Monitor, would increase 
the risk of study participation: 
 
Inadequately controlled arrythmia 
 
Uncontrolled hypertension 
 
Presence of clinically significant abnormality on electrocardiogram (ECG) 
25. History of cancer within the past 5 years, except as follows: 
 
In situ carcinoma of the cervix treated with apparent success with curative therapy 
> 12 months prior to Screening, or 
 
Cutaneous basal cell or squamous cell carcinoma treated with curative therapy. 
26. Receipt of a live vaccine within 4 weeks prior to Day 1.  
27. Participant should be assessed for epidemiologic risk of COVID-19 (ie, recent exposure, high-risk 
housing) and for health-related risk of COVID-19 severity based on current understanding of risk 
factors for severe disease when making a decision regarding the individual’s risk of participation. 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Participants who have COVID-19 or other significant infection, or in the judgment of the 
Investigator, may be at a high risk of COVID-19 or its complications, should not be randomized. 
Disease-Related Criteria 
28. Active severe or unstable neuropsychiatric SLE including, but not limited to: aseptic meningitis, 
cerebral vasculitis, myelopathy, demyelination syndromes (ascending, transverse, acute 
inflammatory demyelinating polyradiculopathy), acute confusional state, impaired level of 
consciousness, psychosis, acute stroke or stroke syndrome, cranial neuropathy, status epilepticus, 
cerebellar ataxia, and mononeuritis multiplex:  
a) That might cause the participant to be unable to fully understand the ICF  
OR 
b) In the opinion of the Investigator, protocol-specified SOC is insufficient to control 
neurologic features of SLE and utilization of a more aggressive therapeutic 
approach, such as adding IV cyclophosphamide and/or high dose IV pulse 
corticosteroid therapy or other treatments not permitted in the protocol, is 
indicated or anticipated. 
29. Documented history of systemic sclerosis or diagnosis of SLE with overlapping systemic sclerosis. 
30. History of, or current diagnosis of, catastrophic anti-phospholipid syndrome (APS) or APS-related 
thromboembolic event or pregnancy loss within 1 year prior to signing the ICF. Participants with 
APS adequately controlled by anticoagulants or aspirin for at least 12 weeks may be recruited to 
the study. 
31. History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids 
for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF. 
Prior and Concomitant Therapy Criteria 
32. Receipt of any of the following treatments within the following timeframes. 
 
6 weeks prior to Randomization: 
o Opioid use above 40 mg/day morphine-equivalent, unstable dosing, or initiation of 
regular dosing 
o IV corticosteroids > 3.0 gm (cumulative dose) 
 
8 weeks prior to Randomization: 
o Immunoglobulins (except anti-SARS-CoV-2 therapeutic antibodies) 
o Calcineurin inhibitors (eg, cyclosporin, voclosporin, tacrolimus), mechanistic target 
of rapamycin inhibitors, retinoids, thalidomide, lenalidomide, or Janus kinase 
inhibitors 
o Transfusion with blood, packed red blood cells, platelets or treatment with 
plasmapheresis, plasma exchange, or Therakos® photopheresis 
 
12 weeks (or 5 half-lives, whichever is longer) prior to Randomization: 
o IV cyclophosphamide >2 pulses of high dose (≥ 0.5 gm/m2) or > 4 doses of low dose 
(500 mg every 2 weeks)  
o Alkylating agents other than cyclophosphamide (eg, chlorambucil) 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
o Cytokine or cytokine receptor antagonists, including but not limited to interleukin 
(IL)-1, IL-6, IL 17, IL-12/23, IL-23, IFN, integrin, or TNFα antagonists (except for 
IFN-α kinoid, for which receipt at any time is exclusionary) 
o Belimumab, abatacept, or eculizumab 
o Other biologics used for immunosuppression or immunomodulation (eg, IFN therapy, 
IL-2)  
o Investigational drugs 
o IPP-201101 (Lupuzor™) 
 
24 weeks prior to Randomization: 
o B cell-depleting therapies (eg, rituximab, ocrelizumab, ofatumumab, inebilizumab, 
telitacicept) other than atacicept or obinutuzumab 
o Receipt of systemic glucocorticoids (ie, PO, rectal, IV or IM) for more than a total of 
2 weeks for any concurrent illness, including asthma, inflammatory bowel disease, or 
drug-induced SLE 
 
40 weeks prior to Randomization: 
o Atacicept 
 
1 year prior to Randomization: 
o Bacille-Calmette-Guerin (BCG) vaccination 
 
1.5 years prior to Randomization: 
o Obinutuzumab 
 
The following medications must be discontinued prior to the day of Randomization (because 
of potential interaction with MMF):  
o Methotrexate 
o Azathioprine 
o Leflunomide 
o Mizoribine 
o Proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole, 
etc.) 
o Cholestyramine 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Dosage Form and Strength of Formulation, Dosing and Administration: 
Placebo is to be procured by the study sites as commercially available Normal Saline. 
Study treatment (daxdilimab and placebo) is to be administered SC. To maintain the same number and 
volume of injections across all groups, the required dose will be administered by two 1.5 mL injections. 
The first day of dosing is considered Day 1. To reduce the risk of unblinding to the study personnel who 
will be evaluating the participant, study intervention will be administered by an unblinded pharmacist/IP 
Manager or a study site staff member who is not otherwise involved in the participant’s participation in the 
study. The study intervention administrator should be experienced in performing SC injections. The skin 
surface of the anterolateral thigh, upper outer triceps area, upper buttocks, or abdomen (avoiding a 2-inch 
[5 cm] radius around the umbilicus) should be prepared with an alcohol wipe and allowed to air dry. The 
skin will be pinched to isolate SC tissue from the muscle. The needle will be inserted at a 90-degree angle 
to the skin surface approximately halfway into the SC tissue. The prepared study intervention will be slowly 
injected (at least a 5 second duration is recommended per 1.5 mL syringe) into the SC tissue using gentle 
pressure. The area should not be massaged after injection. The SC injection site may be changed during the 
study as per the participant’s preference. 
Further guidance and information for the preparation and administration of study intervention are provided 
in the Pharmacy Manual. 
Duration of Treatment and Follow-up: 
Screening: Completed within 28 days prior to the Day 1 Visit.  
Double-Blind Treatment Period (Day 1 through 
 Study treatment (daxdilimab or placebo) is 
administered SC 
 with an additional dose 
, all participants 
will be assigned to a quarterly dosing maintenance regimen based upon the renal response observed at 
 and will either receive daxdilimab or placebo 
 (last dose 
administered at 
). Final evaluation will occur at 
. 
 
End-of-Study/Early Termination Visit: Week 112 or earlier if the participant withdraws consent to 
participate in the trial.  
Safety Follow-Up: Participants should be followed to assess AE/SAEs for at least 12 weeks after the last 
study intervention administration, approximately 4, 8, and 12 weeks after the last study intervention dose, 
unless the participant withdraws consent. Participants who do not agree to in-person follow-up site visits 
will be contacted (through telehealth visits – video call/phone/email) to assess AE/SAEs, unless the 
participants withdraw consent. Assessments will include of any AE/SAEs that have occurred within the last 
4 weeks and will confirm if any previous AE/SAEs have resolved.  
Criteria for Evaluation: 
Efficacy: 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Efficacy will be assessed by renal responses, change in proteinuria, and GFR. 
Participant’s experience will be assessed by the Patient Global Assessment (PtGA) and the Patient Global 
Impression of Change (PGI-C) scales. 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity 
The PK of daxdilimab will be assessed by serum PK concentrations.  
Daxdilimab immunogenicity will be assessed by the rate and titer of ADA.  
 
 
 
Safety: 
Safety will be assessed and will include monitoring and recording of all AEs, whether or not drug-related, 
measurement of vital signs, physical examinations, and monitoring of hematology, blood chemistry, and 
urinalysis. 
Statistical Analysis on Efficacy and Safety Parameters 
Efficacy Analyses 
Analyses of the Primary Efficacy Endpoint:  
The proportion of participants achieving CRR at Week 48 and sustained through Week 52 in the 
daxdilimab group will be compared to that of the placebo group using a logistic regression model with 
treatment, baseline eGFR value and baseline UPCR value included in the model.  
Analyses of the Secondary Efficacy Endpoints:  
ORR at Week 48 and sustained through Week 52 will be analyzed using a logistic regression model with 
treatment, baseline eGFR value and baseline UPCR value included in the model. Response in sustained 
reduction of OCS dose will be analyzed similarly using a logistic regression model with treatment, 
randomization stratification factor and baseline OCS dose included in the model. 
Change from baseline in eGFR at Week 52 will be analyzed using mixed models for repeated measures 
(MMRM) with treatment, visit, visit by treatment interaction, randomization stratification factor (UPCR 
only) and baseline eGFR value included in the model. 
Safety Analyses 
AEs will be coded using the most recent version of Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of participants reporting TEAEs will be summarized for each 
treatment group by MedDRA System Organ Class and preferred terms (PT), by severity, and by 
relationship to the study intervention. The number and percentage of participants reporting TESAEs and 
TEAESIs will also be summarized.  
Other safety parameters, including but not limiting to laboratory assessments and vital signs will also be 
summarized as appropriate. 
Pharmacokinetic Analyses 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
Page 28 of 118 
Name of Sponsor/Company:  
Horizon Therapeutics Ireland 
DAC 
Name of Investigational Product:  
Daxdilimab (HZN-7734) 
Name of Active Ingredient:  
Daxdilimab (HZN-7734) 
Serum concentrations will be summarized descriptively by treatment and by visit. 
/Immunogenicity Analyses 
 rate of positive ADA and ADA titer will be summarized 
descriptively by treatment and by visit. 
Sample Size Estimate 
A sample size of approximately 210 participants (up to approximately 70 participants per treatment group) 
is planned for this trial. The sample size was calculated based on the primary efficacy endpoint. Assuming 
a placebo response rate of 25%, 70 participants per treatment group will provide approximately 80% power 
to detect an increase in response of 20% in a daxdilimab group as compared to the placebo group at the 
2-sided alpha level of 0.10 using a Chi-square test. The minimum detectable difference is 13% between the 
daxdilimab group and placebo group. The assumption of 25% responder rate for placebo is based upon 
published results (Mejia-Vilet et al, 2021). 




Protocol Version: 2.0 (HZNP-DAX-203) 
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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1.3. 
Schedule of Activities (SoA) 
Table 2 and Table 3 summarize the Screening and treatment assessments and procedures for the first 
year of the trial and Table 4 summarize the treatment and follow-up procedures and assessments for the 
second year of the trial. 
Table 2 
Screening Procedures and Assessments 
Period 
Screening Period 
Study Day 
-28 to -1 
Visit Number 
1 
General 
Informed consent 
X 
Inclusion/exclusion criteria review 
X 
Renal biopsy a 
See footnote a 
EULAR/ACR SLE classification criteria 
X 
Demographic data 
X 
Medical/Surgical/SLE/LN history 
X 
TB assessment b 
X 
Physical examination c 
X 
Vital signs, height, and weight d 
X 
12-lead ECG (after 10 minutes rest in supine position) e 
X 
Laboratory Assessments 
 
 
24-hour UPCR 
X 
Pregnancy (serum β-hCG) test (in women of childbearing potential) 
X 
FSH (to confirm postmenopausal status, as appropriate) f 
X 
Serum virology g 
X 
Routine chemistry h 
X 
Hematology (CBC with differential) 
X 
HbA1c 
X 
Lipid profile i 
X 
Urinalysis j 
X 
 
 
 
 
 
 
 
 
 
 
Safety 
Concomitant medications k 
X 
AEs, SAEs, and/or AESIs 
X 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
Page 31 of 118 
Table 2 
Screening Procedures and Assessments 
Period 
Screening Period 
Study Day 
-28 to -1 
Visit Number 
1 
ACR = American College of Rheumatology; AE = adverse event; AESI = AE of special interest; 
; βhCG = β-human chorionic gonadotropin; 
 CBC = complete blood count; 
 ECG = electrocardiogram; EULAR = European League Against Rheumatism; 
FSH = follicle-stimulating hormone; HbA1c = glycosylated hemoglobin; 
; LN = lupus 
nephritis; 
 SAE = serious AE; SLE = Systemic 
Lupus Erythematosus; 
 
 TB = tuberculosis; UPCR = urine protein to creatinine ratio; X = to be performed. 
a  
A local biopsy report indicating active, proliferative lupus nephritis will be used to confirm participant 
eligibility. Availability of the Screening biopsy sample (tissue, slides, or digital pathology images) for 
adjudication submission must also be confirmed. If a participant has not had a recent kidney biopsy within 
the 6 months prior to Screening, one may be performed to assess eligibility for the study provided informed 
consent has been given and the local biopsy report is received prior to Randomization. If a renal biopsy is 
performed as part of standard of care after Randomization, the results will be recorded in the electronic case 
report form. 
b  
The results of an IFN-gamma release assay (ie, QuantiFERON-TB Gold Plus or TSPOT) performed within 
12 weeks of the Screening Visit (if available) are acceptable, provided there is no reason to suspect any 
re-exposure. 
c  
A complete physical examination including assessment of head, ears, eyes, nose, throat, lungs, heart, 
abdomen, skin, and extremities. 
d  
Vital signs include systolic and diastolic blood pressure obtained after at least 5 minutes at rest in a seated 
position, heart rate, respiratory rate (breaths/min), and body temperature. Height will be measured at 
Screening only.  
e  
Should be performed after vital signs are collected. 
f  
FSH testing does not have to be repeated if performed within 12 weeks prior to Screening (eg, re-screening).  
g  
Includes human immunodeficiency virus testing, hepatitis B testing (hepatitis B surface antigen and hepatitis 
core antibody [HBcAb] Serum virology does not have to be repeated if performed within 12 weeks prior to 
Screening (eg, re-screening). 
h  
Refer to the Laboratory Manual for a complete list of routine laboratory assessments. 
i  
Participants must be fasting for at least 8 hours when lipid profiles are obtained. Visit recommended to occur 
in the morning. 
j      Urine collection can be postponed for up to 14 days in women with menstrual bleeding or a urinary tract 
infection at the scheduled visit. Refer to the Laboratory Manual for a complete list of routine urinalysis 
assessments. 
  
 
 
l  
Use of anti-proteinuric agents (eg, ACEI/ARBs) are allowed during the study if they had been started at least 
10 days prior to the assessment of the second screening 24-hour UPCR sample (ie, the first sample for 24 
hour UPCR is collected at the start of the screening process and the second sample is collected within 14 days 
prior to the expected date of Randomization). 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
Page 32 of 118 
Table 3 
First Year Treatment Procedures and Assessments  
Period 
Treatment Period 
Study Week 
Study Day 
Visit Window (± Days) 
- 
3 
3 
5 
5 
5 
5 
5 
7 
7 
7 
7 
7 
7 
7 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Eligibility review a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Weight 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Vital signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (after 10 minutes rest in supine position) 
d 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Randomization e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC/ACR Damage Index (SDI) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (urine) test g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour UPCR h 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Routine chemistry i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology (CBC with differential) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Lipid profile j 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urinalysis k 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3 
First Year Treatment Procedures and Assessments  
Period 
Treatment Period 
Study Week 
Study Day 
Visit Window (± Days) 
- 
3 
3 
5 
5 
5 
5 
5 
7 
7 
7 
7 
7 
7 
7 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daxdilimab PK (serum) m 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
Daxdilimab ADA n 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening biopsy sample shipment for adjudication p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration 
Local injection site assessment 
MMF/MPA/OCS dispensing r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
IV methylprednisolone administration s 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral corticosteroid reduction (tapering)  
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Concomitant medications t 
Continuous 
AEs, SAEs, and/or AESIs u 
Continuous 
ADA = antidrug antibody; AE = adverse event; AESI = AE of special interest; CBC = complete blood count; ECG = electrocardiogram; 
 IP =  investigational 
product; MMF = mycophenolate mofetil; MPA = mycophenolic acid; mSFI = modified 
; 
 OCS = oral 
corticosteroids; 
 
 PK = pharmacokinetics; 
 
 SAE = serious AE; 
; 
SLICC/ACR = Systemic Lupus International Collaborating Clinics/American College of Rheumatology; 
 X = to be performed. 
a  
Participant eligibility (based on Screening assessments, including non–laboratory-based assessments at Baseline [Day 1] as per the inclusion and exclusion criteria) must be 
checked again on Day 1 prior to Randomization. 
b  
Focused physical examination including assessment of head, ears, eyes, nose, throat, lungs, heart, abdomen, skin, and extremities. 
CCI


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c  
Vital signs include systolic and diastolic blood pressure obtained after at least 5 minutes at rest in a seated position, heart rate, respiratory rate (breaths/min), and body 
temperature. 
d  
Should be performed after vital signs are collected. 
  
 
 
  
g  
Women of childbearing potential or women who are postmenopausal for less than 2 years.  
h  
24-hour urine collection should begin 2 days prior to the scheduled study visit in order not to coincide with the 
 sampling due on the day of the study visit. 
i  
Refer to the Laboratory Manual for a complete list of routine laboratory assessments.  
j 
Participants must be fasting for at least 8 hours when lipid profiles are obtained. Visit recommended to occur in the morning. 
k  
Urine collection can be postponed for up to 14 days in women with menstrual bleeding or a urinary tract infection at the scheduled visit. Refer to the Laboratory Manual for a 
complete list of routine urinalysis assessments. 
 
 
 
 
m 
Blood samples will be collected in serum separator collection tubes to evaluate PK at the following visits: pre- and 6 hours (± 1 hour) post-injection on Day 1, prior to SC 
administration on 
 a single sample will be collected at the End-of-Study Visit. 
n  
Daxdilimab immunogenicity will be assessed by the incidence and titer of anti-drug antibodies prior to the daxdilimab administration. 
  
 
p 
The submission of the Screening biopsy sample (tissue block, slides, or digital pathology images) for adjudication should be provided within 2 months post-randomization. 
  
 
 
 
r  
For participants not on MMF or MPA during Screening, MMF/MPA therapy will start on Day 1 (Baseline – Visit 2). A quantity sufficient for a 12-week supply should be 
dispensed at Week 52. 
s  
IV methylprednisolone administered 500 mg on Day 1 (Baseline – Visit 2). If IV corticosteroids must be administered during Screening, then the 
 specimens will be 
collected prior to the infusion. 
t  
At each visit, use of any rescue therapy for worsening LN and restricted or prohibited medication beyond the protocol allowed threshold will also be assessed. 
u 
Participants who choose to discontinue study intervention will be contacted (either in-person at the site or through telehealth visits – video call/phone/email), if participant 
agrees, to assess AE/SAEs approximately 4, 8, and 12 weeks after last study intervention dose. Assessments will include of any AE/SAEs that have occurred within the last 4 
weeks and will confirm if any previous AE/SAEs have resolved. 
 
 
 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Table 4 
Second Year Treatment and Follow-Up Procedures and Assessments 
Period 
Treatment Period 
Safety Follow-
Study Week 
In-Clinic Visit 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Telephone or Telehealth Visit a 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Visit Window (± Days) 
3 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 (End-of-
Study or Early 
Termination) 
Physical examination b 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Weight 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs c 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
12-lead ECG (after 10 minutes rest in supine 
position) d 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Pregnancy (urine) test e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour UPCR f 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Routine chemistry g 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Hematology (CBC with differential) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Lipid profile h 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis i 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daxdilimab PK (serum) l 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Table 4 
Second Year Treatment and Follow-Up Procedures and Assessments 
Period 
Treatment Period 
Safety Follow-
Up Period 
Study Week 
In-Clinic Visit 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Telephone or Telehealth Visit a 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Visit Window (± Days) 
3 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 (End-of-
Study or Early 
Termination) 
Daxdilimab ADA l 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC/ACR Damage Index (SDI) m 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration 
Local injection site assessment 
MMF/MPA/OCS dispensing q 
  
  
X 
  
 
X 
 
  
X 
 
  
X 
 
 
Oral corticosteroid reduction (discontinuation) r 
X 
 
 
 
 
 
 
 
 
Concomitant medications s 
Continuous 
AEs, SAEs, and/or AESIs t 
Continuous 
ADA = antidrug antibody; AE = adverse event; AESI = AE of special interest; CBC = complete blood count; ECG = electrocardiogram; EOT = end-of-treatment; 
IFN = interferon;IP =  investigational product; MMF = mycophenolate mofetil; MPA = mycophenolic acid; 
 
 OCS = oral corticosteroids;  
 
PK = pharmacokinetics; 
 SAE = serious AE;
 
 SLICC/ACR = Systemic Lupus International Collaborating Clinics/American College of Rheumatology; 
 X = 
to be performed. 


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a  
During the second year, participants are not required to visit the clinical site at Weeks 56, 60, 68, 72, 80, 84, 92, and 96; applicable assessments may instead be performed as a 
telehealth visit – video call or phone call with the participant (ie, OCS reduction, concomitant medication, and adverse event review), unless an in-person site visit is clinically 
indicated. 
b 
Focused physical examination including assessment of head, ears, eyes, nose, throat, lungs, heart, abdomen, skin, and extremities. 
c  
Vital signs include systolic and diastolic blood pressure obtained after at least 5 minutes at rest in a seated position, heart rate, respiratory rate (breaths/min), and body 
temperature. 
d  
Should be performed after vital signs are collected. 
e  
Women of childbearing potential or women who are postmenopausal for less than 2 years.  
f  
24-hour urine collection should begin 2 days prior to the scheduled study visit in order not to coincide with the 
 sampling due on the day of the study visit. 
g  
Refer to the Laboratory Manual for a complete list of routine laboratory assessments.  
h  
Participants must be fasting for at least 8 hours when lipid profiles are obtained. Visit recommended to occur in the morning. 
i  
Urine collection can be postponed for up to 14 days in women with menstrual bleeding or a urinary tract infection at the scheduled visit. Refer to the Laboratory Manual for a 
complete list of routine urinalysis assessments. 
 
 
 
 
k 
Blood samples will be collected in serum separator collection tubes to evaluate PK at the following visits: pre- and 6 hours (± 1 hour) post-injection on Day 1, prior to SC 
administration on 
; a single sample will be collected at the End-of-Study Visit. 
l 
Daxdilimab immunogenicity will be assessed by the incidence and titer of anti-drug antibodies prior to the daxdilimab administration. 
m  
May be completed more frequently if clinically indicated. 
 
  
 
 
 
 
p 
Additional follow-up after Week 100 will be performed for any ongoing injection site reactions during the SFU Period. 
q 
A quantity sufficient for a 12-week supply should be dispensed at Weeks 64, 76, 88, and 100. 
r 
Continued tapering of OCS is recommended for all participants after the Week 52 Visit with the goal of achieving discontinuation (ie, 0 mg) by Week 76. Due to variability in 
participant responses to OCS treatment and tolerability of taper, Investigators will have flexibility of when the OCS dose is reduced at each visit. 
s 
At each visit, use of any rescue therapy for worsening LN and restricted or prohibited medication beyond the protocol allowed threshold will also be assessed. 
t 
Participants who choose to discontinue study intervention will be contacted (either in-person at the site or through telehealth visits – video call/phone/email), if participant 
agrees, to assess AE/SAEs approximately 4, 8, and 12 weeks after last study intervention dose. Assessments will include of any AE/SAEs that have occurred within the last 4 
weeks and will confirm if any previous AE/SAEs have resolved. 


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2. 
INTRODUCTION 
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown 
etiologies. Lupus nephritis (LN) is the most common major organ manifestation of SLE. 
It affects approximately 31-60% of lupus patients and is more prevalent in certain ethnic groups, 
such as African Americans, Asians, and Hispanics (Borchers et al, 2010; Hanly et al, 2016; 
Mahajan et al, 2020; Anders et al, 2020). Although renal outcomes have improved with the 
introduction of immunosuppressive treatment, LN still represents a major risk factor for the 
long-term outcome of patients with SLE and adversely affects the prognosis, as measured by 
patient and renal survival rates as well as quality of life and work disability (Furst et al, 2013; 
Li et al, 2009; Mok et al, 2013; Pelletier et al, 2009; Parikh et al, 2020). Renal survival rates 
(ie, survival without dialysis) in recent studies ranged from 83% to 92% at 5 years of follow-up 
and from 74% to 84% at 10 years of follow-up (summarized in Mok et al, 2013). The risk of 
end-stage renal disease (ESRD) is particularly high in patients with diffuse proliferative 
glomerulonephritis (reviewed in Mok et al, 2013). Several studies have shown that the 
standardized mortality ratio of patients with LN is 6-9-fold higher compared to the general 
population and about 3-fold higher compared to patients with non-renal SLE (reviewed in 
Mok et al, 2013; Hanly et al, 2016). The mortality rate increases with accumulation of renal 
damage and is highest in LN patients with ESRD. The life expectancy of SLE patients with renal 
disease and those with renal damage is reduced by approximately 15 years and 23 years, 
respectively, compared to the general population (Mok et al, 2013). Lupus nephritis is also a 
major factor contributing to SLE related hospitalizations and overall health care costs 
(Furst et al, 2013; Li et al, 2009; Pelletier et al, 2009; Thompson et al, 2021).  
2.1. 
Background 
There is substantial unmet medical need in the treatment of LN, particularly for patients with 
proliferative LN. Belimumab and voclosporin have recently been approved for LN (Mejia-Vilet 
et al, 2021) but real world and long-term experience with these drugs is not yet available. 
Various other treatment regimens are widely used as local standards of care. The standard 
treatment for proliferative LN consists of 6 to 12 months of intensive immunosuppressive 
therapy (usually either mycophenolate mofetil [MMF] or cyclophosphamide with 
corticosteroids) followed by a longer period of less intensive maintenance therapy (Bertsias et al, 
2012; Hahn et al, 2012; Fanouriakis et al, 2020). Corticosteroid dosing frequently includes pulse 
intravenous (IV) methylprednisolone (500 mg to 1,000 mg/day for 1-3 days) followed by daily 
oral glucocorticoids (0.3 to 0.5 mg/kg/day of prednisone-equivalent) with a goal of reducing the 
dose to around ≤7.5 mg/day of prednisone-equivalent by 3 to 6 months. MMF is the 
recommended agent by the American College of Rheumatology (ACR) (Hahn et al, 2012) and 
the European League Against Rheumatism (EULAR) (Bertsias et al, 2012; Fanouriakis et al, 
2020) with a total daily dose of 2 to 3 gm/day orally for 6 months, followed by an extended 
period of treatment with lower doses of MMF.  
Two regimens of IV cyclophosphamide are recommended as alternatives: 1) low-dose “Euro 
Lupus” cyclophosphamide (500 mg IV once every 2 weeks×3 months), followed by maintenance 
therapy with daily oral azathioprine or daily oral MMF or 2) high-dose cyclophosphamide 


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(500 to 1000 mg/m2 IV once a month×6 months), followed by maintenance treatment with MMF 
or azathioprine. 
Maintenance therapy is recommended for a minimum of 12 months with lower intensity 
immunosuppression with or without low-dose corticosteroids (≤7.5 mg/day). Mycophenolate 
mofetil (≤2 gm/day) or azathioprine are the most commonly used agents for maintenance 
(Bertsias et al, 2012;Fanouriakis et al, 2020; Hahn et al, 2012; Radhakrishnan et al, 2012; ). 
In this study, MMF was chosen as standard-of-care (SOC) background therapy. While the target 
dose of MMF recommended by various management guidelines (ACR, EULAR, and KDIGO) is 
2 to 3 gm/day orally for 6 months followed by an extended period of treatment with lower doses 
of MMF, several studies in Asian and Caucasian LN populations have shown doses ≤2 gm/day 
lead to similar renal responses but a lower frequency of adverse events (AEs) compared to doses 
of 3 gm/day (Chan, 2012; Li et al, 2012; Mulic-Bacic et al, 2008; Ong et al, 2005). Consistent 
with these observations, the ACR guidelines recommend a target of 2 gm/day for induction in 
Caucasian patients with LN (Hahn et al, 2012), which is the higher end of the range used for 
induction in Asian countries. Although a higher target dose is frequently used in patients of 
African descent, there is no evidence to support this distinction. 
Multiple lines of evidence indicate a role of plasmacytoid dendritic cells (pDCs) and type I IFN 
in the pathogenesis of SLE and LN. For example, type I IFN and proteins induced by type I IFN 
have been associated with greater disease activity and organ system involvement in SLE and LN 
(Bengtsson et al, 2000; Dall’Era et al, 2005; Kirou et al, 2005; ). High serum levels of type I IFN 
have been associated with high anti-double stranded deoxyribonucleic acid (anti-dsDNA) 
antibody titers, LN, and progressive skin rashes (Bengtsson et al, 2000). 
The disease pathogenesis of SLE includes activation of innate immunity, with increased 
production of type I IFN, including IFN-α, and increased number of pDCs and myeloid dendritic 
cells in involved tissue (Baechler et al, 2003;  Banchereau et al, 2004; Bengtsson et al, 2000; 
Crow, 2010; Crow and Wohlgemuth, 2003; Dall’Era et al, 2005; Rönnblom and Alm, 2003). 
Specific humoral and cellular immune systems are activated. Autoantibodies are universally 
present and may precede development of clinically apparent disease by many years (Arbuckle et 
al, 2003). Systemic lupus erythematosus-associated autoantibodies include anti-dsDNA, anti-
nucleosomes, anti-ribonucleoprotein (anti-RNP) complex, and anti-Smith antibodies (Rahman 
and Isenberg, 2008). Immune complexes containing anti-dsDNA or anti RNP antibodies can 
activate type I IFN production by plasmacytoid dendritic cells (Bengtsson et al, 2000; Rönnblom 
and Alm, 2003). 
A potential role of pDCs in the pathogenesis of LN has been suggested by both animal and 
human data. Systemic IFN-α accelerated LN in several murine models (Fairhurst et al, 2008, 
Liu et al, 2011). Additionally, a type I interferon response was induced in lupus-prone mice 
treated with a synthetic double-stranded RNA ligand, which was accompanied by high titers of 
anti-dsDNA antibodies, increased immune complex deposition, increased metalloproteinase 
activity, and accelerated LN and death (Triantafyllopoulou et al, 2010). pDCs are the most potent 
producers of type I IFNs (Baccala et al, 2013) and pDCs from mice susceptible to developing 
lupus-like disease demonstrate an increased capacity to produce type I IFNs after TLR9 
stimulation (Klarquist et al, 2016) suggesting that pDCs, and the type I IFNs they produce, may 
play a key role in the pathogenesis of lupus in these models. Indeed, when pDCs were depleted 


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in lupus-prone mice there were marked reductions in type I IFN, interferon gene signature, 
autoantibody production, and the severity of kidney pathology (Baccala et al, 2013; Klarquist et 
al, 2016; Rowland et al, 2014).  
In humans, a role for pDCs and IFN-α in the LN disease process has been suggested by several 
studies. For example, the formation of endothelial cell tubuloreticular inclusions found in LN is 
thought to be driven by type I IFN, and other than in LN, they can only be seen in viral and 
IFN-induced nephropathies (Anders et al, 2014). Elevated serum IFN-induced chemokine levels 
were strongly associated with the risk of renal flare (Bauer et al, 2009) and urine IFN-induced 
chemokines have been proposed as biomarkers for active LN (Aragon et al, 2020; Manoharan 
et al, 2010). The type I gene signature is increased in the glomeruli of a subset of LN patients 
(Peterson et al, 2004) and cross-sectional studies showed a positive correlation between the 
blood IFN signature and active LN or risk of renal flare (Feng et al, 2006; Landolt-Marticorena 
et al, 2009). Plasmacytoid dendritic cells are the main producers of type I IFN in SLE. In LN 
patients, there are decreased frequencies of pDCs in the blood and increased numbers in the 
kidneys (Tucci et al, 2008) suggesting that pDCs are recruited from the circulation to areas of 
active inflammation in the kidney (Baccala et al, 2013). pDCs are mostly localized in the 
tubulointerstitial area of LN kidneys with increased infiltrate seen in patients with class III-IV 
disease (Fiore et al, 2008). In severe tubulointerstitial inflammation, pDCs are associated with 
increased T cell infiltration and can contribute further to local inflammation by presenting 
antigen to CD4+ T cells (Liarski et al, 2019). 
Together, these pre-clinical and clinical data strongly support the hypothesis that pDCs, and their 
production of type I IFNs, are involved in the immunopathogenesis of LN; therefore, depleting 
pDCs with daxdilimab may be a novel and efficacious therapy for the treatment of LN. 
2.1.1. 
Trial Rationale 
Daxdilimab (previously known as MEDI7734, VIB7734, and HZN-7734) is an IgG1 lambda 
(IgG1λ) afucosylated monoclonal antibody (mAb) specific for immunoglobulin-like transcript 7 
(ILT7), a cell-surface protein that is unique to pDCs in human and the nonhuman primate. 
Daxdilimab binds to ILT7 on the surface of pDCs, which leads to the recruitment of 
macrophages and natural killer cells, thus inducing apoptosis and depletion of pDCs in vivo. 
The afucosylation of daxdilimab is designed to enhance the potency of daxdilimab for 
antibody-dependent cellular cytotoxicity against pDCs. Since pDCs are the major cell type that 
secretes type I IFNs in response to nucleic acid-containing immune complexes, it is hypothesized 
that depletion of pDCs will reduce disease activity for patients with autoimmune diseases that are 
partially driven by abnormally high levels of type I IFNs. 
Data from a Phase 2 trial with another type-1-IFN-blocking agent have demonstrated 
improvement in LN disease activity, supporting the rationale for blocking the IFN pathways and 
pDCs in patients with proliferative LN (Jayne et al, 2021). Given the lack of highly efficacious 
and safe treatments for active proliferative LN and the significant morbidity and increased 
mortality associated with LN, there is currently a significant unmet need for new targeted 
therapies in this indication. Based on its mechanism of action of pDC depletion, daxdilimab has 
the potential to decrease LN disease activity. In addition, based on data currently available, 
daxdilimab presents an acceptable safety profile, and hence it is justified to evaluate its potential 
efficacy in patients with active proliferative LN. 


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2.2. 
Risk/Benefit Assessment 
2.2.1. 
Known Potential Risks 
Daxdilimab was tested in a first-in-human, single-ascending dose study (Study D6080C00001). 
The key objectives of the study were to evaluate the single dose safety, pharmacokinetics (PK), 
and pharmacodynamics (PD). The study enrolled 36 adult subjects with dermatomyositis (DM), 
polymyositis (PM), Sjogren’s syndrome, systemic lupus erythematosus (SLE), or systemic 
sclerosis. Subjects received a single subcutaneous (SC) injection of daxdilimab 1, 5, 15, 50, or 
150 mg, or placebo. After single SC administration, serum peak concentrations were observed 5 to 
8 days post-dose. Daxdilimab PK exposures increased in an approximately dose-proportional 
manner. Apparent clearance (CL/F) ranged from 0.468 to 1.03 L/day. Apparent volume of 
distribution (Vz/F) ranged from 9.89 to 19.0 L. The estimated terminal elimination half-life (t1/2) 
ranged from 13 to 20 days across dose levels. No serious adverse events (SAEs) occurred that were 
considered related to the investigational product (IP). Two subjects had treatment-emergent 
adverse events (TEAEs) considered related to the IP by the Investigator: one subject in the placebo 
group with nausea (Grade 1) and one subject in the daxdilimab 50 mg group with tongue 
discolouration (Grade 1). The most common adverse events (AEs) reported in the 
daxdilimab-treated subjects were diarrhoea (11.5%) and upper respiratory tract infection (11.5%). 
There was no imbalance of AEs between the daxdilimab and placebo groups. No injection site 
reactions or hypersensitivity reactions were reported. No anti-drug antibodies (ADAs) occurred. 
Mean reductions of at least 50% in the pDC level of daxdilimab-treated subjects were evident at 
24 hours after dosing in all dose groups. Increasing doses were associated with a non-linear 
increase in pDC reduction. Increasing doses were generally associated with a longer duration of 
pDC reduction. 
Study HZN7734.P1b.S1 evaluated the PK, PD, and safety of 3 monthly doses of daxdilimab. 
The study enrolled 31 subjects with SLE, cutaneous lupus erythematosus (CLE), Sjogren’s 
syndrome, systemic sclerosis, PM, or DM. Subjects received placebo or daxdilimab at 5, 50, and 
150 mg by SC injection. Daxdilimab PK exposure was approximately dose proportional over the 
dose range investigated. Apparent steady-state clearance (CLss/F) values were similar across dose 
groups and ranged from 0.62 to 1.18 L/day. The t1/2 was 14.6 days for subjects receiving 150 mg 
daxdilimab. Sixteen of 22 (72.7%) daxdilimab-treated subjects and 6 of 9 (66.7%) placebo treated 
subjects experienced at least one TEAE. There were no deaths in the trial. One placebo-treated 
subject and no daxdilimab-treated subjects experienced treatment emergent SAEs. No subject 
experienced an AE leading to treatment discontinuation. No treatment-emergent ADA was 
observed in subjects treated with daxdilimab. In subjects with CLE, Cutaneous Lupus 
Erythematosus Disease Area and Severity Index-Activity (CLASI-A) scores improved more in the 
daxdilimab 150 mg group than the placebo group. After 3 monthly SC doses of daxdilimab 50 mg 
or 150 mg, the median change in percent pDCs at Day 85 was -54.1% in the daxdilimab group, 
compared to a +9.8% in the placebo group.  
To date, no adverse drug reactions (ADRs) for daxdilimab have been identified. Important 
potential risks for daxdilimab include viral infection and viral reactivation, opportunistic infection, 
malignancy (other than non-melanoma skin cancer), and hypersensitivity reactions including 
anaphylaxis. Other potential risks include injection site reactions, vaccine interaction, drug-drug 
interactions, and reproductive toxicity. 


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2.2.2. 
Known Potential Benefits 
In this Phase 2 trial, it is hypothesized that participants with active, proliferative LN may see an 
improvement in their condition as a result of participating in the trial.  
Participation in this trial may help generate future benefit for larger groups of patients with LN if 
daxdilimab proves to be successful in treating this disease. 
2.2.3. 
Overall Benefit Risk Conclusion 
All quality, pharmacology and toxicology data, and satisfactory safety and tolerability data 
demonstrated in nonclinical and clinical studies are considered sufficient to expect a positive 
benefit/risk assessment for the treatment of patients with active, proliferative LN with daxdilimab, 
and therefore to initiate this trial. 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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3. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
To evaluate the efficacy of 
daxdilimab in combination 
with SOC compared to 
placebo in combination 
with SOC in participants 
with active, proliferative 
LN. 
Proportion of participants achieving Complete Renal Response 
(CRR) at 
 
CRR is defined as meeting all of the following: 
 Estimated glomerular filtration rate (eGFR) ≥ 60 
mL/min/1.73m2 or no worse than 15% below baseline 
 24-hour UPCR ≤ 0.5 mg/mg  
 No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
Secondary Objectives  
Secondary Endpoints 
To assess overall renal 
response (ORR) (defined 
as CRR plus partial renal 
response [PRR]) with 
daxdilimab versus placebo 
in participants with active, 
proliferative LN. 
 
 
Proportion of participants achieving ORR at 
 
 
See above for definition of CRR. PRR is defined as meeting all 
of the following: 
 eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below 
baseline 
 Improvement in 24-hour UPCR:  
 For participants with a baseline UPCR ≤ 3.0 mg/mg: 
< 1.0 mg/mg 
 For participants with a baseline UPCR > 3.0 mg/mg: 
> 50% improvement from baseline and ≤ 3.0 mg/mg 
 No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
To assess the change from 
baseline in eGFR with 
daxdilimab versus placebo 
in participants with active, 
proliferative LN. 
 Change from baseline in eGFR at Week 52. 


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To evaluate the ability to 
improve dose requirements 
of oral corticosteroids 
(OCS) with daxdilimab 
versus placebo in 
participants with active, 
proliferative LN. 
Proportion of participants able to taper OCS to ≤ 2.5 mg/day 
prednisone-equivalent by Week 24 and maintain this dose 
through Week 52. 
Sustained reduction of OCS dose: 
 Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and 
not exceeding this dose through Week 52 and 
 No discontinuation of study intervention or use of restricted 
medication beyond the protocol allowed threshold before 
assessment 
To characterize the PK and 
immunogenicity of 
daxdilimab in participants 
with active, proliferative 
LN. 
 Serum concentration of daxdilimab. 
 Rate of ADA directed against daxdilimab and ADA titer for 
the duration of the study. 
To evaluate the safety and 
tolerability of daxdilimab 
in combination with SOC 
in participants with active, 
proliferative LN. 
 Incidence of treatment-emergent adverse events (TEAEs). 
 Incidence of treatment-emergent serious adverse events 
(TESAEs). 
 Incidence of treatment-emergent AEs of special interest 
(TEAESIs): hypersensitivity reaction, including 
anaphylaxis, severe (Grade 3 or higher) viral 
infection/reactivation, herpes zoster, opportunistic infection, 
and malignancy (except non-melanoma skin cancer). 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This trial is a Phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group 
trial to assess the efficacy and safety of daxdilimab in patients with active, proliferative lupus 
nephritis despite standard of care. An overview of the trial design is presented in the schematic 
provided in Section 1.2 and details of trial activities are provided in Section 1.3. 
Approximately 210 participants will be randomized in a ratio of 1:1:1 (70 participants per group) 
to receive either daxdilimab 
 mg or 
mg SC or placebo SC in addition to SOC background 
therapy as described below in Table 5. Randomization will be stratified by: 
 Pre-randomization urine protein to creatinine ratio (UPCR) < 3.0 mg/mg vs. ≥ 3.0 mg/mg 
 Screening eGFR < 60 mL/min/1.73m2 vs. ≥ 60 mL/min/1.73m2 
Table 5 
First Year Treatment Assignment 
Group 
1 
2 
3 
 
 
 
 
Table 6 
Second Year Treatment Assignment 
Group 
1 
2 
3 
 


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Participants may enter the study taking daily OCS at a maximum dose of 0.5 mg/kg/day of 
prednisone-equivalent, not to exceed 40 mg/day, and must be on a stable dose for at least 10 days 
prior to Randomization. In addition, participants will receive IV methylprednisolone pulse 
500 mg on the day of Randomization, prior to receiving the study intervention, unless they 
received a methylprednisolone pulse of ≥ 500 mg within 10 days prior to Randomization 
followed by a reducing taper of OCS for participants already taking OCS prior to entry. 
For participants who are not already taking prescribed MMF prior to Randomization, the dosing 
of MMF will start at 500 mg twice a day (BID) for a total daily dose of 1 gm/day for the first 
week, increasing to 1 gm BID for a total daily dose of 2 gm/day for the second and subsequent 
weeks (ie, beginning on Day 8). Prior to initiation of MMF, please refer to the restricted 
medications section in prior and concomitant therapy criteria because of potential interaction 
with MMF. An equivalent dose of mycophenolic acid (MPA) may be used as an alternative to 
MMF. 
This trial will comprise a Screening Period of approximately 4 weeks (Days -28 to -1), 
a Treatment Period with Randomization on Day 1 followed by treatment through 
 (
 
 totaling 
 
 
 
 Under exceptional circumstances such as delayed laboratory results, drug washout, 
or the impact of COVID-19, the Screening Period may be increased by 2 weeks, upon approval 
by the Medical Monitor. In general, re-screening of participants may occur only in consultation 
with and approval by the Medical Monitor. The trial will be conducted on an outpatient basis. 
For all administrations, study intervention will be administered by site staff in the clinic and the 
participant will be observed for at least 60 minutes after the first three doses as well as at 
 
 Participants who prematurely stop dosing prior to Week 52 will be followed for regularly 
scheduled visits through Week 52 unless participants withdraw consent of trial participation (See 
Section 7.1.3) or are lost to follow-up (See Section 7.2). Participants should be followed to 
assess AE/SAEs for at least 12 weeks after the last study intervention administration, 
approximately 4, 8, and 12 weeks after the last study intervention dose, unless the participant 
withdraws consent. Participants who prematurely stop dosing after Week 52 but remain in the 
study will complete the End-of-Treatment (EOT) Visit and the SFU Period, unless the participant 
withdraws consent. Participants will not automatically be removed from the trial if any 
administration of study intervention is missed.  
Rescue therapy for worsening LN may be administered at the discretion of Investigators as 
clinically indicated. Rescue therapy includes the initiation of any new treatment for lupus or 
lupus nephritis or an increase from baseline in the standard-of-care background therapy 
(MMF/MPA, or corticosteroids). For any rescue medications, study intervention may be 
continued after discussion with and approval by the Horizon Medical Monitor. However, if the 
participant receives a prohibited medication as a rescue, study intervention will be discontinued 
(See Section 6.7.2). Participants who receive rescue therapy will be considered treatment failures 
for subsequent endpoint analyses (such as CRR). 
The primary assessment of the efficacy endpoints will be performed at 
. The 


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final evaluation of the double-blind Treatment Period will occur at 
. The SFU Period 
will begin after completion of the 
 EOT Visit and will last for 8 weeks. All participants 
will continue to receive SOC immunosuppressive background therapy with MMF/MPA and 
OCS, unless the participant has successfully discontinued OCS. Participants will continue to 
follow all trial requirements and will return to the clinical site for the Week 112 End-of-Study 
Visit for final safety assessments, as described in the Schedule of Activities (SoA), and return all 
remaining trial-related supplies not previously returned. 
Safety assessments, including monitoring and recording of all AEs, whether or not drug-related, 
measurement of vital signs, physical examinations, and monitoring of hematology and blood 
chemistry, will be performed. 
4.2. 
Scientific Rationale for Study Design 
The proposed trial design is considered appropriate for assessing the efficacy, safety, tolerability, 
PK, and immunogenicity of daxdilimab in participants with active, proliferative lupus nephritis. 
4.3. 
Justification for Dose 
Daxdilimab has been tested in a first-in-human single-ascending dose trial in adult subjects with 
type I IFN-mediated autoimmune diseases, and a phase 1 multiple-ascending dose (MAD) trial in 
adult participants with autoimmune disease with up to 
. Daxdilimab 
treatment resulted in rapid and durable depletion of blood pDCs. In the MAD trial, the median 
percent change from Baseline in CLASI-A was -dose responsive for subjects administered
 
 Both SAD and MAD trials demonstrated acceptable safety profiles. A Phase 2 trial 
(Study VIB7734.P2.S1) currently enrolling participants with SLE is dosing daxdilimab at
 
 followed by an open-label extension study (HZNP-DAX-
204) to evaluate long-term safety and tolerability of daxdilimab up to Week 96. 
In this Phase 2 trial in participants with active, proliferative LN, daxdilimab will be compared to 
placebo in addition to SOC background therapy. In a Phase 2 study in a similar population of 
proliferative LN patients evaluating anifrolumab up to 
, a Type-1 IFNAR antagonist 
mAb, the dosage approved for the treatment of moderate to severe SLE 
 was 
no different from placebo in inducing renal responses whereas an intensified dosing regimen 
consisting of 3 months of induction with anifrolumab 
 demonstrated a trend 
towards a higher proportion of patients achieving renal response at 1 year. This difference may 
be explained by potential IFN overexpression in the kidneys and potential loss of anifrolumab 
concentration due to proteinuria. One of the main mechanism of actions of pDC depletion is 
through suppression of the overactivated Type-1 IFN system and prompt suppression of IFN 
activity in the kidney is thought to be key to achieving meaningful therapeutic responses. Given 
the overlapping mechanism of action and potential urinary loss of daxdilimab in patients with 
proteinuria, we propose to initiate treatment with daxdilimab 
 SC or placebo 
at baseline,
 to minimize the risk of undertreatment due to an insufficient 
dose or urinary loss of daxdilimab. Starting at Week 8, participants on daxdilimab will receive 
either daxdilimab
 or daxdilimab
 through 
; at 
 
 all participants will be assigned to a 
 based upon the 
renal response observed at 
 and will either receive daxdilimab or placebo every 
 through 
 (last dose administered at 
) in addition to SOC therapy. 


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A 52-week treatment duration is considered sufficient to demonstrate an effect on the primary 
and secondary outcome measures selected for this study. The second year of the trial will provide 
additional data to evaluate long-term safety as well as the 
 
 Current nonclinical safety data, the clinical study currently 
enrolling participants with SLE that will dose daxdilimab for 
, and belimumab’s 
Phase 3 trial dosing through 
 support this treatment duration. 
4.4. 
End-of-Study Definition 
A participant is considered to have completed the trial if he or she was followed through the last 
protocol-specified visit (ie, Week 112), regardless of the number of doses of study intervention 
that were received as shown in the SoA (See Section 1.3). 
The end of study date is defined as the date when the last participant across all sites is assessed (ie, 
last subject last visit), including any additional parts in the study (eg, long-term follow-up, 
additional antibody testing), as applicable. 
 
 


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
All participants must meet/provide all of the following criteria to be eligible for trial 
participation: 
1. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act [HIPAA] in the United States) obtained from the 
participant prior to performing any protocol-related procedures, including screening 
evaluations. 
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the 
duration of the trial. 
3. Adult men or women ≥ 18 and ≤ 80 years of age. 
4. Fulfill the 2019 European League Against Rheumatism/American College of 
Rheumatology Classification Criteria for SLE (Aringer et al, 2019). 
5. Have at least one of the following at Screening per central lab: 
 Antinuclear antibodies (ANA) ≥ 1:80. 
 Anti-dsDNA antibodies elevated to above normal range as established by the 
central laboratory (ie, positive results). 
 Anti-Smith antibodies elevated to above normal (ie, positive results). 
6. Diagnosis of proliferative LN based on a renal biopsy obtained within 6 months prior to 
signing the informed consent form (ICF) or during the Screening Period: 
 Class III (± class V) or class IV (± class V) LN according to the World Health 
Organization (WHO) or 2003 ISN/RPS classification (based on local evaluation 
of renal biopsy). 
 Note: the local biopsy report will be used to confirm participant eligibility. The 
submission of Screening biopsy sample (archived or fresh tissue block, slides, or 
digital pathology images) for adjudication is required to participate in the study. 
7. Urine protein to creatinine ratio ≥1.5 mg/mg (113.17 mg/mmol), obtained via a 24-hour 
urine collection at both: 
 The start of Screening and 
 Within 14 days of expected date of Randomization. Without the results of the 
second sample, which will be used for stratification, participants cannot be 
randomized. The second sample may be collected after a minimum of 10 days 
after the Screening sample was obtained. The second sample may be repeated 
once, upon approval by the Medical Monitor (this will not be considered a 
re-screen). Typical turn-around time for results from central laboratory is up to 
7 days. On rare occasion, an extension of the 28-day screening window is allowed 


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if re-collection of the sample is necessary or the results needed for Randomization 
are delayed. 
8. Estimated glomerular filtration rate (as calculated by the MDRD formula, with screening 
laboratory results for serum creatinine value) ≥35 mL/min/1.73 m2. 
9. Negative serum β human chorionic gonadotropin (β-hCG) test at Screening (females of 
childbearing potential only).  
 Note: if the result of the serum β-hCG test is borderline or thought to be false 
positive, the test may be repeated during the Screening Period. The participant 
may continue if the repeat test is negative. Women of childbearing potential 
(WOCBP) (including those with an onset of menopause < 2 years prior to 
Screening, non-therapy-induced amenorrhea for < 12 months prior to Screening, 
or not surgically sterile [absence of ovaries and/or uterus]) must have negative 
serum and urine pregnancy tests during Screening and Randomization, 
respectively. Women of childbearing potential are defined as those who are not 
surgically sterile (ie, surgical sterilization includes bilateral salpingectomy, 
bilateral oophorectomy, or hysterectomy) or those who are not postmenopausal 
(defined as 12 months with no menses without an alternative medical cause and a 
follicle-stimulating hormone [FSH] within the postmenopausal range as 
established by the central laboratory during the Screening Period, unless on 
postmenopausal hormone replacement therapy 
 WOCBP who are sexually active with a non-sterilized male partner must agree to 
use a highly effective method of contraception (Table 7) from signing of the 
informed consent and must agree to continue using such precautions through the 
end of the study follow-up or 6 months (approximately 5 half-lives) following the 
last dose of IP in the case of early withdrawal from the study, and refrain from 
egg retrieval/egg donation during this period. A decision about contraception after 
this point should be made by the participant and her regular healthcare providers.  
 Sustained abstinence is an acceptable practice; however periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of 
contraception. 
Table 7 
Highly Effective Methods of Contraception 
Physical Methods  
Hormonal Methods a  
 
Intrauterine device   
 
Intrauterine hormone-releasing system b  
 
Bilateral tubal occlusion  
 
Vasectomized partner c  
 
Sexual abstinence d  
Combined (estrogen and 
progestogen-containing hormonal 
contraception)  
 
PO (combined pill)  
 
Injectable  
 
Transdermal (patch)  
Progestogen-only hormonal contraception 
associated with inhibition of ovulation e  
 
Injectable  
 
Implantable  
 
Intravaginal  


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NOTE: because mycophenolate affects the 
metabolism of hormonal contraceptives and 
may reduce their effectiveness in women 
receiving MMF or MPA who are using 
hormonal contraceptives for birth control, the 
participant must employ an additional 
contraceptive method (eg, barrier method). 
PO: oral(ly).  
a Any change in hormonal birth control during the study requires use of at least two methods of highly 
effective contraception for at least two months.   
b This is also considered to be a hormonal method.  
c A vasectomized partner is a highly effective method of birth control provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success.  
d Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the participant.  
e Progestogen-only hormonal contraception where inhibition of ovulation is not the primary mode of action 
(minipill) is not accepted as a highly effective method.  
10. Men who are not vasectomized must agree to use appropriate contraception so as to not 
impregnate a female partner of reproductive potential during the trial and continuing for 
at least 3 months (approximately 5 half-lives) after receipt of the last dose of daxdilimab 
and refrain from donating sperm during this period.  
5.2. 
Exclusion Criteria  
Participants will be ineligible for trial participation if they meet any of the following criteria at 
the Screening and/or Day 1 Visits, as applicable: 
General Exclusion Criteria 
1. Individuals involved in the conduct of the study, their employees, or immediate family 
members of such individuals. 
2. Any condition that, in the opinion of the Investigator or the Sponsor/Central Review 
Committee, would interfere with evaluation of the IP or interpretation of participant safety 
or study results. 
3. Weight > 160 kg (352 pounds) at Screening. 
4. History of allergy, hypersensitivity reaction, or anaphylaxis to any component of the IP or 
to a previous mAb or human Ig therapy. 
5. Known intolerance to ≤1.0 gm/day of MMF or equivalent dose of MPA. 
6. Participation in another clinical study with an investigational drug within 4 weeks prior to 
Day 1 or within 5 published half-lives, whichever is longer. 
7. Breastfeeding or pregnant women or women who intend to become pregnant anytime 
from signing the ICF through 6 months after receiving the last dose of IP. 
8. History of drug or alcohol abuse that, in the opinion of the Investigator, might affect 
participant safety or compliance with visits, or interfere with other study assessments. 


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9. Major surgery within 8 weeks prior to Screening or elective surgery planned from 
Screening through the end of the trial. 
10. Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to 
Screening through Randomization. 
11. A diagnosis of pure Class V membranous LN based on a renal biopsy obtained within 
6 months prior to signing ICF or during the Screening Period. 
12. History of dialysis within 12 months prior to signing the ICF or expected need for renal 
replacement therapy (dialysis or renal transplant) within a 12-month period after 
enrollment. 
13. History of, or current renal diseases (other than LN) that in the opinion of the Investigator 
could interfere with the LN assessment and confound the disease activity assessment 
(eg, diabetic nephropathy). 
14. Known history of a primary immunodeficiency or an underlying condition such as known 
human immunodeficiency virus (HIV) infection, a positive result for HIV infection per 
central laboratory, splenectomy, or any underlying condition that in the opinion of the 
Investigator significantly predisposes the participant to infection. 
15. During Screening, any of the following per central laboratory (tests may be repeated once 
within the same Screening Period to confirm results prior to Randomization):  
 Aspartate aminotransferase > 2.5× upper limit of normal (ULN) 
 Alanine aminotransferase > 2.5× ULN 
 Total bilirubin > 1.5× ULN (unless due to Gilbert’s syndrome) 
 Serum IgG < 600 mg/dL (or < 6 g/L) or < 400 mg/dL (<4 g/L) if due to active 
SLE/LN 
 Neutrophil count < 1000/μL (or < 1.0×109/L) or < 500/μL (< 0.5×109/L) if due to 
active SLE 
 Platelet count < 50,000/μL (or < 50×109/L) or < 25,000/μL (< 25×109/L) if due to 
active SLE 
 Hemoglobin < 8 g/dL (or < 80 g/L) or < 7 g/dL (< 70 g/L) if due to active SLE 
 Glycosylated hemoglobin > 8% (or > 0.08) 
 Total lymphocyte count < 200 cells/mm3 
16. Confirmed positive test for hepatitis B serology defined as: 
 Hepatitis B surface antigen, or  
 Hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA detected 
above the lower limit of quantitation (LLOQ) by reflex testing by the central 
laboratory at Screening. 
Note that participants who are HBcAb positive at Screening will be tested every 3 months for 
HBV DNA. IP will be discontinued if the participant’s HBV DNA levels are confirmed to 
exceed the LLOQ as per the central laboratory. 
17. Positive test for hepatitis C virus antibody unless documented as having had successful 
treatment of active hepatitis C infection. 
18. Active tuberculosis (TB), or a positive IFN-gamma release assay (IGRA) test at 
Screening, unless documented history of appropriate treatment for active or latent TB. 
Note that participants with an indeterminate IGRA test result with well-documented 


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previous treatment do not need to repeat testing and are eligible for randomization. 
Participants with an indeterminate IGRA test result can repeat the test, but if the repeat 
test is also indeterminate, they are excluded. 
19. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus 
[CMV]) at any time prior to Randomization, including, but not limited to, disseminated 
herpes, herpes encephalitis, recent recurrent herpes zoster (defined as 2 episodes within 
the last 2 years), or ophthalmic herpes. 
20. Any herpes zoster, CMV, or Epstein-Barr virus infection that was not completely resolved 
12 weeks prior to Randomization. 
21. Any of the following within 30 days prior to signing the ICF and through Randomization: 
 Clinically significant active infection in the opinion of the Investigator, including 
ongoing, and chronic infection requiring antibiotics or antiviral medication (chronic 
nail infections are allowed). 
 Any infection requiring hospitalization or treatment with intravenous anti-infectives. 
 A participant with a documented positive SARS-CoV-2 test may be rescreened: 
o At least 2 weeks after a positive test if the participant is asymptomatic (no 
negative test result is required). 
o At least 3 weeks after symptomatic COVID-19 illness (no negative test result 
is required). 
22. Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment 
within 2 years prior to Randomization. 
23. Any acute illness or evidence of clinically significant active infection on Day 1. 
24. Clinically significant cardiac disease including unstable angina, myocardial infarction, 
congestive heart failure within 6 months prior to Randomization. Any cardiac condition 
including, but not limited to the following, if in the opinion of the Investigator or Medical 
Monitor, would increase the risk of study participation: 
 Inadequately controlled arrythmia 
 Uncontrolled hypertension 
 Presence of clinically significant abnormality on ECG 
25. History of cancer within the past 5 years, except as follows: 
 In situ carcinoma of the cervix treated with apparent success with curative therapy 
> 12 months prior to Screening, or 
 Cutaneous basal cell or squamous cell carcinoma treated with curative therapy. 
26. Receipt of a live vaccine within 4 weeks prior to Day 1.  
27. Participant should be assessed for epidemiologic risk of COVID-19 (ie, recent exposure, 
high-risk housing) and for health-related risk of COVID-19 severity based on current 
understanding of risk factors for severe disease when making a decision regarding the 
individual’s risk of participation. Participants who have COVID-19 or other significant 
infection, or in the judgment of the Investigator, may be at a high risk of COVID-19 or its 
complications, should not be randomized. 
Disease-Related Criteria 
28. Active severe or unstable neuropsychiatric SLE including, but not limited to: aseptic 
meningitis, cerebral vasculitis, myelopathy, demyelination syndromes (ascending, 


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transverse, acute inflammatory demyelinating polyradiculopathy), acute confusional state, 
impaired level of consciousness, psychosis, acute stroke or stroke syndrome, cranial 
neuropathy, status epilepticus, cerebellar ataxia, and mononeuritis multiplex:  
a) That might cause the participant to be unable to fully understand the ICF. 
OR  
b) In the opinion of the Investigator, protocol-specified SOC is insufficient to control 
neurologic features of SLE and utilization of a more aggressive therapeutic 
approach, such as adding IV cyclophosphamide and/or high dose IV pulse 
corticosteroid therapy or other treatments not permitted in the protocol, is 
indicated or anticipated. 
29. Documented history of systemic sclerosis or diagnosis of SLE with overlapping systemic 
sclerosis. 
30. History of, or current diagnosis of, catastrophic anti-phospholipid syndrome (APS) or 
APS-related thromboembolic event or pregnancy loss within 1 year prior to signing the 
ICF. Participants with APS adequately controlled by anticoagulants or aspirin for at least 
12 weeks may be recruited to the study. 
31. History of any non-SLE disease that has required treatment with oral or parenteral 
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing 
the ICF. 
Prior and Concomitant Therapy Criteria 
32. Receipt of any of the following treatments within the following timeframes. 
 6 weeks prior to Randomization: 
o Opioid use above 40 mg/day morphine-equivalent, unstable dosing, or 
initiation of regular dosing 
o IV corticosteroids > 3.0 gm (cumulative dose) 
 8 weeks prior to Randomization: 
o Immunoglobulins (except anti-SARS-CoV-2 therapeutic antibodies) 
o Calcineurin inhibitors (eg, cyclosporin, voclosporin, tacrolimus), mechanistic 
target of rapamycin inhibitors, retinoids, thalidomide, lenalidomide, or Janus 
kinase inhibitors 
o Transfusion with blood, packed red blood cells, platelets or treatment with 
plasmapheresis, plasma exchange, or Therakos® photopheresis 
 12 weeks (or 5 half-lives, whichever is longer) prior to Randomization: 
o IV cyclophosphamide > 2 pulses of high dose (≥ 0.5 gm/m2) or > 4 doses of 
low-dose (500 mg every 2 weeks)  
o Alkylating agents other than cyclophosphamide (eg, chlorambucil) 
o Cytokine or cytokine receptor antagonists, including but not limited to 
interleukin (IL)-1, IL-6, IL 17, IL-12/23, IL-23, IFN, integrin, or TNFα 
antagonists (except for IFNα kinoid, for which receipt at any time is 
exclusionary) 
o Belimumab, abatacept, or eculizumab 


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o Other biologics used for immunosuppression or immunomodulation (eg, IFN 
therapy, IL-2)  
o Investigational drugs 
o IPP-201101 (Lupuzor™) 
 24 weeks prior to Randomization: 
o B cell-depleting therapies (eg, rituximab, ocrelizumab, ofatumumab, 
inebilizumab, telitacicept) other than atacicept or obinutuzumab 
o Receipt of systemic glucocorticoids (ie, PO, rectal, IV or IM) for more than a 
total of 2 weeks for any concurrent illness, including asthma, inflammatory 
bowel disease, or drug-induced SLE 
 40 weeks prior to Randomization: 
o Atacicept 
 1 year prior to Randomization: 
o Bacille-Calmette-Guerin (BCG) vaccination 
 1.5 years prior to Randomization: 
o Obinutuzumab 
 The following medications must be discontinued prior to the day of Randomization 
(because of potential interaction with MMF):  
o Methotrexate 
o Azathioprine 
o Leflunomide 
o Mizoribine 
o Proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, 
pantoprazole, etc.) 
o Cholestyramine 
5.3. 
Restrictions 
5.3.1. 
Fasting Lipid Profile 
Participants will be required to fast for at least 8 hours prior to assessment of lipid profile at the 
visits described in the SoA (See Section 1.3). If the participant has not fasted, he/she should fast 
before the next visit, and the test can be done at that visit.  
5.3.2. 
Perioperative Management of Investigational Product  
Planned surgeries should be avoided during the study if clinically feasible.  
5.3.3. 
Major Surgeries  
Pre-operative management of study intervention: If a non-urgent major surgery becomes 
necessary during the study, it should be scheduled at least 4 weeks after the last administration of 
study intervention, if clinically feasible. The determination of whether or not a surgery is 
“urgent” will be at the discretion of the Investigator, preferably in consultation with 
the Sponsor/Designee Medical Monitor.  


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5.3.4. 
Non-Major Surgeries  
The decision to withhold study intervention administration is at the Investigator’s discretion.   
Post-operative management of study intervention: study intervention administration may be 
resumed at the Investigator’s discretion after all of the following criteria are met:  
External wound healing is complete and   
Any post-operative antibiotic course is completed and  
All acute surgical complications have resolved.  
5.3.5. 
Blood Donation  
Participants must not donate blood from date of Randomization until 6 weeks after the last dose 
of MMF/MPA. 
5.4. 
Screen Failures 
Screen failures are defined as individuals who consent to participate in the clinical trial but are not 
subsequently enrolled in the trial. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAEs. 
Individuals who do not meet the criteria for participation in this trial (“Screen Failure”) may be 
rescreened once, if both the Investigator and Sponsor are in agreement regarding rescreening and 
if the Investigator determines that the participant can satisfy all of the eligibility criteria. All 
procedures planned at the Screening Visit, including signature of a new informed consent form, 
will be performed. Additional information regarding rescreening will be provided in the 
Interactive Response Technology (IRT) Manual. 


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6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
6.1. 
Study Interventions Administered 
This trial involves SC administration of daxdilimab 
 or 
 mg or placebo 
 
 based upon the renal 
response observed at 
 of either daxdilimab 
 or 
 mg or placebo 
 
 (See Table 5 and 
Table 6). The study intervention (IP and placebo) will be administered by trial site staff in the 
clinic. On 
, participants will remain under observation for 
at least 1 hour after administration of study intervention. In addition, The IP will be provided by 
the Sponsor. Further details regarding the IP and placebo can be found in Table 8. 
Table 8 
Study Interventions Administered 
Intervention Label 
Investigational Product 
Placebo 
Intervention Name 
Daxdilimab 
Placebo 
Intervention Description 
Normal Saline 
Type 
Active Drug 
Placebo 
Dose Formulation 
2R vial 
See Pharmacy Manual. 
Dosage Level(s) 
Route of Administration 
SC injection  
SC injection 
Sourcing 
Horizon Therapeutics 
Commercially available normal saline 
Packaging and Labeling 
Please refer to the study-specific Pharmacy Manual for information on packaging 
and labeling.  
The label text for the study interventions will comply with applicable regional, 
national, and local laws and regulations and will include at a minimum the 
protocol number, contents of the vial, the appropriate regional cautionary 
statements, lot number, storage conditions, and the name of the Sponsor. 
Administration Instructions 
Daxdilimab should be administered by 
clinic staff trained in best practices for 
SC administration of treatments. More 
details on the administration method 
are described in the Pharmacy 
Manual. 
Placebo should be administered by 
clinic staff trained in best practices for 
SC administration of treatments. More 
details on the administration method 
are described in the Pharmacy Manual. 
2R = 2 mL injection vial; HCl = hydrochloric acid;
 
; 
SC = subcutaneous. 
The contents of the label will be in accordance with all applicable regulatory requirements. 


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In addition to study intervention, participants will be expected to adhere to SOC 
immunosuppressive background therapy, consisting of the combination of MMF/MPA and 
corticosteroids. Participants may enter the study taking daily OCS at a maximum dose of 
0.5 mg/kg/day of prednisone-equivalent, not to exceed 40 mg/day, and must be on a stable dose 
for at least 10 days prior to Randomization. In addition, participants will receive IV 
methylprednisolone pulse 500 mg on the day of Randomization, prior to receiving the study 
intervention, unless they received a methylprednisolone pulse of ≥ 500 mg within 10 days prior 
to Randomization followed by a reducing taper of OCS for participants already taking OCS prior 
to entry. For participants who are not already taking prescribed MMF prior to Randomization, 
the dosing of MMF will start at 500 mg BID for a total daily dose of 1 gm/day for the first week, 
increasing to 1 gm BID for a total daily dose of 2 gm/day for the second and subsequent weeks 
(ie, beginning on Day 8). An equivalent dose of MPA may be used as an alternative to MMF. 
See Section 6.7.4.1 for additional details. 
6.2. 
Preparation, Handling, Storage, and Accountability 
6.2.1. 
Preparation and Administration 
Placebo is to be procured as commercially available Normal Saline. 
Study intervention (daxdilimab and placebo) is to be administered SC. To maintain the same 
number and volume of injections across all groups, the required dose will be administered by 
 
. 
The first day of dosing is considered Day 1. To reduce the risk of unblinding to the study 
personnel who will be evaluating the participant, study intervention will be administered by an 
unblinded pharmacist/IP Manager or a study site staff member who is not otherwise involved in 
the participant’s participation in the study. The study intervention administrator should be 
experienced in performing SC injections. The skin surface of the anterolateral thigh, upper outer 
triceps area, upper buttocks, or abdomen (avoiding a 2-inch [5 cm] radius around the umbilicus) 
should be prepared with an alcohol wipe and allowed to air dry. The skin will be pinched to 
isolate SC tissue from the muscle. The needle will be inserted at a 90-degree angle to the skin 
surface approximately halfway into the SC tissue. The prepared study intervention will be slowly 
injected (at least 5 second duration is recommended per 
 syringe) into the SC tissue using 
gentle pressure. The area should not be massaged after injection. The SC injection site can be 
changed during the study as per the participant’s preference. 
Further guidance and information for the preparation and administration of study intervention are 
provided in the Pharmacy Manual. 
6.2.2. 
Labeling 
Trial drug packaging will be in compliance with Sponsor standard procedures and will meet all 
local requirements.  


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6.2.3. 
Storage 
Daxdilimab vials must be refrigerated at 2-8°C (36°F to 46°F) until the day of use. 
IP will be dispensed by the trial site only for administration to trial participants. 
6.2.4. 
Drug Accountability 
The Principal Investigator at each site is responsible for the control of all trial drugs and 
delegating preparation and drug accountability responsibilities to a pharmacist (or designee in 
accordance with institutional policies and local regulations), who must maintain adequate records 
of the receipt and disposition of all trial drugs shipped to the site. Records will include receipt 
dates, condition at time of receipt, quantities received, quantities dispensed, quantities returned 
or destroyed and the identification numbers of the participant who received trial drug. 
As permitted by site policy, all empty, partially empty, and full vials of trial drug must be 
retained by the site under locked storage until drug accountability has been completed. 
Periodically throughout the trial and at the conclusion of the trial, inventory checks and 
accountability of trial materials will be conducted by a representative of the Sponsor. 
Once accountability is completed, the Sponsor’s representative will either authorize onsite 
destruction or the return of trial drug (all used, partially used and unused vials) to Almac Clinical 
Services, or contracted depots, for central destruction.  
The completed Drug Accountability and Drug Return/Destruction Record(s) will be returned to 
the Sponsor’s representative. The Investigator’s copy of the Drug Accountability and Drug 
Return/Destruction Record(s) must document accurately the return and/or destruction of all trial 
drug and be maintained by the pharmacist or designee. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.3. 
Assignment to Study Intervention 
An interactive voice/web response system (IXRS) will be used for Randomization on Day 1 to a 
Treatment Group (daxdilimab 
 mg, 
 mg, or placebo) and assignment of study intervention 
kit numbers. A participant is considered randomized into the study when the Investigator or 
appropriate designee notifies the IXRS that the participant meets eligibility criteria and the IXRS 
provides the assignment of treatment group. 
 
(See Section 4.1). After the Investigator or 
appropriate designee notifies the IXRS of the participants’ observed renal responses from the 
 the IXRS provides the assignment of study intervention kit 
numbers. 
Additional details are provided in the IRT Manual. 
The Randomization dates are to be documented in the participant’s medical record and on the 
enrollment case report form (CRF). 


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6.4. 
Blinding/Masking 
This is a double-blind trial; therefore, the Sponsor, Investigator and participants will not know 
the treatment administered. 
To reduce the risk of unblinding to the trial personnel who will be evaluating the participant, an 
otherwise uninvolved, unblinded third party (eg, a pharmacist/IP Manager or trial-site staff 
member) will be responsible for the dispensation and administration of all trial interventions and 
will endeavor to ensure that there are no differences in time taken to dispense following 
randomization.  
This third party will instruct the participant to avoid discussing the dosing or packaging of the 
trial intervention with the Investigator.  
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded trial 
intervention records at the site(s) to verify that randomization/dispensing has been conducted 
accurately.  
In the event of unblinding, the instructions in the IRT Manual will apply. 
6.5. 
Treatment Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
pharmacist/IP Manager, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.  
The Principal Investigator is responsible for ensuring that dosing is administered in compliance 
with the protocol. Delegation of this task must be clearly documented and approved by the 
Investigator. 
An inventory of the trial drug supplies will be performed by the authorized site designee and 
recorded onto the Drug Accountability Log in the participant’s source document records or 
equivalent. 
A record of the quantity of daxdilimab or placebo dispensed and administered by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose reductions 
will also be recorded. 
6.6. 
Treatment of Overdose 
In the event of an overdose, the Investigator/treating physician should: 
 Evaluate the participant to determine, in consultation with the Medical Monitor, if 
possible, whether study intervention should be interrupted or whether the dose should be 
reduced. 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities 
 Consultation with the Medical Monitor is required for prompt reporting of clinically 
apparent or laboratory adverse events possibly related to overdosage.  Consultation with 


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the Medical Monitor is also required even if there are no adverse events, in order to 
discuss further management of the participant.  If the overdose results in clinically 
apparent or symptomatic adverse events, the participant should be followed carefully 
until all signs of toxicity are resolved or returned to baseline and the AE(s) should be 
recorded/reported. 
6.7. 
Prior and Concomitant Therapy 
6.7.1. 
Concomitant Medications  
Participants must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting the Investigator.  
Concomitant (including immunosuppressant) medications should be administered consistently 
and if possible after all visit procedures and assessments, including study intervention 
administration and post-administration PK blood draws (if applicable). 
Participants who are taking concomitant medications must be informed that on the day of the 
study visit, these medications are to be taken only after the study procedures and assessments are 
completed (if clinically appropriate) or as advised by the Investigator. 
At each visit, use of any rescue therapy for worsening LN and restricted or prohibited medication 
beyond the protocol allowed threshold will also be assessed. 
6.7.2. 
Prohibited Medications  
Receipt of any of the following treatments leads to immediate discontinuation of study 
intervention:  
 
IV, intramuscular, or SC immunoglobulins, except anti-SARS-CoV-2 therapeutic 
antibodies 
 
Cyclophosphamide or alkylating agents (eg, chlorambucil) 
 
Calcineurin inhibitors (eg, cyclosporin, voclosporin, tacrolimus), mechanistic 
target of rapamycin inhibitors, retinoids, thalidomide, lenalidomide, or Janus 
kinase inhibitors. 
 
Transfusion with blood, packed red blood cells, platelets or treatment with 
plasmapheresis, plasma exchange, or Therakos® photopheresis. 
 
Live vaccines (the Sponsor recommends that Investigators ensure all participants 
are current with recommended vaccinations per local treatment standards prior to 
entry into the study). 
 
Cytokine or cytokine receptor antagonists, including but not limited to interleukin 
(IL)-1, IL-6, IL 17, IL-12/23, IL-23, IFN, integrin, or TNFα antagonists (except 
for IFNα kinoid, for which receipt at any time is exclusionary). 
 
Belimumab, abatacept, or eculizumab 
 
Other biologics used for immunosuppression or immunomodulation (eg, IFN 
therapy, IL-2) 


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 
Investigational drugs 
 
IPP-201101 (Lupuzor™) 
 
B cell-depleting therapies (eg, rituximab, ocrelizumab, ofatumumab, 
inebilizumab, telitacicept) other than atacicept or obinutuzumab 
 
Receipt of systemic glucocorticoids (ie, PO, rectal, IV or IM) for more than a total 
of 2 weeks for any concurrent illness, including asthma, inflammatory bowel 
disease, or drug-induced SLE 
 
Atacicept 
 
BCG vaccination 
 
Obinutuzumab 
6.7.3. 
Restricted Medications  
As daxdilimab is an investigative immunomodulatory agent, non-protocol permitted changes to 
immune modifiers or immunosuppressants during the study are not allowed. If a participant 
receives one of the following after Randomization, the Investigator must notify the 
Sponsor/Designee Medical Monitor immediately. The Designee Medical Monitor will determine 
with the Sponsor if the participant may continue to receive study intervention; however, the 
participant would be considered a non-responder for efficacy assessments such as CRR.  
 
Azathioprine  
 
Methotrexate  
 
Leflunomide  
 
Mizoribine  
 
Cholestyramine 
 
Increase in corticosteroids (except methylprednisolone pulses) above the protocol 
allowed doses or duration 
 
Corticosteroids with a long biologic half-life (ie, dexamethasone, betamethasone) 
 
MMF/MPA dose above or below protocol required dose or duration 
6.7.4. 
Permitted Therapies 
6.7.4.1. 
Standard of Care Immunosuppressive Background Therapy 
Permitted medications for SOC treatment for LN are described below. The SOC for LN will 
consist of the combination of MMF/MPA and corticosteroids. 
6.7.4.1.1. Mycophenolate Mofetil/Mycophenolic Acid 
The target dose of MMF will be 2 gm/day by mouth (or equivalent) throughout the study, where 
the dose is titrated to the target dose between Randomization and Week 8. For participants who 
are not already taking prescribed MMF prior to Randomization, the dosing of MMF will start at 
500 mg BID for a total daily dose of 1 gm/day for the first week, increasing to 1 gm BID for a 
total daily dose of 2 gm/day for the second and subsequent weeks (ie, beginning on Day 8). 
An equivalent dose of MPA may be used as an alternative to MMF. All participants will take 


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MMF/MPA BID (ie, morning and evening), before meals (ie, on an empty stomach), with a glass 
of water. If a dose is missed, the participant should take the next correct dose rather than 
“doubling up” at the next dosing time point. A stable dose of MMF/MPA should be maintained 
throughout the study. Adjustments of the dose due to suboptimal response, toxicity, or 
intolerability are allowed if needed according to guidelines described below. A maximum dose 
of 3.0 gm/day is allowed up to Week 24 for participants with suboptimal response between 
Weeks 8 and 24 with a reduction to ≤ 2.0 gm/day by Week 32. The dose of MMF must be stable 
from Week 40 to Week 52. 
After Week 52, MMF dose should be ≤2 gm/day. If MMF dose >2 gm/day at Week 52, taper to 
≤2 gm/day is recommended by Week 60. The dose of MMF must be stable from Week 92 to 
. 
It is not mandatory for a participant to receive 2 gm/day of MMF (or equivalent) if local 
treatment standards dictate a lower dose to be given (eg, for constitutionally small 
participants). The minimum dose of MMF is 1.0 gm/day (or equivalent) after Week 8 through 
. Participants who do not tolerate the minimum MMF dose (or equivalent) will be 
considered non-responders for responder analyses (such as CRR) but will be allowed to continue 
to receive study intervention.  However, if MMF/MPA is discontinued and a different 
immunosuppressant is started, the study intervention will be discontinued. A decrease below the 
minimum dose or withholding MMF/MPA for 14 days or less for MMF/MPA related side 
effects, such as gastrointestinal side effects, cytopenias or infection is acceptable at any time 
throughout the study. If MMF/MPA must be withheld or decreased below the minimum dose for 
more than 14 days, the participant will be considered a non-responder for responder analyses 
(such as CRR) but may continue to receive study intervention (this will not be considered as non-
compliance or a protocol deviation because the withdrawal of MMF/MPA is for safety reasons).  
The use of IV forms of mycophenolate is prohibited. 
Initial adjustment of MMF/MPA dose to achieve or maintain the target dose 
(Randomization through Week 8)  
 
Participants who are receiving MMF/MPA at a dose of 2 gm/day (or equivalent) at 
Week 0 (Day 1) will continue this dose without interruption.  
 
Participants who are not taking MMF/MPA at Week 0 (Day 1) or participants who are 
taking less than 2 gm/day (or equivalent), the dose will be titrated up with the goal of 
achieving a dose of 2 gm/day (or the therapeutic target dose if local treatment standards 
dictate a lower dose) by Week 1 (Day 8) (but not later than Week 8 (Day 57), if dose 
escalation is limited by intolerability).   
Titration of MMF/MPA should follow accepted local practice guidelines, including 
appropriate laboratory monitoring for toxicity.  
 
Participants who at Week 0 (Day 1) are taking MMF doses > 2 gm/day will have their 
dose reduced to 2 gm/day by Week 8 (Day 57) unless they meet criteria for suboptimal 
response (see below for suboptimal response).  


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MMF/MPA dose between Week 8 and 24  
The dose of MMF/MPA will be kept stable from Week 8 through Week 24 unless dose 
escalation to a maximum of 3 gm/day is necessary for suboptimal response (defined below) or a 
dose reduction is necessary to manage toxicity or intolerability.  
Criteria for suboptimal response:  
A suboptimal response is defined by UPCR values shown below at two independent 
measurements taken at least 2 weeks apart:  
 
Spot UPCR> 3 mg/mg and   
 
Spot UPCR< 15% decrease compared to baseline spot UPCR  
If a participant meets the criteria at or after Week 8, the dose may be escalated or kept above 
2 gm/day. After initial confirmation of suboptimal response, MMF/MPA can be increased up to 
3 gm/day (or equivalent) until Week 16 without re-testing for the suboptimal response 
criteria. The dose of MMF/MPA must be kept stable from Week 16 unless dose reduction is 
necessary for intolerability or MMF/MPA-related AEs. A temporary decrease below the 
minimum dose or withholding MMF/MPA for 14 days or less for MMF related side effects, such 
as gastrointestinal side effects, for cytopenias or infection is acceptable.   
MMF/MPA dose between Week 24 and Week 52:  
For participants who are taking > 2 gm/day of MMF (or MPA equivalent) at Week 24, the dose 
of MMF/MPA must be decreased to a maximum dose of 2 gm/day (or equivalent) by Week 
32. The dose of MMF/MPA must be stable from Week 40 through Week 52 (unless a dose 
reduction is necessary to manage toxicity or intolerability).   
 
MMF/MPA dose from Week 52 to 
 
The target dose of MMF/MPA will be ≤2 gm/day. If the MMF/MPA dose is >2 gm/day at Week 
52, it should be tapered to ≤2 gm/day by Week 60. 
 
MMF/MPA dose must not be changed from Week 92 to 
. 
6.7.4.1.2. Corticosteroids  
Initial corticosteroid treatment to control LN and SLE:  
Participants may enter the study taking daily OCS at a maximum dose of 0.5 mg/kg/day of 
prednisone-equivalent, not to exceed 40 mg/day, and must be on a stable dose for at least 10 days 
prior to Randomization. In addition, participants will receive IV methylprednisolone pulse 
500 mg on the day of Randomization, prior to receiving the study intervention, unless they 
received a methylprednisolone pulse of ≥ 500 mg within 10 days prior to Randomization. 
Participants may also receive one additional (optional) dose of IV methylprednisolone pulse (≤ 
500 mg) for renal or extra-renal disease activity after the Week 0 (Day 1) Visit up to and 
including the Week 8 Visit. Methylprednisolone pulse can be divided and administered on two 
consecutive days, but the cumulative dose must not exceed 500 mg. 


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Steroid tapering during the study  
Oral corticosteroid dose tapering is required during the study with the goal of fractionally reduce 
OCS to a prednisone-equivalent dose of ≤ 7.5 mg/day by Week 12 and prednisone-equivalent 
dose of ≤ 2.5 mg/day by Week 24. The rate of tapering is at the discretion of the Investigator; 
a recommended tapering schedule is provided below. 
Table 9 
Recommended Oral Prednisone Tapering Schedule 
Starting Prednisone Dose (mg/day) 
10 mg/day 
20 mg/day 
30 mg/day 
40 mg/day 
Week 2 (Day 15) 
10 
15 
25 
35 
Week 4 (Day 29) 
10 
15 
25 
30 
Week 6 (Day 43) 
7.5 
10 
20 
25 
Week 8 (Day 57) 
7.5 
10 
15 
20 
Week 10 (Day 71) 
5 
7.5 
10 
15 
Week 12 (Day 85) 
5 
7.5 
7.5 
7.5 
Week 16 (Day 113) 
2.5 
5 
5 
5 
Week 20 (Day 141) 
2.5 
2.5 
2.5 
2.5 
Week 24 (Day 169) 
2.5 
2.5 
2.5 
2.5 
If participants experience an increase in SLE disease activity upon tapering of OCS, their dose 
may be returned to a dose equal to or less than the dose prior to the taper. The return to 
the pre-taper dose will not be considered an OCS “burst and taper”. The pre-taper dose for 
various periods is defined as follows:  
 
Week 0 to Week 12: dose at Randomization  
 
After Week 12 to Week 24: the Week 12 dose  
 
After Week 24 to Week 44: the Week 24 dose  
Participants unable to taper OCS to ≤ 15 mg/day at Week 12 or ≤ 10 mg/day at Week 24 will be 
discontinued from study intervention treatment (See Section 7.1.1). However, participants who 
exceed the maximum daily OCS dose at the Week 12 or Week 24 Visits may continue to receive 
study intervention if the current dose is part of a protocol allowed temporary OCS dose (eg, burst 
and taper) increase. Participants who cannot be returned to their pre-increase dose within 14 days 
from the start of burst will have their study intervention discontinued at the next visit.  
Participants who prematurely stop dosing prior to Week 52 will be followed for regularly 
scheduled visits through Week 52 unless participants withdraw consent of trial participation (See 
Section 7.1.3) or are lost to follow-up (See Section 7.2). Participants should be followed to 
assess AE/SAEs for at least 12 weeks after the last study intervention administration, 
approximately 4, 8, and 12 weeks after the last study intervention dose, unless the participant 
withdraws consent.  
Participants who prematurely stop dosing after Week 52 but remain in the study will complete 
the EOT Visit and the SFU Period, unless the participant withdraws consent. Participants will not 
automatically be removed from the trial if any administration of study intervention is missed 


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Investigators will not be required, but may continue, to taper OCS dose beyond the target of 
2.5 mg/day up to Week 40, including discontinuation of OCS. Steroid tapering will not be 
permitted from Week 40 to Week 52.  
Continued tapering of OCS is recommended for all participants after the Week 52 Visit with the 
goal of achieving discontinuation (ie, 0 mg) by Week 76. Due to variability in participant 
responses to OCS treatment and tolerability of taper, Investigators will have flexibility of when 
the OCS dose is reduced at each visit. No change in OCS dose will be allowed from Week 92 to 
 
Steroid “burst and taper”  
A steroid burst is defined as one of the following:  
 OCS increase up to a maximum daily dose of 0.5 mg/kg/day (maximum 40 mg/day) 
prednisone-equivalent dose for up to a total of 14 days which must be fully administered 
and tapered to less than or equal to the pre-burst starting dose by the end of the 14th day. 
Any course of OCS burst must not extend beyond Week 40, regardless of when the 
course was started.  
OR  
 A maximum of 1 instance of intra-articular, tendon sheath or bursal injections (for a total 
dose of methylprednisolone ≤ 80 mg or equivalent) can be given. Participants who 
receive any intraarticular/tendon sheath/bursal injections should not receive OCS 
burst (and vice versa).  
Steroid burst is allowed as follows:  
 
From Randomization to Week 40: One burst and taper of corticosteroids for increased 
SLE disease activity or for non-SLE activity is allowed.  
Participants who receive more than one steroid “burst and taper” or who violate 
the above criterion may continue to receive study intervention after approval by 
Sponsor/Designee Medical Monitor, but will be considered non-responders for 
subsequent responder analyses (such as CRR) to be further described in the SAP, 
regardless of whether the OCS “burst” was administered for increased SLE activity or 
non-SLE causes.   
 
Increase in corticosteroids from Week 40 to Week 52: No increase in OCS, or the use 
of IV or intra-articular, tendon sheath or bursal injections is allowed from Week 40 until 
the Week 52 assessment.  
 
One burst and taper will be allowed between Week 52 and Week 92. 
Increase in corticosteroids for the prevention of adrenal insufficiency  
For a severe illness, surgery, or symptoms of adrenal insufficiency, if clinically warranted, the 
following can be used, in addition to the “burst and taper” described above from Randomization 
to Week 40 without the participant being considered a non-responder:  
 
Oral or IV hydrocortisone up to 100 mg every 8 hours on the first day followed by half of 
the previous dose for 2 days before returning to their usual dose OR  


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 
Participants who are taking ≤ 7.5 mg/day prednisone or equivalent will be allowed to 
receive up to an additional 7.5 mg/day to a total of 15 mg/day oral prednisone or 
equivalent for a total of up to 14 days.  
Participants who receive either of these corticosteroid regimens for the prevention of adrenal 
insufficiency between Week 40 and Week 52 will be considered as a non-responder for the 
analyses at Week 52. 
6.7.5. 
Other Concomitant Medications  
Medications other than the SOC immunosuppressive background therapy described above, 
which are considered necessary for the participant’s safety and wellbeing, may be given at the 
discretion of the Investigator and recorded in the appropriate sections of the electronic Case 
Record Form (eCRF). Participants should not start naturopathic, herbal, ayurvedic remedies, 
nutritional/dietary supplements, vitamins, and/or minerals without discussing with the 
Investigator. 
6.7.5.1. 
Anti-Hypertensive Agents and HMG-CoA Reductase Inhibitors (Statins)  
Routine use of Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor 
Blockers (ARB) is recommended for all participants unless contraindicated. Use of 
anti-proteinuric agents are allowed during the study if they had been started at least 10 days prior 
to the assessment of the second screening 24-hour UPCR sample (ie, the first sample for 24-hour 
UPCR is collected at the start of the Screening process and the second sample is collected within 
14 days prior to the expected date of Randomization). The dose may be adjusted to optimize anti-
hypertensive effects or to reduce ACEI/ARB-related side effects up to Week 4. The dose must be 
kept stable from Week 4 through 
. Dose reductions are allowed only to reduce 
ACEI/ARB-related side effects such as hypotension, increase in creatinine, or cough. If cough 
develops, ACEI may be changed to ARB. Changes in other classes of anti-hypertensive agents 
(eg, calcium channel receptor blockers, beta-adrenergic receptor blockers, alpha-adrenergic 
receptor blockers) are allowed as clinically indicated to optimize blood pressure.  
Statins must be kept at stable doses after Day 1. Decreases in the dose are allowed only to reduce 
statin-related side effects.  
Cholestyramine must be discontinued prior to the day of Randomization. 
6.7.5.2. 
Sodium-Glucose Cotransport 2 Inhibitors 
Use of Sodium-Glucose Cotransport 2 (SGLT2) inhibitors is allowed during the study if they had 
been initiated to treat Type 2 diabetes mellitus only. No increase in the dose of or initiation of 
SGLT2 inhibitors should be made between signing the ICF and Randomization. For participants 
receiving SGLT2 inhibitors, the dose must remain stable from Randomization through 
 
and may be reduced only for reasons of toxicity but not for efficacy. 
6.7.5.3. 
Anti-Malarial Agents 
The dose of anti-malarial agents should remain stable throughout the study except where a dose 
reduction is necessary to manage anti-malarial-related AEs. Any anti-malarial-related 
abnormality should be managed according to local standards. Discontinuation of antimalarials is 


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allowed, if necessary, to manage anti-malarial-related AEs. The participant may remain in the 
study even if anti-malarial agents are stopped.   
All participants who have been taking anti-malarial therapy within 12 months of signing the ICF 
must have an eye exam by a qualified professional either within 12 months prior to signing the 
ICF or within 12 weeks after signing the ICF. Anti-malarial-related abnormalities should be 
managed according to local standards. Anti-malarial-related abnormalities do not exclude 
participants if they meet all other eligibility criteria. If an eye exam is not performed within the 
protocol specified timeframe, it will be considered as a protocol deviation. 
6.7.5.4. 
Non-Steroidal Anti-inflammatory Drugs  
No increase in the dose of or initiation of a new prescription non-steroidal anti-inflammatory 
drugs (NSAID) should be made between signing the ICF and Randomization. For participants 
receiving NSAIDs, concomitant histamine H2-receptor antagonists should be considered 
according to local practice and in concordance with considerations in the mycophenolate label.  
The dose of prescription NSAIDs must remain stable from Randomization through 
 
and may be reduced only for reasons of toxicity but not for efficacy. Prescription NSAIDs should 
not be administered with other NSAIDs (including OTC NSAIDs) except for low-dose aspirin 
(≤ 325 mg/day).  
 
Non-prescription NSAIDs  
 NSAIDs for analgesic purposes that never exceed label-approved doses of NSAIDs may 
be used for pain as required, based on Investigator judgement for up to 1 week at a time.  
 Low-dose aspirin (maximum of 325 mg/day) for cardioprotection is permitted. 
6.7.5.5. 
Acetaminophen (Paracetamol)  
Normal release (not extended release) acetaminophen/paracetamol may be used for pain as 
required. 
6.7.5.6. 
Narcotic Analgesics  
Narcotic analgesics may be used during the study as clinically indicated.  
6.7.5.7. 
Topical Therapy  
Concurrent use of topical therapy for cutaneous lupus erythematosus (eg, topical corticosteroids, 
topical immunosuppressants) is permitted. During the study, topical therapy may be reduced or 
discontinued based on clinical manifestations and Investigator discretion. Should cutaneous skin 
manifestations reoccur, the same topical therapy may be resumed at same dose as was being used 
at the time of Randomization.  
It is encouraged that no new dermatologic preparations be initiated for the duration of the study. 
Participants should use sunscreen (list as concomitant medication for SLE) and avoid sun 
exposure for the duration of the study. 


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6.7.6. 
Rescue Medicine 
The study site will supply rescue medication at any time during the study. Although the use of 
rescue medications is allowable, the use of rescue medications should be delayed, if possible. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
Rescue therapy for worsening LN may be administered at the discretion of Investigators as 
clinically indicated. Rescue therapy includes the initiation of any new treatment for lupus or LN 
or an increase from baseline in the SOC background therapy (MMF/MPA or corticosteroids). For 
any rescue medications, study intervention may be continued after discussion with and approval 
by the Horizon Medical Monitor. However, if the participant receives a prohibited medication as 
a rescue, study intervention will be discontinued. Participants who receive rescue therapy will be 
considered treatment failures for subsequent endpoint analyses (such as CRR). 
 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants have the right to withdraw from the trial at any time for any reason without penalty. 
The Investigator also has the right to withdraw participants from treatment if he or she feels it is 
in the best interest of the participant or if the participant is uncooperative or noncompliant.  
Should a participant decide to withdraw and does not plan to participate in the post-treatment SFU 
Period, all efforts will be made to complete and report the observations as thoroughly as possible, 
particularly the examinations outlined in the Early Termination (ET) Visit.  
The Investigator or one of his or her staff members should contact the participant to determine as 
accurately as possible the primary reason for the withdrawal.  
A complete final evaluation at the time of the participant’s withdrawal should be made with an 
explanation of why the participant is withdrawing from the trial. If the reason for withdrawal is an 
AE or an abnormal laboratory test result, the principal specific event or test will be recorded. 
If a participant withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site trial records. 
7.1. 
Discontinuation 
Any participant who decides to discontinue from the trial prematurely and does not plan to 
participate in the post-treatment SFU Period will be requested to complete the ET Visit. 
Participants who discontinue will not be replaced. 
7.1.1. 
Discontinuation of Study Intervention 
Blinded study intervention will be discontinued in participants who meet pre-defined criteria 
for worsening LN or SLE.   
Criteria for discontinuing study intervention for worsening LN or SLE (at any time):  
 > 30% decrease in eGFR compared to baseline due to LN and eGFR < 
60 mL/min/1.73 m2 (compared to the average of the previous two visits, not explained by 
change in comorbidities or concomitant medications. A decrease in eGFR must be 
confirmed on at least two independent samples at least 5 days apart after non-SLE causes 
have been corrected or excluded) OR  
 Increase in renal or extra-renal lupus activity requiring prohibited systemic 
immunosuppressive treatment (eg, cyclophosphamide, rituximab, belimumab) OR   
 Receipt > 1 methylprednisolone pulse after the day of Randomization OR   
 Receipt of any methylprednisolone pulse after Week 8 OR   
 The study intervention will be discontinued if MMF is discontinued, and another 
immunosuppressant is initiated  


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Criteria for discontinuing study intervention for worsening LN or SLE at Week 12 and 
Week 24:  
 eGFR < 75% of baseline and < 60 mL/min/1.73 m2 (compared to the average of the 
previous two visits, not explained by change in comorbidities or concomitant 
medications. A decrease in eGFR must be confirmed on at least two independent samples 
at least 5 days apart after non-SLE causes have been corrected or excluded) OR   
 Nephrotic range UPCR (confirmed by a second measurement at least two weeks after the 
first measurement):  
o Participants with 24-hour UPCR ≤ 3 mg/mg at baseline will be withdrawn if 
24-hour UPCR increases by > 50% from baseline to > 3.5 mg/mg  
o Participants with 24-hour UPCR > 3 mg/mg at baseline will be withdrawn if 
24-hour UPCR at Week 24 > 3.5 mg/mg and there is < 50% improvement from 
baseline  
OR  
 Inability to adhere to corticosteroids requirements:   
o Inability to reduce OCS to ≤ 15 mg/day prednisone-equivalent at Week 12  
o Inability to reduce OCS to ≤ 10 mg/day prednisone-equivalent by Week 24  
Participants who exceed the maximum daily OCS dose at the Week 12 or Week 24 Visits may 
continue to receive study intervention if the current dose is part of a temporary increase in OCS 
dose (eg, protocol allowed burst and taper). Participants who cannot be returned to their pre-
increase dose within 14 days from the start of the increase will have their study intervention 
discontinued at the next visit.  
Participants who prematurely stop dosing prior to Week 52 will be followed for regularly 
scheduled visits through Week 52 unless participants withdraw consent of trial participation (See 
Section 7.1.3) or are lost to follow-up (See Section 7.2). Participants should be followed to 
assess AE/SAEs for at least 12 weeks after the last study intervention administration, 
approximately 4, 8, and 12 weeks after the last study intervention dose, unless the participant 
withdraws consent.  
Participants who prematurely stop dosing after Week 52 but remain in the study will be complete 
the EOT Visit and the SFU Period, unless the participant withdraws consent. Participants will not 
automatically be removed from the trial if any administration of study intervention is missed.  
Early discontinuation of study intervention for reasons other than lack of efficacy 
An individual participant will not receive any further study intervention if any of the following 
occur in the participant: 
 Receipt of Prohibited Medications (See Section 6.7.2). 
 A Common Terminology for Adverse Events (CTCAE v5.0 dated 27 NOV 2017) 
Grade 3 or higher allergic reaction to the study intervention. 
 A CTCAE Grade 3 or higher infection considered related to the study intervention.  
 Other AE that contraindicates further dosing in the opinion of the Investigator and/or the 
Sponsor, or Medical Monitor.  


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 Withdrawal of consent from further treatment with study intervention. 
 Participant is determined to have met one or more of the exclusion criteria or failed to 
meet all the inclusion criteria for study participation and there is a potential safety risk 
associated with continuation identified upon consultation with the Medical Monitor. 
 Pregnancy or a decision to become pregnant. 
 Any of the following liver function abnormalities: 
 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 8× ULN. 
 ALT or AST ≥ 5× ULN for more than 2 weeks. 
 ALT or AST ≥ 3× ULN and total bilirubin ≥ 2× ULN.  
 ALT or AST ≥ 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥ 5%). 
Participants who prematurely stop dosing prior to Week 52 will be followed for regularly 
scheduled visits through Week 52 unless participants withdraw consent of trial participation (See 
Section 7.1.3) or are lost to follow-up (See Section 7.2). Participants should be followed to assess 
AE/SAEs for at least 12 weeks after the last study intervention administration, approximately 4, 
8, and 12 weeks after the last study intervention dose, unless the participant withdraws consent.  
Participants who prematurely stop dosing after Week 52 but remain in the study will be complete 
the EOT Visit and the SFU Period, unless the participant withdraws consent. Participants will not 
automatically be removed from the trial if any administration of study intervention is missed.  
Site Investigators will be trained about the importance of retention of participants through the 
completion of the study, and participants will be informed about the continued scientific 
importance of their data even if they discontinue study intervention early.  
7.1.2. 
Discontinuation from the Trial 
Reasons for discontinuation from the trial include the following: 
 
The participant is lost to follow-up. 
 
The Sponsor or regulatory authorities, for any reason, stop the trial. In this case, all participants 
will be discontinued from the trial. The Investigator will immediately, on discontinuance of 
the trial by the Sponsor, in its entirety or at a clinical trial site, inform both the participants and 
the research ethics board of the discontinuance, provide them with the reasons for the 
discontinuance and advise them in writing of any potential risks to the health of participants or 
other persons. 
7.1.3. 
Withdrawal of Consent from the Trial 
Participants are free at any time to withdraw from the study (study intervention and assessments), 
without prejudice to further treatment (withdrawal of consent). Such participants will always be 
asked about the reason(s) for withdrawal and the presence of any AEs. If a participant withdraws 
participation in the study, then no further study visits or data collection should take place. Further 
details concerning use of samples collected during the study from a participant who withdraws 
consent are provided in Section 10.9. 


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7.2. 
 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and is unable to be contacted by the trial site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required trial 
visit: 
 
The site will attempt to contact the participant and reschedule the missed visit. The site will 
then counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to or should continue in the trial. 
 
Before a participant is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or trial file. 
 
If all attempts to contact the participant fail, he or she will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Description of Study Procedures and Assessments 
Trial procedures and their timepoints are summarized in the SoA (see Section 1.3). Protocol 
waivers or exemptions are not allowed.  
Adherence to the trial design requirements, including those specified in the SoA, is essential and 
required for trial conduct.  
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria.  
The Investigator will maintain a Screening Log to record details of all participants screened and 
to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing of the ICF may be utilized for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the timeframe defined 
in the SoA.  
In the event of a significant trial-continuity issue (eg, caused by a pandemic), alternate strategies 
for participant visits, assessments, medication distribution, and monitoring may be implemented 
by the Sponsor or the Investigator, as per local health authority/ethics requirements.  
Safety, laboratory, and/or analyte results that could unblind the trial will not be reported to 
investigative sites or other blinded personnel.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
All procedures and assessments and laboratory tests (unless otherwise specified) will be done prior 
to administration of study intervention.  
8.1. 
Efficacy Assessments 
Efficacy measurements will be made at the times indicated in the Study Plan (see Table 2 for 
procedures and assessments to be performed at Screening and Table 3 and Table 4 for Treatment 
Period and Follow-Up). 
The efficacy assessments based on laboratory tests include:  
 Urine protein to creatinine ratio: This consists of:  
o 24-hour UPCR: The 24-hour UPCR will be determined via a 24-hour urine 
sample.  
The 24-hour UPCR will be performed as follows: twice during the Screening 
Period, Weeks 0, 12, 24, 36, 48, 52, 64, 76, 88, 100, 104 and at ET Visits.  
During the Screening Period, two samples will be required:   
 Screening sample at the start of the Screening process (after the ICF is 
signed) and   


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 Stratification sample within 14 days prior to the expected day of 
Randomization and after a minimum of 10 days after the Screening 
sample was obtained. Without the results of the second sample, which will 
be used for stratification, participants cannot be randomized. Typical 
turn-around time for results from central laboratory is up to 7 days. On 
rare occasion, an extension of the 28-day screening window is allowed if 
the re-collection of the sample is necessary, or the results needed for 
Randomization are delayed.  
Starting from Week 0 (Day 1), the 24-hour urine sample must always be 
collected before the administration of study intervention. The sample collected 
at Week 0 (Day 1) will be the baseline sample which must be provided on 
Day 1 prior to Randomization and administration of first dose of study 
intervention.   
The collection of the 24-hour urine sample should start preferably in the morning 
of the day before the scheduled visit with the collection starting after the first void 
and end with the first void in the morning of the day of the visit. The urine 
collection may be done within 1 day prior to the visit if the urine sample can be 
kept refrigerated until the day of the visit.  
The sample should be kept refrigerated whenever possible. If refrigeration is not 
possible, participants should select the coolest possible place to store their 
urine sample, eg, a cool room or use a portable cooler with ice/ice pack.  
In the event that a participant has a medical reason which would impact the 
validity of the assessment of proteinuria (eg, urinary tract infection, heavy 
menstruation) or the sample was not collected appropriately, the collection of the 
sample may be completed/repeated as follows:  
 Screening samples: As soon as possible before the next scheduled 
sampling is due.  
 Week 0: Prior to study intervention administration (which may require 
the Day 1 Visit to be postponed). 
 Weeks 12, 24, 36, 48, 52, 64, 76, 88, 100, and 104: Within 2 weeks of 
the actual date of the visit when the collection was due and, if 
applicable, before any changes in SOC or concomitant medications. 
The 24-hour UPCR will be used for the primary and secondary endpoints, the PRR 
and CRR criteria at 
, and to determine withdrawal criteria at 
Weeks 12 and 24. 
 
.  
o 


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 
 
 
 
  
 Estimated glomerular filtration rate based on the MDRD formula calculated by the 
central laboratory. Refer to the Laboratory Manual for further detail.  
The efficacy assessments based on clinical evaluation include 
 
, OCS 
reduction, and SDI.  
8.1.1. 
Training and Certification for Systemic Lupus Erythematosus Assessments  
In order to maintain consistent evaluation of SLE assessments across study sites, training and 
certification of Investigators and designated site personnel who will be completing the disease 
evaluations listed below will be conducted.  
 
  
 
   
 
  
 SDI  
These evaluations must be performed by the Investigator or another qualified physician, unless 
prior Sponsor approval has been obtained for any other clinically trained site personnel with 
documentation of adequate assessment experience.  
After attending study presentations (ie, Investigator Meeting) or after completion of training 
modules, all Investigators and designated site physicians must pass an examination in order to 
obtain certification for all disease evaluation assessments. Investigators and designated site 
personnel must be trained and certified prior to participants entering the Screening Period at their 
respective sites. All assessments and certifications must be renewed via the study online training 
website prior to expiration and must remain current (not expire) throughout the course of the 
study. If there is a change in site personnel over the course of the study, new Investigators or 
physicians must be certified prior to performing the SLE assessments.  
Documentation of all training will be maintained in the site’s study file.  
Over the course of the study, Investigator assessments for a given participant should be 
completed by the same trained and/or certified Investigator, designated physician, or qualified 
site personnel (as described above) whenever possible.  
 
  
 
 
 
 
  


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8.1.1.4. 
Systemic Lupus International Collaborating Clinics/American College Rheumatology 
Damage Index   
The SDI has been developed to assess irreversible damage in SLE participants independently of 
its cause (ie, included damage due to SLE activity, SLE-related scarring, therapy, comorbidities) 
but occurring after disease onset. Damage, ie, irreversible impairment since onset of SLE, is 
usually defined as a clinical feature that must be continuously present for at least 6 months to 
score. In addition, some irreversible events such as myocardial infarction or a cerebrovascular 
accident, score as damage on their occurrence. Briefly, damage is defined for 12 organ systems: 
peripheral vascular, ocular, neuropsychiatric, renal, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, skin, endocrine (diabetes), gonadal, and malignancies. Damage over time can 
be stable or increase, theoretically to a maximum of 47 points (Schwartz et al, 2009). 
 
 
 
 


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8.1.4. 
Renal Biopsy  
Renal biopsy is required within 6 months prior to signing the ICF or during the Screening Period 
for inclusion into the study and must meet inclusion criterion No. 6 and not meet exclusion 
criterion No. 11. (Note: If a renal biopsy is performed during the Screening Period, adequate 
time should be allowed before the next scheduled urine sample collection). If a participant has 
not had a recent kidney biopsy within the 6 months prior to Screening, one may be performed to 
assess eligibility for the study provided informed consent has been given and results are received 
prior to Randomization. If one is performed as part of SOC after Randomization, the results will 
be recorded in the eCRF. 
 
 
 
 
 
 
 
 
 
 
ADJUDICATION COMMITTEE 
Renal Pathology Adjudication  
Renal biopsies will be evaluated locally, and the local classification will be used to confirm the 
eligibility criteria. Screening biopsy slides or digital pathology images (ie, scanned slides) will 
then be submitted for adjudication post-randomization by an external renal pathology 
adjudication committee consisting of nephropathologists with special expertise in LN. The 
biopsies will be assessed for all elements of the ISN/RPS classification, the NIH activity, 
chronicity indices, and the presence of concomitant conditions. The submission of Screening 
biopsies for adjudication is required to participate in the study. The process for adjudication will 
be defined in a separate document (Renal Biopsy Adjudication Charter). 
 
 
  


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Data Safety Monitoring Board 
An external, independent Data Safety Monitoring Board (DSMB) will evaluate safety data at 
regular intervals throughout the trial and make recommendations to the Sponsor as needed. 
 
 
 
 This futility analysis is designed to be non-binding, so the 
DSMB may elect not to recommend terminating the trial after considering all of the data, even if 
the pre-specified futility criteria is met. 
8.2. 
Safety Assessments 
Safety assessments will include physical examinations, measurement of vital signs, 
electrocardiograms, and monitoring of hematology, blood chemistry, urinalysis, and local 
injection site assessment. Planned timepoints for all safety assessments are provided in the SoA 
(See Section 1.3). 
8.2.1. 
Physical Examinations 
The following sites/systems will at least be included in the focused physical examination, which 
will be performed at the visits specified in the SoA (Section 1.3):  
 General appearance 
 Dermatological 
 Head, eyes, ears, nose, throat 
 Respiratory 
 Cardiovascular 
 Abdominal 
 Neurological 
 Musculoskeletal 
 Lymphatic 
Information for all physical examinations must be included in the source document. If deemed 
appropriate by the Investigator, clinically significant findings in the Screening physical 
examination could exclude a participant from trial participation. Any significant change will be 
reported as an AE in the source document and eCRF.  
8.2.2. 
Vital Signs 
The following vital signs will be recorded at the visits specified in Section 1.3 with the participant 
in a seated or supine position, after having sat calmly for at least 5 minutes: systolic and diastolic 
blood pressure (mmHg), pulse (bpm), body temperature (°C), and respiratory rate 
(breaths/minute). 


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Weight (kg) and height (cm) will be collected to calculate the body mass index (BMI) and will be 
recorded at the visits specified in 1.3. The height will only be recorded once at the Screening Visit 
and the same value will be used for BMI calculation at other visits. 
If deemed appropriate by the Investigator, clinically significant findings in the vital signs will 
exclude a participant from trial participation. Any abnormal finding related to vital signs that the 
Investigator considers to be clinically significant must be recorded as an AE. 
8.2.3. 
Electrocardiograms 
Twelve-lead ECGs will be performed as a safety assessment at the visits specified in Section 1.3. 
Clinically significant findings in the ECG should exclude a participant from trial participation 
(as deemed appropriate by the Investigator). Any clinically significant value will be reported as 
an AE. 
8.2.4. 
Clinical Laboratory Tests 
Laboratory tests will be performed in a central laboratory at the visits specified in Section 1.3. The 
tests will include urinalysis, hematology with differential, a standard chemistry panel (including 
liver function tests), immunology, and a serum pregnancy test (Screening) for women of 
childbearing potential (WOCBP). At the visits specified in Section 1.3, a urine pregnancy test will 
be performed for WOCBP (conducted at the Investigator site). The specific tests in these panels 
are listed in Table 10. 
 
 




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8.3.1.2. 
Definition of Treatment-Emergent Adverse Event  
A TEAE is any condition that was not present prior to treatment with the study intervention but 
appeared following treatment, was present at treatment initiation but worsened during treatment, 
or was present at treatment initiation but resolved and then reappeared while the individual was on 
treatment (regardless of the intensity of the AE when the treatment was initiated). 
8.3.1.3. 
Definition of Serious Adverse Event  
A SAE or reaction is any untoward medical occurrence that, at any dose has any of the following 
consequences: 
 
Results in death 
 
Is life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Medically significant 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited 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 participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the participant or participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, which 
have not worsened after initiation of treatment, will not be classed as SAEs. Previously scheduled 
hospitalizations must be documented in the participant’s source documents before the participant 
signed the ICF. A kidney biopsy performed as part of the study will not be considered an SAE. 
Any complication experienced during a kidney biopsy procedure resulting in hospitalization or a 
prolongation of the hospitalization requires SAE reporting. 
8.3.1.4. 
Definition of an Adverse Event of Special Interest (AESI) 
An AESI is an AE of scientific and medical interest specific to understanding of the study 
intervention and may require close monitoring and collection of additional information by the 
Investigator. An AESI may be serious or nonserious. 


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The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the use of this study intervention. 
The following AESIs will be particularly monitored in this trial: 
 Hypersensitivity reaction, including anaphylaxis 
 Severe viral infection/reactivation (CTCAE Grade 3 or higher) 
 Opportunistic infection as listed in Appendix 2 (all cases) 
 Malignancy (except non-melanoma skin cancer) 
8.3.2. 
Classification of an Adverse Event 
8.3.2.1. 
Relationship to Study Intervention 
The Investigator is required to provide an assessment of the relationship of AEs and SAEs to the 
study intervention. An event will be considered “not related” to use of study intervention if any of 
the following are met: 
 An unreasonable temporal relationship between administration of the study 
intervention and the onset of the event (eg, the event occurred either before, or too long 
after, administration of the study intervention for it to be considered study intervention 
related). 
 A causal relationship between the study intervention and the event is biologically 
implausible (eg, death as a passenger in an automobile accident). 
 A clearly more likely alternative explanation for the event is present (eg, typical 
adverse reaction to a concomitant drug and/or typical disease-related event). 
Individual AE/SAE reports will be considered “related” to use of the study intervention if the “not 
related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” meaning 
that there is “a reasonable possibility” that the event may have been caused by the study 
intervention (ie, there are facts, evidence, or arguments to suggest possible causation). 
8.3.2.2. 
Adverse Event Severity 
The guidelines outlined in CTCAE v5.0 will be used for assessing the severity or intensity of the 
event. The general guidelines for assessing the AE grade are provided in Table 11. 
Table 11 
CTCAE v.5.0 General Guidelines 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLa.  
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb. 
Grade 4 
Life-threatening consequences: urgent intervention indicated. 
Grade 5 
Death related to AE. 


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Table 11 
CTCAE v.5.0 General Guidelines 
Grade 
Description 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology for Adverse Events. 
The CTCAE v5.0 is dated to 27 NOV 2017. 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
8.3.2.3. 
Expectedness 
Horizon Therapeutics Ireland DAC will assess the expectedness of each SAE in relation to the 
study intervention. Please refer to Investigator’s Brochure for more details.  
8.3.3. 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of trial personnel during trial visits 
and interviews of a trial participant presenting for medical care, or upon review by a trial monitor. 
All AEs, including local and systemic reactions, will be captured on the appropriate eCRF. 
Information to be collected includes event description, date of onset, clinician’s assessment of 
severity, relationship to study intervention (assessed only by those with the training and authority 
to make a diagnosis), and date of resolution/stabilization of the event. All AEs occurring while on 
trial must be documented appropriately regardless of relationship.  
Trial site personnel will note the occurrence and nature of each participant’s medical condition(s) 
present prior to the informed consent signature in the appropriate section of the source document 
and eCRF. During the trial, site personnel will note any change in the condition(s) and the 
occurrence and nature of any AE.  
Any medical condition that is present prior to informed consent signature will be considered as 
part of medical history and not reported as an AE. However, if the trial participant’s condition 
deteriorates after the consent signature, it will be recorded as an AE. 
Should a participant experience an AE at any time after the informed consent signature until the 
end of participation in the trial, the event will be recorded as an AE in the source document and 
eCRF. Any SAE related to the trial participation (eg, screening procedure) will be recorded in the 
source document and eCRF from the time consent is given to participate in the trial until the end 
of participation in the trial. 
The Investigator is responsible for appropriate medical care of participants during the trial. The 
Investigator also remains responsible for following through with an appropriate health care option 
for all AEs that are ongoing at the end of the trial. The participant should be followed until the 
event is resolved or stable. If an AE is ongoing at the end of trial, the follow-up duration is left to 
the discretion of the Investigator. Follow-up frequency will be performed at the discretion of the 
Investigator.  
Whenever possible, clinically significant abnormal laboratory results are to be reported using the 
diagnostic that resulted in the clinically significant abnormal laboratory results and not the actual 
abnormal test. 


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8.3.4. 
Adverse Event Reporting 
Investigators are responsible for monitoring the safety of participants who are participating in this 
trial and for alerting the Sponsor to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the participant.  
8.3.5. 
Serious Adverse Event Reporting 
Horizon Therapeutics Ireland DAC will be the pharmacovigilance unit responsible for the overall 
pharmacovigilance process for this trial. All SAEs, related to the experimental treatment or not, 
occurring during the course of the trial must be reported by entering the information into the eCRF 
on an SAE form to the pharmacovigilance unit (see below contact information) within 24 hours of 
the knowledge of the occurrence (this refers to any AE that meets one or more of the 
aforementioned seriousness criteria). The SAE reporting period ends at the end of the Follow-Up 
Period or if the participant begins an alternative therapy. 
Reporting should be done by sending the completed SAE form to the following e-mail address 
(faxing may also be done as a second option in case e-mailing is not possible). 
Safety Contact Information:  Horizon Therapeutics  
E-mail:  clinicalsafety@horizontherapeutics.com 
US Fax: (800) 860 -7836 
The pharmacovigilance unit will inform the Medical Monitor, the Sponsor, and the Contract 
Research Organization (CRO) within 1 business day of awareness of a new SAE. The 
pharmacovigilance unit will process and evaluate all SAEs as soon as the reports are received. For 
each SAE received, the pharmacovigilance unit, in consultation with the Sponsor if needed, will 
make a determination as to whether the criteria for expedited reporting to relevant regulatory 
authorities have been met.  
The expedited reporting of relevant safety information to concerned regulatory agencies and ethic 
committees will be performed in accordance with local laws and regulations and will be defined 
in the Safety Management Plan.  
The trial Sponsor will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reactions as soon as possible, but in no 
case later than 7 calendar days after the Sponsor's initial receipt of the information. In addition, the 
Sponsor must notify the FDA and all participating Investigators in an Investigational New Drug 
(IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the Sponsor determines that the 
information qualifies for reporting. 
8.3.6. 
Pregnancy Reporting 
If a female participant becomes pregnant during the trial, the participant should inform the trial 
site as soon as possible. Upon confirmation of the pregnancy, the female participant will be 
discontinued from the trial. If a female partner of a male participant becomes pregnant, the 
participant should inform the trial site as soon as possible. The Investigator must complete a trial-
specific pregnancy form upon confirmation of a pregnancy and send it to the pharmacovigilance 
unit within 24 hours of confirmation of the pregnancy (contact information to be used is the same 


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as for SAE reporting). The pharmacovigilance unit will report all cases of pregnancy to the medical 
monitor, the Sponsor, and the CRO in a timely manner until completion of the pregnancy, until a 
healthy live-born offspring, or until the outcome of any abnormality. Pregnancy is not itself an AE 
or SAE; however, maternal/fetal complications or abnormalities will be recorded as AEs or SAEs, 
as appropriate. The Investigator will follow the pregnancy until completion or until pregnancy 
termination and, in the case of a live-born offspring, to 1 month of age in that infant. The 
Investigator will notify the pharmacovigilance unit and the CRO of the outcome as a follow-up to 
the initial pregnancy form. All pregnancies should be reported to the Sponsor and, when 
applicable, to the ethics committee. 
8.3.7. 
Overdose 
Investigational Product overdose is any accidental or intentional use of study intervention in an 
amount higher than the dose indicated per protocol for a given participant. Study intervention 
compliance (see Section 6.5) should be reviewed to detect potential instances of overdose 
(intentional or accidental). 
Any study intervention overdose during the trial should be recorded on the source document and 
eCRF. In the event of overdose, the participant should be closely monitored for any potential AEs. 
All AEs associated with an overdose should be entered on the Adverse Event eCRF and reported 
using the procedures detailed in Section 8.3.5, Serious Adverse Events Reporting, even if the 
events do not meet seriousness criteria. If the AE associated with an overdose does not meet 
seriousness criteria, it must still be reported using the SAEs reporting procedures and in an 
expedited manner but should be noted as non-serious on the form and the Adverse Event eCRF. 
The excess quantity and duration of the overdose should be recorded. 
8.4. 
Pharmacokinetics 
Blood samples will be collected in serum separator collection tubes to evaluate PK at the 
following visits: pre- and 6 hours (± 1 hour) post-injection on Day 1, prior to SC administration 
on Weeks 2, 4, 8, 12, 16, 20, 24, 36, 48, 52, 64, 76, 88, 100, and 104; a single sample will be 
collected at the End-of-Study Visit.  
PK samples will be collected, processed, and stored at the site until shipment to the central 
laboratory. The central laboratory will store the samples at ≤ -70ºC until shipment to the 
appropriate laboratory for testing. 
Instructions for processing, handling, storing, and shipping of PK samples will be detailed in a 
Laboratory Manual that will be provided to each site prior to site initiation. 
 
 
 
 
 
 
 


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Samples may be stored for up to 15 years after the end of the study to achieve study objectives. 
Additionally, with participants’ consent, samples may be used for further research by sponsor or 
others such as universities or other companies to contribute to the understanding of LN or other 
diseases, the development of related or new treatments, or research methods. 
8.8. 
Immunogenicity Assessments 
Daxdilimab immunogenicity will be assessed by the incidence and titer of anti-drug antibodies 
prior to the daxdilimab administration and at specified time points. Number and percentage of 
participants who develop positive ADA will be summarized by treatment group. The potential 
association of ADA with safety and efficacy may be explored if data allow. 
The detection and characterization of antibodies to study intervention will be performed using a 
validated assay method by or under the supervision of the Sponsor. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study intervention. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of immune responses to study intervention. 
Instructions for processing, handling, storing, and shipping of antidrug antibody samples will be 
detailed in a Laboratory Manual that will be provided to each site prior to site initiation. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The statistical hypotheses are as follows:  
1. Null hypothesis (H0): difference in proportion of responders (daxdilimab vs placebo) = 0 
2. Alternative hypothesis (Ha): difference in proportion of responders (daxdilimab vs 
placebo) ≠ 0 
9.2. 
Sample Size Determination 
A sample size of approximately 210 participants (up to approximately 70 participants per 
treatment group) is planned for this trial. The sample size was calculated based on the primary 
efficacy endpoint. Assuming a placebo response rate of 25%, 70 participants per treatment group 
will provide approximately 80% power to detect an increase in response of 20% in either arm of 
a daxdilimab group as compared to the placebo group at the 2-sided alpha level of 0.10 using a 
Chi-square test. The minimum detectable difference is 13% between the daxdilimab group and 
placebo group. The assumption of 25% responder rate for placebo is based upon published 
results (Mejia-Vilet et al, 2021). 
9.3. 
Analysis Sets 
Analysis Populations: 
Full Analysis Set: The Full Analysis Set will include all randomized participants who receive 
any dose of study intervention in the study. Participants will be analyzed according to the 
treatment randomized. The efficacy analysis will be based on the Full Analysis Set. 
Safety Analysis Set: The Safety Analysis Set will include all participants who receive any dose 
of study intervention in the study. Participants will be analyzed according to the treatment that 
they actually received. Safety, PD, and ADA analyses will be based on Safety Analysis Set. 
PK Analysis Set: The PK Analysis Set will include all participants who receive any dose of 
daxdilimab in the study and have at least one quantifiable serum PK observation post first dose. 
Participants will be analyzed according to the treatment that they actually received. The PK 
analysis will be based on the PK Analysis Set. 
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
Continuous variables will be summarized in tables and will include the number of participants, 
mean, standard deviation (SD), median, minimum, and maximum. Categorical variables will be 
presented in tables as frequencies and percentages. Details of the statistical analysis will be 
specified in a separate SAP. 


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9.4.2. 
Primary Endpoint Analysis 
9.4.2.1. 
Analyses of the Primary Efficacy Endpoint:  
The estimand of primary interest is defined as follows, using composite variable strategy to 
address intercurrent events. 
1. Population: Participants in the Full Analysis Set. 
2. Variable (outcome measure): CRR at 
. CRR is 
defined by meeting the following criteria: 
a. eGFR ≥60 mL/min/1.73m2 or no worse than 15% below baseline. 
b. 24-hour UPCR ≤0.5 mg/mg. 
c. No use of restricted medication beyond the protocol allowed threshold before 
assessment. 
d. No discontinuation of study intervention. 
3. Intercurrent event:  
a. Rescue medications: Captured in the primary variable definition.  
b. Treatment discontinuation: Captured in the primary variable definition.  
4. Population-level summary: Difference in proportions of responders between the 
daxdilimab group and placebo group. 
The proportion of participants achieving CRR at 
 in the 
daxdilimab group will be compared to that of the placebo group using a logistic regression model 
with treatment, baseline eGFR value and baseline UPCR value included in the model. The 
difference in proportions of responders of daxdilimab vs placebo will be estimated together with 
its associated 2-sided 90% confidence interval (CI). 
9.4.2.2. 
Control of Type I Error 
The type I error rate will be controlled at 0.1 level (2-sided) for the primary efficacy analysis 
using a fixed sequence testing procedure.  
1. The primary endpoint will be tested for Daxdilimab 
 mg compared with placebo. 
2. If p-value is ≤ 0.1 in step 1, the primary endpoint will be tested for Daxdilimab 
 mg 
compared with placebo. 
9.4.3. 
Secondary Endpoints Analysis 
The estimand for the binary secondary efficacy endpoints is defined as follows, using composite 
variable strategy to address intercurrent events. 
1. Population:  
a. ORR: Participants in the Full Analysis Set. 
b. Sustained reduction of OCS dose: Participants in the Full Analysis Set whose 
Baseline OCS dose is greater than 2.5 mg/day prednisone equivalent. 
2. Variable (outcome measure): 


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a. ORR at 
 which is an CRR or PRR at 
Week 52. PRR is defined by meeting the following criteria: 
i. eGFR ≥60 mL/min/1.73m2 or no worse than 15% below baseline. 
ii. Improvement in 24-hour UPCR:  
 For participants with a baseline UPCR ≤3.0 mg/mg: <1.0 mg/mg 
 For participants with a baseline UPCR >3.0 mg/mg: >50% 
improvement from baseline and ≤3.0 mg/mg 
iii. No use of restricted medication beyond the protocol allowed threshold 
before assessment.  
iv. No discontinuation of study intervention. 
b. Response in sustained reduction of OCS dose, which is defined by meeting the 
following criteria: 
i. Prednisone-equivalent dose ≤2.5 mg/day by Week 24 and not exceeding 
this dose through Week 52. 
ii. No use of restricted medication beyond the protocol allowed threshold 
before assessment. 
iii. No discontinuation of study intervention. 
3. Intercurrent event:  
a. Rescue medications: Captured in the variable definition.  
b. Treatment discontinuation: Captured in the variable definition.  
4. Population-level summary: Difference in proportions of responders between the 
daxdilimab group and placebo group. 
ORR will be analyzed using a logistic regression model with treatment, baseline eGFR value and 
baseline UPCR value included in the model. Response in sustained reduction of OCS dose will 
be analyzed similarly using a logistic regression model with treatment, randomization 
stratification factors and baseline OCS dose included in the model. 
The estimand of change from baseline in eGFR at Week 52 is defined as follows, using 
hypothetical strategy to address intercurrent event of rescue medications and treatment policy 
strategy to address intercurrent event of treatment discontinuation.  
1. Population: Participants in the Full Analysis Set. 
2. Variable (outcome measure): Change from baseline in eGFR at Week 52. 
3. Intercurrent event: 
a. Rescue medications: The data collected after administration of the rescue 
medications will be excluded. 
b. Treatment discontinuation: Participants who discontinue study intervention will 
be asked to come to scheduled evaluations until the end of study. The data 
collected after discontinuation of study intervention will be included in the 
analysis. 


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2. The population-level summary: Mean difference between the daxdilimab group and 
placebo group. 
Change from baseline in eGFR will be analyzed using mixed models for repeated measures 
(MMRM) with treatment, visit, visit by treatment interaction, randomization stratification factor 
(UPCR only), and baseline eGFR value included in the model. 
 
 
 
9.4.5. 
Handling Plan for Missing Data: 
For the categorical endpoint, the intermittent missing data will be imputed using last observation 
carried forward approach (LOCF). Participants with missing outcomes due to early 
discontinuation from the study will be considered as non-responders. If any of the criteria cannot 
be evaluated at a visit, that criterion will be imputed using LOCF. For the continuous endpoint, 
the missing data will be handled using the MMRM approach. 
9.4.6. 
Safety Analyses 
AEs will be coded using the most recent version of Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment emergent AEs will be summarized by the number of participants reporting 
the events, as well as by System Organ Class, Preferred Term (PT), severity, seriousness, and 
relationship to study intervention. For the summary of AEs by severity, each participant will be 
counted only once within a System Organ Class or a PT by using the AEs with the highest intensity 
within each category. For the summary of AEs by relationship to study intervention, each 
participant will be counted only once within a System Organ Class or a PT by using the AEs with 
the greatest reported relationship within each category. The number and percentage of participants 
reporting treatment-emergent SAEs and treatment-emergent AESIs will also be summarized. 
Clinically significant changes in laboratory analyses, vital signs, ECGs, and new findings on 
physical examination will be recorded as AEs or SAEs. Laboratory assessments, vital signs, and 
ECGs, as well as their changes from Baseline at each visit will also be summarized descriptively. 
9.4.7. 
Pharmacokinetic Analyses 
Serum concentrations will be summarized descriptively by treatment and by visit and the mean 
(±SD) serum concentration versus scheduled time profiles will be presented graphically. 
Individual serum concentration vs. actual time profiles for each participant will be listed. 


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9.4.9. 
Planned Analyses 
 
 
 
 
 
 
 
 
 
 
9.4.9.2. 
Planned Primary Analysis 
The primary analysis will be conducted after the last participant has completed the Week 52 
Visit or discontinued from study early. For the primary analysis, all the efficacy and safety data 
collected prior to the data cut-off will be analyzed. 
9.4.9.3. 
Planned Final Analysis 
The final analysis will be conducted after all participants have completed Week 112 Visit or 
discontinued early from the study. 
 
 


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10. 
REGULATORY, ETHICAL, AND TRIAL OVERSIGHT 
CONSIDERATIONS 
10.1.  Local Regulations/Declaration of Helsinki 
This trial will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with ICH Tripartite Guideline for GCP and the 
applicable laws and regulations of the country in which the research is conducted, whichever 
affords greater protection to the individual. 
10.2.  Ethical Review  
It is the understanding of the Sponsor that this protocol (and any amendments) as well as 
appropriate consent procedures, will be reviewed and approved by a research ethics board (REB)/ 
institutional review board (IRB). This board must operate in accordance with the current federal 
regulations. For sites with a local ethics committee, a letter or certification of approval will be sent 
by the Investigator to the Sponsor (or CRO) before initiation of the trial and also whenever 
subsequent modifications to the protocol are made. 
10.3.  Informed Consent Process 
An ICF describing in detail the study intervention, trial procedures, and risks will be given to the 
participant, along with an assent form when required. 
It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable 
by local regulation), to obtain written informed consent from each individual participating in this 
trial, after adequate explanation of the aims, methods, objectives, and potential hazards of the trial. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
trial and continues throughout the individual’s trial participation. Consent forms will be IRB/REB 
approved, and the participant will be asked to read and review the document. The Investigator will 
explain the research trial to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the trial and of his or her rights as a research participant. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants should have the opportunity to discuss the trial with 
their family or surrogates or think about it prior to agreeing to participate. 
The participant will sign the informed consent document prior to any procedures being done 
specifically for the trial. Participants must be informed that participation is voluntary and that they 
may withdraw from the trial at any time for any reason, without prejudice. A copy of the signed 
informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any trial-specific procedures. 
The rights and welfare of the participants will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate in this trial. 
If new safety information results in significant changes in the risk/benefit assessment, or if any 
new information becomes available that may affect the willingness of a participant to continue to 
participate, the consent form should, if necessary, be reviewed and updated by the IRB/REB. All 


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participants (including those already being treated) should be informed of the new information, 
given a copy of the revised form, and asked to give their consent to continue in the trial. 
10.4.  Trial Discontinuation and Closure 
This trial may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for trial suspension or termination, will be 
provided by the suspending or terminating party to trial participants, Investigators, the Sponsor, 
and regulatory authorities. If the trial is prematurely terminated or suspended, the principal 
Investigators will promptly inform trial participants and the IRB/REB and will provide the 
reason(s) for the termination or suspension. Trial participants will be contacted, as applicable, and 
be informed of changes to trial visit schedule. 
Circumstances that may warrant termination or suspension of the trial include, but are not limited 
to the following: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete or evaluable 
 
Scientific or corporate reasons 
The trial may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the Sponsor, IRB/REB, and applicable regulatory authorities. 
10.5.  Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating Investigators, 
their staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples in addition to the clinical information relating to participants. Therefore, the 
trial protocol, documentation, data, and all other information generated will be held in strict 
confidence. 
The Investigator must assure that the participants’ anonymity will be maintained, and that 
participants’ identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the Sponsor, participants should not be identified by their names, but by an 
identification code. The Investigator should keep a participant log relating codes with the names 
of participants. The Investigator should maintain in strict confidence documents not for submission 
to Horizon Therapeutics Ireland DAC (eg, participants’ written consent forms). 
All research activities will be conducted in a setting as private as possible. 
The trial monitor, other authorized representatives of the Sponsor, and representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying IP may inspect all documents and 
records required to be maintained by the Investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this trial. The clinical trial 
site will permit access to such records. 
The trial participant’s contact information will be securely stored at each clinical site for internal 
use during the trial. At the end of the trial, all records will continue to be kept in a secure location 
for as long a period as dictated by the applicable legal or regulatory requirements, the reviewing 


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IRB, institutional policies, or Sponsor requirements. 
10.6.  Clinical Monitoring 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial 
participants are protected; that the reported trial data are accurate, complete, and verifiable; and 
that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
ICH GCP guidelines, and with applicable regulatory requirement(s). Centralized monitoring, 
which consists of remote review of accumulating data from all sites, will be performed as detailed 
in the Centralized Monitoring Plan.  
10.7.  Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of trial conduct, data and biological 
specimen collection, documentation, and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry system, and 
data QC checks, which will be run on the database, will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
During the trial, the Sponsor or its representative will conduct monitoring visits at regular intervals. 
The monitoring visits will be conducted to ensure protocol adherence, quality of data, accuracy of 
entries on the eCRFs, IP accountability, compliance with regulatory requirements, and continued 
adequacy of the trial site and its facilities. 
The site may be audited, monitored, or inspected by a quality assurance officer named by the 
Sponsor, by the REB or IRB, and/or by the regulatory authorities. The Investigator will be given 
notice before an audit occurs and will be expected to cooperate with any audit and provide 
assistance and documentation (including source data) as requested. The trial site will provide direct 
access to all trial-related sites, source data/documents, and reports for the purpose of monitoring 
and auditing by the Sponsor and inspection by local and regulatory authorities. 
10.8. Data Handling and Record Keeping 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
The Investigator must maintain adequate and accurate records to enable the conduct of the trial to 
be fully documented and the trial data to be subsequently verified. These documents should be 
classified into two separate categories: Investigator’s study files and participant clinical source 
documents. 
The Investigator must maintain source documents for each participant in the trial. These source 
documents will consist of case and visit notes (clinical medical records) containing demographic 
and medical information and the results of any tests or assessments. All information on the eCRFs 
must be traceable to the source documents in the participant’s file. Data not requiring a written or 
electronic record will be defined before trial start and will be recorded directly on the eCRFs, 
which will be documented as being the source data. 
The records should be retained by the Investigator according to ICH guidelines, local regulations, 
or as specified in the Clinical Trial Agreement, whichever retention period is longer. 


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Participant data will be entered by site personnel using electronic data capture (EDC). This 
application will be set up for remote entry. Fully validated EDC software conforming to Title 21 
of the Code of Federal Regulations, Part 11 requirements will be utilized in this study. Investigator 
site staff will not be given access to the EDC system until they have been fully trained. Designated 
Investigator staff will enter the data required by the protocol into the eCRFs using this web-based 
application. Automatic validation programs check for data discrepancies in the eCRFs and, by 
generating appropriate error messages, allow modification or verification of the entered data by 
the Investigator staff before confirming the data. The Investigator must certify that the data are 
complete and accurate by applying an electronic signature to the eCRFs. 
The data collected will be encoded and stored electronically in a database system. Validated data 
may subsequently be transferred to the Sponsor. 
10.9. Biological Specimens and Data 
Study data are protected by the use of a sample identification (SID) number, which is a number 
specific to the participant. The Investigator is in control of the information that is needed to connect 
a study sample to a participant; a participant may withdraw consent at any time by notifying the 
Investigator. If consent is withdrawn, any samples collected prior to that time may still be given 
to and used by the Sponsor, but no new data or samples will be collected unless specifically 
required to monitor the safety of the participant.  
Leftover samples stored for future research with participant consent will be labeled with a sample 
identification number. If the participant consents to have his/her samples used for future research, 
this additional research may not start immediately and may start at any time during the storage 
period. The participant’s sample(s) will be stored by the Sponsor with similar samples in a secure 
laboratory. The participant’s samples will not be kept for more than 15 years after the end of the 
study in which they were collected. If the participant chooses not to allow his/her study samples 
to be used for future research, the samples will be destroyed by the Sponsor once they are no longer 
required for the main study. If future use consent is withdrawn, the Sponsor and the Investigator 
will ensure that the participant’s sample(s) are destroyed unless the identification number has been 
removed and the participant can no longer be linked to any samples. However, if the participant’s 
sample has already been used for research, the Sponsor is not required to destroy the results of this 
research. In this case, only the remaining sample(s) will be destroyed. 
10.10. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
non-compliance may be either on the part of the participant, the Investigator, or the trial site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly. The CRA must ensure that a prompt action is taken to secure compliance. If a 
non-compliance that significantly affects or has the potential to significantly affect human 
participant protection or reliability of trial results is discovered, the CRO and the Sponsor should 
perform a root cause analysis and implement appropriate corrective and preventive actions 
Protocol deviations must be sent to the reviewing IRB per their policies. The Investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 


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10.11. Publication Policy 
The publication policy will be addressed in the Research and Financial Agreement, and all details 
outlined in the agreement will apply to this protocol. The trial will be registered on 
ClinicalTrials.Gov prior to the first participant being dosed. 
 


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11. 
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interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with 
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12. 
APPENDIX  
APPENDIX 1 
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE 
AND FOOD AND ALLERGY ANAPHYLAXIS NETWORK 
GUIDANCE FOR ANAPHYLAXIS DIAGNOSIS 
National Institute of Allergy and Infectious Disease (NIAID) and Food and Allergy Anaphylaxis 
Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in onset and may 
cause death (Sampson et al, 2006). They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (Category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula), AND 
AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory function [PEF], hypoxemia). 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence). 
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula). 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia). 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence). 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting). 
Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children ─ low systolic blood pressure (age specific) or greater than 30% 
decrease in systolic blood pressure. 
b. Adults ─ systolic blood pressure of less than 90 mmHg or greater than 30% decrease 
from that participant’s baseline. 
 
 


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APPENDIX 2 
STUDY-SPECIFIED OPPORTUNISTIC INFECTIONS  
 
Definite a,b Opportunistic Infection 
Probable c Opportunistic Infection 
Pneumocystis jirovecii 
BK virus disease, including polyomavirus-associated 
nephropathy  
CMV disease 
Post-transplant lymphoproliferative disorder (EBV) 
Progressive multifocal leukoencephalopathy 
Bartonellosis (disseminated disease only) 
Blastomycosis 
Toxoplasmosis 
Coccidioidomycosis 
Histoplasmosis 
Aspergillosis (invasive disease only) 
Candidiasis (invasive disease or pharyngeal) 
Cryptococcosis 
Other invasive fungi: Mucormycosis (zygomycosis) 
(Rhizopus, Mucor, and Lichtheimia), 
Scedosporium/Pseudallescheria boydii, Fusarium) 
Legionellosis 
Listeria monocytogenes (invasive disease only) 
TB 
Nocardiosis 
Non-tuberculous mycobacterium disease 
Salmonellosis (invasive disease only) 
HBV reactivation 
Herpes simplex (invasive disease only) 
Herpes zoster (any form) 
Strongyloides  
(hyperinfection syndrome and disseminated forms 
only) 
Paracoccidioides infections 
Penicillium marneffei (talaromyces) 
Sporothrix schenckii 
Cryptosporidium species  
(chronic disease only) 
Microsporidiosis 
Leishmaniasis (visceral only) 
Trypanosoma cruzi infection  
(Chagas’s disease) (disseminated disease only) 
Campylobacteriosis (invasive disease only) 
Shigellosis (invasive disease only) 
Vibriosis  
(invasive disease due to Vibrio vulnificus) 
HCV progression 
CMV = cytomegalovirus; EBV = Epstein-Barr virus; HBV = hepatitis B virus; HCV = hepatitis C virus; TB = 
tuberculosis. 
Source: Winthrop et al, 2015. 
a Generally does not occur in the absence of immunosuppression, but whose presence indicates a potential or 
likely alteration in host immunity. 
b Can occur in patients without recognized forms of immunosuppression, but whose presence indicates a potential 
or likely alteration in host immunity. 
c Published data are currently lacking, but expert opinion believes that risk is likely elevated in the setting of 
biologic therapy. 
 
 


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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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APPENDIX 3 
2019 EUROPEAN LEAGUE AGAINST RHEUMATISM/AMERICAN 
COLLEGE OF RHEUMATOLOGY CLASSIFICATION SYSTEM FOR 
SYSTEMIC LUPUS ERYTHEMATOSUS 
 
β2GP1 = β2-glycoprotein 1; C = complement; dsDNA = double-stranded DNA; Hep-2 = human epithelial type 2 
cells; SLE = systemic lupus erythematosus. Source: Aringer et al, 2019. 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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APPENDIX 4 
INTERNATIONAL SOCIETY OF NEPHROLOGY AND THE RENAL 
PATHOLOGY SOCIETY (ISN/RPS) 2003 CLASSIFICATION OF 
LUPUS NEPHRITIS 
 
Class I 
 
Minimal mesangial lupus nephritis 
Normal glomeruli by light microscopy, but mesangial immune deposits by 
immunofluorescence 
Class II 
 
Mesangial proliferative lupus nephritis 
Purely mesangial hypercellularity of any degree or mesangial matrix 
expansion by light microscopy, with mesangial immune deposits 
May be a few isolated subephithelial or subendothelial deposits visible by 
immunofluorescence or electron microscopy, but not by light microscopy 
Class III 
 
Focal lupus nephritisa 
Active or inactive focal, segmental or global endo- or extracapillary 
glomerulonephritis involving <50% of all glomeruli, typically with focal 
subendothelial immune deposits, with or without mesangial alterations 
Class III (A)  
Active lesions: focal proliferative lupus nephritis 
Class III (A/C) 
Active and chronic lesions: focal proliferative and sclerosing lupus 
nephritis 
Class III (C) 
Chronic inactive lesions with glomerular scars: focal sclerosing lupus 
nephritis 
Class IV 
 
Diffuse lupus nephritisb 
Active or inactive diffuse, segmental or global endo- or extracapillary 
glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse 
subendothelial immune deposits, with or without mesangial alterations. 
This class is divided into diffuse segmental (IV-S) lupus nephritis when 
≥50% of the involved glomeruli have segmental lesions, and diffuse 
global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have 
global lesions. Segmental is defined as a glomerular lesion that involves 
less than half of the glomerular tuft. This class includes cases with diffuse 
wire loop deposits but with little or no glomerular proliferation. 
Class IV-S (A)  
Active lesions: diffuse segmental proliferative lupus nephritis 
Class IV-G (A)  
Active lesions: diffuse global proliferative lupus nephritis 
Class IV-S (A/C)  
Active and chronic lesions: diffuse segmental proliferative and sclerosing 
Class IV-G (A/C)  
Active and chronic lesions: diffuse global proliferative and sclerosing 
lupus nephritis 
Class IV-S (C)  
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus 
nephritis 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Class IV-G (C)  
Chronic inactive lesions with scars: diffuse global sclerosing lupus 
nephritis 
Class V 
 
Membranous lupus nephritis 
Global or segmental subephithelial immune deposits or their morphologic 
sequelae by light microscopy and by immunofluorescence or electron 
microscopy, with or without mesangial alterations 
Class V lupus nephritis may occur in combination with class II or IV in 
which case both will be diagnosed 
Class V lupus nephritis show advanced sclerosis 
Class VI 
 
Advanced sclerosis lupus nephritis 
≥90% of glomeruli globally sclerosed without residual activity 
 
Source: Weening et al, 2004 
a Indicate the proportion of glomeruli with active and with sclerotic lesions. 
b Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. 
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of 
arteriosclerosis or other vascular lesions. 
 
 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
HORIZON THERAPEUTICS IRELAND DAC 
Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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APPENDIX 5 
PREDISONE EQUIVALENT OF ORAL GLUCOCORTICOID DOSE 
 
Glucocorticoid 
Prednisone Equivalent Dose 
PO prednisone 
5 mg 
7.5 mg 
10 mg 
20 mg 
30 mg 
40 mg 
Prednisolone 
5 mg 
7.5 mg 
10 mg 
20 mg  
30 mg 
40 mg 
Methylprednisolone 
4 mg 
6 mg 
8 mg 
16 mg 
24 mg 
32 mg 
Hydrocortisone 
20 mg 
30 mg 
40 mg 
80 mg 
120 mg 
160 mg 
Cortisone 
25 mg 
37.5 mg 
50 mg 
100 mg 
150 mg 
200 mg 
Triamcinolone 
4 mg 
6 mg 
8 mg 
16 mg 
24 mg 
32 mg 
PO: oral(ly). 
ie, 
1 mg prednisone = 1 mg prednisolone 
1 mg prednisone = 5 mg cortisone 
1 mg prednisone = 4 mg hydrocortisone (cortisol) 
1 mg prednisone = 0.8 mg methylprednisolone 
1 mg prednisone = 0.8 mg triamcinolone 
1 mg prednisone = 0.15 mg dexamethasone 
 
 
 


Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
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Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Protocol Version: 2.0 (HZNP-DAX-203) 
 
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Indication: Lupus Nephritis  
 
Date: 17 MAY 2022 
CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
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Protocol Version: 2.0 (HZNP-DAX-203) 
 
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SAP_001.pdf: 


Daxdilimab (HZN-7734) 
HZNP-DAX-203 
Statistical Analysis Plan 
 
Version 1.0 
 
CONFIDENTIAL 
Page 2 
31 January 2023 
 
 
 
NOTICE OF CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
The information contained in this document is confidential belonging to Horizon 
Therapeutics Ireland DAC. Acceptance of this document constitutes agreement by the 
recipient that no information contained herein will be published or disclosed without 
prior written authorization from an official of Horizon Therapeutics Ireland DAC. 
However, this document may be disclosed to appropriate Institutional Review Board and 
Ethics Committees or duly authorized representatives of a national regulatory authority 
under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Horizon Therapeutics Ireland DAC should 
be notified promptly. 
 
 
 
LIST OF TABLES 
Table 1 
Trial Objectives and Endpoints ..............................................................7 
Table 2 
Stage I Treatment Assignment .............................................................10 
Table 3 
Stage II Treatment Assignment ...........................................................11 
Table 4 
Study Periods .......................................................................................18 
Table 5 
TEAEs for Different Study Periods .....................................................35 
Table 6 
Definition of ADA Status ....................................................................42 
Table 7 
Prednisone Equivalent of OCS Dose ...................................................48 
  
LIST OF FIGURES 
Figure 1 
Study Flow Diagram ..............................................................................1 
 


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HZNP-DAX-203 
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LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
Confidence interval 
COA 
clinical outcome assessment 
CRR 
complete renal response 
CSR 
clinical trial report 
eGFR 
estimated glomerular filtration rate 
IFN 
interferon 
LN 
lupus nephritis 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF/MPA 
Mycophenolate Mofetil/Mycophenolic Acid 
MMRM 
mixed model for repeated measures 
mSFI 
modified SELENA-SLEDAI Flare Index 
MxA 
myxovirus resistance protein A 
OCS 
oral corticosteroids 
PD 
pharmacodynamics 
 
 
 
 
 
 
PK 
pharmacokinetics 
PRO 
patient report outcome 
PRR 
Partial renal response 
PT 
preferred term 
 
 
Q1, Q3 
first quartile, third quartile 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 


Daxdilimab (HZN-7734) 
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Version 1.0 
 
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SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
subcutaneously 
SD 
standard deviation 
SDI 
Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index 
SE 
Standard error 
SFU 
Safety Follow-Up 
SLE 
systemic lupus erythematosus 
 
 
SLICC/ACR 
Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
SOC 
system organ class 
SPP 
statistical programming plan 
TEAE 
treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse events 
TEAESI 
treatment-emergent adverse events of special interest 
VAS 
visual analog scale 
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
WHO-DD 
World Health Organization Drug dictionary 


Daxdilimab (HZN-7734) 
HZNP-DAX-203 
Statistical Analysis Plan 
 
Version 1.0 
 
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SAP REVISION 
 
Revision Date 
(DD MMM YYYY) 
Section 
Summary of Revision 
Reason for Revision 
31 JAN 2023 
 
 
Initial Draft 
 
 
 
 


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1 
INTRODUCTION 
This document describes the statistical analysis for protocol “HZNP-DAX-203, a 
multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the 
efficacy and safety of daxdilimab in adult participants with active proliferative lupus 
nephritis”. Standard data presentation instructions, and table, figure, and listing specifications 
are contained in the Statistical Programming Plan (SPP) in a separate document. 
There are three planned analyses for this study, which include the primary efficacy and safety 
analysis at Week 52, the final analysis at Week 112 and an 
 
 
. 
 
 


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2 
TRIAL OVERVIEW 
2.1 
Trial Objectives and Endpoints 
The objectives and corresponding endpoints are listed in Table 1 below: 
  
Table 1 
Trial Objectives and Endpoints 
Primary Objective 
Primary Endpoint 
To evaluate the efficacy 
of daxdilimab in 
combination with SOC 
compared to placebo in 
combination with SOC 
in participants with 
active, proliferative LN 
 Complete Renal Response (CRR) at Week 48 and sustained through Week 52. CRR 
is defined as meeting all of the following criteria: 
 
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 or no 
worse than 15% below baseline 
 
24-hour UPCR ≤ 0.5 mg/mg  
 
No discontinuation of study intervention or use of restricted medication 
beyond the protocol allowed threshold before assessment 
Secondary Objectives  
Secondary Endpoints 
To assess overall renal 
response (ORR) with 
daxdilimab versus 
placebo in participants 
with active, 
proliferative LN 
 
 
 ORR (defined as CRR or partial renal response (PRR)) at Week 48 and sustained 
through Week 52 
See above for definition of CRR. PRR is defined as meeting all of the following 
criteria: 
 
eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below baseline 
 
Improvement in 24-hour UPCR:  
o 
For participants with a baseline UPCR ≤ 3.0 mg/mg: < 1.0 mg/mg 
o 
For participants with a baseline UPCR > 3.0 mg/mg: > 50% 
improvement from baseline and ≤ 3.0 mg/mg 
 
No discontinuation of study intervention or use of restricted medication 
beyond the protocol allowed threshold before assessment 
To assess the change 
from baseline in eGFR 
with daxdilimab versus 
placebo in participants 
with active, 
proliferative LN 
 
Change from baseline in eGFR at Week 52 
To evaluate the ability 
to improve dose 
requirements of oral 
corticosteroids (OCS) 
with daxdilimab versus 
placebo in participants 
with active, 
proliferative LN. 
Able to taper OCS to ≤ 2.5 mg/day prednisone-equivalent by Week 24 and maintain 
this dose through Week 52. 
Sustained reduction of OCS dose: 
 
Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and not exceeding 
this dose through Week 52 and 
 
No discontinuation of study intervention or use of restricted medication 
beyond the protocol allowed threshold before assessment 
To characterize the PK 
and immunogenicity of 
daxdilimab in 
participants with active, 
proliferative LN. 
 
Serum concentration of daxdilimab over time. 
 
Rate of ADA directed against daxdilimab and ADA titer for the duration of 
the study. 


Daxdilimab (HZN-7734) 
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Table 1 
Trial Objectives and Endpoints 
To evaluate the safety 
and tolerability of 
daxdilimab in 
combination with SOC 
in participants with 
active, proliferative LN. 
 
Incidence of treatment-emergent adverse events (TEAEs) over time. 
 
Incidence of treatment-emergent serious adverse events (TESAEs) over 
time. 
 
Incidence of treatment-emergent AEs of special interest (TEAESIs) over 
time: hypersensitivity reaction, including anaphylaxis, severe (Grade 3 or 
higher) viral infection/reactivation, herpes zoster, opportunistic infection, 
and malignancy (except non-melanoma skin cancer). 
 
 
 


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Daxdilimab (HZN-7734) 
HZNP-DAX-203 
Statistical Analysis Plan 
 
Version 1.0 
 
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Page 10 
31 January 2023 
2.2 
Trial Design 
This trial is a Phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-
group trial to assess the efficacy and safety of daxdilimab in patients with active, 
proliferative lupus nephritis despite standard of care.  
Approximately 210 participants will be randomized in a ratio of 1:1:1 (70 participants per 
group) to receive either daxdilimab 
mg or
 mg SC or placebo SC in addition to SOC 
background therapy as described below in Table 2. Randomization will be stratified by: 
 Pre-randomization urine protein to creatinine ratio (UPCR) < 3.0 mg/mg vs. ≥ 3.0 
mg/mg 
 Screening eGFR < 60 mL/min/1.73m2 vs. ≥ 60 mL/min/1.73m2 
Table 2 
Stage I Treatment Assignment 
 


Daxdilimab (HZN-7734) 
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Table 3 
Stage II Treatment Assignment 
 
The basic study flow diagram is presented in Figure 1 
 
 




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2.3 
Sample Size 
A sample size of approximately 210 participants (up to approximately 70 participants 
per treatment group) is planned for this trial. The sample size was calculated based on 
the primary efficacy endpoint. Assuming a placebo response rate of 25%, 70 participants 
per treatment group will provide approximately 80% power to detect an increase in 
response of 20% in either arm of a daxdilimab group as compared to the placebo group 
at the 2-sided alpha level of 0.10 using a Chi-square test. The minimum detectable 
difference is 13% between the daxdilimab group and placebo group. The assumption of 
25% responder rate for placebo is based upon published results (Mejia-Vilet et al., 
2021). 
 


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3 
PLANNED ANALYSES 
 
 
 
 
  
3.2 
Planned Primary Analysis 
The primary analysis will be conducted after the last participant has completed the Week 
52 Visit or discontinued from study early. For the primary analysis, all the efficacy and 
safety data collected prior to the data cut-off will be analyzed. 
3.3 
Planned Final Analysis 
The final analysis will be conducted after all participants have completed Week 112 
Visit or discontinued early from the study. 


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4 
STATISTICAL METHODS 
4.1 
General Considerations for Data Analyses 
All statistical calculations will be primarily performed using SAS® System Version 9.4 
or higher (SAS Institute Inc., Cary, NC, USA).  
The primary comparison will be between the daxdilimab 
 mg or 
 mg group and 
the placebo group. For primary and second efficacy analyses, the data up to the 
 
Visit will be used. The applied methods for statistical descriptive analysis and 
presentations will be based on the types of variables being tested.  
1) Overall summary of descriptive statistics for continuous variables will include, 
not limited to, the number of observations, mean, standard deviation, median, 
minimum, and maximum, first quartile, and third quartile values in each 
treatment group 
2) Overall summary of descriptive statistics for categorical variables will include, 
not limited to, frequency counts, percentage of patients of point estimate  
Data summaries for Stage I of the Treatment Period will be presented by randomized 
treatment group (i.e., “daxdilimab 
 mg”, “daxdilimab 
 mg” and “Placebo”) and 
overall. Data summaries for Treatment Period Stage II (i.e., the Stage II period 
beginning at the
 Visit) will be presented according to the reassigned treatment 
regimen with respect to achievement of PRR (or CRR) at Weeks 48 and maintained 
through Week 52 (e.g., “daxdilimab 
 mg 
 mg 
”, “daxdilimab 
 mg 
 mg 
”, “daxdilimab 
 mg 
 mg 
”, “Placebo 
/Placebo 
”, and “Placebo 
/daxdilimab 
 mg 
”). For the 
longitudinal analysis covering two-stage periods (Stage I and Stage II) of treatment, 
participants will be analyzed according to the combination of treatment that they 
actually received in Stage I and Stage II treatment period.  
Summaries of study and participant characteristics (e.g., demographics and baseline 
characteristics, medical history, protocol deviations) will be reported.  
For additional details on data presentation, refer to the Statistical Programming Plan 
(SPP). 
Table 4 provides the overview of the study periods for reporting purposes. All major 
analysis endpoints will be reported for Stage I and Stage II. All assessments, unless 
otherwise specified, will be included in by-patient listings. Data collected at 
unscheduled visits may be used in the data analysis and will not be presented in the 
summary statistics report. 
Table 4 
Study Periods 
Study Period 
Description 
Stage I 
Day 1 to 
 trial intervention administration and safety/efficacy assessments 
Stage II 
Post 
 trial intervention administration and safety/efficacy assessments + safety 
follow-up 


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4.1.1 Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing valid observation 
prior to the first dose of trial intervention. In cases where baseline measurements are 
taken on the same day as trial intervention and no times are reported, it will be assumed 
that these measurements are taken prior to trial intervention being administered. 
At 
 participants from all three Treatment Groups will be assigned to a 
 
 based upon the renal response observed at 
 
 All participants who did not achieve the primary endpoint will be re-baselined at 
. A re-baseline is defined as the last available assessment prior to the first 
quarterly dose of study intervention administered at 
  
4.1.2 Analysis Windows 
Analysis visit windows will be used for all visit-based assessments to map longitudinal 
observations to scheduled visits and thereby allow for by-visit analyses, since not all 
assessments are performed on the scheduled day. Unless otherwise specified, all 
longitudinal efficacy, safety, and 
 will be based on the analysis 
visit windows. The analysis visit windows will be calculated by bisecting the interval 
between adjacent scheduled visit days except for the first post-treatment visit and the 
 visit. The first post-treatment visit will start at Day 2. When mapping to the 
 analysis window, this should only occur for assessments on or before the date 
of the nominal
 dosing. Assessments after this date will be mapped to the 
following analysis visit windows. The detailed analysis visit windows will be specified 
in the SPP. The actual assessment day will be mapped to the windows defined for each 
scheduled study visit by the following rules:  
 If more than one assessment falls within a visit window, the closest non-missing 
assessment to the scheduled day will be used in the analysis. 
 If 2 non-missing assessment actual dates are equidistant from the target day, the 
later visit will be used in the analysis. 
 For retest values of laboratory data, the retest value will be chosen. 
4.1.3 Missing Data 
In general, missing data will not be imputed unless methods for handling missing data 
are specified.  
 
4.2 
Protocol Deviations  
 The protocol deviations are reviewed and categorized as significant and non- 
significant prior to the database lock.  
- 
Significant protocol deviation: a protocol deviation that affects primary 
efficacy and safety assessments (as applicable), the safety or mental 
integrity of a subject, or the scientific value of the project. 


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- 
Non-significant protocol deviation: a protocol deviation that is identified 
but does not impact the endpoints (as applicable), the safety or mental 
integrity of a subject, or the scientific value of the project.   
 
All the protocol deviations will be listed. The number and percentage of participants 
with significant protocol deviations by deviation reason (e.g., nonadherence to study 
drug, violation of select inclusion/exclusion criteria) will be summarized.  
A by-participant listing will be provided for those participants who did not meet at least 
one eligibility (inclusion or exclusion) criterion. The listing will present the eligibility 
criterion (or criteria if more than one deviation) that participants did not meet and related 
comments, if collected. 
4.3 
Statistical Hypotheses 
The statistical hypotheses are as follows:  
 Null hypothesis (H0): difference in proportion of CRR responders (daxdilimab 
vs placebo) = 0 
 Alternative hypothesis (Ha): difference in proportion of CRR responders 
(daxdilimab vs placebo) ≠ 0 
4.4 
Analysis Sets 
4.4.1 Full Analysis Set 
The Full Analysis Set will include all randomized participants who receive any dose of 
trial intervention in the study. Participants will be analyzed according to the treatment 
randomized. The efficacy analysis will be based on the Full Analysis Set. 
4.4.2 Safety Analysis Set 
Safety Analysis Set will include all participants who receive any dose of trial 
intervention in the study. Participants will be analyzed according to the treatment that 
they actually received. Safety, PD, and ADA analyses will be based on the Safety 
Analysis Set. 
4.4.3 Pharmacokinetic (PK) Analysis Set 
The PK Analysis Set will include all participants who receive any dose of daxdilimab in 
the study and have at least one quantifiable serum PK observation post first dose. 
Participants will be analyzed according to the treatment that they actually received. The 
PK analysis will be based on the PK Analysis Set 
4.4.4 Stage II Analysis Set 
The stage II analysis set includes all participants who received at least one dose of trial 
intervention during the Stage II treatment period starting from 
.  


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4.4.5 Any Daxdilimab Set 
The any daxdilimab analysis set includes all participants who receive at least one dose of 
daxdilimab during the trial.  
4.5 
Participant Disposition  
A summary of participant disposition will be presented into two sections: 
 
Stage I 
 
Stage II 
In Stage I section, the participants will be presented using the categories presented 
below. 
 
Screened 
 
Screen failed with reasons 
 
Randomized 
 
Randomized but not treated 
 
Randomized and treated 
 
Completed Stage I treatment 
 
Discontinued Stage I treatment with reasons  
 
Completed Stage I trial 
 
Discontinued Stage I trial with reasons 
In Stage II section, the participants be presented using the categories presented below. 
 
Participants entered into Stage II trial 
 
Completed Stage II treatment 
 
Discontinued Stage II treatment with reasons 
 
Completed Stage II trial 
 
Discontinued Stage II trial with reasons 
4.6 
Trial Intervention Exposure 
 The number of doses received, amount of the trial intervention received, total 
number of doses planned per protocol, durations of the trial intervention 
exposure, and treatment compliance will be summarized by treatment groups. 
For treatment compliance, the number and proportion of patients who had 
treatment compliance percentage in range by increments of 10% (i.e., >= 90% to 
<= 100%; >= 80% to < 90%; >= 70% to < 80% etc.) during treatment period will 
also be summarized by treatment groups. The summary will be produced using 
the Full Analysis Set for Stage I, Stage II and overall study. Duration of the trial 
intervention exposure is defined as follows: 
- 
Stage I:  
 dose date – first dose date  
- 
Stage II: last dose date + 28 – 
 dose date + 1 


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 The amount of trial intervention exposure: if a participant received a partial 
dose at a dosing visit, then the amount of trial intervention at that dosing visit 
will be estimated based on the actual volume administered. 
 Treatment compliance for an individual participant = [Total number of doses 
received]/[Total number of doses planned per protocol] ×100%. 
In addition, the total number of participants with missed doses and reasons for missed 
dose will be summarized by randomized treatment group and overall.   
4.7 
Demographics, Baseline Characteristics, and Medical History 
The demographics (age, gender, race, ethnicity, height, weight, and body mass index) 
will be summarized by randomized treatment group and overall using the Full Analysis 
Set. Participant listings of these data will also be provided. 
A summary of baseline disease characteristics, by randomized treatment group and 
overall, for the Full Analysis Set will include:  
 Time from first diagnosis of proliferative LN based on a renal biopsy at baseline 
(baseline renal biopsy may be obtained within 6 months prior to signing the 
informed consent form (ICF) or during the Screening Period) 
 Pre-randomization urine protein to creatinine ratio (UPCR) (< 3.0 mg/mg vs ≥ 
3.0 mg/mg) (if more than one UPCR measurements available, use the last valid 
measurement),  
 Screening estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73m2 vs ≥ 
60 mL/min/1.73m2),  
 eGFR (calculated by the MDRD formula),  
 24-hour UPCR, 
 Renal-biopsy lupus nephritis class (Class III (± class V) vs class IV (± class V)),  
 
 
 
 The Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index (SDI), 
 
 
 
  
 Baseline OCS use (yes vs. no),  
 Baseline OCS dose (≤7.5 mg/day vs >7.5 mg/day), 
 Baseline MMF/MPA use (yes vs. no),  
 Baseline MMF/MPA dose (≤ 2 gm/day vs > 2 gm/day), 
 
  


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 Antinuclear antibodies (ANA) ≥ 1:80 (yes vs. no),  
 
  
 
 
 
 
Significant medical history findings will be summarized by system organ class (SOC) 
and preferred term (PT) using Medical Dictionary for Regulatory Activities (MedDRA) 
(Version 23 or later), by randomized treatment group and overall. 
4.8 
Efficacy Analyses 
4.8.1 Primary Efficacy Endpoint and Analysis 
4.8.1.1 Primary Efficacy Endpoint and Estimand 
The estimand of primary interest is defined as follows, using composite variable strategy 
to address intercurrent events: participants for receipt of rescue therapy or treatment 
discontinuation will be treated as failure to meet CRR and considered as non-responder. 
For participants who experience multiple intercurrent events, data will be handled 
according to the first intercurrent event. 
1. Population: Participants in the Full Analysis Set 
2. Variable (endpoint measure): CRR at Week 48 and sustained through Week 52. 
CRR is defined by meeting all of the following criteria: 
i. eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below baseline. 
ii. 24-hour UPCR ≤ 0.5 mg/mg. 
iii. No use of restricted medication beyond the protocol allowed threshold 
before assessment. 
iv. No discontinuation of study intervention 
3. Intercurrent event:  
a. Rescue medications: Captured in the primary variable definition.  
b. Treatment discontinuation: Captured in the primary variable definition.  
4. Population-level summary: Difference in proportions of responders between the 
daxdilimab group and placebo group (daxdilimab 
mg or 
 mg vs. placebo) 
4.8.1.2 Primary Efficacy Analysis 
The proportion of participants achieving CRR at Week 48 and sustained through Week 
52 in the daxdilimab group will be compared to that of the placebo group using a logistic 
regression model with treatment, adjusting for baseline eGFR value and baseline 24-
hour UPCR value in the model using the full analysis set. The baseline 24-hour UPCR 
will be derived using the urine sample collected at Week 0 (Day 1) prior to 
randomization and administration of first dose of study intervention. Baseline eGFR will 
be based on the measurement available prior to the first dose of study intervention. The 


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difference in proportions of responders of daxdilimab vs placebo will be estimated 
together with its associated 2-sided 90% confidence interval (CI). Longitudinal 
presentations of results over time up to 
 based on the same analysis will be 
created. A bar chart will also be provided showing the proportion of participants meeting 
the criteria for CRR and individual components of CRR at Week 48 and maintained 
through Week 52 by treatment groups. A line plot over time will also be produced by 
treatment groups. 
4.8.1.3 Subgroup analyses of primary endpoint 
The following subgroups will be investigated for the primary endpoint: 
 Renal-biopsy lupus nephritis class -- the World Health Organization (WHO) or 
2003 ISN/RPS classification (Class III (± class V) vs. class IV (± class V)) 
 Gender (male vs. female) 
 Race (white, black or African American, and other) 
 Ethnicity (Hispanic/Latino vs. not Hispanic/Latino) 
 Baseline IFN gene signature (high vs. low) 
 Age group (<65 vs. ≥65) 
 Region (North America + Western Europe vs. rest of the world) 
 ADA positive at any time (yes vs. no) 
 Pre-randomization urine protein to creatinine ratio (UPCR) (< 3.0 mg/mg vs. ≥ 
3.0 mg/mg) 
 Screening estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73m2 vs. 
≥ 60 mL/min/1.73m2) 
The nominal p-value and 90% CIs of treatment effect will be provided for each 
subgroup analysis. Given that the number of participants in some subgroups may be 
limited, subgroup categories may be combined as appropriate.  Otherwise, the subgroup 
analysis may not be performed if deemed infeasible based on sample size. 
Forest plots will be generated to visually present the consistency of treatment effect in 
different subgroups with overall treatment effect. Other subgroup analyses may be 
explored as needed. 
4.8.1.4 Control of Type I Error 
1. The type I error rate will be controlled at a 0.1 level (2-sided) for the primary 
efficacy analysis using a fixed sequence testing procedure. The primary endpoint 
will be tested for daxdilimab 
 mg compared with placebo. 
2. If p-value is ≤ 0.1 in step 1, the primary endpoint will be tested for daxdilimab 
mg compared with placebo. If step 1 test is not significant, the test for 
Daxdilimab 
 mg will not be performed. 
4.8.1.5 Sensitivity Analysis 
Race and ISN/RPS lupus nephritis disease class have been shown to be associated with 
poor prognosis and responses to treatment in patients with LN.  A sensitivity analysis for 


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the primary endpoint with race and ISN/RPS classification included as additional 
covariates in the logistic regression model as defined in 4.8.1.2 will be performed to 
adjust the potential imbalance across treatment groups.  
4.8.1.6 Supplementary Analyses of the Primary Efficacy Endpoint 
Supplementary analyses will be performed using the same logistic regression model as 
the primary analysis (section 4.8.1.2) based on Stage I data using the full analysis set. 
These supplementary analyses provide additional insights for primary efficacy results. 
Treatment policy will be used to handle rescue medication use and treatment 
discontinuation, i.e., including all observed data collected after rescue medication 
administration and treatment discontinuation regardless of receipt of rescue therapy or 
treatment discontinuation. 
The proportion of subjects that achieved CRR at Week 48 but not at Week 52 will be 
computed by randomized treatment group using the Full Analysis Data Set.  
4.8.1.7 Handling Plan for Missing Data 
4.8.1.7.1 Imputation if Missing a Single Lab Component within a Visit 
The 24-hour UPCR and eGFR values will be used for the primary efficacy endpoint 
evaluation. No imputation will be performed for missing baseline values. If either the 
24-hour UPCR or eGFR is missing at a single treatment visit,  
 the missing 24-hour UPCR will be imputed using the observed spot UPCR from 
the same visit unless a 24-hour UPCR can be obtained from a recent unscheduled 
visit (e.g., within maximum 4-week period), then the 24-hour UPCR from this 
unscheduled visit will be used. Otherwise, the 24-hour UPCR will be imputed 
using Last Observation Carried Forward (LOCF) of the most recent scheduled 
measurement of 24-hour UPCR if available or spot UPCR when 24-hour UPCR 
is unavailable.  
 the missing eGFR will be imputed using LOCF. 
4.8.1.7.2 Imputation for Missing Data 
The intermittent missing data will be imputed using LOCF. Participants with missing 
outcomes due to early discontinuation from the study will be considered as non-
responders.  
4.8.2 Secondary Efficacy Endpoints and Analyses 
4.8.2.1 Secondary Efficacy Endpoints and Estimands 
The estimand for the binary secondary efficacy endpoints is defined as follows, using 
composite variable strategy to address intercurrent events.  
1. Population:  


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a. ORR: Participants in the Full Analysis Set. 
b. Sustained reduction of oral corticosteroids (OCS) dose: Participants in the 
Full Analysis Set whose Baseline OCS dose is greater than 2.5 mg/day 
prednisone equivalent (Appendix 1). 
2. Variables (outcome measures): 
a. ORR at Week 48 and sustained through Week 52 (ORR is defined as CRR or 
PRR). CRR was defined in primary endpoint. PRR is defined by meeting the 
following criteria: 
i. eGFR ≥ 60 mL/min/1.73m2 or no worse than 15% below baseline. 
ii. Improvement in 24-hour UPCR:  
 For participants with a baseline UPCR ≤ 3.0 mg/mg: < 1.0 mg/mg 
 For participants with a baseline UPCR > 3.0 mg/mg: > 50% 
improvement from baseline and ≤ 3.0 mg/mg 
 
The baseline values of 24-hour UPCR and eGFR is defined in Section 
4.8.1.2 
iii. No use of restricted medication beyond the protocol allowed threshold 
before assessment.  
iv. No discontinuation of study intervention. 
 
b. Response in sustained reduction of OCS dose, which is defined by meeting 
the following criteria: 
i. Prednisone-equivalent dose ≤ 2.5 mg/day by Week 24 and not exceeding 
this dose through Week 52. 
ii. No use of restricted medication beyond the protocol allowed threshold 
before assessment. 
iii. No discontinuation of study intervention. 
 
3. Intercurrent event:  
a. Rescue medications: Captured in the variable definition.  
b. Treatment discontinuation: Captured in the variable definition.  
 
4. Population-level summary: Difference in proportions of responders between the 
daxdilimab group and placebo group. 
 
The estimand of change from baseline in eGFR at Week 52 is defined as follows, using 
hypothetical strategy to address intercurrent event of rescue medications by assuming 
data is missing as missing at random (MAR) after rescue medication and treatment 
policy strategy to address intercurrent event of treatment discontinuation by continue 
taking measures regardless of treatment discontinuation. 
1. Population: Participants in the Full Analysis Set. 


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2. Variable (outcome measure): Change from baseline in eGFR at Week 52. 
The baseline values of eGFR are defined in Section 4.8.1.2 
3. Intercurrent event: 
a. Rescue medications: The data collected after administration of the rescue 
medications will be treated as missing and be imputed based on assumption 
of MAR. That is the participants have followed the trend of his or her own 
treatment group 
b. Treatment discontinuation: Participants who discontinue study intervention 
will be asked to come to scheduled evaluations until the end of study. The 
data collected after discontinuation of study intervention will be included in 
the analysis 
4. The population-level summary: Mean difference of change from baseline on 
eGFR between the daxdilimab group and placebo group. 
4.8.2.2 Secondary Efficacy Analyses 
The secondary efficacy analyses will be based on the FAS. No adjustment for 
multiplicity will be performed.  
1) ORR will be analyzed using a logistic regression model with treatment, baseline 
eGFR value and baseline UPCR value included in the model. Response in 
sustained reduction of OCS dose will be analyzed similarly using a logistic 
regression model with treatment, randomization stratification factors and 
baseline OCS dose included in the model. The difference in proportions of 
responders of daxdilimab vs placebo will be estimated together with its 
associated 2-sided 90% confidence interval (CI). 
2) Change from baseline in eGFR will be analyzed using mixed models for repeated 
measures (MMRM) with treatment, visit, visit by treatment interaction, 
randomization stratification factor (UPCR only), and baseline eGFR value 
included in the model. The normality test will be performed on change from 
baseline in eGFR. If it fails for normal assumption, the data of change from 
baseline in eGFR will be log-transformed.  An unstructured covariance matrix 
will be used to model the correlations among repeated measurements within each 
participant. In case of convergence issues, another structure, for instance, a first-
order autoregressive covariance matrix will be used. Covariance parameters will 
be estimated using restricted maximum likelihood method and Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom for the 
tests of fixed effects. The treatment effect will be evaluated at Week 52 along 
with two-sided 90% CI will be reported. 
3) A bar chart will be provided showing the proportion of participants meeting the 
criteria for ORR and individual components of ORR at 
 
 by treatment groups. A line plot up to 
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4) The trajectory of eGFR over time will be visually presented by plotting the mean 
eGFR at each time point by treatment groups. 
 
4.8.2.3 Supplementary Analyses of the Secondary Efficacy Endpoints 
Supplementary analyses using the same models as described in section 4.8.2.2 for 
each secondary endpoint will be performed based on Stage I data using the full 
analysis set. These supplementary analyses provide additional insights for the 
secondary efficacy results. Treatment policy will be used to address intercurrent 
events of rescue medication administration and treatment discontinuation, i.e., 
including all observed data collected after rescue medications administration and 
after discontinuation of treatment.  
4.8.2.4 Handling Plan for Missing Data 
For ORR, the missing data will be handled in the same way as the primary efficacy 
analysis (section 4.8.1.7). Participants with missing outcomes due to early 
discontinuation from the study will be considered as non-responders. If any of the 
criteria cannot be evaluated at a visit, that criterion will be imputed using LOCF. For 
the change from baseline in eGFR, the missing data will be handled using the 
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4.8.3.1.7 SDI 
The Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index (SDI) has been developed to assess irreversible damage in 
SLE participants independently of its cause (ie, included damage due to SLE activity, 


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SLE-related scarring, therapy, comorbidities) but occurring after disease onset. Damage, 
ie, irreversible impairment since onset of SLE, is usually defined as a clinical feature 
that must be continuously present for at least 6 months to score. In addition, some 
irreversible events such as myocardial infarction or a cerebrovascular accident, score as 
damage on their occurrence. Briefly, damage is defined for 12 organ systems: peripheral 
vascular, ocular, neuropsychiatric, renal, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, skin, endocrine (diabetes), gonadal, and malignancies. Damage over 
time can be stable or increase, theoretically to a maximum of 47 points (Schwartz et al., 
2009). 
The following SLICC/ACR SDI endpoints will be explored.  
 Change from baseline in SDI over time. 
 Proportion of participants with any SDI worsening (change from baseline > 0) 
over time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.9 
Safety Analyses 
4.9.1 Adverse Events 
Safety analyses will be based on the actual treatment received and will be performed on 
the Safety Analysis Set, Stage II Analysis Set or Any Daxdilimab Set according to the 
study period being examined. All safety data will be provided in patient listings by 
treatment group.  
No formal hypothesis is planned. In general, if an adverse event (AE) onset is on or after 
the first dose of trial intervention, the AE will be considered as a treatment-emergent 
adverse event (TEAE). Otherwise, the AE will be considered as a non-TEAE. Safety 
data will be presented separately for different study periods as defined in Table 5. In 
addition, the total number of participants with missed doses and reasons for missing 
(COVID-19 related or others) will be summarized by treatment group and overall.  
 
Table 5 
TEAEs for Different Study Periods 
Study Period 
Inclusion of TEAEs for Summary 
Stage I (Safety Analysis Set) 
Include AEs with an onset on or after the first dose of trial intervention 
in Stage I treatment period up to the time prior to the first dose of 
daxdilimab in Stage II treatment period (
) for participants who 
were dosed during the Stage II treatment period, and AEs with an onset 
on or after the first dose of trial intervention in Stage I treatment for 
participants not dosed in Stage II treatment. 
Stage II (Stage II Analysis Set) 
Include AEs with an onset on or after the first dose of daxdilimab in 
Stage II treatment period (
). 


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Table 5 
TEAEs for Different Study Periods 
Study Period 
Inclusion of TEAEs for Summary 
Any Daxdilimab Exposure (Any 
Daxdilimab Analysis Set) 
Include AEs with onset on or after the first daxdilimab dose (either 
during Stage I or Stage II treatment period) 
 
All AEs and TEAEs will be coded using the most recent version of MedDRA, and will 
be summarized by SOC and PT overall, by severity and by relationship to treatment. 
Participants having multiple AEs within a category (eg, overall, SOC, PT) will be 
counted once in that category. Specific AEs will be counted once for each participant for 
calculating rates, but all events will be presented in participant listings. In addition, for 
severity/relationship tables, if the same AE occurs multiple times within a particular 
participant, the highest severity/most related event within a category and level of 
causality will be reported.  
SAEs and TEAEs will be summarized descriptively by treatment group and overall. 
Percentages will be based on the number of treated participants in the safety set within a 
treatment group and overall. Tables will be sorted by descending frequency of SOC and 
by descending frequency of PT within an SOC. Specific AEs will be counted once for 
each participant for calculating rates, but all events will be presented in participant 
listings. Listings will be provided for all TEAEs and non-treatment-emergent AEs. 
TESAEs will be summarized by serious adverse event (SAE) criteria as well.  
The following definitions will be used for AEs: 
 Treatment-emergent adverse event (TEAE): Any AE with an onset on or after 
the first dose of study intervention  
 Treatment-emergent SAE (TESAE): A TEAE that is serious. The details are 
referenced in Section 8.3.1.3 of protocol 
A table will show the number and percentage of participants with at least one event in 
any of the following categories overall as well as by SOC and PT: 
 TEAE 
 Treatment-emergent serious adverse event (TESAE) 
 TEAE resulting in death 
 CTCAE Grade 3 or higher TEAE 
 TEAE leading to discontinuation of trial intervention  
 Serious and/or grade 3 or higher TEAE 
 Trial intervention related TEAE 
 Trial intervention related TESAE 
An AE of special interest (AESI) is an AE of scientific and medical interest specific to 
the understanding of the trial intervention and may require close monitoring and 
collection of additional information by the Investigator. AESIs for this protocol include: 


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 Hypersensitivity reaction, including anaphylaxis 
 Severe viral infection/reactivation (CTCAE v5.0 Grade 3 or higher) 
 Opportunistic infection as listed in protocol appendix 2 
 Malignancy (except non-melanoma skin cancer) 
Treatment emergent AESIs will be summarized by type of AESI as listed above as well 
as SOC and PT.  
Anaphylaxis will be searched using the NIAID (Sampson et al. 2006). The 
hypersensitivity reactions will be defined using Standardized MedDRA Queries (SMQ): 
hypersensitivity (narrow). Severe viral infection will be searched using MedDRA HLGT 
of Viral infectious disorders. Viral reactivation will be searched using MedDRA HLT 
Hepatic viral infection. Malignancy will be searched using MedDRA SMQ Malignant 
tumors. All will be described in the Statistical Programming Plan (SPP). 
 
Individual listings will be presented for AEs leading to study treatment discontinuation, 
AEs leading to withdrawal from the study, AEs starting during administration of study 
intervention, and fatal AEs. 
4.9.2 Additional Safety Assessment 
4.9.2.1 Clinical laboratory Evaluations 
Laboratory assessments are defined in Section 8.2.4 of Protocol. All protocol-required 
laboratory tests must be conducted in accordance with the laboratory manual and the 
Schedule of Activities (SoA). Any clinically significant value will be reported as an AE. 
The laboratory results must be retained with source documents. 
Clinical laboratory evaluations will be summarized for each treatment group and overall. 
The summary of clinical laboratory data will be generated for the Stage I data based on 
the Safety Analysis Set, and for the Stage II data based on Stage II Analysis Set. For 
analysis purposes, laboratory results based upon standardized units will be used. All data 
will be presented in listings, and a specific listing of abnormal results will be provided. 
The following summary will be provided for hematology and biochemistry and lipid 
profile by treatment groups: 
 Observed values and changes from the baseline by visit  
 Worst toxicity grade 
 At least 2-grade shift from baseline to worst toxicity 
 Shift from the baseline relative to the normal range 
In addition, the number and percentage of participants with the following liver-related 
abnormalities will be summarized if the following criteria is met at any post-baseline 
visit: 
 AST or ALT: (a) ≥ 3 × ULN; (b) ≥ 5 × ULN; (c) ≥ 8 × ULN 
 Total bilirubin: ≥ 2 × ULN 


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 ALT or AST ≥ 3 x ULN and total Bilirubin ≥ 2 × ULN  
 ALT or AST ≥ 5 × ULN for more than 2 weeks  
The following summary will be provided for urinalysis by treatment groups: 
 Observed values and changes from the baseline by visit 
 Shift from the baseline relative to the normal range 
 
 
 
 
 
 
4.9.2.2 Vital Signs 
The observed values, along with the changes from baseline, will be summarized at each 
time point by treatment for systolic blood pressure, diastolic blood pressure, body 
temperature, heart rate, and respiratory rate. A listing of vital signs will be presented by 
treatment, patient, vital sign, and visit. 
In addition, a summary of participants with clinically significant vital signs values 
(meeting any of following criteria) will also be provided. The summary of vital signs 
will be generated by visit using the safety analysis set for Stage I and Stage II. 
 Systolic blood pressure: < 90 mmHg, > 160 mmHg 
 Diastolic blood pressure: < 60 mmHg, > 100 mmHg 
 Heart rate: < 50 beats/min, > 100 beats/min 
 Respiratory rate: < 12 breaths/min, > 23 breaths/min 
 Temperature: < 36°C, >38°C 
4.9.2.3 Prior and Concomitant Medications 
Prior and concomitant medications and procedures will be summarized using the safety 
analysis sets accordingly. The details of prior and concomitant medications are 
described in Section 6.7 of the protocol. 
Medications collected at Screening and during the trial will be coded using the current 
version of the World Health Organization Drug dictionary (WHO-DD). Number (%) of 
participants who received prior medications and concomitant medications will be 
summarized by treatment presented by WHO-DD Anatomical Therapeutic Chemical 
(ATC) category and PT. At each level of summarization, a participant is counted once if 
the participant reported one or more medications at that level. The summary of prior and 
concomitant medications during Stage I will be based on safety analysis set. The 
concomitant medications during Stage II will be summarized based on the second-year 
analysis set. The prior and concomitant medications are defined as below. 
 Prior medications are defined as medications with a stop date occurring before 
the first trial intervention administration date. 


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 Concomitant medications during Stage I are defined as follows: 
- 
Medications with a start date before Week 64 trial intervention 
administration and stop date on or after the first trial intervention administration 
date for the participants entering the second-year treatment period. 
- 
Medications with stop date on or after the first trial intervention 
administration date for participants not entering the second-year treatment 
period. 
 Concomitant medications for Stage II are defined as medications with a stop date 
on or after Week 64 daxdilimab administration date. 
Rescue therapy for worsening LN may be administered at the discretion of Investigators 
as clinically indicated. Final rescue therapy will be reviewed and determined before 
unblinding at the end of Stage I.  
Rescue therapy includes: 
The initiation of any new treatment for lupus or LN with the selected restricted 
medications or prohibited medications as a rescue. Participants who receive 
rescue therapy will be considered treatment failures for subsequent endpoint 
analyses (such as CRR). Detailed prohibited medications are defined in the 
protocol Section 6.7.2, restricted medications are defined in the protocol Section 
6.7.3, and rescue medicine is defined in the protocol Section 6.7.6. Additionally, 
certain other concomitant medications initiated after randomization beyond those 
allowed in protocol Section 6.7.5 may also constitute rescue therapy. 
The number and percentage of participants who received rescue therapy will be 
summarized by treatment group according to the defined criteria using the Safety 
Analysis Set for Stage I and using Stage II Analysis Set for Stage II by WHO-DD ATC 
category and PT set. 
 
 New Treatment 
The number and percentage of participants who received the new treatment will 
be summarized. 
 
 MMF/MPA 
The number and percentage of participants who received MMF/MPA at above 
allowed dose by the time window will be summarized.  
 
 Corticosteroids 
The number and percentage of participants who received corticosteroids beyond 
the one allowed steroid bursts, increases in corticosteroids for the prevention of 
adrenal insufficiency, or during the required stable dose time window from 
baseline will be summarized. 


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4.9.2.4 Electrocardiogram Results 
12-lead ECGs will be performed as a safety assessment at the visits specified in Section 
Error! Reference source not found. of protocol. Any clinically significant value will 
be reported as an AE. 
The observed values, along with the changes from baseline, will be summarized at 
baseline and each postbaseline time point for ventricular heart rate, PR interval, QRS 
duration, QT interval, and the corrected QT interval (QTc) using the safety analysis. The 
number (%) of participants meeting the following criteria will be summarized: 
 QTc > 450 msec 
 QTc > 480 msec 
 QTc > 500 msec 
 QTc increases from baseline > 30 msec 
 QTc increases from baseline > 60 msec 
Corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) and 
Bazett's correction (QTcB). In addition, the overall clinical evaluation of 
electrocardiogram results (normal, abnormal, not clinically significant abnormal, 
clinically significant abnormal) will also be summarized. The summary will be produced 
using the Safety Analysis Set for the overall study. 
4.9.2.5 Other Safety Measures 
4.9.2.5.1 Overdose 
The incidence of TEAEs associated with overdose will be summarized by MedDRA 
SOC and PT, if applicable. 
4.9.2.5.2 Physical Examination and Weight 
A complete physical examination will include, at a minimum, assessments of the 
following organs/body systems: head, ears, eyes, nose, throat, lungs, heart, abdomen, 
skin, and extremities. The observed values and the changes from baseline in the weight 
and body mass index (BMI) will be summarized. Adverse changes from baseline in 
physical examination findings will be classified as AEs and analyzed accordingly. 
4.9.2.5.3 Local injection tolerability 
The incidence of TEAEs associated with local injection tolerability will be summarized 
by MedDRA HLT injection site, if applicable. 
4.10 
Pharmacokinetic (PK) Analyses 
Individual PK data will be collected for all participants. PK analyses will be performed 
on the PK analysis set. 
Serum concentrations will be summarized descriptively by treatment and by visit with 
descriptive statistics including the number of observations, arithmetic mean, SD, 


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median, minimum, maximum, coefficient of variation, geometric mean, and geometric 
coefficient of variation.  
Mean (±SD) serum concentration versus scheduled time profiles will be presented 
graphically. Actual dose administration and sampling times will be used for all 
calculations. 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
4.13 
Immunogenicity 
The ADA status will be summarized by the categories defined in Table 6. The ADA 
incidence rate may also be summarized by treatment group at each time point, where the 
incidence is the proportion of the participants with ADA positive results post-baseline 
only or boosted their pre-existing ADA during the study period. The cutoff for the 




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4.15 
Final Analysis 
The final analysis will be conducted after all participants have completed the Week 112 
Visit or discontinued early from the study. 
By study design, the participants may undergo the different 
 
based upon the renal response observed at Week 48 and Week 52. Thus, in the final 
analysis, the participants will be divided into two subgroups based on their PRR/CRR 
status at the Week 48 through Week 52: 
 PRR/CRR Subgroup: Participants who achieved PRR or CRR at Week 48 and 
sustained through Week 52 will remain in their treatment groups. Statistical 
modeling can be used to examine the treatment effect between treatment groups 
over the Stage II of treatment (i.e., 
 mg 
 vs. placebo and 
 mg 
 vs. placebo), as applicable. All endpoints defined in primary, secondary 
and 
 will be analyzed. Some 
key endpoints examples are highlighted below.  
 Non-PRR/CRR Subgroup: Participants who did not achieve PRR or CRR at 
either 
 will be administered daxdilimab 
 mg SC 
 
through 
 (last dose administered at 
). The final analysis for 
this subgroup will be descriptive only. No statistical modeling will be performed 
and no formal statistical comparison between treatment groups will be tested. All 
endpoints defined in primary, secondary and 
 except for all time-to-
event endpoints, will be analyzed. Some key endpoints examples are highlighted 
below.  
 
In the final analysis, all analyses planned for the primary analysis will be rerun with the 
Full Analysis Set. 
For the non-PRR/CRR subgroup, the following analyses up to the Week 112 visit will 
be covered in the final analysis using Stage II Analysis Set: 
 Proportion of participate achieving PRR or CRR or 
 in the Stage II 
 Change from baseline in eGFR. In addition, change from re-baseline (Week 64) 
in eGFR will be explored descriptively 
 Change from baseline in UPCR. In addition, change from re-baseline (Week 64) 
in UPCR will be explored descriptively 


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 Proportion of participants with prednisone-equivalent dose ≤ 2.5 mg/day for 
participants with baseline OCS > 2.5 mg/day until Week 92 
 
 
 
 
For the PRR/CRR subgroup, the following analyses using the data up to the Week 112 
visit will be covered in the final analysis using Stage II Analysis Set: 
 Proportion of participate sustaining PRR or CRR or 
 in the Stage II 
 Time to loss  PRR or CRR  in the Stage II after achieving PRR/CRR at Week 48 
and Week 52  
 eGFR slope  
 Change from baseline in UPCR 
 Proportion of participants with prednisone-equivalent dose ≤ 2.5 mg/day for 
participants with baseline OCS > 2.5 mg/day until Week 104 
 
 
 
In the final safety analysis, the data up to the Week 112 visit (see Section 4.9) will be 
used. 
Summary statistics will be computed and displayed by treatment group for the 
PRR/CRR subgroup or by treatment pathway (
 mg → 
 mg, 
 mg → 
 mg, 
placebo → 
 mg) for the non-PRR/CRR subgroup and by visit, where applicable.  
Descriptive statistics for continuous variables will minimally include the number of 
participants, mean of the observed values/change from baseline, SD, minimum, median, 
and maximum.  For categorical variables, frequencies and percentages will be presented. 
For analyses involved with statistical modeling, the analysis methods are as follow (if 
applicable): 
 Time to loss at least PRR status: Kaplan-Meier cumulative distribution curves 
will be generated for each treatment group. Participants will be censored at the 
earliest of their treatment discontinuation time, receipt of rescue therapy, study 
withdrawal or death or at Week 112 when the event of at least PRR cannot 
sustained after Week 52. A corresponding summary table will present the 
number of participants at risk, the number of participants responding, and the 
number of participants censored at each postbaseline time point by treatment 
groups. The table will also present the median, along with the corresponding 2-
sided 90% CI of time to response. Cox proportional hazards model will be 
explored (if applicable) with treatment group included in the model adjusting for 
eGFR and 24-hour UPCR values collected at Week 52. The hazard ratio with 
associated 2-sided 90% CIs and p-values will be presented 
 For continuous and binary endpoint endpoints, similar analysis methods will be 
applied as described in Section 4.8.3.2 of the SAP 
 
 


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A line plot of proportion of PRR, CRR, 
 over time will also be produced by 
randomized treatment group or treatment pathway within each of the subgroups. 
Boxplots of change of
 will also be 
plotted by randomized treatment group or treatment pathway within each of the 
subgroups. 


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5 
REFERENCES 
Mejia-Vilet et al., 2021 
Mejia-Vilet JM, Malvar A, Arazi A, Rovin BH. The lupus nephritis management 
renaissance [published online ahead of print, 2021 Oct 4]. Kidney Int. 2021;S0085-
2538(21)00874-7. doi:10.1016/j.kint.2021.09.012. 
Guo et al., 2021 
Guo LN, Perez-Chada LM, Borucki R, Nambudiri VE, Werth VP, Merola JF, et al. 
Development of a working core outcome set for cutaneous lupus erythematosus: a 
practical approach to an urgent unmet need. Lupus Sci Med 2021;8(1):e000529. 
doi:10.1136/ lupus-2021-000529 
Schwartz et al., 2009 
Schwartz N, Rubinstein T, Burkly LC, Collins CE, Blanco I, Su L, et al. Urinary 
TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res 
Ther. 2009;11(5):R143 
Sampson et al.  
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, 
et al. 
Second symposium on the definition and management of anaphylaxis: Summary report 
– Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7 


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6 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 


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APPENDIX 1 PREDNISONE EQUIVALENT OF ORAL GLUCOCORTICOID 
DOSE 
Oral corticosteroids (OCS) other than prednisone may be used PO at the equivalent 
doses shown in Table 7. 
Table 7 
Prednisone Equivalent of OCS Dose 
Glucocorticoid 
Prednisone Equivalent Dose 
PO prednisone 
10 mg 
Prednisolone 
10 mg 
Methylprednisolone 
8 mg 
Hydrocortisone 
40 mg 
Cortisone 
50 mg 
Triamcinolone 
8 mg 
PO = oral(ly); OCS = oral corticosteroids