Clinical trial NCT05198310
Conditions: Arthritis, Rheumatoid
Keywords: inadequate responders moderate to severe Rheumatoid Arthritis
Sponsor: Kiniksa Pharmaceuticals, Ltd.
Start date: 2021-12-14; Completion date: 2024-05-06
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis.

Detailed description:
This is a 28-week (up to 4-week screening period, 12-week treatment period, and 12-week safety follow-up period), multicenter, randomized, double-blind, placebo-controlled, multiple dose, proof-of-concept study with PK lead-in designed to assess the safety, PK, efficacy and PD of KPL-404 in subjects with moderate to severe, active Rheumatoid Arthritis (RA) who have an inadequate response to or are intolerant to a Janus kinase inhibitor (JAKi) AND/OR at least one biologic disease-modifying anti-rheumatic drug (bDMARD). The objectives of the study are to evaluate safety, efficacy, and PD of KPL-404 compared with placebo across the estimated therapeutic range and to characterize PK across varying dose levels of KPL-404.

Arms: arm 1: KPL-404 2 mg/kg subcutaneous (SC) q2wk for 12 weeks arm 2: Placebo SC q2wk for 12 weeks arm 3: KPL-404 5 mg/kg SC q2wk for 12 weeks arm 4: Placebo SC q2wk for 12 weeks arm 5: KPL-404 5mg/kg SC once weekly (qwk) for 12 weeks arm 6: KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks arm 7: Placebo SC qwk for 12 weeks arm 8: KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8. arm 9: Placebo SC q4wk for 12 weeks
Interventions: intervention 1: KPL-404 intervention 2: Placebo
Intervention descriptions: intervention 1: Humanized monoclonal antibody intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 
KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 1 
KPL-404 
KPL-404-C211 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects with Moderate to Severe, Active 
Rheumatoid Arthritis with Inadequate Response or Intolerance to at Least One Biologic Disease-
modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor 
Sponsor: 
Kiniksa Pharmaceuticals, Ltd. 
Hamilton, Bermuda  
c/o Kiniksa Pharmaceuticals Corp. 
100 Hayden Ave 
Lexington, MA 02421 
Sponsor Medical Contact
Vice President, Clinical Research & Development 
Kiniksa Pharmaceuticals Corp.
100 Hayden Ave
Lexington, MA 02421 
Protocol Number: 
KPL-404-C211 
Protocol Version: 
Version 6.0  
Protocol Date:  
Original Protocol, Version 1.0: 19 July 2021 
Amendment 1: Version 2.0: 12 Aug 2021 
Amendment 2: Version 3.0: 09 Dec 2021 
Amendment 3: Version 4.0: 12 Aug 2022 
Amendment 4: Version 5.0: 31 Mar 2023 
Amendment 5: Version 6.0: 28 Jun 2023 


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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
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CONFIDENTIALITY STATEMENT 
The information in this document is the property of Kiniksa Pharmaceuticals (“Kiniksa”). This information is 
proprietary and confidential information to be held in strict confidence and not disclosed to any third party, without 
prior written consent of Kiniksa. Persons within your organization to whom any information herein is disclosed is on 
a need-to-know basis solely to carry out the purpose of this document and be informed that such information is 
confidential and shall not be further disclosed by them without Kiniksa’s prior written consent.  Documentation, 
data, and all other information generated during the clinical study is proprietary and confidential information of 
Kiniksa and shall not be disclosed to any third party, without prior written consent of Kiniksa. 
Kiniksa further considers the information in this submission to be privileged and/or confidential information, 
including trade secrets and confidential commercial and/or financial information, under the Freedom of Information 
Act and FDA’s implementing regulations (5 U.S.C. § 552(b)(4) and 21 C.F.R. § 20.61). Accordingly, Kiniksa 
hereby requests that FDA contact Kiniksa if FDA receives a request for further disclosure of any information 
contained herein. 




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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
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INVESTIGATOR’S AGREEMENT
Study Title:
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 
in Subjects with Moderate to Severe, Active Rheumatoid Arthritis with 
Inadequate Response or Intolerance to at Least One Biologic Disease-
modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor 
IND Number: 
EudraCT 
Number: 
155,963 
2022-000169-42 
Protocol 
Number: 
KPL-404-C211 
Protocol Version:
Version 6.0  
Protocol Date: 
28 Jun 2023 
 
I, the undersigned, am responsible for the conduct of the study at this site and affirm that:
 
I understand and will conduct the study according to the clinical study protocol, any approved 
protocol amendments, International Conference for Harmonisation (ICH) Good Clinical 
Practice (ICH Topic E6) and all applicable Health Authority requirements and national 
laws. 
 
 
 
 
Investigator’s Name (Print)
Investigator’s Signature 
Date 


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Study KPL-404-C211 
Clinical Study Protocol 
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PROCEDURES IN CASE OF EMERGENCY
Emergency Contact Information 
Role 
Name 
Address and Telephone 
Number 
Responsible Physician
 
Drug Safety Physician 
 
 
 








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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
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reviewed by the SRC at the initial meeting in Cohort 3.  Subsequent meetings will prioritize review of 
safety data from all active cohorts.  Additional details are specified in the SRC Charter.
Subjects will be observed for at least 60 minutes after the first administration and 30 minutes after 
subsequent administrations. If no safety concerns are identified during that time, subjects will be 
discharged from the study site after all study procedures have been completed. All subjects will return 
to the study site at all treatment and safety follow-up visits as per the Schedule of Activities for 
assessments of RA parameters as well as evaluations of safety, tolerability, PK, 
 
  
If a subject discontinues prematurely (i.e., before the end of treatment visit), the subject should be 
encouraged to complete the procedures for the end-of-treatment visit (Week 12) within approximately 
2 weeks (for Cohorts 1, 2, and 3) or 4 weeks (for Cohort 4) from last dose of study drug, as well as 
visits thereafter through Week 24.  
Number of Subjects (Planned): 
Cohorts 1–2: approximately 16 subjects
Cohort 3: approximately 75 subjects
Cohort 4: approximately 40 subjects
Diagnosis and Main Criteria for Inclusion:  
Subjects 18 to 80 years of age, body weight 
 
140 kg
and fulfills the 2010 ACR/European Union League Against Rheumatism (EULAR) classification 
criteria for RA.  
Investigational Product, Dosage, and Mode of Administration: 
Cohort 1: KPL-404, 2 mg/kg (or matching placebo) SC injection q2wk
Cohort 2: KPL-404, 5 mg/kg (or matching placebo) SC injection q2wk
Cohort 3:
o
5 mg/kg SC every week (qwk)
o
5 mg/kg SC every 2 weeks (q2wk; weekly dosing with alternating administration of
KPL-404 q2wk or placebo q2wk)
o
Placebo SC qwk
Cohort 4:
o
KPL-404 SC q4wk (600 mg loading dose at baseline followed by maintenance dosing
400 mg q4wk at Weeks 4 and 8)
o
Matched Placebo (equivalent volume) SC q4wk (loading dose at baseline followed by
maintenance doses at Weeks 4 and 8)
Duration of Treatment:  
Twelve weeks of double-blind, placebo-controlled study treatment. 
Reference Therapy, Dosage, and Mode of Administration:  
Placebo administered weekly, every other week, or monthly by SC injection. 
Statistical Methods: 
Randomization will be stratified by available documented evidence of prior inadequate response to  1 
versus  2 classes of advanced targeted therapy (bDMARD or tsDMARD: e.g., TNF inhibitors, IL-6 
receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK inhibitors). For 


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efficacy analysis, a 2-sided type 1 error rate of 0.05 will be used if applicable. Details about all 
statistical analyses will be specified in the statistical analysis plan (SAP).
Sample size estimation: 
The sample size for Cohorts 1 and 2 is based on safety and PK considerations. The sample size for 
Cohort 3 is based on a 2-sample t-test assuming an improvement in DAS28-CRP change from baseline 
for the KPL-404 being 1.2 points better than placebo (improvement for placebo = 1.0 point, standard 
deviation = 1.3). If 21 subjects in each of the 3 treatment arms (KPL-404 5 mg/kg qwk, KPL404 5 
mg/kg q2wk, and placebo) complete 12 weeks of DAS28-CRP assessments, the study provides 83% 
power for the treatment comparison with 2-sided 0.05 type 1 error. In order to account for an 
anticipated discontinuation rate of 16%, approximately 25 subjects per arm (a total of approximately 75 
subjects) are required to enroll in Cohort 3 for the study to achieve 21 completers per arm. The sample 
size for Cohort 4 is based on a 2-sample t-test assuming an improvement in DAS28-CRP change from 
baseline for the KPL-404 being 1.3 points better than placebo (improvement for placebo = 1.0 point, 
standard deviation = 1.3). Enrollment of 22 subjects into the KPL-404 arm and 14 subjects into the 
placebo arm (i.e., 3:2 randomization ratio) allows 80% power for the treatment comparison with 2-
sided 0.05 type 1 error if all subjects complete 12 weeks of DAS28-CRP assessments. In order to 
account for an anticipated discontinuation rate of 10%, approximately 24 subjects (KPL-404) and 16 
subjects (placebo) for a total of approximately 40 subjects are required to enroll under Cohort 4.     
Analyses of efficacy: 
For Cohorts 1 and 2, only descriptive statistics and listings will be produced for all efficacy parameters. 
No formal statistical testing for efficacy will be performed.  
For Cohorts 3 and 4, an analysis of covariance (ANCOVA) model will be used to compare the change 
from baseline in DAS28-CRP at Week 12 for each of the KPL-404 dose groups and placebo. Baseline 
value and randomization stratification factor will be included as covariates in the ANCOVA model. No 
testing between the two KPL-404 dose groups in Cohort 3 will be conducted. ACR response rates at 
Week 12 between each of the KPL-404 dose groups and placebo will be compared using Cochran-
Mantel- Haenszel (CMH) test adjusted by stratification factor. In addition, logistic regression models 
may be produced including key baseline characteristics as covariates in addition to treatment. 
Interim analysis: 
An interim analysis may be conducted to support internal decision-making, for example, when at least 
50% of subjects in Cohort 3 have completed the 12-week treatment period. The Cohort 3 interim 
analysis may include cumulative safety, tolerability, PK, 
, clinical response (e.g., DAS28-CRP), 
and 
. Selected Kiniksa personnel will be unblinded to the interim analysis. The data 
from the interim analysis will not be communicated to blinded study team personnel at the clinical 
research organization, investigational sites, or enrolled subjects until all subjects have completed the 
study and database lock has been achieved. Details of the individuals who will see group-level 
unblinded data will be provided in the Unblinding Plan. Further details regarding the interim analysis 
will be provided in the SAP. 


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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
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TABLE OF CONTENTS  
TITLE PAGE ...................................................................................................................................1
SPONSOR APPROVAL SIGNATURE PAGE ..............................................................................3
INVESTIGATOR’S AGREEMENT ...............................................................................................4
1.
SYNOPSIS ...................................................................................................................6
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16
4.
INTRODUCTION ......................................................................................................18
4.1.
Background .................................................................................................................18
4.2.
Study Rationale ...........................................................................................................19
4.3.
Dose Justification ........................................................................................................19
4.3.1. 
Cohorts 1 and 2 Dose Justification .............................................................................19
4.3.2. 
Cohort 3 Dose Justification ........................................................................................21
4.3.3. 
Cohort 4 Dose Justification ........................................................................................21
4.4.
Benefit/Risk Assessment ............................................................................................22
5.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22
6.
INVESTIGATIONAL PLAN .....................................................................................25
6.1.
Overall Study Design ..................................................................................................25
6.2.
Number of Subjects ....................................................................................................28
6.3.
Treatment Assignment ................................................................................................28
6.4.
Safety Review Committee ..........................................................................................28
6.5.
Stopping Rules ............................................................................................................28
6.6.
Study Termination or Temporary Suspension ............................................................29
7.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30
7.1.
Subject Inclusion Criteria ...........................................................................................30
7.2.
Subject Exclusion Criteria ..........................................................................................31
7.3.
Treatment Discontinuation, Withdrawal of Consent, and Lost to Follow-Up 
Criteria ........................................................................................................................34
8.
TREATMENT OF SUBJECTS ..................................................................................36
8.1.
Description of Study Drug ..........................................................................................36
8.2.
Concomitant and Rescue Medications ........................................................................37
8.2.1. 
COVID Vaccines ........................................................................................................37
8.2.2. 
Contraception ..............................................................................................................37




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10.5.1. 
Clinical Laboratory Assessments ...............................................................................43
10.6.
Adverse and Serious Adverse Events .........................................................................44
10.6.1.
Definition of Adverse Events .....................................................................................44
10.6.1.1. 
Adverse Event .............................................................................................................44
10.6.1.2. 
Adverse Drug Reaction ...............................................................................................44
10.6.1.3. 
Adverse Events of Special Interest .............................................................................44
10.6.1.4.
Serious Adverse Events ..............................................................................................45
10.7.
Relationship to Study Drug ........................................................................................46
10.8.
Severity of Adverse Events ........................................................................................47
10.9.
Recording Adverse Events .........................................................................................47
10.9.1. 
Pregnancy ...................................................................................................................48
10.10. 
Reporting Adverse Events ..........................................................................................48
11.
STATISTICAL ANALYSES .....................................................................................49
11.1.
Sample Size Justification ............................................................................................49
11.2.
Interim Analysis ..........................................................................................................49
11.3.
Analysis Populations ..................................................................................................50
11.4.
Analysis of Efficacy ...................................................................................................50
11.4.1. 
Efficacy Endpoints ......................................................................................................50
11.4.1.1. 
DAS28-CRP ...............................................................................................................50
11.4.1.2. 
 
11.4.1.3. 
ACR20/50/70 ..............................................................................................................51
11.4.2. 
Analysis Methods .......................................................................................................51
11.5.
Analysis of Pharmacokinetics .....................................................................................51
11.6.
 
11.7.
Analysis of Safety .......................................................................................................52
12.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................53
12.1.
Study Monitoring ........................................................................................................53
12.2.
Audits and Inspections ................................................................................................53
13.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54
14.
ETHICS ......................................................................................................................55
14.1.
Ethics Review .............................................................................................................55
14.2.
Ethical Conduct of the Study ......................................................................................55
14.3.
Informed Consent .......................................................................................................55


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15.
DATA HANDLING AND RECORD KEEPING ......................................................56
15.1.
Inspection of Records .................................................................................................56
15.2.
Retention of Records ..................................................................................................56
16.
PUBLICATION POLICY ..........................................................................................57
17.
REFERENCES ...........................................................................................................58
18.
APPENDICES ............................................................................................................60
APPENDIX 1. SCHEDULE OF ACTIVITIES .............................................................................61
APPENDIX 2. CLINICAL LABORATORY EVALUATIONS...................................................73
APPENDIX 3. SUMMARY OF CHANGES (VERSION 5.0 COMPARED TO 
VERSION 6.0) ............................................................................................................74
APPENDIX 4 CLINICAL OUTCOME ASSESSMENTS AND PATIENT 
REPORTED OUTCOMES .........................................................................................80


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LIST OF TABLES
Table 1: 
Investigational Product ...............................................................................................36
Table 2:
Clinical Criteria for Diagnosing Anaphylaxis ............................................................45
LIST OF FIGURES  
Figure 1: 
Predicted Plasma Concentration of KPL-404 by Dose Level Following 
Weekly and Biweekly Subcutaneous Administration ................................................20
Figure 2:
Study Schema for KPL-404-C211 ..............................................................................27


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3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or Specialist 
Term 
Explanation 
ACPA 
Anti-citrullinated protein antibody 
ACR  
American College of Rheumatology 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
AUC
Area under the curve
bDMARD 
Biologic Disease-Modifying Anti-Rheumatic Drug 
Cmax 
Maximum concentration 
 
 
CRO 
Clinical research organization 
CRP 
C-reactive protein 
csDMARD 
Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug 
DAS28-CRP 
Disease Activity Score of 28 Joints using C-Reactive Protein 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of study 
EOT 
End-of-Treatment 
EULAR 
European Union League Against Rheumatism 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire-Disability Index 
IB
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
International Ethics Committee 
IMP 
Investigational medicinal product 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  


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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
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Abbreviation or Specialist 
Term 
Explanation 
JAKi 
Janus kinase inhibitor 
KLH 
Keyhole limpet hemocyanin 
 
 
MTX
Methotrexate
NOAEL 
No-observed-adverse-effect level 
PD 
Pharmacodynamics 
PGA 
Patient global assessment 
PhGA
Physician global assessment
PK
Pharmacokinetics
q2wk 
Every 2 weeks 
qwk 
Once weekly 
RA 
Rheumatoid arthritis 
RF 
Rheumatoid factor 
RO 
Receptor occupancy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
 
 
 
 
SJC 
Swollen Joint Count 
SRC
Safety Review Committee
TDAR 
T-cell-dependent antibody response 
TEAEs 
Treatment-emergent adverse events 
TJC 
Tender Joint Count 
TMDD 
Target-mediated drug disposition 
tsDMARDS 
Targeted Synthetic Disease-Modifying Anti-Rheumatic Drug 
ULN 
Upper Limit of Normal 
VAS 
Visual analog scale 


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Study KPL-404-C211 
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4.
INTRODUCTION
4.1.
Background
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology. The 
hallmark of RA is an inflammatory process manifested by persistent symmetric polyarthritis of 
synovial joints, which can ultimately lead to bone erosions, deformity, and disability (McInnes et 
al, 2011). Left untreated, or inadequately treated, progressive functional impairment with 
increasing disability occurs, leading to decreased ability to perform activities of daily living 
resulting in a reduction in quality of life. The prevalence of RA in the general population is 
approximately 1% and increases with age in both sexes, with women being more prone to 
developing RA than men. Standard-of-care treatment includes early therapy with 
disease-modifying anti-rheumatic drug (DMARDs), including conventional synthetic DMARDs 
(csDMARDs) (e.g., methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide). In the 
last 2 decades, targeted biological DMARDs (bDMARDs) have revolutionized the treatment 
paradigm for RA, in which therapy is optimized until clinical remission or at minimum low 
disease activity is achieved. The bDMARDs have greatly improved the clinical, functional, and 
radiographic outcomes for patients with RA (Smolen et al, 2017). Despite a wide therapeutic 
armamentarium of bDMARDs, a blockade of any single cytokine or cellular subset has not 
shown control of disease in all RA patients. In randomized controlled studies and clinical 
practice, approximately 30% to 40% of treated patients show inadequate response to bDMARDs, 
fail to maintain good response over time, or experience adverse events (AEs) leading to 
treatment withdrawal (Favalli et al, 2016). These patients with inadequate response or 
intolerance to one or more bDMARDs, in many of whom multiple csDMARDs have previously 
failed, have few treatment options, and treatment of the disease in this population remains a 
crucial unmet need in the management of RA.  
Studies have shown that patients refractory to specific bDMARDs might benefit from therapy 
with a different mechanism of action (Emery et al., 2008; Genovese et al, 2018). A recent study 
indicates that a switch in mechanism of action (from a Janus kinase inhibitor [JAKi] to a tumor 
necrosis factor inhibitor, or vice versa) in non-responders and incomplete responders leads to 
improvements in disease activity 3 to 6 months after randomization to study medication, with 
minimal risk of flare and without an increase in clinically meaningful adverse events 
(Fleischmann et al, 2020).  
The CD40-CD40L costimulatory pathway is implicated in various autoimmune diseases. 
Numerous CD40-CD40L-mediated inflammatory reactions, such as induction of 
proinflammatory cytokines and upregulation of costimulatory activity of dendritic cells and 
monocytes/macrophages, are known to be important in the pathogenesis of RA (Berner et 
al, 2000). The pathway is thought to play a role in the pathogenesis of RA by stimulating 
autoantibody synthesis, resulting in profound inflammation. However, the role of the pathway in 
RA has yet to be fully elucidated (Guo et al, 2017).
Results in clinical studies have not yet confirmed the role of CD40/CD40L pathway inhibition in 
RA. Visvanathan, et al. (2019) reported a Phase 2 placebo-controlled, randomized clinical study 
of an anti-CD40 monoclonal antibody in which clinical improvements were observed relative to 
placebo, although the primary endpoint did not achieve statistical significance. However, a study 


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of an IV injectable CD40L (CD154 antagonist, (Albulescu, et al, 2018) reported decreased 
disease activity with at least low level of disease activity in 50% to 70% of patients. 
Additional information is available in the Investigator’s Brochure (IB). 
4.2.
Study Rationale
The safety, pharmacokinetics (PK), and pharmacodynamics (PD) of KPL-404 have been 
assessed in a single ascending-dose study in healthy subjects (KPL-404-C101). The clinical 
development plan is designed to focus next on assessing safety, tolerability, PK (primary 
objective), and efficacy (secondary objective) of KPL-404 with multiple-dose administration, 
initially with two ascending-dose cohorts: Cohort 1 (2 mg/kg dose level vs. placebo), 
administered subcutaneously (SC) on alternate weeks (q2wk), and Cohort 2 (5 mg/kg dose level 
vs. placebo SC q2wk). Cohort 3 is designed to assess the comparative efficacy (primary 
objective) as well as the safety, tolerability, and PK (secondary objectives) of KPL-404 using the 
weight-based 5 mg/kg SC dose level administered either weekly or biweekly versus placebo over 
12 weeks.  Cohort 4 is designed to assess the comparative efficacy, safety, tolerability, and PK of 
fixed-mg dose KPL-404 (400 mg) administered SC monthly versus placebo. Efficacy will be 
assessed using the primary endpoint, change from baseline in disease activity score of 28 joints 
using C-reactive protein (DAS28-CRP) at 12 weeks.  
4.3. 
Dose Justification  
4.3.1. 
Cohorts 1 and 2 Dose Justification  
The Cohort 1 starting dose was selected based on the following factors. 
1. Pharmacodynamics: Analysis of receptor occupancy (RO) data from study 
KPL-404-C101 demonstrated full CD40 
across the evaluated dose levels. For IV doses (0.3, 1, 3, and 10 mg/kg), full CD40 RO 
was maintained through Days 2, 9, 29, and 71, respectively. For SC doses (1 and 5 mg/kg 
SC), full CD40 RO was maintained through Days 9 and 43, respectively. Analysis of the 
T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) 
demonstrated that single IV doses of 1, 3, and 10 mg/kg completely suppressed TDAR to 
primary KLH challenge through Days 9, 36, and 57 (last time point analyzed), 
respectively. Similarly, single SC doses of 1 and 5 mg/kg completely suppressed TDAR 
to primary KLH challenge through Days 9 and 29 (last time point analyzed), respectively, 
justifying a bi-weekly dosing frequency for all dose levels to be studied. 
2. Safety Profile: The safety profile of the single ascending-dose study in healthy subjects 
(KPL-404-C101): single doses up to 10 mg/kg IV and 5 mg/kg SC were assessed. There 
were no deaths or related serious adverse events (SAEs), the only serious event being a 
patellar fracture related to a fall. There were no AEs observed that would limit dosing.  
3. Pharmacokinetics: To evaluate optimal dosing regimens for Phase 2 clinical studies, a 
population PK model was developed using KPL-404 concentration-time data from 
healthy volunteers in Study KPL-404-C101. This population PK model simulated PK 
profiles for dose levels of 2.5, 5, and 10 mg/kg SC administered q2wk and for the dose 
level of 5 mg/kg SC administered every week (qwk) (Figure 1).  


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Study KPL-404-C211 
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The model assumed a target mean trough concentration (Ctrough
preliminary estimate for a minimum efficacious plasma concentration (Ceff), consistent 
with the threshold established for similar assets in this class of anti-CD40 monoclonal 
antibody therapeutics (Ulrich 2018, Fisher 2020). Results from the simulations suggested 
that steady state concentrations would be achieved at/after approximately 8 weeks in all 
SC scenarios tested. Mean Ctrough w
examined when administered qwk. Mean Ctrough
KPL-
The simulated PK profiles for KPL-404 2.5 mg/kg q2wk had a mean maximum serum 
concentration (Cmax) and an area under the serum concentration-time curve from time 0 to 
the end of first dosing interval (AUC0-
, respectively, at steady 
state. The mean accumulation ratio was approximately 3-fold following multiple dose 
administration and appeared to be consistent across all the dose range tested.  
4. Safety Margin: KPL-404 was evaluated in 8-week and 26-week repeat-dose toxicity 
studies in Cynomolgus monkeys. The only adverse findings in the studies were an early 
termination on Day 143 of one female at 97 mg/kg SC after exhibiting clinical signs of 
poor health for several days, and another female administered 97 mg/kg SC that exhibited 
bilateral uveitis associated with a small blood clot in the anterior chamber of the eye. The 
no-observed-adverse-effect level (NOAEL) was 12-fold higher than the starting dose in 
this Phase 2 study, and the systemic exposure associated with the NOAEL by the SC 
route was approximately 10.6-fold higher. This provides an adequate safety margin 
between the proposed dose range for this study relative to the nonclinical safety findings. 
Figure 1: 
Predicted Plasma Concentration of KPL-404 by Dose Level Following
Weekly and Biweekly Subcutaneous Administration  


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Abbreviations: QW = qwk, every week; Q2W = q2wk, every 2 weeks. 
Note: Shaded region represents lower limit of quantitation. 
4.3.2.
Cohort 3 Dose Justification  
Cohorts 1 and 2 represent the ascending-dose portion of this study, and Cohort 3 represents the 
proof-of-concept portion, using the highest investigated dose level (5 mg/kg SC) from the 
ascending-dose investigation. Cohort 3 subjects will be randomized in a 1:1:1 ratio to receive 
KPL-404 5 mg/kg SC q2wk, KPL-404 5 mg/kg SC qwk, or placebo SC qwk. While the 5 mg/kg 
SC qwk administration frequency will not have been directly investigated in Cohorts 1 or 2, this 
dose level and exposure will have been investigated, and the weekly administration frequency 
will allow the Sponsor to understand increased KPL-404 exposure without administering larger 
dose levels all at once but rather by increasing dosing frequency from q2wk to qwk. To date, 
KPL-404 has been well tolerated. By maintaining the dose level and increasing the frequency, 
the injected volume and protein amounts will match those from Cohort 2 and are expected to 
represent known safety risks, such as injection site reactions. Additionally, pharmacokinetic 
modeling, using concentration-time data from study KPL-404-C101, demonstrated that expected 
exposures and Ceff are similar for 5 mg/mg SC qwk and 10 mg/kg SC q2wk (Figure 1).  
4.3.3. 
Cohort 4 Dose Justification  
Cohort 4 subjects will be randomized in a 3:2 ratio to receive fixed-mg dosing of KPL-404 SC 
q4wk (a 600 mg SC [or matching placebo] loading dose at the Baseline Visit followed by 
maintenance dosing of 400 mg SC [or matching placebo] at Week 4 and Week 8).  The objective 
is to explore the efficacy of KPL-404 at lower trough concentrations than Cohort 3, 
approximating the minimum level required for T-cell-dependent antibody response suppression, 
as seen in Phase 1.  This dosing regimen (i.e., a fixed-mg dose rather than weight-based dose) 
represents a different approach as compared to Cohort 3, and it does not represent a dose 
escalation. Rather, this fixed-mg (400 mg) administered dose provides a centered administered 
dose level, based upon early PK data showing a relatively neutral effect of weight on the PK of 
KPL-404, as would be expected given that monoclonal antibodies are large macromolecules with 
a volume of distribution restricted to the plasma.  The 400 mg administered dose is 5 mg/kg for 
an average 80 kg subject.  The 600 mg loading dose is intended to facilitate reaching steady state 
trough levels more rapidly, based on PK modeling. This regimen, based on the same modeling, is
expected to provide peak plasma concentrations no greater than those projected in Cohorts 2 and 
3 and trough plasma concentrations lower than the 5 mg/kg q2wk dose level in Cohort 2.   








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6.
INVESTIGATIONAL PLAN
6.1.
Overall Study Design
Figure 2 displays the overall schema for the study. A detailed outline of procedures and activities 
is provided in Appendix 1. 
This is a 28-week (up to 4-week screening period, 12-week treatment period, and 12-week safety
follow-up period), multicenter, randomized, double-blind, placebo-controlled, multiple dose 
proof-of-concept study with PK lead-in designed to assess the safety, PK, efficacy, and PD of 
KPL-404 in subjects with moderate to severe, active RA who have inadequate response to or are 
intolerant to at least one biologic disease-modifying anti-rheumatic drug (bDMARD) or JAKi. 
The objectives of the study are to evaluate safety, efficacy, and PD of KPL-404 compared with 
placebo across the estimated therapeutic range and to characterize PK across varying dose levels 
of KPL-404. 
After signing the informed consent form (ICF), subjects will enter the screening period (Day –28 
to –1), before returning for the baseline visit and administration of the first dose (Day 1). 
Subjects can be rescreened only once, at the discretion of the Investigator and with approval 
from the medical monitor. Abnormal laboratory values may in certain cases be repeated with the 
approval of the medical monitor without the need for rescreening. If a subject is rescreened, a 
new subject number will be provided, and laboratory assessments can be repeated once where 
appropriate.  
All randomized subjects will receive a SC injection of the investigational product (IP) on Day 1 
at the study site. In the first 2 cohorts, subjects will be randomized in a 3:1 ratio to escalating 
doses as follows:  
 Cohort 1: 2 mg/kg KPL-404 or placebo every 2 weeks (q2wk) (n = 8) 
 Cohort 2: 5 mg/kg KPL-404 or placebo q2wk (n = 8) 
Cohorts 1 and 2 will start sequentially, with each escalation approved by a Safety Review 
Committee (SRC), which will assess in an unblinded fashion the safety, and tolerability data 
after all subjects complete through Week 12 and PK through Week 8 (anticipated steady state) 
and applicable data are available. The composition of the SRC, meeting frequency, and 
procedures for review and decision-making will be described in detail in the SRC Charter. 
Following completion of Cohort 2, new subjects will enter Cohort 3. Subjects will be 
randomized in a 1:1:1 ratio to receive: 
 5 mg/kg SC every week (qwk) 
 5 mg/kg SC every 2 weeks (q2wk; weekly dosing with alternating administration of 
KPL 404 q2wk or placebo q2wk) 
 Placebo SC qwk 
To maintain the blind, all subjects will return to the study site weekly. One group (5 mg/kg SC 
qwk) will receive active investigational product every week at each visit. One group (Placebo SC 
qwk) will receive placebo every week at each visit. One group (5 mg/kg SC q2wk) will alternate 
between receiving active investigational product and placebo. 


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At approximately the end of Cohort 3 enrollment, the study will enroll subjects into Cohort 4. 
Subjects will be randomized in a 3:2 ratio to receive one of the following: 
KPL-404 SC q4wk (600 mg loading dose at baseline followed by maintenance dosing 
400 mg q4wk at Weeks 4 and 8) 
Matched Placebo (equivalent volume) SC q4wk (loading dose at baseline followed by 
maintenance dose at Weeks 4 and 8) 
In Cohorts 3 and 4, SRC meetings will occur on a quarterly basis while enrollment is ongoing.  
The initial SRC meeting in Cohort 3 will occur within approximately 90 days of the start of 
enrollment or once 20 subjects are enrolled, whichever occurs first.  All available safety and PK 
data will be reviewed by the SRC at the initial meeting.  Subsequent meetings will prioritize 
review of safety data from all active cohorts. Additional details are specified in the SRC Charter.
Subjects will be observed for at least 60 minutes following the first administration and 
30 minutes after subsequent administrations. If no safety concerns are identified during that time, 
subjects will be discharged from the study site after all study procedures have been completed. 
All subjects will return to the study site at all treatment and safety follow-up visits as per the 
Schedule of Activities (Appendix 1) for assessments of RA parameters as well as evaluations of 
safety, tolerability, PK, 
. 
If a subject discontinues treatment prematurely (i.e., before the end-of-treatment visit), the 
subject should be encouraged to complete the procedures for the end-of-treatment visit (Week 
12) within approximately 2 weeks (for Cohorts 1, 2, and 3) or 4 weeks (for Cohort 4) from last 
dose of study drug, as well as visits thereafter through the Week 24 visit, as per the Schedule of 
Activities.  
At the end of the 12-week treatment period, all subjects will be followed up for safety and 
longevity of any treatment effect for an additional 12 weeks until the EOS visit (Week 24). An 
adverse event that occurs prior to study treatment administration should be recorded in the eCRF 
only if it is an SAE or is an AE related to a study procedure. All AEs/SAEs that occur after the 
first administration of study treatment through the EOS visit, whether or not they are related to 
the study, must be recorded in the eCRF. For subjects who terminate study participation early 
(i.e., before the Week 24 visit), the Investigator will report any SAEs that are reported to the 
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6.2.
Number of Subjects
The study plans to enroll approximately 16 subjects in Cohorts 1 and 2, approximately 
75 subjects in Cohort 3, and approximately 40 subjects in Cohort 4, across approximately 100 
study sites.  
6.3. 
Treatment Assignment  
All subjects will be assigned to randomized study drug as per standard operating procedures 
defined by the Sponsor or designee.  
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a subject’s treatment assignment is warranted. Participant safety must always be 
the first consideration in making such a determination. For further details on blinding, refer to 
Section 8.5. The date and reason that the blind was broken must be recorded.  
6.4. 
Safety Review Committee  
The SRC will consist of expert clinicians, pharmacologists, and/or statisticians. Any individual 
who has any affiliation with Kiniksa will be “firewalled” such that they take no part in 
operational activities and have no project-related communication with the study team. The SRC 
will review cumulative safety and PK data.  
After all subjects in Cohorts 1 and 2 complete treatment through Week 12 and applicable data 
are available for review, an SRC meeting will be held to review unblinded safety and PK data to 
support dose escalation to the next cohort. Further details will be outlined in the SRC Charter. 
In Cohorts 3 and 4, SRC meetings will occur on a quarterly basis while enrollment is ongoing.  
The initial SRC meeting in Cohort 3 will occur within approximately 90 days of the start of 
enrollment or once 20 subjects are enrolled, whichever occurs first.  All available safety and PK 
data will be reviewed by the SRC at the initial meeting.  Subsequent meetings will prioritize
review of safety data from all active cohorts.  Additional details are specified in the SRC Charter, 
and the charter may be amended as necessary for the SRC to review safety and PK data.  
In the event of any concern regarding subject safety or risk mitigation, the SRC may contact the 
Sponsor Head of Global Medical Safety for additional discussion in order to finalize the 
decision. However, the Sponsor Head of Global Medical Safety will not be given access to 
subject-level unblinded data. Details of the review process will be defined in the SRC Charter. 
6.5. 
Stopping Rules  
A subject may be discontinued from treatment due to any Grade 3 (severe) or any Grade 4 (life-
threatening) TEAE, regardless of causality.  
For the study, enrollment in a cohort will be paused for review under any of the circumstances 
below: 
 Two subjects develop the same Grade 3 TEAE  
 One subject has a Grade 4 (life-threatening) or Grade 5 (fatal) TEAE  


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Any such review will be conducted by the SRC in conjunction with the Sponsor Head of Global 
Medical Safety and supported by additional clinical experts as appropriate. At the conclusion of 
the review, the study will resume (or otherwise) upon the approval of the Sponsor Head of 
Global Medical Safety. 
6.6.
Study Termination or Temporary Suspension
The Sponsor reserves the right to temporarily suspend or terminate this study, in part or whole, at 
any time. The reasons for temporarily suspending or terminating the study may include but are 
not limited to:
 The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to subjects 
 Subject enrollment is unsatisfactory
 Noncompliance that might significantly jeopardize the validity or integrity of the 
study 
 Recommendation to suspend or terminate the study by independent body such as 
a health authority 
 Sponsor decision to terminate the study  
Where required by applicable regulations, the Investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/International Ethics Committee (IEC) promptly and 
provide the reason(s) for the suspension/termination. If the study is suspended for safety reasons 
and it is deemed appropriate by the Sponsor to resume the study, approval from the relevant 
regulatory authorities (and IECs when applicable) will be obtained prior to resuming the study. 


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7.
SELECTION AND WITHDRAWAL OF SUBJECTS
7.1.
Subject Inclusion Criteria
For inclusion in the study, subjects must fulfill all of the following criteria: 
1. Voluntarily sign and date an informed consent form, approved by an Independent Ethics 
Committee/Institutional Review Board, prior to the initiation of any screening or study-
specific procedures. 
2. Adult male or female, age 18 to 80 years of age (inclusive) at the time of signing the 
informed consent form. 
3. B
 
 140 kg for all cohorts.  
4. 
ing the 2010 American College of Rheumatology 
(ACR)/European Union League Against Rheumatism (EULAR) classification criteria for 
RA and that is categorized as ACR RA functional Class 1-3.  
5. Treated with a biological disease-modifying anti-rheumatic drug (bDMARDs) AND/OR 
Janus kinase inhibitor (JAKi) 
or had to discontinue bDMARD AND/OR JAKi therapy due to intolerance or toxicity, 
regardless of treatment duration. 
6. 
before the first dose of investigational product.  
a. The following csDMARDs are allowed:  oral or parenteral methotrexate ([MTX]; 
7.5 to 25 
 400 
 20 mg/day). 
b. A combination of up to 2 background csDMARDs is allowed, except the combination 
of MTX and leflunomide. 
7. Meets all of the following disease activity criteria: 
a. Six or 
68 joint counts) at screening and baseline visits; 
b. Level of high-sensitivity C-reactive protein 
3 mg/L ( 0.3 mg/dL) by central 
laboratory; 
c. Documented seropositivity for serum RF and/or ACPA (> ULN) at Screening or by 
prior laboratory evaluation.  
8. Has completed a locally approved authorized COVID-19 vaccine regimen according to 
local guidance at least 3 weeks before the first dose of investigational product. 
9. Must have discontinued all bDMARDs or JAKi prior to the first dose of investigational 
product. The washout period for bDMARDs or JAKi prior to the first dose of 
investigational product is specified below. For bDMARDs or JAKi not listed below, 
washout should be at least 5 times the mean elimination half-life of a drug:  
d. 
 
e. 
tocilizumab, and sarilumab; 


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f.
g.
2 weeks for JAKi (either investigational or commercially available treatment).
10. For potential participants already receiving opiate analgesia, the dose must be limited to 
no greater than 50 mg oral-morphine-equivalents per day (50 MME/day). . 
11. If female, must be either postmenopausal (defined as no menses for 12 months without 
other medical cause), permanently surgically sterile, or, for women of childbearing 
potential, must practice at least one highly effective method of contraception that is 
effective from study Day 1 through at least 30 days after the EOS visit (additional local 
requirements may apply). Sexually active female subjects must be: 
 Nonpregnant, nonlactating, and having agreed to use a highly effective method of 
contraception from the screening visit until 30 days after EOS visit. 
o Note: highly effective methods of contraception include:  
 hormonal contraceptives associated with inhibition of ovulation (stable 
dose for at least 4 weeks prior to first dose of investigational product) 
 intrauterine device 
 intrauterine system 
 bilateral tubal occlusion  
 vasectomized male partner 
 abstinence from heterosexual intercourse 
12. Sexually active male subjects must have documented vasectomy or must agree to use a 
condom or highly effective method of contraception as defined above with their partners 
of childbearing potential from first dose of investigational product until 30 days after 
EOS visit. 
13. Male subjects must agree to refrain from donating sperm from first dose until 30 days 
after the last study drug administration. Female subjects must agree to refrain from 
donating eggs from first dose of investigational product until 30 days after EOS visit. 
14. Female subjects of childbearing potential must have a negative s
-human chorionic 
-hCG) test at the screening visit and negative urine pregnancy test on 
Day 1. 
7.2. 
Subject Exclusion Criteria  
The subject may not enter the study if ANY of the following apply: 
1. Prior exposure to any other anti-CD40/CD40L agent. 
2. Inadequate response to 5 or more classes of advanced targeted therapies (bDMARD or 
tsDMARD; e.g., TNF inhibitors, IL-6 receptor inhibitors, T-cell costimulatory inhibitors, 
anti-CD-20 antibodies, JAK inhibitors). This does not include prior discontinuation due 
to drug intolerance. 


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3. Injectable corticosteroids (including intra-articular) or treatment with > 10 mg/day dose 
oral prednisone or equivalent within 8 weeks prior to randomization. (Note: Concomitant 
treatment with nonsteroidal anti-inflammatory drugs, acetaminophen, oral corticosteroids 
weeks prior to baseline for stable medical conditions is allowed and should be kept at a 
stable dose throughout the study.) 
4. Has received any investigational product within 30 days or 5 half-lives, if the half-life is 
known, of the investigational product (whichever is longer) before the first dose of 
investigational product.  
5. Concurrent enrollment in another clinical study, with the exception of observational 
studies. 
6. Major surgery within 8 weeks prior to screening or planned major surgery within 
6 months after baseline. 
7. Transplanted organs (except corneal transplant performed more than 3 months prior to 
baseline). 
8. Receipt of live (attenuated) vaccine within the 4 weeks before baseline or expected need 
of live vaccination during study participation including 4 weeks after the last dose of 
investigational product. 
9. History of any arthritis with onset prior to age 16 years or current diagnosis of 
inflammatory joint disease other than RA (including but not limited to gout, systemic 
lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing 
spondylitis and nonradiographic axial spondyloarthritis, reactive arthritis, overlap 
connective tissue diseases, scleroderma, polymyositis, dermatomyositis, fibromyalgia 
[currently with active symptoms]). Current diagnosis of secondary Sjogren's syndrome is 
permitted. 
10. Clinically significant active infection, including signs/symptoms suggestive of infection, 
any significant recurrent or chronic infection (including positive hepatitis C virus 
antibody), or any episode of infection requiring hospitalization or treatment with IV 
antibiotics within 12 weeks before screening, or treatment with oral anti-infectives within 
14 days prior to the first dose of investigational product. Subjects with any opportunistic 
infection within 6 months before screening will be excluded from the study. 
11. Presence of symptoms indicative of COVID-19 infection (according to the opinion of the 
Principal Investigator) unless a PCR test for COVID-19 has been reported as negative 
within the previous 7 days or is acquired prior to randomization. 
12. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune 
deficiency disorder), a history of an infected joint prosthesis at any time with that 
prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent 
chest infections. 
13. Subjects testing positive for human immunodeficiency virus infection. HIV test will not 
be required if a subject had a previously documented negative HIV result within 8 weeks 
screening.  


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14. Subjects with chronic active hepatitis B infection as defined below will be excluded from 
the study: 
a. Hepatitis B surface antigen positive.  
b. Hepatitis B anti-core antibody positive but anti-surface antibody negative. 
15. Positive (or 2 indeterminate) QuantiFERON® test results unless confirmation of prior 
completion of appropriate treatment for latent TB and no evidence of active TB (when 
possible, test should be performed at least 4 weeks after receiving an mRNA COVID-19 
vaccine). 
16. History of thromboembolic event, a significant risk of future thromboembolic events 
(defined as a definitive diagnosis of thrombophilia OR an unstable condition associated 
with an increased incidence of thrombosis, such as atrial fibrillation or anti-phospholipid 
syndrome). All history of thrombosis should be approved by the medical monitor. 
17. Laboratory values meeting the following criteria within the screening period (prior to 
randomization) of investigational product:  
a. Serum aspartate aminotransferase > 3 × upper limit of normal (ULN);  
b. Serum alanine aminotransferase > 3 × ULN;  
c. Total bilirubin > 2 × ULN;
d. Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in 
Renal Disease formula < 40 mL/min/1.73 m2; 
e. 
f. Hemoglobin < 9 g/dL; 
g. 
 
h. Platelet count < 150
i. 
 
18. Known history of allergy or reaction to any component of the KPL-404 or placebo 
formulation and/or other products in the same class. 
19. History of cancer within the last 5 years from screening, except for basal and squamous 
cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. 
20. History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months. 
21. History of any of the following cardiovascular conditions: 
a. Moderate to severe congestive heart failure (New York Heart Association class III or 
IV); 
b. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, 
coronary stenting; 
c. Uncontrolled hypertension as defined by a confirmed systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg. 
22. Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG 
with QT interval corrected for heart rate (QTc) > 500 msec. 


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23. Any condition that, in the opinion of the Investigator, could interfere with evaluation of 
the investigational product or interpretation of subject safety or confound the results of 
the study. 
7.3.
Treatment Discontinuation, Withdrawal of Consent, and Lost 
to Follow-Up Criteria  
Subjects are free to discontinue study treatment or withdraw consent from the study at any time, 
without prejudice to their medical care.  
Treatment Discontinuation 
Subjects will be discontinued from study treatment if any of the following criteria are met. 
 Change in compliance with any inclusion/exclusion criterion that is clinically relevant and 
affects subject safety as determined by the Investigator 
 Noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator 
 Pregnancy 
 Thromboembolic event 
 Anaphylactic reaction related to investigational medicinal product (IMP) 
 Severe infection (severe AE or SAE) or opportunistic infections (regardless of 
severity/seriousness) 
 Any clinically relevant sign or symptom, including a RA flare requiring prohibited study 
medications(s), that in the opinion of the Investigator warrants subject discontinuation from 
study treatment. 
Upon decision to discontinue treatment, the Sponsor should be notified immediately. If a subject 
is prematurely discontinued from IP (study treatment), he or she should complete the end of 
treatment (EOT) visit (Week 12) within approximately 2 weeks (for Cohorts 1, 2, and 3) or 
4 weeks (for Cohort 4) from last dose of study drug, as well as visits thereafter through Week 24, 
as per the Schedule of Activities, for all safety and efficacy assessments. The Investigator may 
also request that the subject return for additional visits. 
Withdrawal of Consent 
Subjects are free to withdraw consent from the study at any time, without prejudice to their 
medical care. Only study subjects who withdraw consent will be considered discontinued from 
the study (as differentiated from treatment discontinuation).
If a subject is discontinued from the study (withdraws consent), the Sponsor will be notified, and 
the date and reasons for the study discontinuation / withdrawal of consent will be documented in 
the subject’s electronic case report form (eCRF).  


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Lost to Follow-Up 
Subjects will be defined as lost to follow-up if they have not responded to 3 phone calls and 1 
registered post letter. Missing data due to lost to follow-up will be covered in the Statistical 
Analysis Plan (SAP). 
In the event of an unscheduled visit, only the relevant assessments/activities pertaining to the 
visit need to be performed and entered. All discontinued subjects will be followed until 
resolution of all their AEs or until the EOS visit.  




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8.2.
Concomitant and Rescue Medications
Medication restrictions applicable during the treatment period are described in Section 7.2 
(exclusion criteria). Prior medication will be recorded up to 60 days prior to screening and prior 
medication for RA will be recorded up to 1 year prior to screening. Any medicinal product 
prescribed or over-the-counter, taken by a subject other than the study drug, is considered 
concomitant medication from Baseline (Day 1) to EOS.  
During the treatment period up to Day 85 (EOT), the dose of background csDMARDs and 
corticosteroids or a new additional csDMARD may not be increased. If a subject develops RA 
flares requiring increased doses and/or new RA medications (as rescue medication), the subject 
must discontinue IMP after informing the medical monitor. 
If a subject is discontinued from IP (study treatment), he or she should complete the EOT visit 
and remaining scheduled study visits through Week 24, per the Schedule of Activities, for all 
safety and efficacy assessments. The Investigator may also request that the subject return for 
additional visits.
After Day 85 (EOT), the dose of background csDMARDs and corticosteroids may be adjusted or 
a new additional csDMARD may be added to an existing one (except for combining MTX and 
leflunomide) if this is clinically indicated to improve disease management, in consultation with 
the medical monitor.
8.2.1. 
COVID Vaccines
Subjects are required to have completed a COVID-19 vaccine regimen to be eligible for the 
study. Subjects who desire to receive any additional COVID vaccines during study must 
discontinue treatment and wait at least 4 months after last dose of study drug to receive the 
vaccine in order for KPL-404 to wash out completely.  
8.2.2. 
Contraception  
Nonpregnant, nonlactating sexually active women of childbearing potential must agree to use a 
highly effective method of contraception from the screening visit until 30 days after EOS visit. 
Highly effective methods of contraception include: 
 hormonal contraceptives associated with inhibition of ovulation (stable dose for at 
least 4 weeks prior to first dose) 
 intrauterine device 
 intrauterine system 
 bilateral tubal occlusion 
 vasectomized male partner 
 abstinence from heterosexual intercourse 
Sexually active male subjects must have documented vasectomy or must agree to use a condom 
or highly effective method of contraception, as defined above, with their partners of childbearing 
potential from first dose until 30 days after the EOS visit. 


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8.3.
Treatment Compliance
The following measures will be employed to ensure treatment adherence and study procedure 
compliance with standard operating procedures defined by the Sponsor or designee: 
 Doses will be administered under the supervision of the Investigator or authorized 
designee.  
 Study drug accountability will be performed at the study site.  
8.4. 
Randomization  
All subjects who are eligible for study participation will be randomized on Day 1 prior to study 
drug administration. Each subject will be randomized to receive KPL-404 or placebo as per the 
randomization schedule prepared before the study by the Sponsor or designee. Randomization 
will be stratified by available documented evidence of prior inadequate response to  1 versus 
 2 classes of advanced targeted therapy (bDMARD or tsDMARD; e.g., TNF inhibitors, IL-6 
receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK inhibitors). 
For Cohorts 1 and 2, subjects will be randomized 3:1, KPL-404 to placebo. 
The overall randomization ratio in Cohort 3 is 1:1:1 (5 mg/kg q2wk, 5 mg/kg qwk, placebo). To 
maintain blinding, the placebo volume will be matched to the corresponding 5 mg/kg volume, 
and all subjects will be required to attend weekly visits through the treatment period.  
The overall randomization ratio in Cohort 4 is 3:2 KPL-404 (600 mg loading dose at baseline 
followed by maintenance dosing 400 mg q4wk at Week 4 and Week 8) to matched placebo 
(equivalent volume; SC q4wk; loading dose at baseline followed by maintenance dose at Week 4 
and Week 8).
An Interactive Response Technology (IRT) system will issue a unique randomization code to 
each subject, which will assign the treatment to the subject. The study drug will be assigned, 
prepared, and administered according to instructions in the Pharmacy Manual. 
8.5.
Blinding
This will be a double-blind, placebo-controlled study. Investigators, the subjects, and remaining 
clinical site staff will be blinded to treatment throughout the course of the study.  The Sponsor 
will also be blinded to subject treatment assignment while each cohort’s enrollment and subject 
follow-up is ongoing. Specified Sponsor representatives (and designees) may be unblinded to 
subject treatment assignment in completed cohorts (i.e., all participants in the cohort having 
completed study participation [Week 24/EOS]), and this unblinding will be documented in the 
Unblinding Plan.  
The unblinded treatment assignment for each individual subject may be made available to the 
Investigator through the IRT system only in the event of a medical emergency or an adverse 
reaction that necessitates identification of the study drug for the medical management or welfare 
of that subject. Except in a medical emergency, the Investigator and blinded clinical site staff 
will remain blinded during the conduct of the study. The process and requirements for 
unblinding will be detailed in an Unblinding Plan. The date and reason for breaking the study 
blind should be documented. 




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Complete details regarding study drug dispensing and accountability can be found in the 
Pharmacy Manual. 
9.7. 
Study Drug Handling and Disposal  
Additional details for study drug receipt, handling, and disposal can be found in the Pharmacy 
Manual. 
10.
STUDY ASSESSMENTS  
Should it become necessary (e.g., due to COVID-19), at any point following randomization, 
home health nursing, telemedicine services, or other operational adjustments may be applied to 
in-person visits and dosing, in compliance with local requirements/regulations.  Where permitted 
by local requirements/regulations, study drug administration by a qualified healthcare provider in 
the home setting requires written approval from the Sponsor for each subject and cannot be 
performed prior to Week 2 (i.e., after 2 completed study drug administrations at the clinical site). 
10.1. 
Order of Assessments  
The following assessments should be conducted in the order below, as required, at a pre-dose 
and post-dose time points. Assessments not listed below can be done in any order:  
1. Patient-reported outcomes and clinician assessments  
2. Vital signs 
3. Blood sampling for safety, PK, efficacy, and 
assessments
4. Study drug administration (if applicable) must follow all other assessments 
5. Observational period: subjects will be observed for 60 minutes after dosing on Day 1 and 
30 minutes after dosing through end of treatment.  
10.2.
General Assessments
10.2.1.
Demographics  
Demographic data including sex, age, race, and ethnicity will be collected at screening to study 
their possible association with subject safety and treatment effectiveness, as well as the impact of 
KPL-404 on PK.  
10.2.2. 
Medical and Surgical History  
A complete medical history will be compiled to include drug or alcohol abuse within the last 
6 months, RA history, cancer within the last 5 years from screening, and surgical history.  
10.2.3. 
Medication History
All prior medication will be recorded up to 60 days prior to screening. All prior medication for 
RA that were administered within the last year prior to the screening visit should be recorded. 
All documented prior advanced targeted therapies (bDMARD or tsDMARD; e.g., TNF 


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inhibitors, IL-6 receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK 
ihibitors) for RA should be recorded along with response.  
A COVID vaccine regimen consistent with local guidance must have been completed at least 3 
weeks before the first dose of IP. 
10.2.4. 
Vital Signs  
Vital signs will be measured in a sitting position after 5 minutes rest in a quiet setting without 
distractions (e.g., television, mobile phones) and will include body temperature, systolic and 
diastolic blood pressure, and pulse rate per the Schedule of Assessments (Appendix 1). 
Vital signs may also be measured at other times if judged to be clinically appropriate by the 
Investigator or if the ongoing review of the safety data suggests a more detailed assessment of 
vital signs is required. All measurements will be performed singly and may be repeated if outside 
the relevant clinical reference range. Additional vital sign assessments may be performed if 
clinically indicated, in the opinion of the Investigator. 
10.2.5. 
Weight and Height  
Height and weight will be measured and recorded per Schedule of Assessments in Appendix 1. 
Weight collected at Baseline will be used to calculate dose through all applicable dosing visits.  
10.2.6. 
Physical Examination  
A complete physical examination will be completed per Schedule of Assessments in Appendix 1. 
Complete exams exclude genitourinary/pelvic systems unless clinically indicated. An 
abbreviated physical examination may be performed at the discretion of the Investigator at any 
time during the study.  
10.2.7. 
Electrocardiogram  
Electrocardiogram (ECG) will be performed as per standard of care (e.g., after subject has been 
resting in supine position for 5 minutes). The ECG must include the following measurements: 
heart rate, QRS, QT, QTc, and PR intervals. The ECG at screening will not be required if a 
subject had a previously documented normal ECG within 120 days of screening. 
10.2.8. 
Chest X-ray  
A chest X-ray, 2 views (posterior-anterior and lateral or oblique view), will be performed as part 
of a general baseline screen for underlying pulmonary disease. The chest x-ray will not be 
required if a subject had a previously documented normal chest x-ray within 120 days of 
screening. 
10.3. 
Efficacy Assessments  
10.3.1. 
Tender joint Count/Swollen Joint Count
The 68 joints will be examined and assessed as tender or not tender for Tender Joint Count (TJC) 
and 66 joints will be examined and assessed as swollen or not swollen for Swollen Joint Count 
(SJC) (Felson et al 1993; Smolen et al 1995). The 68 joints (34 joints on each side of the 






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The urine drug screen will include opioid antagonists or agonists. 
10.6. 
Adverse and Serious Adverse Events  
10.6.1.
Definition of Adverse Events
10.6.1.1.
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a medicinal product, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not caused by the medicinal (investigational) 
product. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:
 They induce clinical signs or symptoms 
 They are considered clinically significant
 They require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values, which are considered non-typical in subjects with the 
underlying disease.  
10.6.1.2. 
Adverse Drug Reaction
An adverse drug reaction is defined as, “A response to a medicinal product which is noxious and 
unintended [DIR 2001/83/EC Art 1(11)]. Response in this context means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility” (see 
Annex IV, International Conference for Harmonisation [ICH]-E2A Guideline). 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
10.6.1.3. 
Adverse Events of Special Interest
An AE of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the investigational product and requires close monitoring and communication 
by the Investigator with the Sponsor or designee within 24 hours of knowledge of the event, 
regardless of seriousness criteria. The rapid reporting of AESIs allows ongoing analysis of these 
events in order to characterize and understand them in association with the use of this 
investigational product. AESIs for the purposes of this study are as follows: thrombosis, serious 
infection, serious and non-serious bacterial infections, eye disorders, and 
anaphylaxis/hypersensitivity reactions. Anaphylaxis is defined below in Table 2 using 
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Table 2: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1.
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 PEF, hypoxemia) 
b.
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence)
2. 
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 BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d.
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a.
b.
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline 
PEF, peak expiratory flow; BP, blood pressure. 
 of age, less than 
(70 mm Hg 1  [2  age]) from 1 to 10 years or age, and less than 90 mm Hg from 11 to 17 years of age. 
10.6.1.4. 
Serious Adverse Events  
An SAE is an AE occurring during any study phase after the ICF is signed (ie, screening, 
baseline, treatment, washout, or follow-up), and at any dose of the investigational product, 
comparator, or placebo, that fulfills 1 or more of the following: 
Results in death
 It is immediately life-threatening
Life-threatening in the context of an SAE refers to a reaction in which the subject 
was at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe (refer to the ICH-
E2D Guidelines) 
 It requires in-patient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
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 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. Such 
events should be considered as “medically significant.” Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization or development of dependency 
or abuse.  
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered 
a serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious AE 
irrespective of whether a clinical event has occurred. 
10.7. 
Relationship to Study Drug  
The Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE. The causal relationship between an AE and the study drug 
will be defined as below:
 Not related: when the AE is definitely caused by the subject’s clinical state, or the 
study procedure/conditions 
 Unlikely related: when the temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE  
 Possibly related: when the AE follows a reasonable temporal sequence from the time 
of drug administration but could have been produced by the subject’s clinical state or 
the study procedures/conditions 
 Definitely related: when the AE follows a reasonable temporal sequence from 
administration of the drug, abates upon discontinuation of the drug, follows a known 
or hypothesized cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced 
If the relationship between the SAE and the investigational product is determined to be 
“possibly” or “definitely” related, the event will be considered related to the investigational 
product for the purposes of expedited regulatory reporting. If the relationship between the 


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SAE and investigational product is deemed to be “unlikely related,” the case is considered 
not expedited in the USA or European Union. 
10.8. 
Severity of Adverse Events  
The severity of an AE will be recorded as one of the following: 
Mild = Grade 1: easily tolerated, does not interfere with normal daily activities, does 
not require intervention 
Moderate = Grade 2: causes some interference with daily activities; minimal, local, or 
non-invasive intervention indicated  
 Severe = Grade 3: medically significant event; prevents daily activity and requires 
medical intervention; hospitalization or prolongation of hospitalization indicated 
 Potentially life threatening = Grade 4: urgent intervention indicated; ER visit or 
hospitalization required 
 Death = Grade 5
As appropriate, clinical judgment should be used to determine the severity of adverse events with 
further reference to the FDA Guidance for Industry: National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE). The guidance document should not 
supersede Investigator judgment, as adverse events should be evaluated in the context of the 
clinical situation. 
10.9. 
Recording Adverse Events  
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes in laboratory values, blood pressure, and pulse 
need to be reported as Aes. Abnormal values that constitute an SAE or lead to discontinuation of 
administration of study drug must be reported and recorded as an AE.  
Adverse event collection will begin after the signing of the ICF. An adverse event that occurs 
prior to study treatment administration should be recorded in the eCRF only if it is an SAE or is 
an AE related to a study procedure. All Aes/SAEs that occur after the first administration of 
study treatment through the EOS visit, whether or not they are related to the study, must be 
recorded in the eCRF. 
For subjects who terminate study participation early (i.e., before the Week 24 visit), the 
Investigator will report any SAEs that are reported to the Investigator within 30-day post-last 
dose administration. 
Every reasonable effort will be made to follow subjects who have Aes/SAEs. Any subject who 
has an ongoing AE will be followed until resolution or the EOS visit.  
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the onset (date and time), resolution (date and time), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the subject to discontinue the study. 


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10.9.1.
Pregnancy
Should a pregnancy occur, investigational product must be permanently discontinued, and the 
pregnancy must be reported and recorded on the Pregnancy Report Form. Pregnancy by itself is 
not regarded as an AE unless there is a suspicion that an investigational product may have 
interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as Aes. 
Any AE considered serious by the Investigator, or which meets SAE criteria, or any other event 
or condition regardless of grade, which in their judgment represents a reportable event, must be 
reported to the medical monitor and the Sponsor as soon as the Investigator becomes aware of 
the event. 
10.10. 
Reporting Adverse Events  
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the last study visit, must be reported to the Sponsor or 
designee, within 24 hours of learning of its occurrence. Additionally, Investigator reporting of 
SAEs to IRB/EC and other regulatory health authorities may be required per local rules and 
regulations. The following contact information can be used for SAE reporting: 
US 24 Hour Safety Hotline:
 
 
Europe / Middle East / Africa (EMEA)/Asia Pacific 24 Hour Safety Hotline: 
Additional follow-up information, if required or available, should be sent to the above-mentioned 
Pharmacovigilance contact information as soon as possible and placed with the original SAE 
information. 
The event must also be recorded on the clinical database. Preliminary reports of SAEs must be 
followed by detailed descriptions as soon as possible including clear and redacted photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested as 
applicable and if available. 
If the SAE is not previously documented in the IB as reference safety information (RSI) and is 
thought to be related to the study treatment, then the event is considered a suspected unexpected 
serious adverse reaction (SUSAR), and Kiniksa or designee may need to issue an Investigator 
notification to inform all Investigators involved in any study with the same study treatment that 


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this SAE has been reported. The standard timelines for SUSAR reporting as per ICH E2A will be 
followed.  
The Sponsor or designee will report all SUSARs to the applicable regulatory authorities no later 
than 15 calendar days after the Sponsor’s initial receipt of this information. Fatal or life-
threatening unexpected experiences for which there is a possibility that the experience may have 
been caused by the drug will be reported by the Sponsor or designee to the regulatory authorities 
by telephone or facsimile transmission no later than 7 calendar days after receipt of this 
information.  
Any SAEs experienced after completion of the study should only be reported to the 
Sponsor/Investigator. 
11. 
STATISTICAL ANALYSES  
Statistics to be reported are outlined in this section. Analysis plans will be written and approved 
prior to performing the first interim analysis. All statistical analysis and reporting will be done 
using SAS 9.4 or higher.  
Descriptive statistics and changes from baseline, as applicable, will be calculated for safety 
parameters. The details regarding analyses will be provided in the SAP. Additional exploratory 
and post hoc analyses of the data may be conducted as deemed appropriate. 
11.1. 
Sample Size Justification  
The sample size for Cohorts 1 and 2 are based on safety and PK considerations. The sample size 
for Cohort 3 is based on a 2-sample t-test assuming an improvement in DAS28-CRP change 
from baseline for the KPL-404 being 1.2 points better than placebo (improvement for placebo = 
1.0 point, standard deviation = 1.3). Enrollment of 21 subjects in each of the 3 treatment arms 
(KPL-404 5 mg/kg qwk, KPL404 5 mg/kg q2k, and placebo) allows 83% power for the 
treatment comparison with 2-sided 0.05 type 1 error if all subjects complete 12 weeks of DAS28-
CRP assessments. In order to account for an anticipated discontinuation rate of 16%, up to 25 
subjects per arm and for a total of up to 75 subjects are required to enroll under Cohort 3.  
The sample size for Cohort 4 is based on a 2-sample t-test assuming an improvement in DAS28-
CRP change from baseline for the KPL-404 being 1.3 points better than placebo (improvement 
for placebo = 1.0 point, standard deviation = 1.3). Enrollment of 22 subjects into the KPL-404 
arm and 14 subjects into the placebo arm (i.e., 3:2 randomization ratio) allows 80% power for 
the treatment comparison with 2-sided 0.05 type 1 error if all subjects complete 12 weeks of 
DAS28-CRP assessments. In order to account for an anticipated discontinuation rate of 10%, 
approximately 24 subjects (KPL-404) and 16 subjects (placebo) for a total of approximately 40 
subjects are required to enroll under Cohort 4. 
11.2. 
Interim Analysis  
An interim analysis may be conducted to support internal decision-making, for example, when at 
least 50% of subjects in Cohort 3 have completed the 12-week treatment period. The Cohort 3 
interim analysis may include cumulative safety, tolerability, PK, 
 clinical response (e.g., 
DAS28-CRP), and 
. Should the Sponsor decide to conduct the Cohort 3 


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Interim Analysis, the Sponsor will provide the specifics of the interim analysis in the Statistical 
Analysis Plan (SAP) prior to such analysis as well as the list of unblinded individuals prior to 
unblinding of study data.  The data from the interim analysis will not be communicated to 
blinded study team, personnel at the clinical research organization, investigational sites, or 
enrolled subjects until all subjects have completed the study and database lock has been 
achieved. Details of the individuals who will see group-level unblinded data will be provided in 
the Unblinding Plan.  The SAP will be submitted sufficiently far in advance of any unblinding of 
study data to allow regulators to formulate and communicate any necessary feedback regarding 
the SAP prior to data unblinding. 
11.3.
Analysis Populations  
Analysis populations are defined as follows: 
 Modified intent-to-treat (mITT) population: All randomized subjects who receive 
at least one dose of study drug and have at least one post-baseline assessment for 
primary efficacy endpoint will be included in the mITT population. Efficacy analyses 
will be based on the mITT population.  
 Safety population: All randomized subjects who receive at least one dose of study 
drug will be included in the safety population. Safety analyses will be based on the 
safety population.  
11.4. 
Analysis of Efficacy  
11.4.1. 
Efficacy Endpoints   
11.4.1.1. DAS28-CRP  
The primary endpoint for Cohorts 3 and 4 and a secondary endpoint for Cohorts 1–2 is change 
from baseline in DAS28-CRP at Week 12. The DAS28-CRP score is derived from the number of 
swollen joints (out of 28 assessed), number of tender joints (out of 28 assessed), CRP level, and 
PGA score.
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12.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
12.1.
Study Monitoring
Before the investigational site can enter a subject into the study, a representative study monitor 
of Kiniksa or designee will assess the investigational study site to: 
 Determine the adequacy of the facilities
 Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence and the responsibilities of the Sponsor or designee. This will be 
documented in a Clinical Trial Agreement between the Sponsor and the Investigator. 
During the study, a monitor from the Sponsor or designee will have regular contact with the 
investigational site, for the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability 
checks are being performed. 
 Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts). 
 Record and report any protocol deviations not previously sent to the Sponsor. 
 Confirm that Aes and SAEs have been properly documented and reported, that those 
SAEs have been forwarded to Kiniksa, and that SAEs meeting criteria for reporting 
have been forwarded to the IRB/IEC. 
Specific details will be outlined in the clinical monitoring plan.  
12.2. 
Audits and Inspections  
Authorized representatives of the Sponsor quality assurance unit, a regulatory authority, an IEC,
or an IRB may visit the site to perform audits or inspections, including source data verification. 
The purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice guidelines of the ICH, and any applicable regulatory requirements. The Investigator 
should contact the Sponsor immediately if contacted by a regulatory agency about an inspection. 


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13.
QUALITY CONTROL AND QUALITY ASSURANCE
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Kiniksa may conduct a quality assurance audit. Please see Section 12.2 for more details 
regarding the audit process. 


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14.
ETHICS  
14.1.
Ethics Review
Before initiating a trial, the Investigator/Institution must obtain approval/favorable opinion from 
the IRB or Independent Ethics Committee (IEC) for the trial protocol, written informed consent 
form, consent form updates, subject recruitment procedures, and any other written information to 
be provided to subjects.  
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov. In 
addition, after study completion and finalization of the study report, the results of this trial will 
be submitted for publication and posted in a publicly accessible database of clinical trial results. 
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Investigators will apply due diligence 
to avoid protocol deviations.  
The IRB/EC will be informed by the Investigator of any changes to the approved protocol.  
Any amendments to the protocol will require IRB/IEC approval. Any administrative 
amendments to the protocol will be provided to IRBs/IECs according to IRB/IEC procedures.  
The IRB/IEC will be informed by the Investigator of serious and unexpected SAEs in accordance 
with the IRB/IEC reporting requirements. The Investigator will provide the IRB/IEC with 
progress reports per IRB/IEC procedures. 
14.2. 
Ethical Conduct of the Study  
This clinical study was designed and shall be implemented, executed, and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations US CFR 21, and with the ethical principles laid down in the Declaration of Helsinki. 
14.3. 
Informed Consent  
Eligible subjects may only be included in the study after providing (witnessed, where required by 
law or regulation) IRB/IEC-approved informed consent. 
If applicable, in cases where the subject’s representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable, he/she must indicate agreement by personally 
signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (eg, all 
procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that to 
participate, they must adhere to the contraception requirements specified in this protocol. 
A copy of the approved version of all consent forms will be kept by the Investigator. 


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15.
DATA HANDLING AND RECORD KEEPING
The Investigator is responsible for assuring that the data (recorded on CRFs and entered into the 
eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the subject data for archiving at 
the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
15.1.
Inspection of Records
The Investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The Investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Additional checks of the consistency of the 
source data with the CRFs are performed according to the study-specific monitoring plan. No 
information in source documents about the identity of the subjects will be disclosed. 
15.2. 
Retention of Records  
The principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Kiniksa or the 
regulatory authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 


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16.
PUBLICATION POLICY
Publication of the study results shall be done in accordance with, and are subject to, the 
publication provision in the clinical trial agreement governing this study. 


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17.
REFERENCES
Albulescu M, Müller-Ladner U, Moate R, et al. VIB4920, a novel, engineered cd40l antagonist 
decreased disease activity and improved biomarkers of immune activation in patients with active 
rheumatoid arthritis in a Phase 1b, multiple-ascending dose proof-of-concept study [abstract]. 
Arthritis Rheumatol. 2018;70 (suppl 10).  
Berner B, Wolf G, Hummel KM, Müller GA, Reuss-Borst M. Increased expression of CD40 
ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis. Ann 
Rheum Dis 2000;59:190–195. 
Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves 
treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor 
biologicals: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum 
Dis. 2008;67:1516-1523. 
Favalli EG, Pregnolato F, Biggioggero M, et al. Twelve-year retention rate of first-line tumor 
necrosis factor inhibitors in rheumatoid arthritis: real-life data from a local registry. Arthr Care 
Res. 2016;68(4):432-439. 
Felson D, Anderson J, Boers M, et al. The American College of Rheumatology preliminary core 
set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on 
Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum. 1993;36(6):729-40. 
Fisher B, Szanto A, Ng W-F, Bombardieri M, Posch M, Papas A, Farag A, Daikeler T, Bannert 
B, Kyburz D, Kivitz A, Carsons S, Isenberg D, Barone F, Bowman S, Espie P, Floch D, Dupuy 
C, Ren X, Faerber P, Wright A, Hockey H-U, Rotte M, Milojevic J, Avrameas A, Valentin M-A, 
Rush J, and Gergely P. Assessment of the anti-CD40 antibody iscalimab in patients with primary 
Sjögren’s syndrome: a multicentre, 58andomized, double-blind, placebo-controlled, proof-of-
concept study. Lancet Rheumatology. 2020;2(3):e142-e152. 
Fleischmann RM, Blanco R, Hall S, et al. Switching between Janus kinase inhibitor upadacitinib 
and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid 
arthritis. Ann Rheum Dis. 2020 (Epub ahead of print doi:10.1136/annrheumdis-2020-218412). 
Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients 
with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs 
(SELECT-BEYOND): a double-blind, 58andomized controlled phase 3 trial. Lancet. 
2018;391(10139):2513-2524.  
Guo V, Walsh AM, Fearon U, et al. CD40L-dependent pathway is active at various stages of 
rheumatoid arthritis disease progression. J Immunol. 2017;198(11):4490-4501 
McInnes IB, and Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 
365(23):2205-2219.  
Smolen J, Breedveld F, Eberl G, et al. Validity and reliability of the twenty-eight-joint count for 
the assessment of rheumatoid arthritis activity. Arthritis Rheum. 1995;38(1):38-43. 
Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of 
rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 
update. Ann Rheum Dis. 2017;76:960-977. 


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Ulrich P, Flandre T, Espie P, Sickert D, Rubic-Schneider T, Shaw DA, Rush JS. Nonclinical 
Safety Assessment of CFZ533, a Fc-Silent Anti-CD40 Antibody, in Cynomolgus Monkeys. 
Toxicol Sci. 2018;166(1):192-202. 
Effects of BI 655064, an antagonistic anti-CD40 
antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a 
randomized, double-blind, placebo-controlled, phase Iia study. Ann Rheum Dis. 2019;78:754–
760. 
 


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Study KPL-404-C211 
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18.
APPENDICES


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Study KPL-404-C211 
Clinical Study Protocol 
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Page 61 
APPENDIX 1. SCHEDULE OF ACTIVITIES
SCHEDULE OF ACTIVITIES – COHORTS 1 AND 2
Study Period
Screening 
Period 
Treatment Period
Safety Follow up Period
Week  Screening 
Baseline 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 10  
Wk 12/ 
EOTa
Wk 
14
Wk  
16
Wk 
20
Wk 
24/EOS
Day 
-28 to -1 
1 
8 
15 
29 
43
57
71 
85
99 
113
141
169
Visit Window
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days
± 2 
days 
± 2 days
± 2 
days 
± 2 
days 
± 2 
days 
± 4 
days 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
 
 
Demographics 
X 
Eligibility criteria 
X 
X 
Medical/surgical 
historyb 
X 
X 
  
  
  
  
  
  
  
  
  
 
 
Randomization
X 
  
  
  
  
  
  
  
  
  
 
 
Safety 
assessments 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-rayd 
X 
12-lead ECG 
Xd
X 
Physical 
examinatione
X 
X 
X 
Vital signsf
X 
X 
X 
X 
X 
X 
Height (screening 
only) and weight 
X 
X 
 
X 


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Study Period 
Screening 
Period 
Treatment Period 
Safety Follow up Period 
Week 
Screening
Baseline
Wk 1
Wk 2
Wk 4
Wk 6 
Wk 8 
Wk 10 
Wk 12/ 
EOTa
Wk 
14
Wk  
16
Wk 
20
Wk 
24/EOS
Day 
-28 to -1 
1 
8  
15  
29  
43 
57 
71  
85 
99  
113 
141 
169 
Visit Window
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days
± 2 
days 
± 2 days
± 2 
days 
± 2 
days 
± 2 
days 
± 4 
days 
Prior/concomitant 
medications and 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RA assessments 
 
 
TJC68/SJC66 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACR20/50/70
X 
X 
X 
X 
X 
X 
X 
X 
X 
DAS28-CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
HAQ-DIg
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood 
collectionn: 
QuantiFERON 
test 
X 
HBV/HCV
X 
HIV (local 
laboratory)h
X 
-hCG for 
WOCBPi
X 
 
X 
Central hs-CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 






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Page 65 
SCHEDULE OF ACTIVITIES – COHORT 3 
Study Period 
Screening 
Period 
Treatment Period 
Safety Follow up Period 
Week  Screening 
Base
- 
line 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Wk  
8 
Wk 9 
Wk 10  
Wk 
11 
Wk 12/ 
EOTa
Wk 
14
Wk 
16
Wk 
20
Wk 
24/EOS
Day 
-28 to -1 
1 
8 
15 
22
29 
36
43
50
57
64
71 
78
85
99 
113
141
169
Visit Window
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days
± 4 
days 
± 4 
days 
± 4 
days 
± 4 
days 
Informed 
consent 
X 
  
  
  
 
  
 
  
 
  
 
  
 
  
  
  
 
 
Demographics 
X 
  
Eligibility 
criteria 
X 
X 
Medical/surgical 
historyb 
X 
X 
  
  
 
  
 
  
 
  
 
  
 
  
  
  
 
 
Randomization
X 
  
  
 
  
 
  
 
  
 
  
 
  
  
  
 
 
Safety 
assessments 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-rayd 
X 
12-lead ECG 
Xd
 
X 
Physical 
examinatione
X 
X 
 
X 
Vital signsf 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
Height 
(screening only) 
and weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Prior/concomita
nt medications 
and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


KPL-404 
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Page 66 
Study Period
Screening 
Period 
Treatment Period
Safety Follow up Period
Week 
Screening
Base
- 
line 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Wk  
8 
Wk 9 
Wk 10  
Wk 
11 
Wk 12/ 
EOTa 
Wk 
14 
Wk 
16 
Wk 
20 
Wk 
24/EOS 
Day 
-28 to -1 
1 
8  
15  
22 
29  
36 
43 
50 
57 
64 
71  
78 
85 
99  
113 
141 
169 
Visit Window 
 
 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days 
± 4 
days 
± 4 
days 
± 4 
days 
± 4 
days 
RA 
assessments 
TJC68/SJC66 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
ACR20/50/70 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
DAS28-CRP 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
HAQ-DIg
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
collectionn: 
 
 
 
 
 
 
 
QuantiFERON 
test 
X 
HBV/HCV 
X 
HIV (local 
laboratory)h
X 
-hCG 
for WOCBPi
X 
 
X 
Central hs-CRP 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Blood 
chemistryj
X 
X 
X 
 
X 
 
 
X 
 
 
X 






KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
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Page 69 
Schedule of Activities – Cohort 4 
Study Period 
Screening 
Period 
Treatment Period 
Safety Follow up Period 
Week  Screening 
Baseline 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12/ 
EOTa
Wk 14 
Wk 16 
Wk 20 
Wk 
24/EOS
Day 
-28 to -1 
1 
8  
15  
29  
57 
85 
99  
113 
141 
169 
Visit Window 
 
 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 4 days 
± 4 days 
± 4 days 
± 4 days 
Informed 
consent
X 
  
Demographics 
X 
  
Eligibility 
criteria 
X 
X 
  
  
  
  
  
  
 
 
Medical/surgica
l historyb 
X 
X 
Randomization
X 
Safety 
assessments 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-rayd 
X 
12-lead ECG 
Xd
X 
Physical 
examinatione
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
Height 
(screening only) 
and weight 
X 
X 
X 
Prior/concomita
nt medications 
and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Kiniksa Pharmaceuticals, Ltd
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Page 70 
Study Period
Screening 
Period 
Treatment Period
Safety Follow up Period
Week 
Screening
Baseline
Wk 1
Wk 2
Wk 4
Wk 8 
Wk 12/ 
EOTa 
Wk 14 
Wk 16 
Wk 20 
Wk 
24/EOS 
Day 
-28 to -1 
1 
8 
15 
29 
57
85
99 
113
141
169
Visit Window
± 2 days
± 2 days
± 2 days
± 2 days
± 2 days
± 4 days
± 4 days
± 4 days
± 4 days
RA 
assessments 
 
 
 
 
 
 
 
 
 
 
TJC68/SJC66 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACR20/50/70
X 
X 
X 
X 
X 
X 
X 
X 
X 
DAS28-CRP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
HAQ-DIg 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood 
collectionn: 
QuantiFERON 
test 
X 
HBV/HCV 
X 
HIV (local 
laboratory)h
X 
-hCG 
for WOCBPi
X 
X 
Central hs-CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
chemistryj
X 
X 
X 
X 
X 
X 






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Clinical Study Protocol 
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Page 73 
 
APPENDIX 2. CLINICAL LABORATORY EVALUATIONS
See Appendix 1 for timing of evaluations. 
Blood chemistry 
Albumin, alkaline phosphatase, anion gap, total bilirubin 
(indirect and direct), bicarbonate, calcium, chloride, total 
cholesterol, creatinine, gamma GT, globulin, glucose, 
lactate dehydrogenase, phosphorus, potassium, total 
protein, AST, ALT, sodium, triglycerides, urea, and uric 
acid
Coagulation
d-Dimer, PT, INR, and PTT; anti-phospholipid 
antibodies (screening only)
Serology
HbsAg, HbsAb, HbcAb and HCVAb, HIV
Hematology 
Absolute neutrophil count, differential, hematocrit, 
hemoglobin, MCH, MCHC, MCV, platelet count, 
erythrocytes, leukocytes (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) 
Urinalysis
Bilirubin, blood, color, glucose, ketone, leukocytes, 
nitrite, pH, protein, specific gravity, turbidity, 
urobilinogen. 
If blood, leukocytes, nitrite, or protein are out of range, 
then microscopic exam (includes bacteria, cast, crystals, 
epithelial cells, red blood cell, white blood cell) will be 
automatically run. 
Urine drug screen 
Amphetamines (includes methamphetamines and 
ecstasy/MDMA), cocaine metabolites, opiates (includes 
heroin, codeine, and oxycodone) methadone, 
phencyclidine 
Other 
Serum pregnancy test 
Note: All laboratory tests will be collected locally. 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, GT = glutamyl transferase, HbsAg = hepatitis 
B surface antigen, HbsAb = hepatitis B surface antibody, HbcAb = hepatitis B core antibody; HCVAb = hepatitis 
C antibody; HIV = human immunodeficiency virus, INR = International Normalization Ratio, MCH = mean 
corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, MCV = mean corpuscular 
volume, MDMA = methylenedioxymethamphetamine, PT = prothrombin time; PTT = partial thromboplastin time 
 


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Page 74 
 
APPENDIX 3. SUMMARY OF CHANGES (VERSION 5.0 COMPARED TO 
VERSION 6.0)  
The following table shows changes to the KPL-404-C211 protocol (Version 5.0 versus Version 
6.0), which summarize the changes to the protocol. Additional minor changes were also made 
with respect to typos, minor edits for clarification, adding new abbreviations to the list of 
abbreviations, and updating the table of contents. 


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Protocol Section 
Modification 
Rationale
Throughout
Added/changed to Protocol Version 6.0, dated 28 Jun 2023.
Administrative edits to correct typographical errors, minor edits for clarification, adding new 
abbreviations to the list of abbreviations, and updating the table of contents 
Changes were made to identify 
the new protocol version and 
date and administrative 
changes for clarity, 
conciseness, and correctness. 
Synopsis
5.0 Study 
Objectives and 
Endpoints 
Primary and Secondary Objective and Endpoint were modified to include Cohort 4 alongside 
Cohort 3. 
The objectives and endpoints 
for the new Cohort 4 were 
prespecified. 
Synopsis 
6.1 Overall Study 
Design 
 
At approximately the end of Cohort 3 enrollment, the study will enroll subjects into Cohort 4. 
Subjects will be randomized in a 3:2 ratio to receive one of the following:
• 
KPL-404 SC q4wk (600 mg loading dose at baseline followed by maintenance dosing 400 mg 
q4wk at Weeks 4 and 8) 
• 
Matched Placebo (equivalent volume) SC q4wk (loading dose at baseline followed by 
maintenance doses at Weeks 4 and 8)
Text was added to describe 
Cohort 4 dose levels and dose
administration. 
 
Synopsis 
6.1 Overall Study 
Design 
6.4 Safety Review 
Committee
In Cohorts 3 and 4, SRC meetings will occur on a quarterly basis while enrollment is ongoing.  The 
initial SRC meeting in Cohort 3 will occur within approximately 90 days of the start of enrollment or 
once 20 subjects are enrolled, whichever occurs first.  All available safety and PK data will be 
reviewed by the SRC at the initial meeting in Cohort 3.  Subsequent meetings will prioritize review of 
safety data from all active cohorts.   
Text was added to describe 
when SRC meeting will begin 
and how frequently they will 
occur for Cohorts 3 and 4. 
Synopsis
6.1 Overall Study 
Design 
7.3 Treatment 
Discontinuation, 
Withdrawal of 
Consent, and Lost 
to Follow-Up 
Criteria 
If a subject discontinues prematurely (i.e., before the end of treatment visit), the subject should be 
encouraged to complete the procedures for the end-of-treatment visit (Week 12) within approximately 
2 weeks (for Cohorts 1, 2, and 3) or 4 weeks (for Cohort 4) from last dose of study drug as well as 
visits thereafter through Week 24. 
Upon decision to discontinue treatment, the Sponsor should be notified immediately. If a subject is 
prematurely discontinued from IP (study treatment), he or she should complete the end of treatment 
(EOT) visit (Week 12) within approximately 2 weeks (for Cohorts 1, 2, and 3) or 4 weeks (for Cohort 
4) from last dose of study drug as well as visits thereafter through Week 24, as per the Schedule of 
Activities, for all safety and efficacy assessments. The Investigator may also request that the subject 
return for additional visits.
These paragraphs were 
modified for clarity to describe 
when subjects should return for 
an end-of-treatment visit 
following premature 
discontinuation of treatment. 


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Protocol Section 
Modification 
Rationale
Synopsis
6.2 Number of 
Subjects 
Number of Subjects (Planned): 
• 
Cohort 4: approximately 40 subjects 
 
The study plans to enroll approximately 16 subjects in Cohorts 1 and 2, approximately 75 subjects in 
Cohort 3, and approximately 40 subjects in Cohort 4, across approximately 100 study sites. 
Text was revised to describe 
the Cohort 4 sample size.
Synopsis
Reference Therapy, Dosage, and Mode of Administration:  
Placebo administered weekly, every other week, or monthly by SC injection. 
Text was revised to describe 
the dose administration 
frequency being evaluated in 
this clinical trial.
Synopsis 
11.1 Sample Size 
Justification 
The sample size for Cohort 4 is based on a 2-sample t-test assuming an improvement in DAS28-CRP 
change from baseline for the KPL-404 being 1.3 points better than placebo (improvement for placebo 
= 1.0 point, standard deviation = 1.3). Enrollment of 22 subjects into the KPL-404 arm and 14 
subjects into the placebo arm (i.e., 3:2 randomization ratio) allows 80% power for the treatment 
comparison with 2-sided 0.05 type 1 error if all subjects complete 12 weeks of DAS28-CRP 
assessments. In order to account for an anticipated discontinuation rate of 10%, approximately 24 
subjects (KPL-404) and 16 subjects (placebo) for a total of approximately 40 subjects are required to 
enroll under Cohort 4. 
Text was revised to describe 
the Cohort 4 sample size.
4.2 Study Rationale
The safety, pharmacokinetics (PK), and pharmacodynamics (PD) of KPL-404 have been assessed in a 
single ascending-dose study in healthy subjects (KPL-404-C101). The clinical development plan is 
designed to focus next on assessing safety, tolerability, and PK (primary objective), and efficacy 
(secondary objective) of KPL-404 with multiple-dose administration, initially with two ascending-
dose cohorts: Cohort 1 (2 mg/kg dose level vs. placebo), administered subcutaneously (SC) on 
alternate weeks (q2wk), and Cohort 2 (5 mg/kg dose level vs. placebo SC q2wk). Cohort 3 is 
designed to assess the comparative efficacy (primary objective) as well as the safety, tolerability, and 
PK (secondary objectives) of KPL-404 using the weight-based 5 mg/kg SC dose level administered 
either weekly or biweekly versus placebo over 12 weeks.  Cohort 4 is designed to assess the 
comparative efficacy, safety, tolerability, and PK of fixed-mg dose KPL-404 (400 mg) administered 
SC monthly versus placebo. Efficacy will be assessed using the primary endpoint, change from 
baseline in disease activity score of 28 joints using C-reactive protein (DAS28-CRP) at 12 weeks.
Study Rationale was revised to 
describe the inclusion of 
Cohort 4. 


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Protocol Section 
Modification 
Rationale
4.3 Dose 
Justification
Subheadings are added to clarify dose justifications for Cohorts 1 and 2, Cohort 3, and Cohort 4.
 
Cohort 4 subjects will be randomized in a 3:2 ratio to receive fixed-mg dosing of KPL-404 SC q4wk 
(a 600mg SC [or matching placebo] loading dose at the Baseline Visit followed by maintenance 
dosing of 400mg SC [or matching placebo] at Week 4 and Week 8).  The objective is to explore the 
efficacy of KPL-404 at lower trough concentrations than Cohort 3, approximating the minimum level 
required for T-cell-dependent antibody response suppression, as seen in Phase 1.  This dosing 
regimen (i.e., a fixed-mg dose rather than weight-based dose) represents a different approach as 
compared to Cohort 3, and it does not represent a dose escalation. Rather, this fixed-mg (400 mg) 
administered dose provides a centered administered dose level, based upon early PK data showing a 
relatively neutral effect of weight on the PK of KPL-404, as would be expected given that 
monoclonal antibodies are large macromolecules with a volume of distribution restricted to the 
plasma.  The 400 mg administered dose is 5 mg/kg for an average 80 kg subject.  The 600 mg loading 
dose is intended to facilitate reaching steady state trough levels more rapidly, based on PK modeling. 
This regimen based on the same modeling is expected to provide peak levels no greater than those 
projected in Cohorts 2 and 3 and trough plasma concentrations lower than the 5 mg/kg q2wk dose 
level in Cohort 2.   
Text was added to explain and 
justify the KPL-404 dose level, 
administration, and frequency 
of the Cohort 4 dosing. 
Figure 2: Study 
Schema for KPL-
404-C211
Figure 2 was updated to include Cohort 4.
Figure was revised to include 
Cohort 4.


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Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
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Page 78 
Protocol Section 
Modification 
Rationale
Table 1: 
Investigational 
Product 
Unit Dose 
Cohort 1: 2 mg/kg KPL-404 q2wk  
Cohort 2: 5 mg/kg KPL-404 q2wk  
Cohort 3:  
 
5 mg/kg SC qwk 
 
5 mg/kg SC q2w (weekly 
dosing with alternating 
administration of KPL 404 
q2wk or placebo q2wk) 
Cohort 4: 
 
KPL-404 SC q4wk (600 mg 
loading dose followed by 400 
mg q4wk) 
Placebo volume will be matched to 
KPL-404 at the corresponding dosage 
level.   
In Cohort 3 in the placebo group, 
placebo will be given qwk; in the 
q2wk group, placebo will be 
alternated with KPL-404 
administration. 
 
In Cohort 4, placebo will be 
administered as a volume-equivalent 
of KPL-404:  a loading dose (i.e., 3 
mL) followed by maintenance dosing 
(i.e., 2 mL) q4wk   
Text was added to describe the 
KPL-404 dose level, 
administration, and frequency 
of the Cohort 4 dosing and to 
describe placebo administration 
in Cohorts 3 and 4. 
8.4 Randomization 
The overall randomization ratio in Cohort 4 is 3:2 KPL-404 (600 mg loading dose at baseline 
followed by maintenance dosing 400 mg q4wk at Week 4 and Week 8) to matched placebo 
(equivalent volume; SC q4wk; loading dose at baseline followed by maintenance dose at Week 4 and 
Week 8). 
Cohort 4 randomization was 
described.
11.3 Analysis 
Populations
•
Modified intent-to-treat (mITT) population: All randomized subjects who receive at least one 
dose of study drug and have at least one post-baseline assessment for primary efficacy endpoint will 
be included in the mITT population. Efficacy analyses will be based on the mITT population. 
Text was added to clarify the 
mITT population definition and 
to align this definition with the 
Statistical Analysis Plan.




KPL-404 
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Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 80 
APPENDIX 4
CLINICAL OUTCOME ASSESSMENTS AND PATIENT 
REPORTED OUTCOMES 
This appendix provides paper depictions of the outcome measures employed in 
Study KPL-404-C211.  These paper depictions are provided for conceptual clarity 
and are for REFERENCE ONLY.  These clinical outcome assessments and patient 
reported outcomes will be administered, and the responses collected, electronically 
via a provisioned tablet device that will remain at the clinical study sites. 


KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 81 
1. ARC20/50/70


KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 82 


KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 83 




KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 






KPL-404 
Kiniksa Pharmaceuticals, Ltd
Study KPL-404-C211 
Clinical Study Protocol 
Version 6.0: 28 Jun 2023 
{Confidential} 
Page 88 
 













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