Conditions: Giant Cell Arteritis
Keywords: GCA temporal arteritis Horton's disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of mavrilimumab (KPL-301) versus placebo, co-administered with a 26-week corticosteroid taper, for maintaining sustained remission for 26 weeks in subjects with new onset or relapsing/refractory giant cell arteritis (GCA).

Detailed description:
This Phase 2 randomized, double-blind, placebo-controlled proof of concept study will evaluate the efficacy and safety of mavrilimumab co-administered with a 26-week corticosteroid taper in subjects with GCA. The study will consist of a screening period (up to 6 weeks), a 26-week double-blind placebo-controlled period during which subjects will receive blinded mavrilimumab or placebo co-administered with a 26-week corticosteroid taper, and a 12-week washout safety follow-up period during which subjects will discontinue and wash off blinded mavrilimumab or placebo.

Arms:
arm 1: Subjects randomized to mavrilimumab will receive 150 mg every other week by subcutaneous injection co-administered with a 26-week corticosteroid taper. arm 2: Subjects randomized to placebo will receive placebo every other week by subcutaneous injection co-administered with a 26-week corticosteroid taper.

Interventions: intervention 1: mavrilimumab intervention 2: placebo intervention 3: prednisone
Intervention descriptions: intervention 1: 1 mL of 150 mg in a pre-filled syringe intervention 2: 1 mL of placebo in a pre-filled syringe intervention 3: Prednisone tablets for oral administration containing either 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg or 50 mg of prednisone United States Pharmacopeia (USP)

Protocol document:
Prot_002.pdf: 








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by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have neither 
signs/symptoms of GCA nor new or worsening vasculitis by imaging by Week 26 
• 
Time to elevated ESR by Week 26  
• 
Time to elevated CRP by Week 26  
• 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
• 
Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up Period 
 
 
 
 
 
 
 
 
Safety Endpoints: 
• 
Incidence of treatment emergent adverse events 
• 
Change in physical exam results 
• 
Change in vital signs 
• 
Change in clinical laboratory parameters  
o Serum chemistry 
o Hematology 
o Urinalysis 
Methodology: 
This Phase 2 randomized, placebo-controlled Proof of Concept (POC) study will evaluate the efficacy and 
safety of KPL-301 coadministered with a 26-week corticosteroid taper in patients with GCA. The study 
will consist of a Screening Period (up to 6 weeks), a 26-week Double-Blind placebo-controlled Period 
during which subjects will receive blinded KPL-301 or placebo coadministered with a 26-week 
corticosteroid taper, and a 12-week Washout Safety Follow-up Period during which subjects will 
discontinue and wash off blinded KPL-301 or placebo.  
Screening/Diagnostic Period: 
Following signing of the informed consent form (ICF), potential subjects 50-85 years of age (inclusive) 
will be screened for meeting study-specified diagnostic criteria for GCA.  
• 
Acute Phase Reactants - Westergren erythrocyte sedimentation rate (ESR) > 30 mm/hour or 
C-reactive protein (CRP) ≥ 1 mg/dL  
AND 
• 
Signs/Symptoms - At least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp, or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 


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ii. 
Unequivocal extra-cranial symptoms of GCA, such as claudication of the extremities 
iii. 
Symptoms of polymyalgia rheumatica (PMR), defined as shoulder and/or hip girdle pain 
associated with inflammatory morning stiffness 
AND  
• 
Diagnostic Criteria - At least one of the following: 
i. 
Temporal artery biopsy (TAB) or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such 
as magnetic resonance imaging (MRI), computed tomography (CT)/computed 
tomography angiography (CTA) or positron emission tomography (PET)-CT of the aorta 
or other great vessels 
Upon successful completion of the screening procedures, diagnosis criteria will be entered into an IWRS, 
and eligible subjects will be stratified for randomized study treatment into two cohorts according to 
whether subjects have new-onset disease or relapsing/refractory (hereafter, “relapsing” for brevity) 
disease. 
• 
New-onset - The new-onset disease cohort includes subjects who have been diagnosed within 
6 weeks of Day 0 using the above Acute Phase Reactants, Signs/Symptoms and Diagnostic 
Criteria. 
• 
Relapsing/refractory – (either or) 
o The relapsing disease cohort includes subjects having prior documented diagnosis of GCA as 
per Diagnostic Criteria above > 6 weeks before Day 0 and who have active GCA disease 
defined by Acute Phase Reactants and Signs/Symptoms within 6 weeks of Day 0.  
o The refractory nonremitting disease subject has had no remission since the diagnosis of 
disease as per clinical expectations. Thus, the subject has documentation of prior diagnosis of 
GCA as per Diagnostic criteria above > 6 weeks before Day 0; however, presence of Acute 
Phase Reactants and Signs/Symptoms as per above persists within 6 weeks of Day 0. 
Subjects who complete screening procedures and are not considered eligible (screen failures) may be 
rescreened one time provided there is reason to believe that eligibility criteria will be met.  
Base Treatment Period: 
Stratified eligible subjects will enter the double-blind treatment period after randomization 3:2 to blinded 
treatment with KPL-301 150 mg or placebo administered subcutaneously (SC) every other week (every 
2 weeks). All subjects will also receive an unblinded 26-week oral prednisone taper according to a 
standardized tapering protocol.  
Prior to first administration of KPL-301 or placebo, all subjects are required to have achieved remission 
(i.e., resolution of GCA symptom(s) and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour). Should a 
subject in screening not achieve remission within the initial screening period they can be rescreened using 
their prior flare documentation following the relapsing/refractory non-remitting inclusion criteria. 
The first administration of SC KPL-301/placebo and oral prednisone taper will take place at the study site 
on Day 0. Subsequent doses of KPL-301/placebo will be administered at the study site in conjunction with 
a scheduled study visit or administered by the subject on an outpatient basis in accordance with the dosing 
schedule. The oral steroid taper will be self-administered by study subjects on a daily basis.  
Subjects will be followed at the study site at Weeks 1, 2, 3, 4, and approximately every 4 weeks thereafter 
(see Table 1). Subjects reporting worsening of GCA symptoms or any safety issues may be brought in for 
an unscheduled visit at the study site at any time.  


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If a flare/relapse is suspected during the treatment period, the Investigator must consult the Contract 
Research Organization (CRO)-designated Medical Expert to review and harmonize the elements of the 
diagnostic work-up. Flare/relapse is defined as a re-increase of CRP from normal to 1 mg/dL or greater 
and/or of ESR from less than 20 mm in the first hour to 30 mm or greater AND at least one of the 
following signs or symptoms attributed by the Investigator to new, worsening, or recurrent GCA: 
• 
Cranial symptoms 
o New or recurrent headache or pain or tenderness of the scalp or the temporal artery 
o Visual signs/symptoms such as ischemic retinopathy, optic neuropathy, diplopia, amaurosis 
fugax, etc. 
o New or recurrent claudication of the tongue, masseter muscle, or worsening temporal artery 
signs and symptoms  
o Transient ischemic attack (TIA) or stroke related to GCA in the opinion of the Investigator  
• 
Extracranial symptoms 
o Classic PMR-like symptoms, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
o New or recurrent claudication in the peripheral circulation (i.e., in one of the extremities)  
• 
New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the 
aorta or other great vessels or via ultrasound of the temporal arteries  
Supportive findings could include other symptoms in the opinion of the Investigator related to worsening 
GCA, such as sustained daily recurrent fever with a temperature over 38°C for more than 1week, chronic 
anemia, or unexplained weight loss. 
Although either acute phase reactant (CRP or ESR) may be used during the study for eligibility and to 
determine remission or flares, it is advisable that the same acute phase reactant used to determine 
remission at screening also be used to determine flares during the treatment period. 
All elements of the diagnostic work-up pertinent to the Investigator diagnosis of a flare/relapse (i.e., the 
primary efficacy endpoint) should be reviewed with the CRO-designated Medical Expert and entered into 
the electronic Case Report Form (eCRF) promptly.  
Flare/relapse is defined as major if cranial symptoms or ischemia-related visual loss are present or if there 
is clear evidence of new onset large vessel vasculitis (e.g., subclavian artery). In all other situations, 
flare/relapse attributed to PMR, vascular or other symptoms should be regarded as minor.  
Subjects who experience a flare or subjects who cannot adhere to the protocol-defined steroid taper due to 
a flare should be managed to ensure the best possible care of the subject: 
• 
The subject must discontinue the assigned study drug (KPL-301 or placebo) and should receive 
escape therapy in accordance with local SoC, as determined by the Investigator, which may 
include, for example, dose modifications of corticosteroids, other immunomodulatory agents, 
and/or approved therapies (e.g., tocilizumab). The dosages of all concomitant medications used to 
treat the GCA flare must be entered into the eCRF. 
• 
Escape corticosteroid therapy can be escalated immediately.  Due to possible safety and 
pharmacologic effects resulting from overlapping exposures to immunomodulatory agents on top 
of co-administered corticosteroids, the investigator should consider a washout period of at least 35 


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days (based on elimination half-lives) after the last dose of study drug if deemed clinically 
appropriate. 
Any subject who prematurely discontinues the study drug treatment for safety or other reason will have an 
End-of-Treatment (EOT) visit and will be followed for the intended duration of study treatment (i.e., 
through Week 26 and Washout Safety Follow-up) to address potential issues of informative censoring. 
Any subject who withdraws consent from the trial (i.e., all study procedures in addition to study drug 
administration) must complete at a minimum the Final Washout Safety Follow-up visit 84 ± 3 days from 
the last dose administered.  Additional follow up using public records may be captured where possible. 
Washout Safety Follow-up: 
After subjects complete the 26-week double blind treatment period, they will discontinue and wash off of 
blinded KPL-301 or placebo during a 12-week Washout Period, which includes close safety follow-up and 
monitoring for potential GCA flares.  During this time, it is recommended that subjects, regardless of 
remission status, receive SoC oral prednisone therapy, taking into consideration that they have just 
completed treatment with what may have been an efficacious therapy which supported the tapering off of 
standard of care concomitant oral corticosteroids.  Clinicians may choose to observe subjects closely 
during the washout period without any change in concomitant medications or may choose (consistent with 
current SoC guidelines) to increase the daily corticosteroid dose prophylactically/empirically by 
approximately 10 mg above the prednisone dose administered at Week 26.  The prednisone dose can then 
be tapered, increased or maintained throughout the remainder of the 12-week Washout Period as per 
Investigator discretion.  After the Final Washout Safety Follow-up visit (Week 38) has been completed, 
the subjects will exit the trial and should be transitioned to SoC per investigator judgement.  It is not 
required that the steroid taper have been completed (0 mg) prior to subjects exiting the trial at Week 38. 
Number of Subjects: 
Approximately 70 subjects will be randomized at a 3:2 allocation ratio.  Approximately 42 subjects will be 
assigned to KPL-301, and approximately 28 subjects will be assigned to placebo. Of the study population, 
the aim is to have 50% with new-onset disease and 50% with relapsing disease. 
Eligibility Criteria: 
Inclusion Criteria 
1. Able and willing to provide written informed consent and to comply with the study protocol 
2. Age of ≥ 50 to 85 inclusive 
3. Diagnosis of new-onset or relapsing GCA classified according to the following criteria: 
New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined as:  
a) Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL  
b) AND at least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 
ii. 
Unequivocal extracranial symptoms of GCA such as claudication of the extremities 
iii. 
Symptoms of PMR, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
c) AND at least one of the following: 


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i. 
TAB or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such 
as MRI, CT/CTA, or PET-CT of the aorta or other great vessels 
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND: 
Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s) as per above and 
Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/ dL  
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 0 AND: 
No remission since the diagnosis of disease as per clinical expectations. i.e. Presence of 
sign/symptoms as per above and Westergren ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks 
of Day 0.  
4. Remission of GCA at or before Day 0 (resolution of GCA symptom(s) and CRP < 1.0 mg/dL or 
ESR < 20 mm in the first hour), such that the subject can safely participate in the study and follow the 
protocol-defined procedures, including initiation of the prednisone taper at the protocol-specified 
starting dose (i.e., ≤60 mg/day) 
5. At Day 0, receiving or able to receive oral prednisone up to 60 mg/day for the treatment of GCA 
6. If using methotrexate (MTX), oral or parenteral up to 25mg/week is permitted in screening if started 
more than 6 weeks prior to Day 0 and should be tapered to zero by Day 0 
7. Willing to receive antiplatelet therapy depending on the Investigator’s decision 
8. Willing to receive treatment for prevention of corticosteroid-induced osteopenia/osteoporosis 
depending on the Investigator’s decision 
9. Female subjects must be:  
a) postmenopausal, defined as at least 12 months post cessation of menses (without an alternative 
medical cause), or  
b) permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the 
subject, or  
c) nonpregnant, nonlactating, and if sexually active having agreed to use a highly effective method of 
contraception (i.e., hormonal contraceptives associated with inhibition of ovulation or intrauterine 
device [IUD], or intrauterine hormone-releasing system [IUS], or sexual abstinence) from 
Screening Visit until the Final Washout Safety Follow-up visit 84 ± 3 days from EOT Visit.   
10. Male subjects must have documented vasectomy or if sexually active must agree to use a highly 
effective method of contraception with their partners of childbearing potential (i.e., hormonal 
contraceptives associated with the inhibition of ovulation or intrauterine device [IUD], or intrauterine 
hormone-releasing system [IUS], or sexual abstinence) from Day 0 until the Final Washout Safety 
Follow-up visit 84± 3 days from EOT Visit. Male subjects must agree to refrain from donating sperm 
during this time period. 
Exclusion Criteria: 
General Exclusion Criteria 
1. Major surgery within 8 weeks prior to Screening or planned major surgery within 12 months after 
randomization 
2. Transplanted organs (except corneal transplant performed more than 3 months prior to randomization) 
3. Major ischemic event unrelated to GCA within 12 weeks of Screening 
 


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Exclusions Related to Prior or Concomitant Therapy 
4. Concurrent enrollment in another clinical study, with the exception of observational studies 
5. Previous treatment with KPL-301 
6. Treatment with any non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the 
study agent, whichever was longer, prior to Screening 
7. Any cell-depleting biological therapies (e.g., anti-CD20) within 12 months prior to Day 0; or previous 
treatment with noncell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], 
anakinra, anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-
lives, whichever is longer) prior to Screening 
8. Treatment with alkylating agents within 12 weeks prior to Screening 
9. Intramuscular, Intra-articular or IV corticosteroids within 4 weeks prior to Screening 
10. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0 
11. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or 
mycophenolate mofetil (MMF) within 4 weeks of Screening 
Relating to Medical History 
12. Female subjects who are pregnant, intending to become pregnant, or are breastfeeding 
13. Any condition that, in the opinion of the Investigator, could interfere with evaluation of KPL-301 or 
interpretation of subject safety or confound the results of the study 
14. Known history of allergy or reaction to any component of the KPL-301 or placebo formulation or to 
any other biologic therapy or prednisone or any of its excipients 
15. Positive (or 2 indeterminate) QuantiFERON test results. 
16. Clinically significant active infection including signs/symptoms suggestive of infection, any 
significant recurrent or chronic infection (including positive hepatitis C virus antibody [HCVAb]), or 
any episode of infection requiring hospitalization or treatment with IV antibiotics within 12 weeks 
before Screening. Subjects with any opportunistic infection within 6 months before Screening will be 
excluded from the study.  
17. Subjects with chronic active hepatitis B infection as defined below will be excluded from the study: 
• 
Hepatitis B surface antigen (HbsAg) positive 
• 
Hepatitis B anti-core antibody positive but anti-surface antibody negative 
18. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder 
including a history of known human immunodeficiency virus [HIV] infection), 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 
19. History of cancer within the last 10 years - except for basal and squamous cell carcinoma of the skin 
or in situ carcinoma of the cervix treated and considered cured 
20. Evidence of clinically uncontrolled respiratory disease. The Investigator should review the data from 
subjects’ respiratory assessments including chest x-ray and pulmonary function tests (PFTs) including 
DLCO performed during the screening period or within 12 weeks prior to Day 0 if results of prior 
assessments are available. Available PFT and DLCO assessments must have had values ≥ 60% of 
predicted for measurements performed and no uncontrolled lung disease. A subject’s medical regimen 
should not have been significantly intensified to control lung disease within 12 weeks prior to Day 0. 
21. History of chronic respiratory tract infections 
22. Congestive heart failure of New York Heart Association classification III or IV 


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23. At screening blood tests, any of the following: 
a) Aspartate transaminase (AST) > 2 × upper limit of normal (ULN) 
b) Alanine transaminase (ALT) > 2 × ULN 
c) Hemoglobin < 75 g/L 
d) Neutrophils < 1.5 × 109/L 
e) Creatinine clearance (CrCl) <30 mL/min 
Test Products, Dosage, and Mode of Administration: 
Subjects will be permitted to have received steroids (prednisone or equivalent) prior to inclusion in the 
study.  
During the double-blind period, subjects will receive blinded KPL-301 150 mg or placebo, every 2 weeks, 
by SC injection, in addition to a protocol-specified oral corticosteroid taper. 
Oral prednisone will be started at a dose between 20 mg/day to 60 mg/day (inclusive) at Day 0 depending 
on the subject’s previous corticosteroid treatment, disease status, and Investigator discretion. The 
prednisone dose will then be tapered over the subsequent 26 weeks in accordance with the following 
tapering schedule shown in Table 3, with subjects entering the taper at different points, depending on their 
prednisone dose at Day 0.  
After subjects have completed the 26-week double-blind treatment period, they will discontinue and wash 
off blinded KPL-301 or placebo during a 12-week Washout Period.  During the Washout Safety Follow-
up Period, patients may be closely observed with no additional therapeutic or may receive prophylactic 
prednisone and tapered as per Investigator discretion.  After the Final Washout Safety Follow-up visit 
84 ± 3 days from the EOT Visit has been completed, subjects will exit the trial and should be transitioned 
to SoC per investigator judgement, regardless of what dose of prednisone subjects are on. 
Concomitant Medication: 
Subjects should receive concomitant medications in line with current SoC practices for GCA. Such 
medications may include but not limited to the equivalent of the following examples: low-dose aspirin 
(dose allowed per SoC), pantoprazole (40 mg daily), calcium (1000 mg daily), cholecalciferol (800 U 
daily), and IV ibandronate 3 mg every 3 months, for the duration of the study. 
Duration of Treatment: 
Subjects will receive SC KPL-301 or placebo as well as coadministered study-supplied oral prednisone, 
which will be tapered over a period of up to 26 weeks, unless the subject experiences a flare of GCA. 
Upon completion of the 26-week double-blind period subjects will discontinue KPL-301 or placebo and 
enter the 12-week Washout Safety Follow-up period in which they may receive study-supplied oral 
prednisone per the Investigator’s discretion.  Thus, the total study duration will be up to approximately 38-
44 weeks (including 6-week Screening Period). 
Efficacy Measures: 
• 
Clinical laboratory analyses (e.g., CRP, ESR, signs/symptoms) 
• 
Clinical GCA assessments, including, signs/symptom(s), 
 
 
• 
Imaging studies (as applicable), including ultrasound, MRI, CT/CTA, PET-CT, TAB (if 
applicable) 
• 
 


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Safety Measure(s): 
Safety measures include adverse events and clinical laboratory analyses (including chemistry, hematology, 
urinalysis, liver profiles, lipid panel, hemoglobin A1c [HbA1c], and anti-drug antibodies), vital sign 
measurements, electrocardiograms (ECGs), and physical examination findings. 
 
. 
Overview of Trial Design  
 
 
Statistical Methods: 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical study data will be 
presented in subject data listings. Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile (Q1), median, third quartile (Q3), 
minimum and maximum for continuous variables, and frequency and percentage for categorical and 
ordinal variables. The preliminary SAP is presented here, with the final SAP to be confirmed in a separate 
document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo and at least have 1 assessment 
in the double blind treatment period will be included in the modified intent-to-treat (mITT) analysis set. 
Efficacy analyses will be based on the mITT analysis set. All mITT analyses will be based on each 
subject’s randomized treatment assignment.  
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo will be included in the Safety 
Analysis Set. Safety analyses will be based on the medication that was actually administered to each 
subject. 
Per Protocol Analysis Set 


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All mITT subjects without important protocol deviations deemed to impact efficacy or ethical conduct 
will be included in the per-protocol (PP) analysis set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time from randomization to the first 
flare occurring within the treatment period. Detailed censoring rules will be provided in the SAP.  
The number and percentage of subjects who remain in remission (no flare), who flare, and who are lost to 
follow-up prior to a flare during the treatment period will be summarized for each treatment group.  Time 
to flare by Week 26 will be summarized by the 25th, 50th (median), and 75th percentiles calculated using 
the Kaplan-Meier method to estimate the survival functions for each treatment group. The 95% confidence 
interval (CI) for the percentiles will also be calculated. A log-rank test stratified by randomization strata 
will be used to compare KPL-301 and placebo with respect to time to flare by Week 26.  To describe the 
magnitude of treatment effect, the hazard ratio for KPL-301 compared to placebo and the corresponding 
95% CI will be calculated based on a Cox proportional-hazards model with treatment as a covariate and 
stratified by the randomization strata.  
The protocol definition of flare includes multiple components. Supportive analyses will be performed 
based on each individual component.  The details will be described in the SAP.  In addition, a sensitivity 
analysis will be performed using the same method described above for the per-protocol analysis set. 
Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared using the Kaplan-Meier method  
The following endpoints will be analysed using the Cochran-Mantel-Haenszel test, stratified by the 
randomized stratum: 
• 
Percentage of subjects who have completed the corticosteroid taper and who have a normal ESR 
by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have a normal CRP 
by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have no 
signs/symptoms of GCA nor new or worsening vasculitis by imaging by Week 26 
The following time to event endpoints will be analyzed using the same methods used for the primary 
efficacy endpoint: 
• 
Time to elevated ESR by Week 26  
• 
Time to elevated CRP by Week 26  
• 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
The following continuous secondary efficacy endpoints will be analyzed. The analyses will include 
two-sided 95% CIs for the difference of treatment means, as appropriate. Details will be described in the 
SAP: 
• 
Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up period 
 
 
 
 
 
 




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Table 1: 
Schedule of Activities 
 
 
Screening 
Double – Blind Treatment Period (± 3 days) 
 
Washout Safety Follow-up 
(± 3 days) 
Assessment 
Up to 6 
weeks 
Baseline/ 
Day 0 
Wee
k 1 
Week 
2 
Week 
3 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 / 
EOTac 
UNSb 
Week 
30 
Week 
34 
Final Safety 
Follow-upc / 
Week 
38 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Chest X-ray 
Xg 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
Clinical GCA assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temporal biopsy 
Xf 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
 
Imaging (ultrasound)  
Xm 
Xn 
 
 
 
 
 
Xm 
 
 
 
Xm 
Xm 
 
 
Xm 
Imaging (MRI, CT/CTA, 
or PET-CT) 
Xm 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local CRP  
Xl 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Pulmonary function tests 
Xgh 
 
 
 
 
 
 
Xh 
 
 
 
Xh 
X 
 
 
Xh 
DLCO 
Xgh 
 
 
 
 
 
 
Xh 
 
 
 
Xh 
X 
 
 
Xh 
Dyspnea score and O2 
saturation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Hematology 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Liver profile 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Fasting lipid panel and 
HbA1c 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 


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Screening 
Double – Blind Treatment Period (± 3 days) 
 
Washout Safety Follow-up 
(± 3 days) 
Assessment 
Up to 6 
weeks 
Baseline/ 
Day 0 
Wee
k 1 
Week 
2 
Week 
3 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 / 
EOTac 
UNSb 
Week 
30 
Week 
34 
Final Safety 
Follow-upc / 
Week 
38 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KPL-301 or PBO 
administration/dispensing 
 
Xde 
 
Xe 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
 
Prednisone dispensingk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CRP=C-reactive protein; CT=computed tomography; CTA=computed tomography angiography; DLCO= diffusing capacity for carbon monoxide; EOT=end of treatment; ESR= erythrocyte 
sedimentation rate; GCA= giant cell arteritis; Hb1Ac= haemoglobin A1c (glycolysed haemoglobin); IMP = KPL-301 or placebo; MRI=magnetic resonance imaging; 
 
O2=oxygen; PBO=placebo; PET=positron emission tomography; 
; TB=tuberculosis; UNS=unscheduled visit; 
a. 
EOT visit must be conducted in the event the subject permanently discontinues KPL-301 or placebo. After the EOT visit, subjects who discontinue treatment should continue attending their 
remaining scheduled visits for the duration of the study. 
b. 
In the event of an unscheduled visit, only the relevant assessments/activities pertaining to the visit need to be captured. Subjects reporting worsening of GCA symptoms or any safety issues may be 
brought in for an unscheduled visit at the study clinic at any time. This visit can be combined with the EOT visit in which all necessary EOT related assessments/activities should be completed. 
c. 
All subjects, including subjects who prematurely discontinue the study (i.e., withdraw consent), must complete at a minimum the Final Safety Follow up visit 84 ± 3 days after the EOT Visit.  
Additional follow up using public records may be captured if possible. 
d. 
At baseline, subject and/or caregiver should be trained on proper self-administration and handling and accountability of study drug. This training should be documented and can be repeated as 
necessary throughout the study. 
e. 
If a study site or clinic visit coincides with the subject’s scheduled dose, study treatment will be administered at the study site or clinic.  Study drug treatment should be dispensed as necessary to the 
subject for home administration to ensure dosing compliance.  Investigator staff may contact patients between visits to ensure compliance with protocol-specified treatment regimens. 
f. 
New-onset subjects can have an optional temporal artery biopsy taken at Screening (or otherwise available from diagnostic workup) and Week 26 as part of the study. For relapsing/refractory 
patients, if the subject has not had a prior a temporal biopsy an optional biopsy can be done at Screening and Week 26. If the subject has an existing biopsy sample available this can be submitted as 
the screening/predose sample and an optional biopsy can be performed at Week 26.  
g. 
Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at Screening, or existing documentation (if available) within 12 weeks of Day 0 can be used and reviewed by the Investigator or 
designee. 
h. 
PFTs and DLCO should be performed at Screening within 6 weeks prior to Day 0 (or documented report available from PFT &/or DLCO from within 12 weeks prior to Day 0). They should also be 
performed at Weeks 12 and 26 and 38 with a window of ±14 days. 
 
  
 
 
k. 
Subjects will be given prednisone as necessary and instructed to dose in alignment with their prednisone taper. Investigator staff may contact patients between visits to ensure compliance with 
protocol specified treatment regimens. 
l. 
Clinical decisions for determination of inclusion and flare will be based upon local laboratory values either ESR and/or CRP. 
m. 
The imaging technique used during screening to diagnose GCA should be repeated at week 26 for the study.  If ultrasound is available at screening for diagnosis of GCA this should be conducted 
again at weeks 12, 26 and 38, or in case of a suspected flare of GCA with no other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, CT/CTA or PET-CT was used at screening for diagnosis 
of GCA and no ultrasound is available, the same imaging technique used at screening should be repeated at week 26 or as necessary for diagnosis in case a suspected flare. 
n. 
Ultrasound imaging if clinically relevant should be performed at or before Day 0 to support clinical remission decision making unless there is no evidence of temporal artery inflammation and 
diagnosis of GCA is confined to large vessels (By MRI or CT). 
 


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4 Table of Contents 
1 
Protocol Approval ........................................................................................................ 2 
2 
Investigator and Administrative Structure ................................................................. 3 
3 
Synopsis ........................................................................................................................ 4 
4 
Table of Contents ....................................................................................................... 17 
5 
List of Abbreviations and Definition of Terms ......................................................... 22 
6 
Introduction ............................................................................................................... 24 
6.1 
Overview .................................................................................................................... 24 
6.2 
GM-CSF Biology ........................................................................................................ 26 
6.3 
Non-Clinical and Clinical Experience with KPL-301 ............................................... 28 
6.3.1 
Clinical Development Plan for KPL-301 in GCA ........................................ 29 
7 
Study Objectives ........................................................................................................ 29 
7.1 
Objectives ................................................................................................................... 29 
7.1.1 
Primary Objective........................................................................................ 29 
7.1.2 
Secondary Objective(s) ................................................................................ 29 
7.1.3 
Exploratory Objective.................................................................................. 30 
8 
Study Design............................................................................................................... 30 
8.1 
Rationale of Study Design .......................................................................................... 30 
8.2 
Selection of Doses in the Study .................................................................................. 31 
8.3 
Justification for Placebo ............................................................................................ 32 
8.4 
Methodology ............................................................................................................... 32 
8.4.1 
Main Study .................................................................................................. 32 
8.4.2 
Washout Safety Follow-up .......................................................................... 35 
8.5 
Study Duration ........................................................................................................... 35 
8.6 
Number of Planned Subjects ..................................................................................... 35 
8.7 
Eligibility Criteria ...................................................................................................... 35 
8.7.1 
Inclusion Criteria ......................................................................................... 35 
8.7.2 
Exclusion Criteria ........................................................................................ 37 
8.8 
Removal of Subjects from Therapy or Assessments ................................................. 38 
9 
Investigational Medicinal Products ........................................................................... 39 
9.1 
KPL-301 ..................................................................................................................... 39 
9.2 
Placebo ....................................................................................................................... 39 
9.3 
Prednisone .................................................................................................................. 40 
9.4 
Method of Assigning Subjects to Treatment Groups ............................................... 42 
9.5 
KPL-301 or Placebo Administration ......................................................................... 42 
9.6 
Blinding ...................................................................................................................... 43 
9.6.1 
Methods for Ensuring Blinding .................................................................... 43 
9.6.2 
Unblinding .................................................................................................. 43 
10 
Concomitant Therapy and Treatment Compliance.................................................. 43 




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13 
Safety Assessments ..................................................................................................... 50 
13.1 Adverse Events ........................................................................................................... 50 
13.1.1 
Adverse Event Definition ............................................................................ 50 
13.1.2 
Management of Specific Disease Related Events ......................................... 51 
13.1.3 
Adverse Events of Special Interest ............................................................... 51 
13.1.3.1 
Hepatic Function Abnormality ..................................................................... 51 
13.1.3.2 
Acute and Delayed Hypersensitivity Reactions ............................................ 51 
13.1.3.3 
Clinically Significant Pulmonary Abnormality ............................................ 51 
13.1.3.4 
Neutropenia ................................................................................................. 52 
13.1.3.5 
Serious Infection ......................................................................................... 52 
13.1.4 
Adverse Reactions ....................................................................................... 52 
13.1.5 
Unexpected Adverse Event .......................................................................... 52 
13.1.6 
Serious Adverse Event ................................................................................. 52 
13.1.7 
Suspected Unexpected Serious Adverse Reaction ........................................ 53 
13.2 Adverse Event Assessment ........................................................................................ 53 
13.2.1 
Relationship to Study Drug .......................................................................... 53 
13.2.2 
Intensity ...................................................................................................... 53 
13.3 Recording Adverse Events ......................................................................................... 54 
13.3.1 
Adverse Events Based on Signs and Symptoms ........................................... 54 
13.3.1 
Adverse Events Based on Examinations and Tests ....................................... 54 
13.4 Time Period for Collection of Adverse Events .......................................................... 54 
13.5 Follow-Up of Unresolved Adverse Events ................................................................. 54 
13.6 Reporting Serious Adverse Events ............................................................................ 54 
13.7 Pregnancy ................................................................................................................... 55 
14 
Statistical Methods ..................................................................................................... 55 
14.1 General Considerations ............................................................................................. 55 
14.1.1 
Handling Dropouts and Missing Data .......................................................... 56 
14.1.2 
Multiplicity Adjustment............................................................................... 56 
14.2 Determination of Sample Size ................................................................................... 56 
14.3 Analysis Sets ............................................................................................................... 56 
14.3.1 
Modified Intent-to-Treat Analysis Set .......................................................... 56 
14.3.2 
Safety Analysis Set ...................................................................................... 56 
14 3 3
Per Protocol (PP) Analysis Set 
 56
14.4 Endpoints ................................................................................................................... 57 
14.5 Analysis of Efficacy .................................................................................................... 57 
14.5.1 
Primary Efficacy Endpoint Analysis ............................................................ 58 
14 5 2 
Secondary Efficacy Endpoint Analysis 
 58 
14.6 Analysis of Safety ....................................................................................................... 59 
14.6.1 
Adverse Events ............................................................................................ 59 
14.6.2 
Clinical and Laboratory Events and Analyses .............................................. 59 


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14.6.3 
Vital Signs ................................................................................................... 59 
14.6.4 
Physical Examination .................................................................................. 59 
14 6 5 
Concomitant Medications 
 59 
14.8 Quality Assurance and Quality Control ................................................................... 60 
14.8.1 
Audit and Inspection .................................................................................... 60 
14.8.2 
Monitoring .................................................................................................. 60 
14.8.3 
Data Management and Coding ..................................................................... 60 
14.8.4 
Record Keeping ........................................................................................... 60 
15 
Records and Supplies ................................................................................................. 61 
15.1 Drug Accountability ................................................................................................... 61 
16 
Ethics .......................................................................................................................... 61 
16.1 Institutional Review Board ........................................................................................ 61 
16.2 Ethical Conduct of the Study ..................................................................................... 61 
16.3 Subject Information and Consent ............................................................................. 61 
16.4 Subject Confidentiality .............................................................................................. 62 
17 
Study Termination ..................................................................................................... 62 
17.1 Study Stopping Criteria ............................................................................................. 62 
18 
Reporting and Publication ......................................................................................... 63 
19 
References .................................................................................................................. 64 
20 
Appendices ................................................................................................................. 66 
20.1 Appendix 1: Investigator Signature Page ................................................................. 66 
20.3 Appendix 3: Summary of Changes ............................................................................ 68 
20.3.1 
Protocol Amendment v2.0 ........................................................................... 68 
20.3.2 
Protocol Amendment v3.0 ........................................................................... 85 
20.3.3 
Protocol Amendment v4.0 ........................................................................... 91 
 


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List of Tables 
Table 1: 
Schedule of Activities ............................................................................................ 15 
Table 2:  
Overview of KPL-301 Clinical Trials in RA .......................................................... 28 
Table 3:  
Prednisone Tapering Schedule ............................................................................... 41 
 
List of Figures 
Figure 1:  Diagnosis Algorithm for GCA ............................................................................... 25 
Figure 2:  GCA Treatment Algorithm .................................................................................... 26 
Figure 3:  GM-CSF Biology and KPL -301 Mechanism of Action ......................................... 27 
Figure 4:  Reduction of Inflammatory Markers in RA Patients Treated with KPL-301 ........... 29 
Figure 5: 
Overview of Trial Design ...................................................................................... 30 
 


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5 List of Abbreviations and Definition of Terms 
ACR20 
American College of Rheumatology definition of improvement by 20% 
ADA 
antidrug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CDUS 
color Doppler ultrasound 
CI 
confidence interval 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CT 
computed tomography 
CTA 
computed tomography angiography 
DLCO 
diffusing capacity for carbon monoxide 
DMARD 
disease modifying anti-rheumatic drug 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End of Treatment 
ESR
erythrocyte sedimentation rate 
GCA 
giant cell arteritis 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte-macrophage colony growth factor 
HbA1c 
hemoglobin A1c (glycosylated hemoglobin) 
HbsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
Interactive Web Response System 
KPL-301 
Study Drug; nomenclature of mavrilimumab in this protocol 
mITT 
modified intent to treat 
MMF 
mycophenolate mofetil 
MoDC 
monocyte-derived dendritic cell 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
OLE 
open-label extension 


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PD 
pharmacodynamic 
PET 
positron emission tomography 
PFT 
pulmonary function test 
PK 
pharmacokinetics 
PMR 
polymyalgia rheumatica 
POC 
proof of concept 
PP 
per protocol 
Q1 
first quartile 
Q3 
third quartile 
RA 
rheumatoid arthritis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SoC 
standard of care 
TAB 
temporal artery biopsy 
TB 
tuberculosis 
TIA 
transient ischemic attack 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
US 
United States of America 
 


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6 Introduction 
6.1 Overview  
Giant cell arteritis (GCA) is a disease characterized by blood vessel inflammation and infiltration of 
monocytes, macrophages and the accumulation of giant cells (i.e., multinucleated fusions of macrophages) 
and has high unmet medical need (Dejaco et al, 2017; Roberts and Clifford, 2017). GCA, unless treated 
(either with long-term systemic corticosteroid treatment or tocilizumab with corticosteroid treatment), can 
lead to blindness, aortic aneurysm and/or death (Weyand and Goronzy, 2014). Granulocyte-macrophage 
colony growth factor (GM-CSF) is a key growth factor for many of the key inflammatory cell types at the 
site of the vascular lesion (i.e., macrophages, monocytes and giant cells; Wicks and Roberts, 2016), and 
additionally, GM-CSF is found in high concentrations at the site of damage in the vessel wall (Weyand et 
al, 1994). These data provide solid rationale for antagonizing this signaling pathway in GCA. 
Mavrilimumab (also known as KPL-301 for this development program, or previously as CAM-3001) is a 
fully human monoclonal antibody that antagonizes GM-CSF biological activity by binding to its receptor 
alpha subunit (GM-CSFRα) and thereby preventing downstream signalling. KPL-301 has been studied in 
over 500 patients with rheumatoid arthritis (RA) and recently achieved its primary endpoint in a Phase 2b 
trial in this indication with a well-tolerated safety profile. KPL-301 may provide a treatment option in high 
unmet need indications where there is a strong mechanistic rationale for modulating key cell types in 
diseases in which GM-CSF signalling is critical for proper functioning (e.g., monocytes, macrophages, 
and granulocytes). Refer to the current version of the Investigator Brochure for further details. 
GCA is an inflammatory disease of large- and medium-sized arteries that causes headaches, ischemic 
visual loss, and jaw and other muscle claudication (Dejaco et al, 2017). If left untreated, GCA can lead to 
monocular or binocular blindness, aortic aneurysm, myocardial infarction, and, rarely, stroke and death 
(Weyand and Goronzy, 2014). GCA presents with a wide and variable spectrum of signs and symptoms 
(Weyand and Goronzy, 2014). Diagnosis is usually made provisionally on the basis of clinical signs and 
symptoms and then confirmed by color Doppler ultrasound or by temporal artery biopsy (TAB) (Dejaco et 
al, 2018) (Figure 1). In the United States (US), the lifetime risk of developing GCA has been estimated at 
approximately one percent in women and 0.5 percent in men (Crowson et al, 2011). GCA generally affects 
adults over 50 years of age, with a 3:1 imbalance of women to men (Weyand and Goronzy, 2014). The 
reported prevalence of proven GCA in populations aged over 50 years varies significantly geographically 
and ranges between 24 to 200 per 100,000 individuals in the European Union and 24 to 278 per 100,000 
individuals in the US (Salvarani et al, 2004; Lawrence et al, 2008; Lee et al, 2008). 


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Figure 1:  Diagnosis Algorithm for GCA 
 
Abbreviations: TAB, temporal artery biopsy; CDUS: color Doppler ultrasound; MRA: magnetic resonance angiography; CTA: 
computed tomography angiography; PET-CT: positron emission tomography-computed tomography.  
 
Glucocorticoids are the mainstay of treatment (Figure 2) because they normalize inflammatory markers; 
however, many patients receive long courses of this therapy to prevent disease flare-up, and long-term use 
is associated with significant and serious side effects, including glaucoma, fluid retention, hypertension, 
mood changes, memory changes, other psychological effects, weight gain, and diabetes (Roberts and 
Clifford, 2017). 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2:  GCA Treatment Algorithm 
 
 
While corticosteroids are effective for some patients, many times patients are unable to wean from 
corticosteroids because they continue to experience disease flares as the dose is reduced (Dejaco et al, 
2017; Salvarani et al, 2012). In one study cohort published in the literature that followed 106 patients with 
GCS over 4.5 to 10.1 years, 68 patients (64%) experienced at least one relapse, and 38 (36%) experienced 
two or more relapses during or after corticosteroid weaning (Alba et al, 2014). 
Experimental evidence in SCID mice (severe combined immunodeficiency model) suggests that 
glucocorticoid treatment inhibits the T-cell mediated pathology but does not adequately suppress tissue-
infiltrating macrophage function—a key cell type generated and maintained by GM-CSF signaling, the 
target of KPL-301—and may explain why many patients require long-term chronic treatment and are 
unable to wean off corticosteroids (Brack et al, 1997). By blocking GM-CSF signaling at the receptor, 
KPL-301 may provide additional benefit to these patients by reducing long-term sequelae that result from 
chronic vessel inflammation and reducing steroid dependency.  
ACTEMRA® (tocilizumab), an IL-6 receptor inhibitor, recently received marketing approval in the US 
and certain Europe countries in GCA for use concomitantly with a corticosteroid taper; however, an unmet 
need still remains for improved therapeutic options, as just under 50% of patients did not achieve 
sustained remission over 52 weeks on tocilizumab after a 26-week corticosteroid taper (Stone et al, 2017).  
6.2 GM-CSF Biology 
GM-CSF is a growth factor first identified as an inducer of differentiation and proliferation of myeloid 
cells (e.g., neutrophils, basophils, eosinophils, monocytes, and macrophages) (Wicks and Roberts, 2016). 
Studies using different approaches have demonstrated that with GM-CSF overexpression, pathological 
changes almost always follow (Hamilton and Anderson, 2004). Figure 3 illustrates an overview of the 
mechanism of action of KPL-301 and of key pathways involving GM-CSF. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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Figure 3:  GM-CSF Biology and KPL -301 Mechanism of Action 
 
 
The following reported data suggest GM-CSF is a key mediator of inflammation and autoimmunity 
(Wicks and Roberts, 2016): 
• GM-CSF enhances trafficking of myeloid cells through activated endothelium of blood vessels 
and can also contribute to monocyte and macrophage accumulation in blood vessels during 
inflammation. 
• GM-CSF promotes activation, differentiation, survival, and proliferation of monocytes and 
macrophages as well as resident tissue macrophages in inflamed tissues. 
• Local GM-CSF production leads to activation of the vasculature and bone marrow and also 
promotes the differentiation of effector T cells at inflamed sites and draining lymph nodes. 
• GM-CSF also regulates the phenotype of antigen-presenting cells in inflamed tissues by 
promoting the differentiation of infiltrating monocytes into M1 macrophages and monocyte-
derived dendritic cells (MoDCs). 
• The production of IL-23 by macrophages and MoDCs, in combination with other cytokines such 
as IL-6 and IL-1, modulates T-cell differentiation. 
• Locally-produced GM-CSF acts on sensory neurons expressing the GM-CSF receptor, 
transmitting painful stimuli to ascending nociceptive pathways in the spinal cord and brain. 
 
 
 
 
 
 
 


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Additionally, GM-CSF is a confirmed key mediator of at least one autoimmune disease, as demonstrated 
by the successful, clinically relevant, and statistically significant effect KPL-301 had on primary and 
secondary efficacy measures in multiple Phase 2 trials in patients with RA.  
6.3 Non-Clinical and Clinical Experience with KPL-301 
MedImmune studied KPL-301 in over 550 patients with RA through Phase 2b development. A summary 
of clinical trials conducted in RA is provided in Table 2. These studies provide proof-of-efficacy in an 
autoimmune disease and are an accurate representation of the safety profile of KPL-301 to-date. More 
detailed information on the safety profile and pulmonary test threshold values can be found in the IB. 
Table 2:  
Overview of KPL-301 Clinical Trials in RA  
Trial Name 
Phase 
Identifiers 
Patient Segment 
Results 
Dose-Escalation Study to 
Evaluate The Safety and 
Tolerability of Single Doses 
of CAM-3001 (KPL-301) in 
Patients with RA 
Phase 1 
CAM-3001-
0702; 
NCT00771420 
Mild rheumatoid arthritis 
patients (remission/inactive) 
controlled on methotrexate  
Achieved primary 
endpoint 
EARTH: Study to Evaluate 
the Efficacy and Safety of 
CAM-3001 (KPL-301) in 
Subjects With Rheumatoid 
Arthritis 
Phase 2a 
NCT01050998; 
MI-CP219 
Active rheumatoid despite 
stable methotrexate dose 
Achieved primary 
endpoint 
A Double-blind, Placebo-
controlled, Single-dose 
Study to Evaluate the PK, 
IM and Safety in Japanese 
Subjects 
Phase 1 
NCT02213315; 
D2190C00016 
Healthy Japanese  
Adults 
Achieved primary 
endpoint 
EARTH EXPLORER 1 
Phase 2b 
CP1071; 
NCT01706926 
Moderate to severe rheumatoid 
arthritis patients with 
inadequate responders to 
disease modifying anti-
rheumatic drugs 
Achieved primary 
endpoint 
EARTH EXPLORER 2 
Phase 2b 
CD1107; 
NCT01715896 
Moderate to severe rheumatoid 
arthritis patients with 
inadequate response to anti-
tumor necrosis factor alpha 
Achieved primary 
endpoint 
EXPLORER X 
Phase 2b 
LTE 
CP1109; 
NCT01712399 
Patients from EARTH 
EXPLORER 1and 2 
Achieved primary 
endpoint 
 
In addition to the reductions to the primary endpoint demonstrated in the Phase 2b trials, other markers of 
inflammation (e.g., CRP, ESR, and IL-6) were similarly reduced and may provide evidence for KPL-301’s 
utility across a broad range of indications with a similar biomarker profile, including GCA (Figure 4). 
 


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Figure 4:  Reduction of Inflammatory Markers in RA Patients Treated with KPL-301 
 
 
6.3.1 Clinical Development Plan for KPL-301 in GCA 
Results from Phase 2b studies in RA have provided important information about the safety and efficacy 
profile of KPL-301. GCA is an appropriate indication for the study of KPL-301 due to the mechanistic 
rationale of inhibiting GM-CSF, a key growth factor for the cell types involved in the pathology of GCA 
(e.g., monocytes, macrophages and giant cells). Additionally, administration of KPL-301 in patients with 
RA markedly reduced key markers of disease activity that are also seen in GCA (i.e., CRP, ESR, and IL-6 
receptor the target of tocilizumab). This patient population has a high level of unmet need owing to the 
number of patients who continue to experience relapsing disease despite currently existing therapies.  
7 
Study Objectives 
7.1 Objectives 
7.1.1 Primary Objective 
The primary objective of the study is to evaluate the efficacy of KPL-301 versus placebo, coadministered 
with a 26-week steroid taper, for maintaining sustained remission for 26 weeks in subjects with new-onset 
or relapsing/refractory giant cell arteritis (GCA). 
7.1.2 Secondary Objective(s) 
The secondary objectives of the study, in subjects with new-onset and relapsing/refractory GCA, are: 
a) To evaluate the effect of KPL-301 vs placebo on cumulative corticosteroid dose. 
 
c) To evaluate the safety and tolerability of KPL-301. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 




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-resistant patients. KPL-301 may permit tapering of steroids, or their replacement, in steroid-responsive 
patients and achieve a response in steroid-refractory patients. 
The steroid taper chosen for this study is based on a standard taper used in clinical practice as well as prior 
clinical trials (Stone et al, 2017), with patients starting the study on the dose of prednisone they were 
previously taking and following the taper accordingly. For subjects starting on 20 mg or 25 mg 
prednisone, their dose will be held at ≥ 20 mg for the first 3 weeks of the study, as these subjects may be 
more liable to flare if their taper were to proceed too rapidly. 
For this study, the SC route of administration, via prefilled syringe, was chosen over the IV route as it 
provides a more convenient method of administration in this elderly population of patients with GCA 
(e.g., home administration, no requirement for venous access). 
8.2 Selection of Doses in the Study 
Subjects randomized to KPL-301 will receive 150 mg every other week by SC injection coadministered 
with a 26-week steroid taper. This dose was chosen based on the outcomes of previous dose-ranging 
assessments in Phase 2 clinical trials in patients with RA and on PK/PD modeling.  
Study CD-IA-CAM-3001-1071 (randomized, double-blind, placebo-controlled, parallel group, multicenter 
study evaluating the efficacy and safety of 3 SC doses of KPL-301 (CAM-3001) [30, 100, and 150 mg] 
administered every other week for 24 weeks in combination with MTX to 326 subjects with adult onset 
RA, and an inadequate response to one or more conventional disease modifying anti-rheumatic drugs 
(DMARDs) and at least moderately active disease (Disease Activity Score of 28 joints based on CRP 
[DAS28 (CRP) ≥ 3.2] and at least 4 swollen joints despite treatment with MTX) identified the greatest 
treatment effect in the 150 mg dose group. Both co-primary endpoints were met; the change from Day 1 in 
DAS28 (CRP) score at Week 12 and the American College of Rheumatology definition of improvement 
by 20% (ACR20) response rate at Week 24 were statistically significantly greater for all three KPL-301 
(CAM-3001) groups compared with placebo.  
• For mean change in DAS28 (CRP) the magnitude of response was dose dependent and 
statistically significant (p < 0.001), with the greatest treatment effect observed in the 150 mg dose 
group (more than 73.4% of subjects in the 150 mg KPL-301 [CAM-3001] group achieved an 
ACR20 response at Week 24, compared to 24.7% on placebo) 
• Secondary efficacy analyses identified significant treatment effects (p < 0.001) vs placebo in the 
150 mg KPL-301 (CAM-3001) group (ACR50 response at day 169, 40.5% vs 12.3%; DAS28 
(CRP) < 2.6 sustained at day 169, 16.5% vs 0; DAS28 (CRP) low disease activity at day 169, 
41.8% vs 8.6%), and the 150 mg group included the highest proportion of European League 
Against Rheumatism (EULAR) (Aletaha et al, 2010; Felson et al, 2011) moderate and good 
responders.  
• Anti-drug antibodies (ADA) were absent in the 150 mg KPL-301 (CAM-3001) group (detected in 
subjects in the placebo and 30 mg and 100 mg KPL-301 [CAM-3001] groups) 
A mechanistic population PK model was developed to describe the observed single-dose PK profiles of 
KPL-301 (CAM-3001) in subjects with RA. From stochastic clinical trial simulations using the population 
PK/PD model, maximum efficacy (ACR20 response rate) is reached at 150 mg KPL-301 (CAM-3001) 
every other week. The 150 mg KPL-301 (CAM-3001) dose is predicted to be more effective than the 
100 mg dose, and the steady-state serum concentrations of KPL-301 (CAM-3001) were maintained above 
ACR20 90% efficacy concentration (3.4 μg/mL) in more than 90% of RA subjects.  


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8.3 Justification for Placebo 
The proposed study is a placebo-controlled, double-blind study of SC doses of KPL-301 coadministered 
with a 26-week taper of oral prednisone. The double-blind, placebo-controlled, randomized clinical study 
design is considered the gold standard for the safety and efficacy assessment of a new therapy both by 
clinicians and regulatory authorities. In this study subjects will receive oral prednisone starting at 20 to 
60 mg/day as per the Investigators judgment in addition to KPL-301 or placebo to control their disease 
activity. Subjects are also allowed to receive permitted concomitant medications in line with current SoC 
practices for GCA. Any subject who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse must discontinue the assigned study drug (KPL-301 or placebo) and should receive escape 
therapy in accordance with local SoC. Subjects are not allowed to receive biologic DMARDs while 
receiving KPL-301 during the study to mitigate potential safety risks of administering KPL-301 
concomitantly with other biologics. In addition, any subject who discontinues treatment will have an EOT 
and will be followed for the intended duration of the study. 
8.4 Methodology 
8.4.1 Main Study 
This Phase 2 randomized, placebo-controlled POC study will evaluate the efficacy and safety of KPL-301 
co-administered with a 26-week corticosteroid taper in patients with GCA. The study will consist of a 
Screening Period (up to 6 weeks); a 26-week Double-Blind placebo-controlled Period during which 
subjects will receive blinded KPL-301 or placebo coadministered with a 26-week corticosteroid taper and 
a 12-week Washout Safety Follow-up Period. 
Following signing of the ICF, potential subjects 50-85 years of age (inclusive) will be screened for 
meeting study-specified diagnostic criteria for GCA.  
• 
Acute Phase Reactants - Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL  
AND  
• 
Signs/Symptoms - At least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp, or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 
ii. 
Unequivocal extra-cranial symptoms of GCA, such as claudication of the extremities 
iii. 
Symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory 
morning stiffness 
AND  
• 
Diagnostic Criteria - At least one of the following: 
i. 
TAB or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as 
MRI, CT/ CTA, or PET-CT of the aorta or other great vessels 


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Upon successful completion of the screening procedures, eligible subjects will be stratified for 
randomized study treatment into two cohorts according to whether subjects have new-onset disease or 
relapsing/refractory (hereafter, “relapsing” for brevity) disease: 
• 
New-onset - The new-onset disease cohort includes subjects who have been newly diagnosed 
within 6 weeks of Day 0 using the above Acute Phase Reactant, Signs/Symptoms and Diagnosis 
criteria. 
• 
Relapsing/refractory – (either or) 
o The relapsing disease cohort includes subjects having prior documented diagnosis of 
GCA as per above Diagnostic Criteria > 6 weeks before Day 0 and who have active GCA 
disease defined as Acute Phase Reactants and Signs/Symptoms within 6 weeks of Day 0. 
o The refractory nonremitting disease subject has no remission since the diagnosis of 
disease as per clinical expectations Thus, the subject has documentation of prior diagnosis 
of GCA as per above Diagnostic Criteria > 6 weeks before Day 0; however, presence of 
Acute Phase Reactants and Signs/Symptoms as per above persists within 6 weeks of 
Day 0. 
Subjects who complete screening procedures and are not considered eligible (screen failures) may be 
rescreened one time provided there is reason to believe that eligibility criteria will be met.  
Stratified eligible subjects will enter the double-blind treatment period after randomization 3:2 to blinded 
treatment with KPL-301 150 mg or placebo administered SC every other week (every 2 weeks). All 
subjects will also receive an unblinded 26-week oral prednisone taper according to a standardized tapering 
protocol.  
Prior to first administration of KPL-301 or placebo, all subjects are required to achieve remission (i.e., 
resolution of GCA symptom(s) and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour). Should a subject 
in screening not achieve remission by > 6 weeks of onset they can be rescreened using their prior flare 
documentation following the relapsing/refractory non-remitting inclusion criteria. 
The first administration of subcutaneous KPL-301/placebo and oral prednisone taper will take place at the 
study site on Day 0. Subsequent doses of KPL-301/placebo will be administered at the study site in 
conjunction with a scheduled study visit or administered by the subject on an outpatient basis in 
accordance to the dosing schedule. The oral steroid taper will be self-administered by study subjects on a 
daily basis.  
Subjects will be followed at the study site at Weeks 1, 2, 3, 4, and approximately every 4 weeks thereafter 
(see Table 1). Subjects reporting worsening of GCA symptoms or any safety issues may be brought in for 
an unscheduled visit at the study site at any time.  
If a flare/relapse is suspected, the Investigator must consult the Contract Research Organization 
(CRO)-designated Medical Expert to review and harmonize the elements of the diagnostic work-up. 


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Flare/relapse is defined as a re-increase of CRP from normal to 1 mg/dL or greater and/or of ESR from 
less than 20 mm in the first hour to 30 mm or greater AND at least one of the following signs or 
symptoms attributed by the Investigator to new, worsening, or recurrent GCA: 
• 
Cranial symptoms 
o New or recurrent headache or pain or tenderness of the scalp or the temporal artery 
o Visual signs/symptoms such as ischemic retinopathy, optic neuropathy, diplopia, amaurosis 
fugax, etc. 
o New or recurrent claudication of the tongue, masseter muscle, or worsening temporal artery 
signs and symptoms  
o Transient ischemic attack (TIA) or stroke related to GCA in the opinion of the Investigator  
• 
Extracranial symptoms 
o Classic PMR-like symptoms, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
o New or recurrent claudication in the peripheral circulation (i.e., in one of the extremities)  
• 
New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the 
aorta or other great vessels or via ultrasound of the temporal arteries  
Supportive findings could include other symptoms in the opinion of the Investigator related to worsening 
GCA, such as sustained daily recurrent fever with a temperature over 38°C for more than 1 week, chronic 
anemia, or unexplained weight loss. 
All elements of the diagnostic work-up pertinent to the Investigator diagnosis of a flare/relapse (i.e., the 
primary clinical endpoint) should be reviewed with the CRO-designated Medical Expert and entered into 
the eCRF promptly.  
Flare/relapse is defined as major if cranial symptoms or ischemia-related visual loss are present, or if there 
is clear evidence of new onset large vessel vasculitis (e.g., subclavian artery). In all other situations 
flare/relapse attributed to PMR, vascular or other symptoms should be regarded as minor.  
Subjects who experience a flare or subjects who cannot adhere to the protocol-defined steroid taper due to 
a flare should be managed to ensure the best possible care of the subject. The subject must discontinue the 
assigned study drug (KPL-301 or placebo) and should receive escape therapy in accordance with local 
SoC, which may include, for example, dose modifications of corticosteroids, other immunomodulatory 
agents, and/or approved therapies (e.g. tocilizumab). Escape corticosteroid therapy can be escalated 
immediately.  Due to possible safety and pharmacologic effects resulting from overlapping exposures to 
immunomodulatory agents on top of coadministered corticosteroids, the investigator should consider a 
washout period of at least 35 days (based on elimination half-lives) after the last dose of study drug if 
deemed clinically appropriate. The dosages of all concomitant medications used to treat the GCA flare 
must be entered into the eCRF.  
Any subject who prematurely discontinues the study drug treatment for safety or other reason will have an 
EOT visit and will be followed for the intended duration of study treatment (i.e., through Week 26 and 
Washout Safety Follow-up) to address potential issues of informative censoring. Any subject who 
withdraws consent from the trial (i.e., all study procedures in addition to study drug) must complete at a 
minimum the Final Washout Safety Follow-up visit 84 ± 3 days from the last dose administered.  
Additional follow-up using public records may be captured where possible. 
An analysis of the study will be performed when the last subject reaches Week 26 according to the SAP. 


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8.4.2 Washout Safety Follow-up 
After subjects complete the 26-week double-blind treatment period, they will discontinue and wash off of 
blinded KPL-301 or placebo during a 12-week Washout Safety Follow-up Period, which includes close 
safety follow-up and monitoring for potential GCA flares.  During this time, it is recommended that 
subjects, regardless of remission status, receive SoC therapy, taking into consideration that they have just 
completed treatment with what may have been an efficacious therapy which supported the tapering off of 
standard of care concomitant oral corticosteroids.  Clinicians may choose to observe subjects closely 
during the washout period without any change in concomitant medications or may choose (consistent with 
current SoC guidelines) to increase the daily corticosteroid dose prophylactically/empirically by 
approximately 10mg above the prednisone dose administered at Week 26.  The prednisone dose can then 
be tapered, increased or maintained throughout the remainder of the 12-week Washout Safety Follow-up 
Period as per Investigator discretion.  After the Final Washout Safety Follow-up visit (Week 38) has been 
completed, the subjects will exit the trial and should be transitioned to SoC per investigator judgement.  It 
is not required that the steroid taper have been completed (0 mg) prior to subjects exiting the trial at 
Week 38. 
8.5 Study Duration 
Subjects will complete the screening period in up to 6 weeks. Eligible subjects will be randomized and 
receive KPL-301 or placebo for 26 weeks (unless a subject discontinues treatment prematurely). Upon 
completion of the 26-week double-blind period subjects will discontinue KPL-301 or placebo and enter 
the 12-week Washout Safety Follow-up period in which they may receive study supplied oral prednisone 
per the Investigator’s discretion.  Thus, the total study duration will be up to approximately 38-44 weeks 
(including Screening Period). 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study.  
8.6 Number of Planned Subjects  
Approximately 70 patients with GCA will be randomized as study subjects.  For the primary endpoint 
analysis, the aim is to have 42 subjects assigned to KPL-301 and 28 subjects assigned to placebo, with 
balanced randomization in the two randomization cohorts. 
The sample size was chosen on an empirical basis, based on experience with other KPL-301 trials and 
other research in this patient population. 
8.7 Eligibility Criteria 
8.7.1 Inclusion Criteria 
To be eligible to participate in the trial, a subject must meet all of the following criteria: 
Inclusion Criteria 
1. Able and willing to provide written informed consent and to comply with the study protocol 
2. Age of ≥ 50 to 85 inclusive 


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3. Diagnosis of new-onset or relapsing GCA classified according to the following criteria: 
New-onset: Initial diagnosis of GCA within 6 weeks of Day 0  
a) Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL  
b) AND at least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 
ii. 
Unequivocal extracranial symptoms of GCA such as claudication of the extremities 
iii. 
Symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory 
morning stiffness 
c) AND at least one of the following: 
i. 
TAB or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as 
MRI, CT/CTA, or PET-CT of the aorta or other great vessels 
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND  
Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s) and Westergren ESR 
> 30 mm/hour or CRP ≥ 1 mg/ dL  
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 0 AND 
No remission since the diagnosis of disease as per clinical expectations i.e. Presence of 
sign/symptoms as per above and Westergren ESR > 30mm/hour or CRP ≥ 1 mg/dL within 
6 weeks of Day 0 
4. Remission of GCA at or before Day 0 (resolution of GCA symptom(s) and CRP < 1.0 mg/dL or 
ESR < 20 mm in the first hour), such that the subject can safely participate in the study and follow the 
protocol defined procedures, including initiation of the prednisone taper at the protocol-specified 
starting dose (i.e., ≤60 mg/day) 
5. At Day 0, receiving or able to receive oral prednisone up to 60 mg/day for the treatment of active 
GCA 
6. If using MTX, oral or parenteral up to 25mg/week is permitted during screening if started more than 
6 weeks prior to Day 0 and should be tapered to zero by Day 0. 
7. Willing to receive antiplatelet therapy depending on the Investigator’s decision 
8. Willing to receive treatment for prevention of corticosteroid-induced osteopenia/osteoporosis 
depending on the Investigator’s decision 
9. Female subjects must be:  
a) postmenopausal, defined as at least 12 months post cessation of menses (without an alternative 
medical cause), or  


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b) permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the 
subject, or  
c) nonpregnant, nonlactating, and if sexually active having agreed to use a highly effective method 
of contraception (i.e., hormonal contraceptives associated with inhibition of ovulation or 
intrauterine device [IUD], or intrauterine hormone-releasing system [IUS], or sexual abstinence) 
from Screening Visit until the Final Washout Safety Follow-up visit 84± 3 days from EOT Visit.   
10. Male subjects must have documented vasectomy or if sexually active must agree to use a highly 
effective method of contraception with their partners of childbearing potential (i.e., hormonal 
contraceptives associated with inhibition of ovulation or intrauterine device [IUD], or intrauterine 
hormone-releasing system [IUS], or sexual abstinence) from Day 0 until the Final Washout Safety 
Follow-up visit 84± 3 days from EOT Visit. Male subjects must agree to refrain from donating sperm 
during this time period. 
8.7.2 Exclusion Criteria 
A subject who meets any of the following criteria will not be eligible to participate in the trial: 
General Exclusion Criteria 
1. Major surgery within 8 weeks prior to Screening or planned major surgery within 12 months after 
randomization 
2. Transplanted organs (except corneal transplant performed more than 3 months prior to randomization) 
3. Major ischemic event unrelated to GCA within 12 weeks of Screening 
Exclusions Related to Prior or Concomitant Therapy 
4. Concurrent enrollment in another clinical study, with the exception of observational studies 
5. Previous treatment with KPL-301 
6. Treatment with any non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the 
study agent, whichever was longer, prior to Screening 
7. Any cell-depleting biological therapies (e.g., anti-CD20) within 12 months prior to Day 0; or previous 
treatment with noncell-depleting biologic therapies (such as anti-TNF, anakinra, anti-IL-6 
[tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer) prior to Screening 
8. Treatment with alkylating agents within 12 weeks prior to Screening 
9. Intramuscular, Intra-articular, or IV corticosteroids within 4 weeks prior to Screening 
10. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0 
11. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or MMF 
within 4 weeks of Screening 
Relating to Medical History 
12. Female subjects who are pregnant, intending to become pregnant, or are breastfeeding 
13. Any condition that, in the opinion of the Investigator, could interfere with evaluation of KPL-301 or 
interpretation of subject safety or confound the results of the study 


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14. Known history of allergy or reaction to any component of the KPL-301 or placebo formulation or to 
any other biologic therapy or prednisone or any of its excipients 
15. Positive (or 2 indeterminate) QuantiFERON test results. 
16. Clinically significant active infection including signs/symptoms suggestive of infection, any 
significant recurrent or chronic infection (including positive HCVAb), or any episode of infection 
requiring hospitalization or treatment with IV antibiotics within 12 weeks before Screening. Subjects 
with any opportunistic infection within 6 months before Screening will be excluded from the study.  
17. Subjects with chronic active hepatitis B infection as defined below will be excluded from the study: 
• 
HbsAg positive 
• 
Hepatitis B anti-core antibody positive but anti-surface antibody negative 
18. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder 
including a history of known HIV infection), 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 
19. History of cancer within the last 10 years except for basal and squamous cell carcinoma of the skin or 
in situ carcinoma of the cervix treated and considered cured 
20. Evidence of clinically uncontrolled respiratory disease. The Investigator should review the data from 
subjects’ respiratory assessments including chest x-ray and PFTs including DLCO performed during 
the screening period or within 12 weeks prior to Day 0 if results of prior assessments are available. 
Available PFT and DLCO assessments must have had values ≥ 60% of predicted for measurements 
performed and no uncontrolled lung disease. A subject’s medical regimen should not have been 
significantly intensified to control lung disease within 12 weeks prior to Day 0. 
21. History of chronic respiratory tract infections 
22. Congestive heart failure of New York Heart Association classification III or IV 
23. At screening blood tests, any of the following: 
a) AST > 2 × ULN 
b) ALT > 2 × ULN 
c) Hemoglobin < 75 g/L 
d) Neutrophils < 1.5 × 109/L 
e) CrCl < 30 mL/min 
8.8 Removal of Subjects from Therapy or Assessments 
Subjects may withdraw from the study drug treatment or from the study as a whole at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to discontinue treatment 
with and withdraw subjects from the study for any of the following reasons: 
• Adverse event or Life threatening or other unacceptable toxicity, for example: 
o Hepatic function abnormality defined as any increase in ALT or AST to greater than 3 × 
ULN and concurrent increase in bilirubin to greater than 2 × ULN, assessed as related to 
investigational product  




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colorless liquid, free from visible particles, in a 1 ml prefilled syringe at a nominal fill volume of 1.0 mL, 
stoppered with a Teflon-faced elastomeric stopper, accessorized with a needle guard and extended finger 
flange and a plunger rod.  
9.3 Prednisone 
Prednisone Tablets USP are available for oral administration containing either 1 mg, 2.5 mg, 5 mg, 10 mg, 
20 mg or 50 mg of prednisone USP. Each tablet contains the following inactive ingredients: lactose 
monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch 
glycolate, and stearic acid (1 mg, 2.5 mg, and 5 mg only). 
Prednisone tablets contain prednisone which is a glucocorticoid. Glucocorticoids are adrenocortical 
steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. 
The chemical name for prednisone is 17,21-dihydroxypregna-1,4-dienne-3,11,20-trione.  
 
Prednisone is a white to partially white, crystalline powder. It is very slightly soluble in water; slightly 
soluble in alcohol, chloroform, dioxane, and methanol. 
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining 
properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are 
primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Prednisone 
is used as adjunctive therapy for short-term administration (to tide the patient over an acute episode or 
exacerbation) in rheumatoid inflammation such as GCA. 
On Day 0, each subject will begin the steroid taper, using oral prednisone tablets provided by the Sponsor 
to the study site. To ensure subjects perform the taper according to the protocol, they will be provided 
with a written schedule, specific to their starting dose, that instructs them on the daily dose to be taken in 
each week of the study. Investigator staff may contact patients between visits to ensure compliance with 
prednisone taper. 
The duration of the steroid taper, in the absence of a GCA flare, is planned to take up to 26 weeks, 
depending on the starting dose of prednisone the subject was taking before enrolling in the study 
(see Table 3). Any subject who cannot adhere to the protocol-defined steroid taper due to flare/relapse will 
be allowed escape therapy per the Investigator. During the Washout Safety Follow-up Period, the 
prednisone dose can then be tapered, increased or maintained throughout the remainder of the 12-week 
Washout Period as per the discretion of the Investigator.  After the Final Washout Safety Follow-up visit 
(Week 38) has been completed the subjects will exit the trial and should be transitioned to SoC per 
investigator judgement.    
 
 
 


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Table 3:  
Prednisone Tapering Schedule 
 
Prednisone Dose at Study Start (Day 0) 
Prednisone 
Dose (mg/day) 
60 mg 
50 mg 
40 mg 
35 mg 
30 mg 
25 mg 
20 mg 
60 
Week 1 
 
 
 
 
 
 
50 
Week 2 
Week 1 
 
 
 
 
 
40 
Week 3 
Week 2 
Week 1 
 
 
 
 
35 
Week 4 
Week 3 
Week 2 
Week 1 
 
 
 
30 
Week 5 
Week 4 
Week 3 
Week 2 
Week 1 
 
 
25 
Week 6 
Week 5 
Week 4 
Week 3 
Week 2 
Week 1 
 
20 
Week 7 
Week 6 
Week 5 
Week 4 
Week 3 
Week 2-3 
Week 1-3 
17.5 
Week 8 
Week 7 
Week 6 
Week 5 
Week 4 
Week 4 
Week 4 
15 
Week 9 
Week 8 
Week 7 
Week 6 
Week 5 
Week 5 
Week 5 
12.5 
Week 10 
Week 9 
Week 8 
Week 7 
Week 6 
Week 6 
Week 6 
12.5 
Week 11 
Week 10 
Week 9 
Week 8 
Week 7 
Week 7 
Week 7 
10 
Week 12 
Week 11 
Week 10 
Week 9 
Week 8 
Week 8 
Week 8 
9 
Week 13 
Week 12 
Week 11 
Week 10 
Week 9 
Week 9 
Week 9 
8 
Week 14 
Week 13 
Week 12 
Week 11 
Week 10 
Week 10 
Week 10 
7 
Week 15 
Week 14 
Week 13 
Week 12 
Week 11 
Week 11 
Week 11 
6 
Week 16 
Week 15 
Week 14 
Week 13 
Week 12 
Week 12 
Week 12 
5 
Week 17 
Week 16 
Week 15 
Week 14 
Week 13 
Week 13 
Week 13 
5 
Week 18 
Week 17 
Week 16 
Week 15 
Week 14 
Week 14 
Week 14 
4 
Week 19 
Week 18 
Week 17 
Week 16 
Week 15 
Week 15 
Week 15 
4 
Week 20 
Week 19 
Week 18 
Week 17 
Week 16 
Week 16 
Week 16 
3 
Week 21 
Week 20 
Week 19 
Week 18 
Week 17 
Week 17 
Week 17 
3 
Week 22 
Week 21 
Week 20 
Week 19 
Week 18 
Week 18 
Week 18 
2 
Week 23 
Week 22 
Week 21 
Week 20 
Week 19 
Week 19 
Week 19 
2 
Week 24 
Week 23 
Week 22 
Week 21 
Week 20 
Week 20 
Week 20 
1 
Week 25 
Week 24 
Week 23 
Week 22 
Week 21 
Week 21 
Week 21 


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Prednisone Dose at Study Start (Day 0) 
Prednisone 
Dose (mg/day) 
60 mg 
50 mg 
40 mg 
35 mg 
30 mg 
25 mg 
20 mg 
1 
Week 26 
Week 25 
Week 24 
Week 23 
Week 22 
Week 22 
Week 22 
 
9.4 Method of Assigning Subjects to Treatment Groups 
Subjects who are candidates for enrollment will be evaluated for eligibility by the Investigator to ensure 
that the criteria given in Section 8.7 have been satisfied and that the subjects are eligible for 
randomization. 
Subjects will be randomized at a 3:2 ratio to receive either 150 mg KPL-301 or placebo. Randomization 
will be stratified according to whether subjects have new-onset disease or relapsing disease.   
9.5 KPL-301 or Placebo Administration 
The first administration of KPL-301 or placebo will take place at the study site on Day 0 by the 
Investigator or qualified study center staff. At this visit, subjects will be trained on self-administration of 
KPL-301 or placebo, such that subsequent doses, which will be administered every other week 
(14 ±3 days), may be self-administered by the subject or subject’s caregiver as an outpatient. If a clinic 
visit coincides with the subject’s scheduled dose, KPL-301 or placebo will be administered at the study 
site. If a subject is unable or does not wish to self-administer at home outside of a scheduled visit, clinic 
staff may administer the injections to the subject as part of an unscheduled visit. The location of and 
occasions when the subject or caregiver administered the SC injection should be recorded in the patient’s 
study notes. Subjects will be instructed in proper syringe disposal and will be cautioned against reuse of 
these items. All used syringes must be disposed in a provided sharps container and returned to the study 
site for destruction. All unused KPL-301 or placebo must be returned to the study site for accountability. 
Before administration, the prefilled syringe of study drug should be allowed to come to room temperature. 
The label on the prefilled syringe should be removed just before use and placed on the corresponding 
dosing diary form. Study drug will be injected in the upper arm, thigh, or abdomen and will be 
administered using a 27G needle. The person administering the dose will wipe the skin surface of the 
upper arm, thigh, or abdomen with alcohol and allow to air dry. The skin will be pinched to isolate the SC 
tissue from the muscle. The needle will be inserted at a 90-degree angle approximately halfway into the 
SC tissues overlaying the muscle. The study drug should be injected slowly (at least 5-second duration is 
recommended) into the SC tissue using gentle pressure. The area should not be massaged after injection. 
The site as well as date and time of the injection should be documented. Immediately after injections at 
home, subjects must place the used syringe in a sharps container provided by the study site. 
The interval between KPL-301 or placebo administrations must be at least 11 days and no more than 
17 days. 
Additional information regarding preparation, administration, and storage of KPL-301 or placebo will be 
described in the Pharmacy Manual.  


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9.6 Blinding 
9.6.1 Methods for Ensuring Blinding 
This is a double-blind study in which KPL-301 and placebo are identical in appearance/viscosity. Neither 
the subject nor any of the Investigator or Sponsor staff who are involved in the treatment or clinical 
evaluation of the subjects will be aware of the treatment received (International Conference on 
Harmonisation [ICH] E9). If the treatment allocation for a subject becomes known to the Investigator or 
other study staff involved in the management of study subjects, the Sponsor must be notified immediately. 
If the Investigator intends to unblind treatment allocation for a subject, then the Sponsor should be notified 
immediately. 
9.6.2 Unblinding 
In the event of a medical emergency, the Investigator may unblind an individual subject’s treatment 
allocation and notify the Sponsor. In general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received active drug. In most cases, the 
management of a medical emergency would be the same whether or not active drug was being received by 
the subject. If this were to be the case, the treatment allocation should not be unblinded. 
10 Concomitant Therapy and Treatment Compliance 
10.1 Concomitant Medications 
Subjects should receive concomitant medications in line with current SoC practices for GCA. Such 
medications may include but not limited to the equivalent of the following examples: low-dose aspirin 
(dose allowed per SoC), pantoprazole (40 mg daily), calcium (1000 mg daily), cholecalciferol (800 U 
daily), and IV ibandronate 3 mg every 3 months, for the duration of the study. 
Investigators may also prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “excluded” as listed in Section 10.2. 
The following concomitant medications are permitted during the study: 
1. Inactivated vaccines. Subjects who are eligible for yearly influenza vaccine or who require 
booster vaccinations for other diseases can receive vaccination with killed/toxoid vaccines 
consistent with normal clinical practice. The effect of KPL-301 on vaccine response is not known. 
2. Vitamins and nutritional supplements. 
It is strongly recommended to avoid herbal or traditional medicine treatments since no formal assessment 
of potential interactions, risk benefit, or a safety profile for these products is available in the context of 
experimental drug testing. All concomitant medications, including any changes in vitamins, supplements, 
and herbal or traditional remedies during the study are to be recorded. 
10.2 Excluded Concomitant Medication 
The introduction of the following medications is not permitted from initiation of screening through the end 
of the study unless indicated for escape therapy. The Sponsor is to be notified if any of the following 
medications are introduced to a subject during the study: 
1. Investigational drug therapy other than KPL-301 
2. Biologic DMARD therapies (such as anti-TNF, recombinant interleukin-1 receptor antagonist, 
anti-IL-6 receptor [tocilizumab], CTLA4 immunoglobulin, B-cell depleting therapies, etc) 


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3. Azathioprine, cyclosporine, MTX, mycophenolate mofetil, cyclophosphamide, and other 
alkylating agents 
4. Immunization with any live or live attenuated vaccine  
5. Immunoabsorption columns, plasmapheresis, and IV immunoglobulin therapy 
10.3 Escape Therapy 
Subject who cannot adhere to the protocol-defined steroid taper due to flare/relapse must discontinue 
study drug (KPL-301 or placebo) and should receive escape therapy in accordance with local SoC per the 
Investigator.  Escape therapy may include, for example, prednisone or similar > 60mg/day, IV 
corticosteroids, other immunomodulatory agents, and/or approved therapies (e.g., tocilizumab). These 
subjects are considered to have met the primary endpoint provided the flare occurs prior to Week 26. 
Escape corticosteroid therapy can be escalated immediately. Due to unknown possible safety and 
pharmacological effects from overlapping exposures to immunomodulatory agents on top of 
co-administered corticosteroids, the investigator should consider a washout period of at least 35 days 
(based on elimination half-lives) after the last dose of study drug (KPL-301 or placebo) if deemed 
clinically appropriate.  
10.4 Treatment Compliance 
Subject compliance will be assessed by maintaining adequate administration records. Adherence to study 
drug administration (KPL-301/placebo and prednisone for the steroid taper) will be assessed during the 
study site visits. Subjects will be given a diary to record home injections of KPL-301 or placebo and 
intake of prednisone tablets. Subjects will be asked to return all used supply containers as well as any 
unused study medication at each visit along with their diary as a measure of drug accountability and 
subject compliance. Investigator staff may contact patients between visits to ensure compliance with 
protocol specified treatment regimens.     
Sharps containers for any used prefilled syringes will be provided to the subjects for home usage. After 
home injections the used syringes must be placed into the sharps containers immediately. The sharps 
containers should be returned to the sites and discarded by the site staff as per local site procedure. 
11 Study Periods 
11.1 Screening Period 
After provision of written informed consent for the study, patients will be screened for study eligibility 
within 6 weeks before Day 0 (first dose). 
Results of SoC tests or examinations performed prior to obtaining informed consent within 6 weeks prior 
to Day 0 may be used; such tests do not need to be repeated for screening. Other tests required by the 
protocol will be conducted and reimbursed by the Sponsor as necessary.  Written informed consent for 
study participation must be obtained before performing any study-specific screening tests or evaluations. 
All screening activities must be completed and eligibility confirmed before randomizing subjects and 
administering study drug. 
The Investigator will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. Prior to first administration of KPL-301, 
all subjects are required to have achieved remission (i.e., resolution of GCA symptom(s) and CRP 
< 1.0 mg/dL or ESR < 20 mm in the first hour). Should a subject in screening not achieve remission by 


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> 6 weeks of onset they can be rescreened following the relapsing/refractory non-remitting inclusion 
criteria. 
Refer to the Schedule of Activities in Table 1 for activities required during screening. 
11.2 Double-blind Period  
Following signing of the ICF and successful completion of the screening procedures, eligible subjects will 
be randomized 3:2 to blinded treatment with KPL-301 or placebo administered SC every other week 
(every 2 weeks) in the double-blind treatment period coadministered with a 26-week oral corticosteroid 
taper. 
The first administration of subcutaneous KPL-301/placebo and oral prednisone taper will take place at the 
study site on Day 0. Subsequent doses of KPL-301/placebo will be administered at the study site in 
conjunction with a scheduled study visit or dispensed to the subject for outpatient administration. All 
subjects will receive oral prednisone, which will be tapered down during the double-blind base period 
according to a standardized tapering protocol. The steroid taper will be self-administered by study subjects 
on a daily basis. Subjects will be followed at the study site at Weeks 1, 2, 3, 4, and approximately every 
4 weeks thereafter until week 26 (see Table 1). Subjects reporting worsening of GCA symptoms or any 
safety issues may be brought in for an unscheduled visit at the study site at any time.  
Subjects who experience a flare or who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse must discontinue the assigned study drug (KPL-301 or placebo) and should receive escape 
therapy in accordance with local SoC. These subjects will be considered to have met the primary endpoint 
if a flare has occurred prior to Week 26.  
Any subject who prematurely discontinues the study drug treatment for safety or other reason will have an 
EOT visit and will be followed for safety for the intended duration of the study to address potential issues 
of informative censoring. Any subject who withdraws consent from the trial (i.e., all study procedures in 
addition to study drug) must complete an EOT visit then proceed to the Washout Safety Follow-up Period 
or at a minimum have a Final Washout Safety Follow-up visit 84 ± 3 days from the last dose administered.  
Additional follow up using public records may be captured where possible. 
12 Study Procedures 
12.1 Screening and Randomization Procedures 
12.1.1 Informed Consent 
Written informed consent for participation in the study must be obtained before performing any study-
specific screening test or evaluations. ICFs for all patients who are enrolled or who failed screening will 
be maintained at the study site. 
12.1.2 Medical History and Demographics 
General medical history and subject demographic information will be recorded on eCRF. Additional 
information will be captured related to GCA including disease duration, history of prior flare/relapse, as 
well as history of allergy or anaphylaxis. In addition, subjects will be asked to report their current use and 
history of tobacco and smoking as well as provide more detailed information on pulmonary history. 
12.1.3 Eligibility 
All subjects screened will be assessed for eligibility for randomization into the study according to the 
inclusion/exclusion criteria (Section 8.7). A master log will be maintained of all enrolled subjects and will 


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document all screening failures (i.e., subjects who are enrolled but not randomized), including reason for 
screen failure. 
12.1.4 Subject Randomization 
An Interactive Web Response System (IWRS) will be used for assignment of the Subject Identification 
Number at enrollment, randomization to a treatment arm (KPL-301 or placebo), and assignment of 
blinded investigational product. A subject is considered randomized into the study when the Investigator 
confirms the eligibility criteria in the IWRS and the pharmacist has been provided with the investigational 
product number. 
12.2 Clinical GCA Related Assessments 
12.2.1 Clinical GCA Assessments 
Ideally clinical assessments of GCA signs/symptoms should occur prior to the investigator reviewing 
subject imaging, lab or acute phase reactant results at any given visit to minimize potential for assessment 
bias. 
• 
Cranial symptoms 
o New or recurrent headache or pain or tenderness of the scalp or the temporal artery 
o Visual signs/symptoms such as ischemic retinopathy, optic neuropathy, diplopia, 
amaurosis fugax, etc. 
o New or recurrent claudication of the tongue, masseter muscle, or worsening temporal 
artery signs and symptoms  
o TIA or stroke related to GCA in the opinion of the Investigator  
• 
Extracranial symptoms 
o Classic PMR-like symptoms, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
o New or recurrent claudication in the peripheral circulation (i.e., in one of the extremities)  
• 
New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the 
aorta or other great vessels or via ultrasound of the temporal arteries  
Supportive findings could include other symptoms in the opinion of the Investigator related to worsening 
GCA, such as sustained daily recurrent fever with a temperature over 38°C for more than 1-week, chronic 
anaemia, or unexplained weight loss. 
All elements of the diagnostic work-up pertinent to the Investigator diagnosis of GCA should be reviewed 
with the CRO-designated Medical Expert and entered into the eCRF promptly.  
12.2.2 TAB 
New-onset subjects can have an optional temporal artery biopsy taken at Screening and Week 26 as part of 
the study. For relapsing/refractory patients, if the subject has not had a prior a temporal biopsy an optional 
biopsy can be done at Screening and Week 26. If the subject has an existing biopsy sample available this 
can be submitted as the screening/predose sample and an optional biopsy can be performed at Week 26. 
Temporal biopsy specimens if available will be submitted to the central laboratory. 


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12.2.3 Imaging (MRI, CT, PET, or Ultrasound) 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as MRI, 
CT/CTA, or PET-CT of the aorta or other great vessels should be performed according the schedule of 
activities (Table 1). 
In cases where ultrasound of temporal artery was captured during the diagnosis of GCA at Screening, this 
procedure should be repeated at Weeks 12, 26, EOT and Week 38 as well as any instances of suspected 
flare over the course of the study.  Imaging and relevant data should be included in any elements of the 
diagnostic work-up pertinent to the Investigator diagnosis of GCA. 
12.2.4 CRP and ESR  
Central laboratory assessments of CRP and local assessment of ESR will be performed at each study visit. 
Centrally determined laboratory values will be used for statistical evaluations and report writing. CRP 
changes and the time course to decrease and resolve CRP to normal values ≤ 0.5 mg/dL will be assessed. 
If necessary local CRP tests can be used by the site to support the Investigator’s clinical decisions 
regarding the GCA status. 
12.3 Physical Examination and Vitals 
12.3.1 Physical Exam 
A complete physical examination as possible by local practice should include an evaluation of the head, 
eye, ear, nose, and throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Any abnormality identified at baseline should be 
recorded on the Medical History and Physical Examination eCRFs. 
At subsequent visits, limited symptom-directed physical examinations may need to be performed in order 
to determine changes from baseline abnormalities and should be recorded in the subject’s trial notes. New 
or worsened abnormalities should be recorded as AEs on the Adverse Event CRF. 
12.3.2 Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressure, 
and temperature. Blood pressure measurements should be obtained after the subject has been seated for at 
least 5 minutes. 
12.3.3 Body Weight and Height 
Body weight and height will be measured as per SoC at the study site and will be recorded in the eCRF. 
12.4 Electrocardiogram 
Twelve-lead ECGs will be performed at Screening at the study site and may be performed at an 
unscheduled visit if determined necessary by the Investigator during the treatment period. To minimize 
variability, ECGs should be performed prior to meals and any scheduled vital sign measurements and 
blood draws. Subjects should be in a resting position for ≥ 10 minutes prior to ECG and body position 
should be consistently maintained and environmental distractions (e.g., TV, radio) should be avoided to 
prevent changes in heart rate during recording. 
The digital ECG recording must be obtained and reviewed by the Investigator or designee. For safety 
monitoring purposes, the Investigator or designee must sign and date all ECG tracings and place the paper 


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copy as part of the subject’s permanent study file at the site and overall ECG interpretation will be 
documented in eCRF. 
12.5 Respiratory Evaluations 
12.5.1 PFTs and DLCO 
PFTs and DLCO should be obtained at Screening within 6 weeks prior to Day 0, or existing 
documentation within 12 weeks of day 0 can be used and reviewed by the Investigator or designee. During 
the course of the study PFTs and DLCO should be obtained at Weeks 12, 26 and 38 with a window of 
± 14 days.  
12.5.2 Chest X-Ray 
Chest X-rays in accordance with local requirements should be obtained at Screening (or existing chest 
X-ray within 12 weeks of Day 0 can be used) and reviewed by the Investigator or designee. X-rays should 
be reviewed to show no clinically significant abnormality and no signs or symptoms suggestive of 
pulmonary disease that would exclude the potential subject. 
12.5.3 TB Screening 
Eligibility will be determined based on a central QuantiFERON TB test performed during screening in 
order to evaluate (active, untreated, or partially treated latent) infection with TB.  
If a patient is suspected to have contracted tuberculosis during the study the study site may conduct a TB 
test in accordance with the site’s normal practice to diagnose TB (PPD or local QuantiFERON). 
12.5.4 Dyspnea Score and O2 Saturation 
The modified Borg scale (Borg and Borg, 2010) is a validated patient reported outcome and will be used 
to assess subjects’ perceived sensation of difficulty in breathing (dyspnea) while resting. This scale is a 
linear scale of numbers ranking the magnitude of difficulty in breathing, ranging from 0 (nothing at all) to 
10 (maximal). A validated version of the Borg scale in local language will be provided. 
Oxygen saturation will be assessed as part of respiratory system assessment. Pulse oximetry must be 
performed before PFTs and should be done with the subject in a seated position after a 10-minute period 
of rest. It is important that the pulse oximetry be performed in the same center throughout the study since 
oximetry readings vary with changes in altitude.  
12.6 Laboratory Assessments 
Laboratory assessments should be collected as per the schedule of activities (Table 1). Unscheduled 
laboratory assessments for safety issues are permitted as deemed necessary by the Investigator. The 
procedures for the collection, handling, and shipment of laboratory samples are specified in the 
Laboratory Manual supplied to sites by the central laboratory.  
Local laboratory tests and values may be used by the Investigator as necessary to support clinical 
decisions but will not be captured as part of the study for analysis. 
12.6.1 Serology 
Rheumatoid factor, protein electrophoresis, HbsAg, HbsAb, HbcAb and HCVAb: collected at Screening 
only unless clinically indicated during the study. 


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12.6.2 Hematology 
White blood cell count with differential, platelet count, red blood cell count, mean corpuscular volume, 
hemoglobin, mean corpuscular hemoglobin concentration. 
12.6.3 Chemistry 
Urea, uric acid, creatinine, glucose, potassium, sodium, chloride, calcium, phosphorus, total protein, 
albumin, creatinine phosphokinase, C3, and C4. 
12.6.4 Liver Profile 
AST, ALT, alkaline phosphatase (ALP), and total bilirubin (direct and indirect will be performed if total 
bilirubin is greater than the ULN). 
Tests for AST, ALT, ALP and total bilirubin must be conducted and assessed concurrently.  Additional 
test may be used for follow up if values come back abnormal. 
12.6.5 Fasting Lipid Panel and HbA1c 
Whenever possible laboratory samples should be drawn in the morning. Subjects should fast overnight 
(> 8 hours) prior to blood sampling at clinic visits. Subjects will be allowed to drink only water during this 
time. The following panels will be taken: HbA1c, total cholesterol, triglycerides, high-density lipoprotein, 
low-density lipoprotein, apolipoprotein A, and apolipoprotein B. 
12.6.6 Urinalysis 
Specific gravity, pH, protein, urobilinogen, ketones, glucose, blood, bilirubin, nitrite, leukocyte esterase, 
creatinine. 
12.6.7 Pregnancy Test 
For women of child bearing potential a serum pregnancy test should be performed prior to randomization 
at the site. Urine pregnancy tests should be performed at Day 0, Week 12, Week 26 and the Final Washout 
Safety Follow-up Visit.  Abnormal laboratory results should be repeated as soon as possible (preferably 
within 24 to 48 hours). 


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13 Safety Assessments 
13.1 Adverse Events 
13.1.1  Adverse Event Definition 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product. An AE 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 related to the medicinal (investigational) product. 


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AEs also include: any worsening (i.e., any clinically significant change in frequency and/or intensity) of a 
pre-existing condition that is temporally associated with the use of the study drug; abnormal laboratory 
findings considered by the reporting Investigator to be clinically significant; and any untoward medical 
occurrence. 
13.1.2 Management of Specific Disease Related Events 
Signs, symptoms and abnormal findings associated with active GCA should not be captured as Adverse 
Events in this study but rather as flare related efficacy endpoint findings. If there are questions regarding 
how to classify these events, Investigators should consult with the CRO-designated Medical Expert. 
13.1.3 Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and requires close monitoring and rapid communication by 
the investigator to the sponsor. An AESI may be serious or non-serious. 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. 
13.1.3.1 Hepatic Function Abnormality  
Adverse events of hepatic function abnormality of special interest to the sponsor are defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin to greater than 2 × 
ULN. Concurrent findings are those that derive from a single blood draw or from separate blood draws 
taken within 8 days of each other. In the event of hepatic function abnormality where the etiology is 
unknown, timely follow-up investigations and inquiries should be initiated by the investigational site, 
based on medical judgment, to make an informed decision regarding the etiology of the event. 
Investigational product will not be administered to any subject reporting ALT or AST to greater than 3 × 
ULN and concurrent increase in bilirubin to greater than 2 × ULN  
13.1.3.2 Acute and Delayed Hypersensitivity Reactions  
Biologic therapies are known to be associated with an increased risk of immediate and delayed 
hypersensitivity reactions as well as anaphylaxis. Anaphylaxis and severe hypersensitivity reactions are 
required to be reported within 24 hours of knowledge of the event, 
 
  
13.1.3.3 Clinically Significant Pulmonary Abnormality  
Any subject who develops new clinically significant pulmonary symptoms or signs should be referred to a 
qualified specialist for further specific assessment. Symptoms and signs triggering such referral include 
but are not limited to an increase in shortness of breath or difficulty breathing, exacerbation of current 
respiratory symptoms, or a significant deterioration in dyspnea score. Subjects who are referred for 
evaluation by a specialist will undergo a diagnostic evaluation to determine the nature and origin of the 
pulmonary symptom(s)/sign(s) and to determine if PAP may be present. At the discretion of the 
investigator or specialist additional tests may be required such as a repeat chest x-ray, and/or a chest high 
resolution computed tomography scan, full PFTs including DLCO measurement, bronchoscopy with 
bronchoalveolar lavage, and cytological and/or ultrastructural evaluation of the cells recovered by lavage 
to identify findings consistent with a diagnosis of PAP.  Any subject who has been referred for a specialist 
pulmonary evaluation may be instructed to stop the investigational product until the symptom(s) or sign(s) 
causing the referral have resolved. 


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13.1.3.4 Neutropenia  
Adverse events of neutropenia of special interest to the sponsor are defined as an ANC < 1.0 × 109 
cells/L. Investigational product will not be administered to any subject who has an ANC < 1.0 × 109 
cells/L. Administration of investigational product may continue in the event that the ANC > 1.5 × 109 
cells/L and following agreement with the medical monitor.  
13.1.3.5 Serious Infection  
Grade 3 severity infections that require treatment with IV therapy (antibiotics, antiviral, or antifungal) and 
opportunistic infections will be considered serious even if they do not require in-patient hospitalization. 
Every effort should be made to identify the causative pathogen through prompt and appropriate 
investigation by the investigator or reporting physician. 
13.1.4 Adverse Reactions 
All noxious and unintended responses to an IMP (i.e., where a causal relationship between an IMP and an 
AE is at least a reasonable possibility) related to any dose should be considered adverse drug reactions.  
13.1.5  Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the current 
Investigator Brochure or is not listed at the specificity or severity that has been observed. “Unexpected” 
also refers to AEs or suspected adverse reactions that are mentioned in the Investigator Brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug but are 
not specifically mentioned as occurring with the particular drug under investigation. 
13.1.6  Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose: 
• Results in death – Includes all deaths, even those that appear to be completely unrelated to study 
drug (e.g., car accident where subject is a passenger) 
• Is life-threatening – in the view of the Investigator, the subject was at immediate risk of death 
from the event at the time of the event (i.e., it does not include an AE that might have caused 
death if it had occurred in a more serious form). 
• Requires in-patient hospitalization or prolongs an existing hospitalization. (Complications 
occurring during hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing non-worsening condition is 
not, however, considered an AE. The details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF. Hospitalization is defined as an 
admission to the hospital ward or a short-stay-type unit longer than 24 hours. Prolongation of 
existing hospitalization is defined as hospital stay longer than originally anticipated for the event 
or development of a new AE as determined by the Investigator or treating physician. 
• Results in persistent or significant disability/incapacity (an AE is incapacitating or disabling if it 
results in a substantial and/or permanent disruption of the subject’s ability to carry out normal life 
functions). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event – Important medical events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require intervention to 


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prevent one of the other serious outcomes listed above (e.g., intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse). 
In addition, medical and scientific judgment is required to decide if prompt notification is required in 
situations other than those defined for SAEs above, i.e., any event that the Investigator regards as serious 
that did not strictly meet the criteria above but may have jeopardized the subject or required intervention 
to prevent one of the outcomes listed above, or that would suggest any significant hazard, 
contraindication, side effect, or precaution that may be associated with the use of the IMP. 
All SAEs that occur after signing of study-related informed consent, whether or not the SAEs are related 
to the study drug or study procedures, must be reported.  
13.1.7 Suspected Unexpected Serious Adverse Reaction  
A Suspected Unexpected Serious Adverse Reaction is an adverse reaction, the nature or severity of which 
is not consistent with the applicable product information (e.g. investigator’s brochure for an unauthorized 
investigational product or prescribing information/summary of product characteristics for an authorized 
product). All relevant information about suspected serious unexpected adverse reactions that are fatal or 
life-threatening will be recorded and reported to the competent authorities in all the applicable countries, 
and to the Ethics Committee/Institutional Review Boards in conjunction with Directive 2001/20/EC.  
13.2 Adverse Event Assessment 
13.2.1 Relationship to Study Drug 
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 
• 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.  
13.2.2 Intensity 
The severity of an AE will be recorded as one of the following: 
• Mild: easily tolerated, does not interfere with normal daily activities, does not require intervention 
• Moderate: causes some interference with daily activities; minimal, local, or noninvasive 
intervention indicated  
• Severe: medically significant event; daily activities limited or completely halted; hospitalization 
or prolongation of hospitalization indicated 


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Every reasonable effort will be made to follow subjects who have AEs. Any subject who has an ongoing 
AE at study end or early withdrawal will be followed, where possible, until resolution. 
13.3 Recording Adverse Events 
Each patient should be monitored for the development of any AEs. This information should be collected 
by asking nonleading questions (such as “How are you feeling?”) and from observations of and 
conversations with patients. AEs may also be collected by direct physical exam, diagnostic procedures, or 
any other appropriate source. 
All AEs (serious and non-serious) will be documented in the patient’s source documents and recorded in 
the eCRF. Any clinically relevant (as determined by the Investigator) deterioration in laboratory 
assessments or other clinical findings is considered an AE and must be recorded in the patient’s source 
documents and in the eCRF. 
13.3.1 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question from the study 
personnel or revealed by observation will be collected and recorded in the eCRF. When collecting AEs, 
the recording of a diagnosis is preferred (when possible) to the recording of a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
13.3.1 Adverse Events Based on Examinations and Tests 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated laboratory result/vital sign will be considered as 
additional information. Wherever possible the reporting Investigator uses the clinical rather than the 
laboratory term (e.g., anemia vs low hemoglobin value). In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in nonmandated parameters should be reported as AEs. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
13.4 Time Period for Collection of Adverse Events 
AEs will be collected from the time of signing of informed consent through the Final Washout Safety 
Follow-up period (84 days ± 3 days after the EOT visit). The AE term should be reported in standard 
medical terminology when possible. Also, when possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. For each AE, the Investigator will 
evaluate and report the onset, resolution, intensity, causality, action taken, seriousness, outcome (if 
applicable), and whether or not it caused the patient to discontinue the study. Reported AEs between 
consent and Day 0 will be censored in analysis. 
13.5 Follow-Up of Unresolved Adverse Events 
Any AEs that are unresolved at the patient’s follow-up visit are to be followed up by the Investigator for 
as long as medically indicated. Additional information for any patient with an ongoing AE at the end of 
the follow-up period may be requested by the Sponsor, as needed. 
13.6 Reporting Serious Adverse Events 
All SAEs, whether or not considered causally related to study drug or to the study procedure(s), have to be 
reported. SAEs will be recorded in the eCRF within 24 hours of discovery. 


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In case the eCRF is inaccessible, the Investigator must report all SAEs to the Safety Department and 
Sponsor within 24 hours of discovery via the SAE reporting form to: 
24 Hour Safety Hotline: +44 1223 374 240 
24 Hour Safety Hotline Fax: +44 1223 374 102 
US 24 Hour Safety Hotline: 1 888-483-7729 
US 24 Hour Safety Hotline Fax: 1 888-529-3580 
Additional follow-up information, if required or available, should be sent to the Safety Department within 
1 business day of receipt and placed with the original SAE information and kept with the appropriate 
section of the eCRF and/or study file. 
Information on non-serious AEs that become serious must also be reported to the Safety Department as 
soon as it is available. 
Investigators must report SAEs and follow-up information to their responsible Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) as applicable per institutional policy. 
The Sponsor or designee will provide regulatory authorities, IRBs, IECs, and principal investigators with 
clinical safety updates/reports according to local requirements. 
13.7  Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the study should be 
confirmed and reported to the Investigator without delay. If pregnancy is confirmed, the Investigator must 
notify the Sponsor within 24 hours and the subject must not receive (additional) study drug and must be 
discharged from the study. The subject must be asked regarding their willingness to complete the EOT 
visit.  
In the event that a subject is found to be pregnant after having received at least one study drug dose, the 
pregnancy will be followed to term and the status of mother and child will be reported to the Sponsor after 
delivery.  
Instances of perinatal death or congenital abnormality, if brought to the attention of the Investigator at any 
time after cessation of the study treatment, will be reported to the Sponsor within 24 hours. 
14 Statistical Methods 
14.1 General Considerations 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.4 or later. 
A statistical analysis plan (SAP) will be written and approved prior to performing the first review of the 
data. 
All clinical study data will be presented in subject data listings.  Descriptive statistics will be presented for 
all endpoints and will include number of subjects (n), mean, standard deviation (SD), first quartile (Q1), 
median, third quartile (Q3), minimum and maximum for continuous variables, and frequency and 
percentage for categorical and ordinal variables.   
Unless otherwise specified, all tests will be two-tailed using a 0.05 level of significance. All confidence 
intervals (CIs) will be two-sided 95% confidence intervals. 




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14.4 Endpoints 
Efficacy Endpoints: 
Primary Endpoint:  
• Time to flare by Week 26 defined as time from randomization to the first flare occurring within 
the treatment period 
Secondary Endpoints: 
• Sustained remission rate at Week 26 
• Percentage of subjects who have completed the corticosteroid taper and who have a normal ESR 
by Week 26 
• Percentage of subjects who have completed the corticosteroid taper and who have a normal CRP 
by Week 26 
• 
Percentage of subjects who completed the corticosteroid taper and who have neither 
signs/symptoms of GCA nor new or worsening vasculitis on imaging by Week 26 
• Time to elevated ESR by Week 26 
• Time to elevated CRP by Week 26 
• Time to signs/symptoms of GCA or new or worsening vasculitis on imaging by Week 26 
• Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up Period 
  
 
 
 
 
 
 
 
Safety Endpoints: 
• Incidence of treatment emergent adverse events 
• Change in physical exam results 
• Change in vital signs 
• Change in clinical laboratory parameters  
o Serum chemistry 
o Hematology 
o Urinalysis 
14.5 Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  Analyses will be repeated using the PP 
set to assess the sensitivity of the results to important deviations of the protocol. 


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14.5.1 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time from randomization to the first 
flare occurring within the treatment period.  Detailed censoring rules will be provided in the SAP. 
The number and percentage of subjects who remain in remission (no flare), who flare, and who are lost to 
follow-up prior to a flare during the treatment period will be summarized for each treatment group.  Time 
to flare by week 26 will be summarized by the 25th, 50th (median), and 75th percentiles calculated using 
the Kaplan-Meier method to estimate the survival functions for each treatment group. The 95% confidence 
interval (CI) for the percentiles will also be calculated. A log-rank test stratified by randomization strata 
will be used to compare KPL-301 and placebo with respect to time to flare by Week 26.  To describe the 
magnitude of treatment effect, the hazard ratio for KPL-301 compared to placebo and the corresponding 
95% CI will be calculated based on a Cox proportional-hazards model with treatment as a covariate and 
stratified by randomization strata.  
The protocol definition of flare includes multiple components.  Supportive analyses will be performed 
based on each individual component.  The details will be described in the SAP.  In addition, a sensitivity 
analysis will be performed using the same method described above for the PP analysis set. 
14.5.2  Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared using the Kaplan-Meier method. 
The following endpoints will be analyzed using the Cochran-Mantel-Haenszel test stratified by the 
randomization strata. 
• Percentage of subjects who have completed the corticosteroid taper and who have a normal ESR 
by Week 26  
• Percentage of subjects who have completed the corticosteroid taper and who have a normal CRP 
by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have no 
signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
The following time-to-event endpoints will be analyzed using the same method for the primary efficacy 
endpoint. 
• Time to elevated ESR by Week 26  
• Time to elevated CRP by Week 26  
• 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
The following continuous secondary efficacy endpoints will be analyzed. The analyses will include two-
sided 95% CIs for the difference of treatment means, as appropriate.  Details will be provided in the SAP.   
• Cumulative corticosteroid dose at Week 26 and at the end of the Washout Safety Follow-up 
period 
 
 
 
 






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15 Records and Supplies 
15.1 Drug Accountability 
The sites will receive study drug for on-site administration at study site visits. On receipt of study drug, 
the Investigator (or deputy) will conduct an inventory of the supplies and verify that the supplies are 
received intact and in the correct amounts prior to completing a supplies receipt. The Investigator will 
retain a copy of this receipt at the study site and return the original receipt to the drug depot. The inventory 
of supplies at each study site will be reviewed by the study monitor. 
Study drug will be disseminated to the trial subjects for outpatient self-administration according to a 
supply chain described in the Pharmacy Manual.  
All used and unused study drug containers must be retained by the study site/clinic and subject for 
cataloguing and documentation of compliance. The full process for drug dispensing, documentation and 
destruction will be described in the Pharmacy Manual. 
A full drug accountability log will be maintained at the study site at all times. 
16 Ethics 
16.1 Institutional Review Board 
Before initiation of the study at each investigational site, the protocol, all protocol amendments, the ICF, 
and any other relevant study documentation will be submitted to the appropriate IRB or IEC. Written 
approval of the study and all relevant study information must be obtained before the study site can be 
initiated or the study drug is released to the Investigator. Any necessary extensions or renewals of 
IRB/IEC approval must be obtained, in particular, for changes to the study such as modification of the 
protocol, the informed consent form, the written information provided to subjects and/or other procedures. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely affect the 
safety of the subjects or the conduct of the study. The Investigator will submit written summaries of the 
study status to the IRB/IEC annually, or more frequently if requested by the IRB/IEC. On completion of 
the study, the Sponsor will notify the IRB/IEC that the study has ended. 
16.2 Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, the ICH-GCP guideline, the most recent 
version of the Declaration of Helsinki in which the Sponsor intends to publish the results regardless of the 
study outcome, and local regulations. 
16.3 Subject Information and Consent 
The Investigator is responsible for ensuring that no subject undergoes any study related examination or 
activity before that subject and/or legal guardian has given written informed consent to participate in the 
study. The written consent must be given by the subject and/or the legal guardian of the subject, after 
detailed information about the study has been given and in accordance with any national provisions on the 
protection of clinical study subjects. The verbal explanation will cover all the elements specified in the 
written information provided for the subject. 
Subjects and/or legal guardians will be required to sign and date the ICF. After signatures are obtained, the 
ICF will be kept and archived by the Investigator in the Investigator’s study file for possible inspection by 
regulatory authorities, the IRB/IEC, Sponsor, and/or CRO personnel. 


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It should be emphasized to the subject that he/she is at liberty to withdraw from the study at any time, 
without penalty or loss of benefits to which the subject is otherwise entitled. Subjects who refuse to give 
or who withdraw written informed consent should not be included or continue in the study. 
16.4 Subject Confidentiality 
All personal data collected and processed for the purposes of this study should be managed by the 
Investigator and his/her staff with adequate precautions to ensure confidentiality of those data, and 
according to national and/or local laws and regulations on personal data protection. 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the ethics committees 
approving this research, as well as that of any other applicable agency(ies), will be granted direct access to 
the study subjects’ original medical records for verification of clinical study procedures and/or data, 
without violating the confidentiality of the subjects to the extent permitted by the law and regulations. In 
any presentations of the results of this study or in publications, the subjects’ identity will remain 
confidential. 
17 Study Termination 
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: 
1. The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
subjects  
2. Subject enrollment is unsatisfactory  
3. Non-compliance that might significantly jeopardize the validity or integrity of the study  
4. Recommendation to suspend or terminate the study by independent body such as DMC or Health 
Authority 
5. Sponsor decision to terminate development  
Where required by applicable regulations, the investigator or head of the medical institution must inform 
the IRB/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. 
17.1 Study Stopping Criteria 
If the sponsor receives a report of an event consistent with any one of the following, the medical monitor 
or designee will immediately assess the event by gathering all available information including, where 
possible, direct telephone contact with the reporter. A prompt review of the data will be initiated by the 
sponsor, and the information will be referred to the DMC within 1 business day of the receipt of the initial 
report by the Sponsor.  
1. Any CTCAE grade 5 (death) assessed as related to the investigational product  
2. Any CTCAE grade 4 (life-threatening) assessed as related to the investigational product  
3. Any CTCAE grade 4 (life-threatening) of anaphylaxis  
4. Hepatic function abnormality defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in bilirubin to greater than 2 × ULN, assessed as related to investigational 
product  


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5. Any unforeseen events that, in the opinion of the DMC and the Sponsor, may contraindicate 
further dosing  
6. Clinically-significant pulmonary abnormalities that in the opinion of the DMC and the Sponsor 
may contraindicate further dosing  
If any above-listed events occur, the Sponsor will promptly conduct a cumulative review of safety data, 
including the DMC assessment of the event, and the circumstances of the event in question to determine 
whether the study should be modified, suspended or terminated. 
18 Reporting and Publication 
All data generated in this study are the property of the Sponsor. An integrated clinical and statistical report 
will be prepared at the completion of the study.  
Publication of the results by the Investigator(s) will be subject to mutual agreement between the 
Investigator and Kiniksa as outlined in the study agreement.  






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20 Appendices 
20.1 Appendix 1: Investigator Signature Page 
Protocol Title: 
A Phase 2, randomized, double-blind placebo-controlled study to test the 
efficacy and safety of KPL-301 in giant cell arteritis 
Protocol Number: 
KPL-301-C001 
Confidentiality and cGCP Compliance Statement 
 
I, the undersigned, have reviewed this protocol, including appendices and I will conduct the study as 
described in compliance with this protocol, GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without obtaining 
prior approval of Kiniksa Pharmaceuticals Ltd. (Kiniksa) and of the IEC/IRB. I will submit the protocol 
modifications and/or any ICF modifications to Kiniksa and IEC/IRB, and approval will be obtained before 
any modifications are implemented. 
I understand that all information obtained during the conduct of the study with regard to the subjects’ state 
of health will be regarded as confidential. No subjects’ names will be disclosed. All subjects will be 
identified by assigned numbers on all Case Report Forms, laboratory samples or source documents 
forwarded to the Sponsor. Clinical information may be reviewed by the Sponsor or its agents or regulatory 
agencies. Agreement must be obtained from the subject before disclosure of subject information to a third 
party. 
Information developed in this clinical study may be disclosed by Kiniksa, to other clinical Investigators, 
regulatory agencies, or other health authority or government agencies as required. 
Investigator Signature 
Date 
Printed Name 
Institution 
 


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20.3 Appendix 3: Summary of Changes 
20.3.1 Protocol Amendment v2.0 
Rationale for Amendment – Protocol Amendment v2.0 was completed to clarify aspects of protocol 
version 1.0 as well as to incorporate feedback from global Regulatory and Ethical bodies.  Substantial 
changes to this version include: 
• 
Limiting the double-blind period to 26-weeks total, removing the extended exposure for patients 
who enroll earlier in the study. 
• 
Removal of the Open-Label Extension – Per Regulatory feedback, open-label KPL-301 should 
only be provided to patients after proof of efficacy has been established 
• 
Addition of 12-week Washout Safety Follow-up period to ensure patients have continued access 
to open-label study supplied prednisone and are adequately followed and weaned back to Standard 
of Care 
• 
Updated inclusion criteria regarding pregnancy and contraception methods to ensure highly 
effective methods of contraception are reflected 
• 
Provided clarification on sample size and event calculations 
• 
Addition of Serum Pregnancy test during screening, additional urine pregnancy tests, safety labs, 
 
• 
Addition of Definition of SUSAR and defined Study Termination criteria 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 




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Diagnostic criteria above > 6 weeks before Day 0; however, 
presence of Acute Phase Reactants and Signs/Symptoms as per 
above persists within 6 weeks of Day 0. 
 
8 
Synopsis (pg 6) 
Section 8.4.1 (pg 34) 
Subjects who complete screening procedures and are not considered 
eligible (screen failures) may be rescreened provided there is reason to 
believe that eligibility criteria will be met.  
 
Subjects who complete screening procedures and are not considered 
eligible (screen failures) may be rescreened one time provided there is 
reason to believe that eligibility criteria will be met.  
 
Clarified subjects should only 
be rescreened one time 
9 
Synopsis (pg 6) 
- 
Although either acute phase reactant (CRP or ESR) may be used 
during the study for eligibility and to determine remission or flares, 
it is advisable that the same acute phase reactant used to determine 
remission at screening also be used to determine flares during the 
treatment period. 
Additional text to provide 
guidance for interpretation of 
Acute Phase Reactants from 
remission 
in 
case 
of 
suspected 
flare 
during 
treatment period. 
10 
Synopsis (pg 7) 
Section 8.4.1 (pg 36) 
Section 8.8 (pg 40) 
Section 11.2 (pg 46) 
Any subject who prematurely discontinues the study drug treatment for 
safety or other reason will have an End-of-Treatment (EOT) visit and 
will be followed for the intended duration of study treatment (i.e., until 
the blind is broken) to address potential issues of informative censoring. 
Any subject who withdraws consent from the trial (i.e., all study 
procedures in addition to study drug) must complete a Safety Follow-up 
visit 28 ± 3 days from the last dose administered.  Additional follow up 
using public records may be captured where possible. 
An analysis of the study will be performed when the last subject reaches 
Week 26 according to the Statistical Analysis Plan (SAP). Based on the 
results of this analysis, all subjects will be offered open-label KPL-301 in 
the OLE portion of the trial, or the study will be discontinued. All 
subjects who do not proceed to the OLE must complete a Safety Follow-
up visit 28 ± 3 days from the last dose administered 
Any subject who prematurely discontinues the study drug treatment for 
safety or other reason will have an End-of-Treatment (EOT) visit and 
will be followed for the intended duration of study treatment (i.e., 
through Week 26 and Washout Safety Follow-up) to address 
potential issues of informative censoring. Any subject who withdraws 
consent from the trial (i.e., all study procedures in addition to study drug 
administration) must complete at a minimum the Final Washout 
Safety Follow-up visit 84 ± 3 days from the last dose administered.  
Additional follow-up using public records may be captured where 
possible. 
 
Removed 
and 
replaced 
language 
regarding 
the 
extension of the double-blind 
period past week 26 with 
language for the Washout 
Safety Follow-up Period 
11 
Synopsis (pg 7)  
Section 8.4.2 (pg 36) 
Section 11.3 (pg 46) 
 
Open-Label Extension: 
Depending on the results from the analysis of the 26-week placebo-
controlled base study, all subjects may be offered KPL-301 in an OLE. 
The OLE will continue for up to 6 months. During the OLE, subjects will 
be followed for safety information and will continue to follow study 
protocols from the double-blind period in the event of a flare and for 
steroid tapering procedures. During the OLE subjects may wean off 
KPL-301 onto SoC as determined by the Investigator. 
Washout Safety Follow-up: 
After subjects complete the 26-week double blind treatment period, 
they will discontinue and wash off of blinded KPL-301 or placebo 
during a 12-week Washout Safety Follow-up Period, which includes 
close safety follow-up and monitoring for potential GCA flares.  
During this time, it is recommended that subjects, regardless of 
remission status, receive SoC oral prednisone therapy, taking into 
consideration that they have just completed treatment with what 
may have been an efficacious therapy which supported the tapering 
off of standard of care concomitant oral corticosteroids.  Clinicians 
may choose to observe subjects closely during the washout period 
without any change in concomitant medications or may choose 
(consistent with current SoC guidelines) to increase the daily 
Removed 
open 
label 
extension 
per 
Regulatory 
Agency 
feedback 
and 
replaced with Washout Safety 
Follow-up period to ensure 
subjects 
are 
adequately 
followed and weaned back to 
Standard of Care. 


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corticosteroid dose prophylactically/empirically by approximately 
10 mg above the prednisone dose administered at Week 26.  The 
prednisone dose can then be tapered or maintained throughout the 
remainder of the 12-week Washout Safety Follow-up Period as per 
Investigator discretion.  After the Final Washout Safety Follow-up 
visit (Week 38) has been completed, the subjects will exit the trial 
and should be transitioned to SoC per investigator judgement.   It is 
not required that the steroid taper have been completed, (0 mg) 
prior to subjects exiting the trial at Week 38. 
 
12 
Synopsis (pg 8) 
For the primary endpoint analysis, the aim is to have approximately 36 
subjects assigned to KPL-301 and approximately 24 subjects assigned to 
placebo. Of the study population, the aim is to have 50% with new-onset 
disease and 50% with relapsing disease. 
Approximately 60 subjects will be randomized at a 3:2 allocation 
ratio.  Approximately 36 subjects will be assigned to KPL-301, and 
approximately 24 subjects will be assigned to placebo. Of the study 
population, the aim is to have 50% with new-onset disease and 50% 
with relapsing disease. 
Clarification 
13 
Inclusion Criteria 3 
Synopsis (pg 9)  
Section 8.7.1 (pg 37) 
…New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined 
as: … 
 
…Unequivocal cranial symptoms of GCA (new-onset localized 
headache, scalp or temporal artery tenderness, ischemia-related vision 
loss, or otherwise unexplained mouth or jaw pain upon mastication)… 
 
...Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND at least 
one of the following: 
Active GCA within 6 weeks of Day 0 defined as clinical 
sign/symptom(s) and Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/ 
dL  
OR 
No remission since the diagnosis of disease as per clinical expectations. 
(refractory nonremitting) 
…New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, 
defined as: … 
 
….Unequivocal cranial symptoms of GCA (new-onset localized 
headache, scalp or temporal artery pain or tenderness, ischemia-
related vision loss, or otherwise unexplained mouth or jaw pain upon 
mastication)… 
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND: 
Active GCA within 6 weeks of Day 0 defined as clinical 
sign/symptom(s) as per above and Westergren ESR > 30 mm/hour or 
CRP ≥ 1 mg/ dL 
 
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 
0 AND 
No remission since the diagnosis of disease as per clinical expectations. 
i.e. Presence of sign/symptoms as per above and Westergren 
ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks of Day 0.  
. 
Clarification and formatting 
for ease of understanding 
14 
Inclusion Criteria 4 
Synopsis (pg 9) 
Section 8.7.1 (pg 37) 
Remission of GCA at Day 0 (resolution of GCA symptom(s) and CRP < 
1.0 mg/dL or ESR < 20 mm in the first hour)... 
Remission of GCA at or before Day 0 (resolution of GCA symptom(s) 
and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour)… 
Clarification 


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15 
Inclusion Criteria 6 
Synopsis (pg 9) 
Section 8.7.1 (pg 37) 
If using methotrexate (MTX), oral or parenteral up to 25mg/week is 
permitted in screening if started more than 6 weeks prior to Day 0 and 
should be stable or decreasing with the intention to discontinue use by 
Day 0. 
 
If using methotrexate (MTX), oral or parenteral up to 25mg/week is 
permitted in screening if started more than 6 weeks prior to Day 0 and 
should be tapered to zero by Day 0. 
 
Clarification that MTX use is 
excluded during the study. 
16 
Inclusion Criteria 9 
Synopsis (pg 9,10) 
Section 8.7.1 (pg 38) 
Female subjects must be:..  
...c)  nonpregnant, nonlactating, and having agreed to use an effective 
method of contraception (i.e., hormonal contraceptives, intrauterine 
device (IUD), or double barrier methods such as condom plus 
diaphragm or diaphragm plus spermicide or condom plus spermicide) 
from Screening visit until 12 weeks after final study drug administration 
 
 
Female subjects must be:..  
...c)  nonpregnant, nonlactating, and if sexually active having agreed 
to use a highly effective method of contraception (i.e., hormonal 
contraceptives associated with inhibition of ovulation or intrauterine 
device [IUD], or intrauterine hormone-releasing system [IUS], or 
sexual abstinence) from Screening Visit until the Final Washout 
Safety Follow-up visit 84 ± 3 days from EOT Visit.   
 
Text added per regulatory 
feedback 
17 
Inclusion Criteria 10 
Synopsis (pg 10) 
Section 8.7.1 (pg 38) 
Male subjects must have documented vasectomy or must agree to use 
double barrier methods of contraception (such as condom plus 
diaphragm or diaphragm plus spermicide or condom plus spermicide) or 
use condom plus hormonal contraceptives or condom plus IUD with 
their partners of childbearing potential from Day 0 until the Safety 
Follow-up visit. Male subjects must agree to refrain from donating 
sperm from Day 0 until the Safety Follow-up visit. 
Male subjects must have documented vasectomy or if sexually active 
must agree to use a highly effective method of contraception with 
their partners of childbearing potential (i.e., hormonal contraceptives 
associated with the inhibition of ovulation or intrauterine device 
[IUD], or intrauterine hormone-releasing system [IUS], or sexual 
abstinence) from Day 0 until the Final Washout Safety Follow-up visit 
84± 3 days from EOT Visit. Male subjects must agree to refrain from 
donating sperm during this time period. 
 
18 
Exclusion Criteria 6 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Treatment with any investigational drug therapy within 4 weeks or 5 
half-lives of the study agent, whichever was longer, prior to Screening 
 
Treatment with any non-biologic investigational drug therapy within 4 
weeks or 5 half-lives of the study agent, whichever was longer, prior to 
Screening 
 
Text added for clarification 
19 
Exclusion Criteria 9 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Intramuscular, IV corticosteroids within 4 weeks prior to Screening 
 
Intramuscular, Intra-articular, or IV corticosteroids within 4 weeks 
prior to Screening 
 
Text added for clarification 
20 
Exclusion Criteria 11 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or 
mycophenolate mofetil (MMF) within 4 weeks of Screening 
 
Treatment with hydroxychloroquine, cyclosporine A, azathioprine, 
cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks 
of Screening 
 
Text added for clarification 
21 
Exclusion Criteria 15 
Synopsis (Pg 11) 
Active, untreated or partially treated latent tuberculosis (TB) 
Positive (or 2 indeterminate) QuantiFERON test results. 
Text changed for clarification 


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Section 8.7.2 (pg 39) 
22 
Exclusion Criteria 19 
Synopsis (pg 11) 
Section 8.7.2 (pg 39) 
History of cancer within the last 10 years (20 years for breast cancer) 
except for basal and squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix treated and considered cured 
 
History of cancer within the last 10 years - except for basal and 
squamous cell carcinoma of the skin or in situ carcinoma of the cervix 
treated and considered cured 
 
To allow for consistency of 
exclusion 
of 
all 
cancer 
including breast cancer within 
the last 10 years. 
23 
Exclusion Criteria 20 
Synopsis (pg 11) 
Section 8.7.2 (pg 39) 
Evidence of clinically uncontrolled respiratory disease. The 
Investigator should review the data from subjects’ respiratory 
assessments including chest x-ray and pulmonary function tests (PFTs) 
performed within 12 weeks prior to Day 0. The subjects must have had 
values ≥ 60% of predicted for measurements performed and no 
uncontrolled lung disease. A subject’s medical regimen should not 
have been significantly intensified to control lung disease within 12 
weeks prior to Day 0. 
 
Evidence of clinically uncontrolled respiratory disease. The 
Investigator should review the data from subjects’ respiratory 
assessments including chest x-ray and pulmonary function tests (PFTs)  
including DLCO performed during the screening period or within 
12 weeks prior to Day 0 if results of prior assessments are available. 
Available PFT and DLCO assessments must have had values ≥ 60% 
of predicted for measurements performed and no uncontrolled lung 
disease. A subject’s medical regimen should not have been 
significantly intensified to control lung disease within 12 weeks prior 
to Day 0. 
 
Text added for clarification 
24 
Test Products, Dosage 
and Mode of 
Administration 
Synopsis (pg 12) 
 
Cases of GCA flare should be treated according to the Investigator’s 
judgment and SoC to ensure the best possible care of the subject. In 
general, the subject should continue to receive the assigned KPL-301 or 
placebo and should also receive an increased dose of coadministered 
prednisone, as determined by the Investigator, generally of up to 60 
mg/day. The dosages of all concomitant medications used to treat the 
GCA flare must be documented. If a flare, particularly a major flare, 
should require a dose of corticosteroid higher than prednisone 60 mg/day, 
in the judgment of the Investigator, steroid escape therapy is allowed 
(i.e., doses of prednisone > 60 mg/day, or equivalent, or IV 
corticosteroids) until clinical remission is achieved. 
If the clinical response is positive, after an appropriate period of clinical 
stabilization, as determined by the Investigator, (usually 1-2 weeks) the 
subject may resume the protocol-defined steroid taper, starting at the 
dose at which remission was achieved or prednisone 60 mg/day, 
whichever is lower.  
Any subject who cannot adhere to the protocol-defined steroid taper due 
to flare/relapse will be allowed to receive a more gradual Investigator-
defined steroid taper and will continue to receive the assigned KPL-301 
or placebo.  
 
- 
Text deleted as it is duplicate 
of what is described in the 
Base 
Treatment 
Period 
section of the synopsis on pg 
7. 
25 
Test Products, Dosage 
and Mode of 
During the OLE, subjects will receive open-label KPL-301 150 mg every 
2 weeks for up to 6 additional months and may wean off KPL-301 onto 
After subjects have completed the 26-week double blind treatment 
period, they will discontinue and wash off blinded KPL-301 or 
Removed 
text 
regarding 
Open-label 
Extension 
and 




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30 
Overview 
of 
Trial 
Design 
Synopsis (pg 13)  
Figure 5 (pg 31) 
- 
- 
Design diagram replaced to 
reflect 26-week exposure and 
12-week 
Washout 
Safety 
Follow-up period. 
31 
Statistical Methods 
Synopsis (pg 14) 
Section 14.1 (pg 57) 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or 
higher. All clinical study data will be presented in subject data listings. 
Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile 
(Q1), median, third quartile (Q3), minimum and maximum for 
continuous variables, and frequency and percentage for categorical and 
ordinal variables. If there are missing values, the number missing will be 
presented, but without a percentage.  The preliminary SAP is presented 
here, with the final SAP to be confirmed in a separate document (SAP) 
prior to study unblinding. 
 
General Methods 
All statistical analyses will be performed using SAS® Version 9.3 or 
higher. All clinical study data will be presented in subject data listings. 
Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile 
(Q1), median, third quartile (Q3), minimum and maximum for 
continuous variables, and frequency and percentage for categorical and 
ordinal variables. The preliminary SAP is presented here, with the final 
SAP to be confirmed in a separate document (SAP) prior to study 
unblinding. 
 
Change of text to allow use 
of SAS Version 9.3 or higher 
32 
Statistical Methods 
Synopsis (pg 14) 
Section 14.3.1 (pg 58) 
 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or 
placebo and are assessed for at least 1 day in the double-blind treatment 
period will be included in the modified intent-to-treat (mITT) analysis 
set. Efficacy analyses will be based on the mITT analysis set. All mITT 
analyses will be based on each subject’s randomized treatment 
assignment.  
 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or 
placebo and at least have 1 assessment in the double-blind treatment 
period will be included in the modified intent-to-treat (mITT) analysis 
set. Efficacy analyses will be based on the mITT analysis set. All mITT 
analyses will be based on each subject’s randomized treatment 
assignment.  
 
Text changed for clarification 
33 
Statistical Methods 
Synopsis (pg 14) 
Section 14.3.3 (pg 58) 
Per Protocol Analysis Set 
All randomized subjects who complete Week 26 in the double blind 
period without protocol deviations deemed to impact efficacy or ethical 
conduct will be included in the per-protocol (PP) set. 
 
Per Protocol Analysis Set 
All mITT subjects without protocol deviations deemed to impact 
efficacy or ethical conduct will be included in the per-protocol (PP) set. 
 
Text changed to better reflect 
Per Protocol Analysis set 
after limiting the 26 week 
exposure. 
34 
Statistical Methods 
Synopsis (pg 14,15) 
Section 14.4 (pg 58- 59) 
Section 14.5.1 (pg 
59,60) 
Section 14.5.2 (pg 60) 
Primary Efficacy Endpoint Analysis 
The primary objective of this POC study is to evaluate the efficacy of 
KPL-301 versus placebo, coadministered with a 26 week steroid taper, 
for maintaining sustained remission for 26 weeks in subjects with new-
onset or relapsing/refractory GCA. Sustained remission is defined as the 
absence of flare (as defined above) from the start of double-blind 
treatment through Week 26. The primary efficacy analysis variable is 
time from start of double-blind treatment until the first flare occurring 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as 
time from randomization to the date of first flare occurring within the 
26-week period. Subjects who do not experience a flare during this 
period will be censored at the Week 26 visit. Subjects who drop out or 
are lost to follow-up prior to experiencing a flare during the 26-week 
double-blind period will be censored at the time of their last available 
visit. 
Text changed to provide 
clarification as well as to 
limit endpoint collection to 
the 26 Week exposure. 




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35 
Statistical Methods 
Synopsis (pg 15) 
Section 14.2 (pg 57,58) 
Sample Size Estimation 
With 36 subjects randomized to KPL-301 and 24 subjects randomized to 
placebo, a two-sided log-rank test for equality of survival curves with a 
0.05 significance level will have approximately 89% power to detect a 
37.5% difference (20% placebo vs 57.5% KPL-301) in the proportion of 
subjects who experience sustained remission during the 26-week 
double-blind base period. 
It is expected that the trial will have equal numbers of subjects in the two 
randomization strata. Assuming that the percentage of subjects 
experiencing sustained remission in the new onset stratum is 70% for 
KPL-301 and 30% for placebo. The percentage of subjects experiencing 
sustained remission in the relapsing/refractory stratum is 45% for KPL-
301 and 10% for placebo. A two-sided log-rank test with 0.1 significance 
level will have 75% power to detect a treatment difference within the 
stratum.   
Sample Size Estimation 
Assuming that time to flare follows an exponential distribution and 
the proportion of subjects without a flare by Week 26 will be 20% 
in placebo and 57 5% in KPL-301, the median time to flare would 
be estimated to be approximately 11.20 weeks in placebo and 32.57 
weeks in KPL-301.  The hazard ratio (KPL-301 vs. placebo) would 
be estimated to be approximately 0.3438.  With a 2-sided 
significance level of 0.05 and a 3:2 randomization ratio for KPL-301 
vs. placebo, it would require approximately 34 events to achieve 
86% power using a two- sided log rank test.   
Approximately 60 subjects will be randomized by disease stratum 
(new-onset or relapsing/refractory) to receive KPL-301 or placebo 
at a 3:2 allocation ratio. 
Subject disposition and the flare event accrual will be closely 
monitored during the study. The monitoring activities will be done 
in a blinded fashion. If there is a high dropout rate and/or the event 
accrual rate is significantly slower than anticipated, up to 10 
additional subjects may be randomized to obtain the target number 
of events required for the analysis of primary efficacy endpoint. 
 
Text changed to provide 
clarification 
36 
Schedule of Activities 
Synopsis (pg 16)  
Removed: 
Schedule of Assessments 
• Every 4 weeks thereafter visit and associated assessments 
• OLE visit and assessments 
• Fasting lipid panel and HbA1c during screening 
Added: 
Schedule of Activities 
• Week 30, Week 34, Week 38 Visits 
• Ultrasound at or before Day 0 and at Week 38 
• Pulmonary function tests including DLCO at Week 38 
• Serum pregnancy test during screening 
• Urine pregnancy test at Day 0, Week 12, Week 26 and Week 38 
• Safety Labs (Hematology, Chemistry & Liver profile) at Week 4 and 
Week 38 
• Fasting lipid panel and HbA1c at Day 0 
 
  
Activities removed to limit 
double-blind Period to 26 
Weeks.  Activities changed to 
remove Open-label extension 
and replace with Washout 
Safety 
Follow-up 
Period.  
Additional safety labs and 
procedures added per Ethic 
and Regulatory feedback. 


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CONFIDENTIAL 
 
37 
Schedule of Activities 
Footnotes 
Synopsis (pg 17)  
Footnotes 
a. Monthly visits are conducted until the last subject completes the 26-
week double-blind analysis period and the analysis is complete. 
 
e. Open-label extension visits occur monthly for up to 6 months. During 
the open-label extension subjects may wean off KPL-301 onto standard 
of care at the discretion of the investigator. 
 
f. During the open-label extension all subjects participating will receive 
open-label KPL-301. Any subjects on steroids at the end of the double-
blind period should taper steroids at the discretion of the investigator. 
 
m. Electrocardiogram or chest X-ray (or high res CT) are not required at 
an EOT visit but may be performed at a UNS visit 
- 
Footnotes 
removed 
per 
updated 
schedule 
of 
Activities 
38 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
c. In the event of an unscheduled visit, only the relevant assessments 
pertaining to the visit need to be captured. Subjects reporting worsening 
of GCA symptoms or any safety issues may be brought in for an 
unscheduled visit at the study clinic at any time. This visit can be 
combined with the EOT visit in which all necessary assessments should 
be completed. 
b. In the event of an unscheduled visit, only the relevant 
assessments/activities pertaining to the visit need to be captured. 
Subjects reporting worsening of GCA symptoms or any safety issues 
may be brought in for an unscheduled visit at the study clinic at any 
time. This visit can be combined with the EOT visit in which all 
necessary EOT related assessments/activities should be completed. 
 
Footnotes updated or added 
to provide clarity 
39 
Schedule of Activities 
Footnotes 
Synopsis 
(pg 
17) 
Section 8.8 (pg 40) 
d. All subjects, including subjects who prematurely discontinue the study 
(i.e., withdraw consent), must complete a safety follow up visit 28 ± 3 
days after the last dose of KPL-301 or placebo.  Additional follow up 
using public records may be captured if possible. 
 
c. All subjects, including subjects who prematurely discontinue the 
study (i.e., withdraw consent), must complete at a minimum the Final 
Safety Follow up visit 84 ± 3 days after the EOT Visit.  Additional 
follow up using public records may be captured if possible. 
Footnotes updated or added 
to provide clarity 
40 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
g. At baseline, subject and/or caregiver should be trained on proper self-
administration and handling and accountability of IMP. This training 
should be documented and can be repeated as necessary throughout the 
study. 
 
d. At baseline, subject and/or caregiver should be trained on proper self-
administration and handling and accountability of study drug. This 
training should be documented and can be repeated as necessary 
throughout the study. 
 
Footnotes updated or added 
to provide clarity 
41 
Schedule of Activities 
Footnotes 
h. If a study site or clinic visit coincides with the subject’s scheduled 
dose, study treatment will be administered at the study site or clinic.  
Study treatment should be dispensed as necessary to the subject for home 
e. If a study site or clinic visit coincides with the subject’s scheduled 
dose, study treatment will be administered at the study site or clinic.  
Study drug treatment should be dispensed as necessary to the subject 
Footnotes updated or added 
to provide clarity 


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CONFIDENTIAL 
Synopsis (pg 17) 
administration to ensure dosing compliance.  Investigator staff may 
contact patients between visits to ensure compliance with protocol 
specified treatment regimens. 
 
for home administration to ensure dosing compliance.  Investigator staff 
may contact patients between visits to ensure compliance with protocol-
specified treatment regimens. 
 
42 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
i. New-onset subjects can have an optional temporal artery biopsy taken 
at Screening and Week 26 as part of the study. For relapsing/refractory 
patients, if the subject has not had a prior a temporal biopsy an optional 
biopsy can be done at Screening and Week 26. If the subject has an 
existing biopsy sample available this can be submitted as the 
screening/predose sample and an optional biopsy can be performed at 
Week 26.  
 
f. New-onset subjects can have an optional temporal artery biopsy taken 
at Screening (or otherwise available from diagnostic workup) and 
Week 26 as part of the study. For relapsing/refractory patients, if the 
subject has not had a prior a temporal biopsy an optional biopsy can be 
done at Screening and Week 26. If the subject has an existing biopsy 
sample available this can be submitted as the screening/predose sample 
and an optional biopsy can be performed at Week 26.  
 
Footnotes updated or added 
to provide clarity 
43 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
j. Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at 
Screening, or existing documentation within 12 weeks of Day 0 can be 
used and reviewed by the Investigator or designee. 
 
g. Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at 
Screening, or existing documentation (if available) within 12 weeks of 
Day 0 can be used and reviewed by the Investigator or designee. 
 
Footnotes updated or added 
to provide clarity 
44 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
k. PFTs and DLCO should be performed at Screening 6-12 weeks prior 
to Day 0. They should also be performed at Weeks 12 and 26 with a 
window of ±14 days; after Week 26 PFTs and DLCO should be 
performed every 6 months ± 14 days; if the EOT visit is > 3 months of 
the prior test, the assessment should be performed.  
  
h. PFTs and DLCO should be performed at Screening within 6 weeks 
prior to Day 0 (or documented report available from PFT &/or 
DLCO from within 12 weeks prior to Day 0). They should also be 
performed at Weeks 12 and 26 and 38 with a window of ±14 days;  
 
Footnotes updated or added 
to provide clarity 
45 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
p. Clinical decisions for determination of inclusion and flare will be 
based upon local laboratory values. 
 
l. Clinical decisions for determination of inclusion and flare will be 
based upon local laboratory values either ESR and/or CRP. 
 
Footnotes updated or added 
to provide clarity 
46 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
q. The imaging technique used during screening to diagnose GCA should 
be repeated throughout the study.  If ultrasound is available at screening 
for diagnosis of GCA this should be conducted again at weeks 12, 26 and 
then every 6 months thereafter, or in case of a suspected flare of GCA 
with no other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, 
CT/CTA or PET-CT was used at screening for diagnosis of GCA and no 
ultrasound is available this should be repeated at week 26 then every six 
months thereafter or in case a suspected flare as necessary in order to 
reduce the exposure of radiation to the subject. 
 
m. The imaging technique used during screening to diagnose GCA 
should be repeated at week 26 for the study.  If ultrasound is available 
at screening for diagnosis of GCA this should be conducted again at 
weeks 12, 26 and 38, or in case of a suspected flare of GCA with no 
other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, CT/CTA 
or PET-CT was used at screening for diagnosis of GCA and no 
ultrasound is available, the same imaging technique used at screening 
should be repeated at week 26 or as necessary for diagnosis in case a 
suspected flare. 
 
Footnotes updated or added 
to provide clarity 


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CONFIDENTIAL 
47 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
- 
n. Ultrasound imaging if clinically relevant should be performed at 
or before Day 0 to support clinical remission decision making unless 
there is no evidence of temporal artery inflammation and diagnosis 
of GCA is confined to large vessels (By MRI or CT). 
 
Footnote added to provide 
clarity 
48 
Section 9.1 (pg 40) 
…The investigational product is supplied as a sterile clear to opalescent, 
colorless to slightly brown-yellow liquid, free from visible particles, in a 
prefilled syringe at a nominal fill volume of 1.0 mL, stoppered with a 
Teflon-faced elastomeric stopper, and sealed with an aluminium 
overseal. Each syringe contains 150 mg (nominal) of active 
investigational product. 
 
…The investigational product is supplied as a sterile clear to opalescent, 
colorless to slightly brown-yellow liquid, free from visible particles, in a 
1mL prefilled syringe at a nominal fill volume of 1.0 mL, stoppered 
with a Teflon-faced elastomeric stopper, accessorized with a needle 
guard, and extended finger flange and a plunger rod. Each syringe 
contains 150 mg (nominal) of active investigational product. 
Text changed to provide 
clarity 
49 
Section 9.2 (pg 41) 
…The placebo is supplied as a sterile clear to slightly opalescent, 
colorless to slightly yellow liquid, free from visible particles, in a 
prefilled syringe at a nominal fill volume of 1.0 mL, stoppered with a 
Teflon-faced elastomeric stopper, and sealed with an aluminium 
overseal. 
…The placebo is supplied as a sterile clear to, colorless liquid, free from 
visible particles, in a 1 ml prefilled syringe at a nominal fill volume of 
1.0 mL, stoppered with a Teflon-faced elastomeric stopper, 
accessorized with a needle guard and extended finger flange and a 
plunger rod. 
Text changed to provide 
clarity 
50 
Section 9.3 (pg 42) 
… During the OLE, subjects will continue to follow study protocols from 
the double-blind period in the event of a flare and for steroid tapering 
procedures unless indicated otherwise as per the discretion of the 
Investigator. 
 
... During the Washout Safety Follow-up Period, the prednisone dose 
can then be tapered or maintained throughout the remainder of the 12-
week Washout Period as per the discretion of the Investigator.  After the 
Final Washout Safety Follow-up visit (Week 38) has been completed 
the subjects will exit the trial and should be transitioned to SoC per 
investigator judgement.    
 
Text added to replace OLE 
with Washout Safety Follow-
up Period 
51 
Section 9.4 (pg 42,43) 
Subjects who are candidates for enrollment will be evaluated for 
eligibility by the Investigator to ensure that the criteria given in Section 
8.7 have been satisfied and that the patients are eligible for 
randomization. 
Subjects will be randomized at a 3:2 ratio to receive either 150 mg KPL-
301 or placebo. Randomization will be stratified according to whether 
subjects have new-onset disease or relapsing disease.  Additional strata 
may be identified and described within the SAP. 
Subjects who are candidates for enrollment will be evaluated for 
eligibility by the Investigator to ensure that the criteria given in Section 
8.7 have been satisfied and that the subjects are eligible for 
randomization. 
Subjects will be randomized at a 3:2 ratio to receive either 150 mg KPL-
301 or placebo. Randomization will be stratified according to whether 
subjects have new-onset disease or relapsing disease.   
Text removed 
52 
Section 9.6.2 (pg 43,44) 
In the event of a medical emergency, the Investigator may unblind an 
individual subject’s treatment allocation in consultation with the Sponsor. 
In general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received 
active drug. In most cases, the management of a medical emergency 
would be the same whether or not active drug was received by the 
In the event of a medical emergency, the Investigator may unblind an 
individual subject’s treatment allocation and notify the Sponsor. In 
general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received 
active drug. In most cases, the management of a medical emergency 
would be the same whether or not active drug was being received by the 
Text removed and changed to 
provide clarity 


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KPL-301-C001 (v 4.0) 
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CONFIDENTIAL 
subject. If this were to be the case, the treatment allocation should not be 
unblinded. 
Depending on the results of the Week 26 analysis, all subjects may be 
offered open-label KPL-301 in the OLE portion of the trial or the study 
will be discontinued after the double-blind period. If the study is 
discontinued after the double-blind period, subjects will not be unblinded 
(except for the reasons listed above) until the clinical database has been 
locked. 
subject. If this were to be the case, the treatment allocation should not 
be unblinded. 
 
53 
Section 12.2.1 (pg 47) 
- 
Ideally clinical assessments of GCA signs/symptoms should occur 
prior to the investigator reviewing subject imaging, lab or acute 
phase reactant results at any given visit to minimize potential for 
assessment bias. 
 
Text added for clarity 
54 
Section 12.2.3 (pg 47) 
In cases where ultrasound of temporal artery was captured during the 
diagnosis of GCA at Screening, this procedure should be repeated at 
Weeks 12, 26, EOT and every 6 months thereafter as well as any 
instances of suspected flare over the course of the study.  Imaging and 
relevant data should be included in any elements of the diagnostic work-
up pertinent to the Investigator diagnosis of GCA. 
In cases where ultrasound of temporal artery was captured during the 
diagnosis of GCA at Screening, this procedure should be repeated at 
Weeks 12, 26, EOT and Week 38 as well as any instances of suspected 
flare over the course of the study.  Imaging and relevant data should be 
included in any elements of the diagnostic work-up pertinent to the 
Investigator diagnosis of GCA. 
Text changed to incorporate 
Week 38 visit 
55 
Section 12.3.1 (pg 48) 
A complete physical examination as possible by local practice should 
include an evaluation of the head, eye, ear, nose, and throat as well as 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, 
genitourinary, 
and 
neurological 
systems. 
Any 
abnormality identified at baseline should be recorded on the Medical 
History and Physical Examination eCRFs. 
 
A complete physical examination as possible by local practice should 
include an evaluation of the head, eye, ear, nose, and throat as well as 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, 
genitourinary, 
and 
neurological 
systems. 
Any 
abnormality identified at baseline should be recorded on the Medical 
History and Physical Examination eCRFs. 
 
Text added for clarity 
56 
Section 12.4 (pg 48) 
The digital ECG recording must be obtained and reviewed by the 
Investigator or designee. For safety monitoring purposes, the Investigator 
or designee must sign and date all ECG tracings and place the paper copy 
as part of the subject’s permanent study file at the site. ECG 
characteristics, including heart rate, QS duration, and RR, PR, and QT 
intervals will be recorded on the eCRF. QTcB (Bazett’s correction) and 
QTcF (Fridericia’s corrections) will be calculated. Changes in T-wave 
and U-wave morphology and overall ECG interpretation will be 
documented in eCRF. 
 
The digital ECG recording must be obtained and reviewed by the 
Investigator or designee. For safety monitoring purposes, the 
Investigator or designee must sign and date all ECG tracings and place 
the paper copy as part of the subject’s permanent study file at the site 
and overall ECG interpretation will be documented in eCRF. 
Text removed for consistency 
with data collection 
57 
Section 12.5.1 (pg 49) 
PFTs and DLCO should be obtained at Screening 6 weeks prior to Day 0, 
or existing documentation within 12 weeks of day 0 can be used and 
reviewed by the Investigator or designee. During the course of the study 
PFTs and DLCO should be obtained at Screening 6 weeks prior to Day 
0, or existing documentation within 12 weeks of day 0 can be used and 
reviewed by the Investigator or designee. During the course of the study 
Text 
changed 
to 
reflect 
updated schedule of activities 




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64 
Section 13.1.3.3 (pg 52) 
…Any subject who has been referred for a specialist pulmonary 
evaluation should not receive the investigational product until the 
symptom(s) or sign(s) causing the referral have resolved. 
…Any subject who has been referred for a specialist pulmonary 
evaluation may be instructed to stop the investigational product until 
the symptom(s) or sign(s) causing the referral have resolved. 
Text changed for clarity 
65 
Section 13.1.7 (pg 54) 
- 
Suspected Unexpected Serious Adverse Reaction  
A Suspected Unexpected Serious Adverse Reaction is an adverse 
reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g. investigator’s brochure for an 
unauthorized 
investigational 
product 
or 
prescribing 
information/summary of product characteristics for an authorized 
product). All relevant information about suspected serious unexpected 
adverse reactions that are fatal or life-threatening will be recorded and 
reported to the competent authorities in all the applicable countries, and 
to the Ethics Committee/Institutional Review Boards in conjunction 
with Directive 2001/20/EC.  
Text 
added 
per 
Ethics/Regulatory request 
66 
Section 13.4 (Pg 55) 
AEs will be collected from the time of signing of informed consent 
through the final Safety Follow-up period (24 days ± 3days after the last 
dose of study drug). 
AEs will be collected from the time of signing of informed consent 
through the Final Washout Safety Follow-up period (84 days ± 3 days 
after the EOT visit). 
Text changed for consistency 
with schedule of activities 
67 
Section 14.1.2 (pg 57) 
The primary objective of this study is to evaluate the efficacy of KPL-
301 versus placebo, in combination with steroid taper, for maintaining 
sustained remission for 26 weeks. The primary efficacy analysis entails 
the inferential comparison of KPL-301 to placebo with respect to time 
from start of double-blind treatment until the first flare occurring within 
the first 26-weeks of the double-blind period. The key secondary efficacy 
analysis entails inferential comparison of KPL-301 to placebo with 
respect to time from start of double-blind treatment until the first flare 
anytime during the double-blind period.   
 
Multiplicity with respect to these two inferential efficacy analyses will be 
managed via the gated hierarchical testing procedure.  If and only if the 
primary comparison results in a statistically significant difference 
between KPL-301 and placebo at 0.05 level of significance, the key 
secondary comparison may be conducted at alpha 0.05 as well.   
 
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
Multiplicity with respect to the primary efficacy endpoint and the key 
secondary efficacy endpoints will be managed via the gated 
hierarchical testing procedure.  If and only if the primary comparison 
results in a statistically significant difference between KPL-301 and 
placebo at 0.05 level of significance, the key secondary comparison will 
be conducted at alpha 0.05 as well.   
 
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
 
Text updated for clarity 
68 
Section 16.2 (pg 63) 
This study will be conducted in compliance with the protocol, the ICH-
GCP guideline, the Declaration of Helsinki, and local regulations. 
This study will be conducted in compliance with the protocol, the ICH-
GCP guideline, the most recent version of the Declaration of Helsinki 
Text updated for clarity 


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CONFIDENTIAL 
 
in which the Sponsor intends to publish the results regardless of the 
study outcome, and local regulations. 
 
69 
Section 17 (pg 64) 
- 
Study Termination 
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  
Non-compliance that might significantly jeopardize the validity or 
integrity of the study  
Recommendation to suspend or terminate the study by independent 
body such as DMC or Health Authority 
Sponsor decision to terminate development  
 
Where required by applicable regulations, the investigator or head 
of the medical institution must inform the IRB/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. 
 
Text 
added 
per 
Ethics/Regulatory request 
 
 


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CONFIDENTIAL 
20.3.2 Protocol Amendment v3.0 
Rationale for Amendment – Protocol Amendment v3.0 was completed to clarify aspects of protocol 
version 2.0 as well as to incorporate feedback from global Regulatory bodies.  Substantial changes to this 
version include: 
• 
Discontinuation of study drug (KPL-301 or placebo) in the event of a GCA Flare 
 
 
• 
Clarification of individual patient and study stopping criteria 
• 
Correction of the US Safety contact number 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 
 


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CONFIDENTIAL 
Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
1 
Title Page (pg 1) 
Header throughout 
Date of Protocol: 15 Oct 2018 
Version of Protocol: 2.0 
Date of Protocol: 15 Nov 2018 
Version of Protocol: 3.0 
Administrative 
2 
Section 2 (pg 2)  
Section 13.6 (pg 55) 
US 24 Hour Safety Hotline: 1 888-483-77729 
US 24 Hour Safety Hotline: 1 888-483-7729 
Administrative correction 
3 
Synopsis (pg 7) 
Section 8.4.1 (pg 32) 
Cases of flare should be treated according to the Investigator’s judgment 
and standard of care (SoC) to ensure the best possible care of the subject. 
In general: 
• 
The subject should continue to receive the assigned KPL-301 or 
placebo and should also receive an increased dose of 
coadministered prednisone, as determined by the Investigator, 
generally of up to 60 mg/day. The dosages of all concomitant 
medications used to treat the GCA flare must be entered into the 
eCRF. 
• 
If a flare, particularly a major flare, should require a dose of 
corticosteroid higher than prednisone 60 mg/day, in the judgment 
of the Investigator, steroid escape therapy is allowed (i.e., doses 
of prednisone > 60 mg/day or equivalent, or intravenous (IV) 
corticosteroids) until clinical remission is achieved.  If the 
clinical response is positive, after an appropriate period of 
clinical stabilization, as determined by the Investigator, the 
subject may resume the protocol-defined steroid taper, starting at 
the dose at which remission was achieved or prednisone 60 
mg/day, whichever is lower.  Any subject who cannot adhere to 
the protocol-defined steroid taper due to flare/relapse will be 
allowed to receive a more gradual Investigator-defined steroid 
taper and will continue to receive the assigned KPL-301 or 
placebo. These subjects will be considered to have met the 
primary endpoint if a flare has occurred prior to Week 26.  
Subjects who experience a flare or subjects who cannot adhere to 
the protocol-defined steroid taper due to a flare should be managed 
to ensure the best possible care of the subject: 
• 
The subject must discontinue the assigned study drug (KPL-
301 or placebo) and should receive escape therapy in 
accordance with local SoC, as determined by the Investigator, 
which may include, for example, dose modifications of 
corticosteroids, other immunomodulatory agents, and/or 
approved therapies (e.g., tocilizumab). The dosages of all 
concomitant medications used to treat the GCA flare must be 
entered into the eCRF. 
• 
Escape corticosteroid therapy can be escalated immediately.  
Due to possible safety and pharmacologic effects resulting 
from overlapping exposures to immunomodulatory agents 
on top of co-administered corticosteroids, the investigator 
should consider a washout period of at least 35 days (based 
on elimination half-lives) after the last dose of study drug if 
deemed clinically appropriate. 
Text updated per regulatory 
feedback 




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8 
Section 8.8 (pgs 38-39) 
Subjects may withdraw from the study drug treatment or from the study 
as a whole at any time for any reason, without prejudice to their medical 
care. The Investigator also has the right to discontinue treatment with and 
withdraw subjects from the study for any of the following reasons: 
Adverse event 
Life threatening or other unacceptable toxicity 
Subject requires use of a prohibited concomitant medication or therapy 
General or specific changes in the subject’s condition unacceptable for 
further treatment within the study parameters, in the Investigator’s 
opinion 
Severe noncompliance 
Lost to follow-up 
Subject withdrawal of consent 
A decision to modify or discontinue development of the drug 
Subjects may withdraw from the study drug treatment or from the study 
as a whole at any time for any reason, without prejudice to their medical 
care. The Investigator also has the right to discontinue treatment with 
and withdraw subjects from the study for any of the following reasons: 
Adverse event or Life threatening or other unacceptable toxicity, for 
example: 
Hepatic function abnormality defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater 
than 2 × ULN, assessed as related to investigational product  
CTCAE Grade 4 (life-threatening) anaphylaxis or hypersensitivity 
reactions  
CTCAE Grade 4 (life-threatening) serious infection or opportunistic 
infection (including septic shock). In addition, subjects with a diagnosis 
or reactivation of TB, hepatitis B, or hepatitis C will not receive any 
further investigational product.  
CTCAE Grade 4 (life-threatening) neutropenia  
Adverse events of malignancy of any grade; except for basal and 
squamous cell carcinoma of the skin or in situ carcinoma of the cervix 
treated and considered cured.  
Subject requires use of a prohibited concomitant medication or therapy 
General or specific changes in the subject’s condition unacceptable for 
further treatment within the study parameters, in the Investigator’s 
opinion 
Severe noncompliance 
Lost to follow-up 
Pregnancy or a decision to become pregnant 
Subjects who request to be permanently discontinued from further 
receipt of investigational product, regardless of the reason (Subject 
withdrawal of consent) 
A decision to modify or discontinue development of the drug 
 
Text updated per regulatory 
feedback 
9 
Section 9.3 (pg 40) 
…Any subject who cannot adhere to the protocol-defined steroid taper 
due to flare/relapse will be allowed steroid escape therapy per the 
Investigator such as prednisone or similar > 60 mg/day or IV 
corticosteroids but will continue to receive the KPL-301 or placebo… 
…Any subject who cannot adhere to the protocol-defined steroid taper 
due to flare/relapse will be allowed escape therapy per the 
Investigator…. 
Text removed per regulatory 
feedback 


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10 
Section 10.2 (pg 43) 
The introduction of the following medications is not permitted from 
initiation of screening through the end of the study. 
The introduction of the following medications is not permitted from 
initiation of screening through the end of the study unless indicated for 
escape therapy. 
Text add for clarity 
11 
Section 10.3 (pg 43) 
Subject who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse will be allowed steroid escape therapy per the Investigator, 
such as prednisone or similar > 60mg/day or IV corticosteroids and will 
continue to receive the assigned study drug treatment (KPL-301 or 
placebo). These subjects are considered to have met the primary endpoint 
provided the flare occurs prior to Week 26. 
Subject who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse must discontinue study drug (KPL-301 or placebo) and 
should receive escape therapy in accordance with local SoC per the 
Investigator.  Escape therapy may include, for example, prednisone or 
similar > 60mg/day,IV corticosteroids, other immunomodulatory agents,  
and/or approved therapies (e.g., tocilizumab). These subjects are 
considered to have met the primary endpoint provided the flare occurs 
prior to Week 26. 
Escape corticosteroid therapy can be escalated immediately. Due to 
unknown possible safety and pharmacological effects from overlapping 
exposures to immunomodulatory agents on top of co-administered 
corticosteroids, the investigator should consider a washout period of at 
least 35 days (based on elimination half-lives) after the last dose of 
study drug (KPL-301 or placebo) if deemed clinically appropriate.  
Text updated per regulatory 
feedback 
12 
Section 11.2 (pg 45) 
In cases of flare, the prednisone dose may be increased. Any subject who 
cannot adhere to the protocol-defined steroid taper due to flare/relapse 
will be allowed to receive a more gradual Investigator-defined steroid 
taper and will continue to receive the assigned KPL-301 or placebo. 
These subjects will be considered to have met the primary endpoint if a 
flare has occurred prior to Week 26.  
Subjects who experience a flare or who cannot adhere to the protocol-
defined steroid taper due to flare/relapse must discontinue the assigned 
study drug (KPL-301 or placebo) and should receive escape therapy 
in accordance with local SoC. These subjects will be considered to 
have met the primary endpoint if a flare has occurred prior to Week 26.  
Text updated per regulatory 
feedback 
13 
Section 12.6.7 (pg 49) 
For women of child bearing potential a serum pregnancy test should be 
performed prior to enrolment at the site. Urine pregnancy tests should be 
performed at Day 0, Week 12, Week 26 and the Final Washout Safety 
Follow-up Visit.  Abnormal laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours). 
 
For women of child bearing potential a serum pregnancy test should be 
performed prior to randomization at the site. Urine pregnancy tests 
should be performed at Day 0, Week 12, Week 26 and the Final 
Washout Safety Follow-up Visit.  Abnormal laboratory results should 
be repeated as soon as possible (preferably within 24 to 48 hours). 
 
Text changed for clarification 


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14 
Section 17.1 (pg 63) 
- 
17.1 Study Stopping Criteria 
If the sponsor receives a report of an event consistent with any one of 
the following, the medical monitor or designee will immediately assess 
the event by gathering all available information including, where 
possible, direct telephone contact with the reporter. A prompt review of 
the data will be initiated by the sponsor, and the information will be 
referred to the DMC within 1 business day of the receipt of the initial 
report by the Sponsor.  
Any CTCAE grade 5 (death) assessed as related to the investigational 
product  
Any CTCAE grade 4 (life-threatening) assessed as related to the 
investigational product  
Any CTCAE grade 4 (life-threatening) of anaphylaxis  
Hepatic function abnormality defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater 
than 2 × ULN, assessed as related to investigational product  
Any unforeseen events that, in the opinion of the DMC and the Sponsor, 
may contraindicate further dosing  
Clinically-significant pulmonary abnormalities that in the opinion of the 
DMC and the Sponsor may contraindicate further dosing  
If any above-listed events occur, the Sponsor will promptly conduct a 
cumulative review of safety data, including the DMC assessment of the 
event, and the circumstances of the event in question to determine 
whether the study should be modified, suspended or terminated. 
Text added per regulatory 
feedback 


Kiniksa Pharmaceuticals Ltd. 
 
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Page 91 of 101 
 
 
CONFIDENTIAL 
20.3.3 Protocol Amendment v4.0 
Rationale for Amendment – Protocol Amendment v4.0 was completed to clarify aspects of protocol 
version 3.0 as well as to incorporate feedback from global Regulatory bodies.  Substantial changes to this 
version include: 
• 
Updated secondary endpoints and analysis; and inserted study endpoints into the Synopsis 
Objective section. 
• 
The planned number of subjects to be enrolled in the study was updated from approximately 60 to 
approximately 70 subjects (42 subjects planned to be assigned to the KPL-301 arm and 
28 subjects planned to be assigned to the placebo arm) to align with the updated sample size 
estimation. 
• 
Added clarification that SAEs will be recorded in the eCRF within 24 hours of discovery. 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 
 






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Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
 
Safety Endpoints: 
• 
Incidence of treatment emergent adverse events 
• 
Change in physical exam results 
• 
Change in vital signs 
• 
Change in clinical laboratory parameters  
o 
Serum chemistry 
o 
Hematology 
o 
Urinalysis 
5 
Synopsis: Number of 
Subjects and  
Overview of Trial 
Design Figure 
Approximately 60 subjects will be randomized at a 3:2 allocation ratio.  
Approximately 36 subjects will be assigned to KPL-301, and approximately 
24 subjects will be assigned to placebo. Of the study population, the aim is 
to have 50% with new-onset disease and 50% with relapsing disease. 
Approximately 70 subjects will be randomized at a 3:2 allocation ratio.  
Approximately 42 subjects will be assigned to KPL-301, and approximately 
28 subjects will be assigned to placebo. Of the study population, the aim is 
to have 50% with new-onset disease and 50% with relapsing disease. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
6 
Synopsis: Statistical 
Methods 
General Methods 
All statistical analyses will be performed using SAS® Version 9.3 or higher. 
All clinical study data will be presented in subject data listings. Descriptive 
statistics will be presented for all endpoints and will include number of 
subjects (n), mean, standard deviation (SD), first quartile (Q1), median, 
third quartile (Q3), minimum and maximum for continuous variables, and 
frequency and percentage for categorical and ordinal variables. The 
preliminary SAP is presented here, with the final SAP to be confirmed in a 
separate document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo 
and at least have 1 assessment in the double blind treatment period will be 
included in the modified intent-to-treat (mITT) analysis set. Efficacy 
analyses will be based on the mITT analysis set. All mITT analyses will be 
based on each subject’s randomized treatment assignment. 
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo 
will be included in the Safety Analysis Set. Safety analyses will be based on 
the medication that was actually administered to each subject. 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher. 
All clinical study data will be presented in subject data listings. Descriptive 
statistics will be presented for all endpoints and will include number of 
subjects (n), mean, standard deviation (SD), first quartile (Q1), median, third 
quartile (Q3), minimum and maximum for continuous variables, and 
frequency and percentage for categorical and ordinal variables. The 
preliminary SAP is presented here, with the final SAP to be confirmed in a 
separate document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo 
and at least have 1 assessment in the double blind treatment period will be 
included in the modified intent-to-treat (mITT) analysis set. Efficacy 
analyses will be based on the mITT analysis set. All mITT analyses will be 
based on each subject’s randomized treatment assignment. 
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo will 
be included in the Safety Analysis Set. Safety analyses will be based on the 
medication that was actually administered to each subject. 
Updated text to allow use 
of SAS Version 9.4 or 
higher 
Updated text in Endpoint 
Analysis subsection for 
clarification and new 
statistical assumptions. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint. 
Time to elevated ESR 
and CRP by Week 26 
and time to 
sign/symptoms of GCA 
or new or worsening 
vasculitis by imaging by 
Week 26 were added as 
secondary efficacy 
endpoints in response to 
request from the FDA. 


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Current Text 
Revised Text 
Rationale 
Per Protocol Analysis Set 
All mITT subjects without protocol deviations deemed to impact efficacy or 
ethical conduct will be included in the per-protocol (PP) set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the date of first flare occurring within the 26-week 
period. Subjects who do not experience a flare during this period will be 
censored at the Week 26 visit. Subjects who drop out or are lost to follow-
up prior to experiencing a flare during the 26-week double-blind period will 
be censored at the time of their last available visit. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 26-week 
double-blind period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. Kaplan-Meier estimates of remission 
rate at 26 weeks will be presented with the corresponding 95% CI by 
treatment group. To describe the magnitude of treatment effect, the hazard 
ratio for KPL-301 compared to placebo and the corresponding 95% CI will 
be calculated based on a Cox proportional-hazards model with treatment as 
covariate. 
As a key secondary efficacy endpoint, time to flare by week 26 in the per 
protocol population will be analyzed using the same methods described 
above. Subjects who do not experience flare during double-blind treatment 
will be censored at their last visit of the double-blind treatment period. 
Subjects who drop out or are lost to follow-up prior to experiencing a flare 
at any time during double-blind treatment will be censored at the time of 
their last available visit. 
Additional secondary efficacy endpoints include the following endpoints 
that will be analyzed. Treatment comparisons will be performed using 
Cochran-Mantel-Haenszel test controlling for the randomized stratum. 
• 
Percentage of subjects who have completed the 26-week 
corticosteroid taper and who have a normal ESR 
• 
Percentage of subjects who have completed the 26-week 
corticosteroid taper and who have a normal CRP by Week 26 
Per Protocol Analysis Set 
All mITT subjects without important protocol deviations deemed to impact 
efficacy or ethical conduct will be included in the per-protocol (PP) analysis 
set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the first flare occurring within the treatment period. 
Detailed censoring rules will be provided in the SAP.  
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 
treatment period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. To describe the magnitude of treatment 
effect, the hazard ratio for KPL-301 compared to placebo and the 
corresponding 95% CI will be calculated based on a Cox proportional-
hazards model with treatment as a covariate and stratified by the 
randomization strata. 
The protocol definition of flare includes multiple components. 
Supportive analyses will be performed based on each individual 
component.  The details will be described in the SAP.  In addition, a 
sensitivity analysis will be performed using the same method described 
above for the per-protocol analysis set. 
Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared 
using the Kaplan-Meier method  
The following endpoints will be analysed using the Cochran-Mantel-
Haenszel test, stratified by the randomized stratum: 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal ESR by Week 26 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal CRP by Week 26 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have neither signs/symptoms of GCA nor new or 
The key secondary 
endpoint time to flare by 
Week 26 in the Per 
Protocol population was 
deleted as it will be 
handled as a sensitivity 
analysis. 
Deleted time to 
corticosteroid dose of 
zero mg/day as a 
secondary efficacy 
endpoint because patients 
enter the study with 
varying doses of steroids. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
Updated statistical 
assumptions based on 
review of Phase 3 
Tocilizumab data. 




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Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
Approximately 60 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
Subject disposition and the flare event accrual will be closely monitored 
during the study. The monitoring activities will be done in a blinded 
fashion. If there is a high dropout rate and/or the event accrual rate is 
significantly slower than anticipated, up to 10 additional subjects may be 
randomized to obtain the target number of events required for the analysis 
of primary efficacy endpoint. 
approximately 26 weeks in placebo and 111 weeks in KPL-301.  The hazard 
ratio (KPL-301 vs. placebo) is estimated to be approximately 0.234.  With a 
2-sided significance level of 0.05 and a 3:2 randomization ratio for KPL-301 
vs. placebo, it would require approximately 20 events to achieve 87% power 
using a two-sided log rank test.   
Approximately 70 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
7 
Section 8.6 
Approximately 60 patients with GCA will be randomized as study subjects. 
For the primary endpoint analysis, the aim is to have 36 subjects assigned to 
KPL-301 and 24 subjects assigned to placebo, with balanced randomization 
in the two randomization cohorts. 
Approximately 70 patients with GCA will be randomized as study subjects. 
For the primary endpoint analysis, the aim is to have 42 subjects assigned to 
KPL-301 and 28 subjects assigned to placebo, with balanced randomization 
in the two randomization cohorts. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
8 
Section 12.5.4 
The modified Borg scale (Borg, 1982) is a validated patient reported 
outcome and will be used to assess subjects’ perceived sensation of 
difficulty in breathing (dyspnea) while resting. This scale is a linear scale of 
numbers ranking the magnitude of difficulty in breathing, ranging from 0 
(nothing at all) to 10 (maximal). A validated version of the Borg scale in 
local language will be provided. 
The modified Borg scale (Borg and Borg, 2010) is a validated patient 
reported outcome and will be used to assess subjects’ perceived sensation of 
difficulty in breathing (dyspnea) while resting. This scale is a linear scale of 
numbers ranking the magnitude of difficulty in breathing, ranging from 0 
(nothing at all) to 10 (maximal). A validated version of the Borg scale in 
local language will be provided. 
Updated citation for 
modified Borg scale. 
9 
Section 13.6 
All SAEs, whether or not considered causally related to study drug or to the 
study procedure(s), have to be reported. All SAEs will be recorded in the 
eCRF. 
The Investigator must report all SAEs to the Safety Department and 
Sponsor within 24 hours of discovery via the SAE reporting form to: 
24 Hour Safety Hotline: +44 
1223 374 240 
 
24 Hour Safety Hotline Fax: +44 1223 374 102                  
US 24 Hour Safety Hotline: 1 888-483-7729 
US 24 Hour Safety Hotline Fax: 1 888-529-3580                 
All SAEs, whether or not considered causally related to study drug or to the 
study procedure(s), have to be reported. SAEs will be recorded in the eCRF 
within 24 hours of discovery. 
In case the eCRF is inaccessible, the Investigator must report all SAEs to 
the Safety Department and Sponsor within 24 hours of discovery via the 
SAE reporting form to: 
24 Hour Safety Hotline: +44 
1223 374 240 
 
24 Hour Safety Hotline Fax: +44 1223 374 102                  
US 24 Hour Safety Hotline: 1 888-483-7729 
US 24 Hour Safety Hotline Fax: 1 888-529-3580                 
Updated text upon 
request from Slovenian 
Inspection. 
10 
Section 14.1 
All statistical analyses will be performed using Statistical Analysis 
Software (SAS®) Version 9.3 or later. A statistical analysis plan (SAP) will 
be written and approved prior to performing the first review of the data. 
All statistical analyses will be performed using Statistical Analysis Software 
(SAS®) Version 9.4 or later. A statistical analysis plan (SAP) will be written 
and approved prior to performing the first review of the data. 
Updated text to allow use 
of SAS Version 9.4 or 
higher 


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Current Text 
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11 
Section 14.1.2 
14.1.2 Multiple Comparisons/Multiplicity 
Multiplicity with respect to the primary efficacy endpoint and the key 
secondary efficacy endpoints will be managed via the gated hierarchical 
testing procedure.  If and only if the primary comparison results in a 
statistically significant difference between KPL-301 and placebo at 0.05 
level of significance, the key secondary comparison will be conducted at 
alpha 0.05 as well.   
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
 
14 1 2 Multiplicity Adjustment 
Multiplicity adjustment with respect to the primary efficacy and secondary 
efficacy endpoints will be performed using the gate-keeping hierarchical 
testing procedure. The order of the secondary endpoints will be described 
in the SAP. For each endpoint, the null hypothesis is that there is no 
treatment difference between KPL-301 and placebo. The alternative 
hypothesis is that KPL-301 is superior to placebo.  For each test, the 2-
sided Type I error rate is 0.05.  The primary endpoint will be tested 
first.  If the 2-sided p-value is ≤0.05 and the test statistic shows KPL-301 
is superior than placebo, statistical significance of the primary endpoint 
will be claimed, and the next hierarchical endpoint will be tested.  This 
process will continue until an endpoint is not statistically significant.    
Clarified language in 
response to request from 
the FDA. 
12 
Section 14.2 
Approximately 60 subjects will be randomized 3:2 by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo. 
Assuming that time to flare follows an exponential distribution and the 
proportion of subjects without a flare by week 26 will be 20% in placebo 
and 57.5% in KPL-301, the median time to flare would be estimated to be 
approximately 11.20 weeks in placebo and 32.57 weeks in KPL-301.  The 
hazard ratio (KPL-301 vs. placebo) would be estimated to be approximately 
0.3438.  With a 2-sided significance level of 0.05 and a 3:2 randomization 
ratio for KPL-301 vs. placebo, it would require approximately 34 events to 
achieve 86% power using a two- sided log rank test.  
Approximately 60 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
Subject disposition and the flare event accrual will be closely monitored 
during the study. The monitoring activities will be done in a blinded 
fashion. If there is a high dropout rate and/or the event accrual rate is 
significantly slower than anticipated, up to 10 additional subjects may be 
randomized to obtain the target number of events required for the analysis 
of primary efficacy endpoint. 
Assuming that time to flare follows an exponential distribution and the 
proportion of subjects without a flare by week 26 will be 50% in placebo and 
85% in KPL-301, the median time to flare would be approximately 26 weeks 
in placebo and 111 weeks in KPL-301 arm.  The hazard ratio (KPL-301 vs. 
placebo) would be approximately 0.234.  With a 2-sided significance level 
of 0.05 and a 3:2 randomization ratio for KPL-301 vs. placebo, it would 
require approximately 20 events to achieve 87% power using a two- sided 
log rank test.  
Approximately 70 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
Updated statistical 
assumptions based on 
review of Phase 3 
Tocilizumab data. 
13 
Section 14.4 
Efficacy Endpoints: 
Primary Endpoint:  
• 
Time to flare by Week 26 defined as time from randomization to 
the first flare occurring within the first 26-weeks of the double-
blind period 
Key secondary endpoint: 
Efficacy Endpoints: 
Primary Endpoint:  
• 
Time to flare by Week 26 defined as time from randomization to 
the first flare occurring within the treatment period 
Secondary Endpoints: 
Updated text in Efficacy 
Endpoints for 
clarification. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint.  




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Section(s) 
Current Text 
Revised Text 
Rationale 
o 
Urinalysis 
14 
Section 14.5 
14.5 Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  The 
primary and key secondary efficacy Analyses will be repeated using the PP 
set to assess the sensitivity of the results to major deviations/violations of 
the protocol.  All efficacy data including those collected during the open 
label extension will be listed by subject. 
14.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined in 14.1  
Subjects who do not experience a flare during this period will be censored 
at the Week 26 visit. Subjects who drop out or are lost to follow-up prior to 
experiencing a flare during the 26-week double-blind period will be 
censored at the time of their last available visit. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 26-week 
double-blind period will be summarized for each treatment group. Time to 
flare by week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare. The Kaplan-Meier estimates of remission rate at 26 
weeks will be presented with the corresponding 95% CI by treatment group. 
To describe the magnitude of treatment effect, the hazard ratio for KPL-301 
compared to placebo and the corresponding 95% CI will be calculated 
based on a Cox proportional-hazards model with treatment as covariate.  
14.5.2 Key Secondary Efficacy Analysis 
The key secondary efficacy endpoint is time to flare by week 26 in the per 
protocol population and will be analyzed using the same methods as 
described above. Subjects who do not experience flare during double blind 
treatment will be censored at their last visit of the double-blind treatment 
period.  Subjects who drop out or are lost to follow up prior to experiencing 
a flare at any time during double blind treatment will be censored at the 
time of their last available visit. 
14.5.3 Additional Secondary Efficacy Analysis 
The number and percentage of subjects with normal ESR at Week 26 as 
well as the number and percentage of subjects with normal CRP at Week 26 
will be analyzed.  Treatment groups will be compared using a Cochran-
Mantel-Haenszel test controlling for the randomized strata. Confidence 
14 5 Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  Analyses 
will be repeated using the PP set to assess the sensitivity of the results to 
important deviations of the protocol. 
14 5 1 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the first flare occurring within the treatment 
period. Detailed censoring rules will be provided in the SAP. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 
treatment period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. To describe the magnitude of treatment 
effect, the hazard ratio for KPL-301 compared to placebo and the 
corresponding 95% CI will be calculated based on a Cox proportional-
hazards model with treatment as a covariate and stratified by 
randomization strata.  
The protocol definition of flare includes multiple components. 
Supportive analyses will be performed based on each individual 
component.  The details will be described in the SAP.  In addition, a 
sensitivity analysis will be performed using the same method described 
above for the PP analysis set. 
14 5 2 Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared 
using the Kaplan-Meier method. 
The following endpoints will be analyzed using the Cochran-Mantel-
Haenszel test stratified by the randomization strata. 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal ESR by Week 26  
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal CRP by Week 26 
Updated text for 
clarification and new 
statistical assumptions. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint. 
Time to elevated ESR 
and CRP by Week 26 
and time to 
sign/symptoms of GCA 
or new or worsening 
vasculitis by imaging by 
Week 26 were added as 
secondary efficacy 
endpoints in response to 
request from the FDA. 
The key secondary 
endpoint time to flare by 
Week 26 in the Per 
Protocol population was 
deleted as it will be 
handled as a sensitivity 
analysis. 
Deleted time to 
corticosteroid dose of 
zero mg/day as a 
secondary efficacy 
endpoint because patients 
enter the study with 
varying doses of steroids. 
Updated the planned 
number of subjects to 
address potential early 
drop-out. 
Updated statistical 
assumptions based on 
review of Phase 3 












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by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have neither 
signs/symptoms of GCA nor new or worsening vasculitis by imaging by Week 26 
• 
Time to elevated ESR by Week 26  
• 
Time to elevated CRP by Week 26  
• 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
• 
Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up Period 
 
 
 
 
 
 
 
 
Safety Endpoints: 
• 
Incidence of treatment emergent adverse events 
• 
Change in physical exam results 
• 
Change in vital signs 
• 
Change in clinical laboratory parameters  
o Serum chemistry 
o Hematology 
o Urinalysis 
Methodology: 
This Phase 2 randomized, placebo-controlled Proof of Concept (POC) study will evaluate the efficacy and 
safety of KPL-301 coadministered with a 26-week corticosteroid taper in patients with GCA. The study 
will consist of a Screening Period (up to 6 weeks), a 26-week Double-Blind placebo-controlled Period 
during which subjects will receive blinded KPL-301 or placebo coadministered with a 26-week 
corticosteroid taper, and a 12-week Washout Safety Follow-up Period during which subjects will 
discontinue and wash off blinded KPL-301 or placebo.  
Screening/Diagnostic Period: 
Following signing of the informed consent form (ICF), potential subjects 50-85 years of age (inclusive) 
will be screened for meeting study-specified diagnostic criteria for GCA.  
• 
Acute Phase Reactants - Westergren erythrocyte sedimentation rate (ESR) > 30 mm/hour or 
C-reactive protein (CRP) ≥ 1 mg/dL  
AND 
• 
Signs/Symptoms - At least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp, or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 


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ii. 
Unequivocal extra-cranial symptoms of GCA, such as claudication of the extremities 
iii. 
Symptoms of polymyalgia rheumatica (PMR), defined as shoulder and/or hip girdle pain 
associated with inflammatory morning stiffness 
AND  
• 
Diagnostic Criteria - At least one of the following: 
i. 
Temporal artery biopsy (TAB) or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such 
as magnetic resonance imaging (MRI), computed tomography (CT)/computed 
tomography angiography (CTA) or positron emission tomography (PET)-CT of the aorta 
or other great vessels 
Upon successful completion of the screening procedures, diagnosis criteria will be entered into an IWRS, 
and eligible subjects will be stratified for randomized study treatment into two cohorts according to 
whether subjects have new-onset disease or relapsing/refractory (hereafter, “relapsing” for brevity) 
disease. 
• 
New-onset - The new-onset disease cohort includes subjects who have been diagnosed within 
6 weeks of Day 0 using the above Acute Phase Reactants, Signs/Symptoms and Diagnostic 
Criteria. 
• 
Relapsing/refractory – (either or) 
o The relapsing disease cohort includes subjects having prior documented diagnosis of GCA as 
per Diagnostic Criteria above > 6 weeks before Day 0 and who have active GCA disease 
defined by Acute Phase Reactants and Signs/Symptoms within 6 weeks of Day 0.  
o The refractory nonremitting disease subject has had no remission since the diagnosis of 
disease as per clinical expectations. Thus, the subject has documentation of prior diagnosis of 
GCA as per Diagnostic criteria above > 6 weeks before Day 0; however, presence of Acute 
Phase Reactants and Signs/Symptoms as per above persists within 6 weeks of Day 0. 
Subjects who complete screening procedures and are not considered eligible (screen failures) may be 
rescreened one time provided there is reason to believe that eligibility criteria will be met.  
Base Treatment Period: 
Stratified eligible subjects will enter the double-blind treatment period after randomization 3:2 to blinded 
treatment with KPL-301 150 mg or placebo administered subcutaneously (SC) every other week (every 
2 weeks). All subjects will also receive an unblinded 26-week oral prednisone taper according to a 
standardized tapering protocol.  
Prior to first administration of KPL-301 or placebo, all subjects are required to have achieved remission 
(i.e., resolution of GCA symptom(s) and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour). Should a 
subject in screening not achieve remission within the initial screening period they can be rescreened using 
their prior flare documentation following the relapsing/refractory non-remitting inclusion criteria. 
The first administration of SC KPL-301/placebo and oral prednisone taper will take place at the study site 
on Day 0. Subsequent doses of KPL-301/placebo will be administered at the study site in conjunction with 
a scheduled study visit or administered by the subject on an outpatient basis in accordance with the dosing 
schedule. The oral steroid taper will be self-administered by study subjects on a daily basis.  
Subjects will be followed at the study site at Weeks 1, 2, 3, 4, and approximately every 4 weeks thereafter 
(see Table 1). Subjects reporting worsening of GCA symptoms or any safety issues may be brought in for 
an unscheduled visit at the study site at any time.  


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If a flare/relapse is suspected during the treatment period, the Investigator must consult the Contract 
Research Organization (CRO)-designated Medical Expert to review and harmonize the elements of the 
diagnostic work-up. Flare/relapse is defined as a re-increase of CRP from normal to 1 mg/dL or greater 
and/or of ESR from less than 20 mm in the first hour to 30 mm or greater AND at least one of the 
following signs or symptoms attributed by the Investigator to new, worsening, or recurrent GCA: 
• 
Cranial symptoms 
o New or recurrent headache or pain or tenderness of the scalp or the temporal artery 
o Visual signs/symptoms such as ischemic retinopathy, optic neuropathy, diplopia, amaurosis 
fugax, etc. 
o New or recurrent claudication of the tongue, masseter muscle, or worsening temporal artery 
signs and symptoms  
o Transient ischemic attack (TIA) or stroke related to GCA in the opinion of the Investigator  
• 
Extracranial symptoms 
o Classic PMR-like symptoms, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
o New or recurrent claudication in the peripheral circulation (i.e., in one of the extremities)  
• 
New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the 
aorta or other great vessels or via ultrasound of the temporal arteries  
Supportive findings could include other symptoms in the opinion of the Investigator related to worsening 
GCA, such as sustained daily recurrent fever with a temperature over 38°C for more than 1week, chronic 
anemia, or unexplained weight loss. 
Although either acute phase reactant (CRP or ESR) may be used during the study for eligibility and to 
determine remission or flares, it is advisable that the same acute phase reactant used to determine 
remission at screening also be used to determine flares during the treatment period. 
All elements of the diagnostic work-up pertinent to the Investigator diagnosis of a flare/relapse (i.e., the 
primary efficacy endpoint) should be reviewed with the CRO-designated Medical Expert and entered into 
the electronic Case Report Form (eCRF) promptly.  
Flare/relapse is defined as major if cranial symptoms or ischemia-related visual loss are present or if there 
is clear evidence of new onset large vessel vasculitis (e.g., subclavian artery). In all other situations, 
flare/relapse attributed to PMR, vascular or other symptoms should be regarded as minor.  
Subjects who experience a flare or subjects who cannot adhere to the protocol-defined steroid taper due to 
a flare should be managed to ensure the best possible care of the subject: 
• 
The subject must discontinue the assigned study drug (KPL-301 or placebo) and should receive 
escape therapy in accordance with local SoC, as determined by the Investigator, which may 
include, for example, dose modifications of corticosteroids, other immunomodulatory agents, 
and/or approved therapies (e.g., tocilizumab). The dosages of all concomitant medications used to 
treat the GCA flare must be entered into the eCRF. 
• 
Escape corticosteroid therapy can be escalated immediately.  Due to possible safety and 
pharmacologic effects resulting from overlapping exposures to immunomodulatory agents on top 
of co-administered corticosteroids, the investigator should consider a washout period of at least 35 


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days (based on elimination half-lives) after the last dose of study drug if deemed clinically 
appropriate. 
Any subject who prematurely discontinues the study drug treatment for safety or other reason will have an 
End-of-Treatment (EOT) visit and will be followed for the intended duration of study treatment (i.e., 
through Week 26 and Washout Safety Follow-up) to address potential issues of informative censoring. 
Any subject who withdraws consent from the trial (i.e., all study procedures in addition to study drug 
administration) must complete at a minimum the Final Washout Safety Follow-up visit 84 ± 3 days from 
the last dose administered.  Additional follow up using public records may be captured where possible. 
Washout Safety Follow-up: 
After subjects complete the 26-week double blind treatment period, they will discontinue and wash off of 
blinded KPL-301 or placebo during a 12-week Washout Period, which includes close safety follow-up and 
monitoring for potential GCA flares.  During this time, it is recommended that subjects, regardless of 
remission status, receive SoC oral prednisone therapy, taking into consideration that they have just 
completed treatment with what may have been an efficacious therapy which supported the tapering off of 
standard of care concomitant oral corticosteroids.  Clinicians may choose to observe subjects closely 
during the washout period without any change in concomitant medications or may choose (consistent with 
current SoC guidelines) to increase the daily corticosteroid dose prophylactically/empirically by 
approximately 10 mg above the prednisone dose administered at Week 26.  The prednisone dose can then 
be tapered, increased or maintained throughout the remainder of the 12-week Washout Period as per 
Investigator discretion.  After the Final Washout Safety Follow-up visit (Week 38) has been completed, 
the subjects will exit the trial and should be transitioned to SoC per investigator judgement.  It is not 
required that the steroid taper have been completed (0 mg) prior to subjects exiting the trial at Week 38. 
Number of Subjects: 
Approximately 70 subjects will be randomized at a 3:2 allocation ratio.  Approximately 42 subjects will be 
assigned to KPL-301, and approximately 28 subjects will be assigned to placebo. Of the study population, 
the aim is to have 50% with new-onset disease and 50% with relapsing disease. 
Eligibility Criteria: 
Inclusion Criteria 
1. Able and willing to provide written informed consent and to comply with the study protocol 
2. Age of ≥ 50 to 85 inclusive 
3. Diagnosis of new-onset or relapsing GCA classified according to the following criteria: 
New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined as:  
a) Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL  
b) AND at least one of the following: 
i. 
Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal 
artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or 
jaw pain upon mastication) 
ii. 
Unequivocal extracranial symptoms of GCA such as claudication of the extremities 
iii. 
Symptoms of PMR, defined as shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness 
c) AND at least one of the following: 


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i. 
TAB or ultrasound revealing features of GCA 
ii. 
Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such 
as MRI, CT/CTA, or PET-CT of the aorta or other great vessels 
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND: 
Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s) as per above and 
Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/ dL  
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 0 AND: 
No remission since the diagnosis of disease as per clinical expectations. i.e. Presence of 
sign/symptoms as per above and Westergren ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks 
of Day 0.  
4. Remission of GCA at or before Day 0 (resolution of GCA symptom(s) and CRP < 1.0 mg/dL or 
ESR < 20 mm in the first hour), such that the subject can safely participate in the study and follow the 
protocol-defined procedures, including initiation of the prednisone taper at the protocol-specified 
starting dose (i.e., ≤60 mg/day) 
5. At Day 0, receiving or able to receive oral prednisone up to 60 mg/day for the treatment of GCA 
6. If using methotrexate (MTX), oral or parenteral up to 25mg/week is permitted in screening if started 
more than 6 weeks prior to Day 0 and should be tapered to zero by Day 0 
7. Willing to receive antiplatelet therapy depending on the Investigator’s decision 
8. Willing to receive treatment for prevention of corticosteroid-induced osteopenia/osteoporosis 
depending on the Investigator’s decision 
9. Female subjects must be:  
a) postmenopausal, defined as at least 12 months post cessation of menses (without an alternative 
medical cause), or  
b) permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the 
subject, or  
c) nonpregnant, nonlactating, and if sexually active having agreed to use a highly effective method of 
contraception (i.e., hormonal contraceptives associated with inhibition of ovulation or intrauterine 
device [IUD], or intrauterine hormone-releasing system [IUS], or sexual abstinence) from 
Screening Visit until the Final Washout Safety Follow-up visit 84 ± 3 days from EOT Visit.   
10. Male subjects must have documented vasectomy or if sexually active must agree to use a highly 
effective method of contraception with their partners of childbearing potential (i.e., hormonal 
contraceptives associated with the inhibition of ovulation or intrauterine device [IUD], or intrauterine 
hormone-releasing system [IUS], or sexual abstinence) from Day 0 until the Final Washout Safety 
Follow-up visit 84± 3 days from EOT Visit. Male subjects must agree to refrain from donating sperm 
during this time period. 
Exclusion Criteria: 
General Exclusion Criteria 
1. Major surgery within 8 weeks prior to Screening or planned major surgery within 12 months after 
randomization 
2. Transplanted organs (except corneal transplant performed more than 3 months prior to randomization) 
3. Major ischemic event unrelated to GCA within 12 weeks of Screening 
 


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Exclusions Related to Prior or Concomitant Therapy 
4. Concurrent enrollment in another clinical study, with the exception of observational studies 
5. Previous treatment with KPL-301 
6. Treatment with any non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the 
study agent, whichever was longer, prior to Screening 
7. Any cell-depleting biological therapies (e.g., anti-CD20) within 12 months prior to Day 0; or previous 
treatment with noncell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], 
anakinra, anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-
lives, whichever is longer) prior to Screening 
8. Treatment with alkylating agents within 12 weeks prior to Screening 
9. Intramuscular, Intra-articular or IV corticosteroids within 4 weeks prior to Screening 
10. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0 
11. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or 
mycophenolate mofetil (MMF) within 4 weeks of Screening 
Relating to Medical History 
12. Female subjects who are pregnant, intending to become pregnant, or are breastfeeding 
13. Any condition that, in the opinion of the Investigator, could interfere with evaluation of KPL-301 or 
interpretation of subject safety or confound the results of the study 
14. Known history of allergy or reaction to any component of the KPL-301 or placebo formulation or to 
any other biologic therapy or prednisone or any of its excipients 
15. Positive (or 2 indeterminate) QuantiFERON test results. 
16. Clinically significant active infection including signs/symptoms suggestive of infection, any 
significant recurrent or chronic infection (including positive hepatitis C virus antibody [HCVAb]), or 
any episode of infection requiring hospitalization or treatment with IV antibiotics within 12 weeks 
before Screening. Subjects with any opportunistic infection within 6 months before Screening will be 
excluded from the study.  
17. Subjects with chronic active hepatitis B infection as defined below will be excluded from the study: 
• 
Hepatitis B surface antigen (HbsAg) positive 
• 
Hepatitis B anti-core antibody positive but anti-surface antibody negative 
18. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder 
including a history of known human immunodeficiency virus [HIV] infection), 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 
19. History of cancer within the last 10 years - except for basal and squamous cell carcinoma of the skin 
or in situ carcinoma of the cervix treated and considered cured 
20. Evidence of clinically uncontrolled respiratory disease. The Investigator should review the data from 
subjects’ respiratory assessments including chest x-ray and pulmonary function tests (PFTs) including 
DLCO performed during the screening period or within 12 weeks prior to Day 0 if results of prior 
assessments are available. Available PFT and DLCO assessments must have had values ≥ 60% of 
predicted for measurements performed and no uncontrolled lung disease. A subject’s medical regimen 
should not have been significantly intensified to control lung disease within 12 weeks prior to Day 0. 
21. History of chronic respiratory tract infections 
22. Congestive heart failure of New York Heart Association classification III or IV 


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23. At screening blood tests, any of the following: 
a) Aspartate transaminase (AST) > 2 × upper limit of normal (ULN) 
b) Alanine transaminase (ALT) > 2 × ULN 
c) Hemoglobin < 75 g/L 
d) Neutrophils < 1.5 × 109/L 
e) Creatinine clearance (CrCl) <30 mL/min 
Test Products, Dosage, and Mode of Administration: 
Subjects will be permitted to have received steroids (prednisone or equivalent) prior to inclusion in the 
study.  
During the double-blind period, subjects will receive blinded KPL-301 150 mg or placebo, every 2 weeks, 
by SC injection, in addition to a protocol-specified oral corticosteroid taper. 
Oral prednisone will be started at a dose between 20 mg/day to 60 mg/day (inclusive) at Day 0 depending 
on the subject’s previous corticosteroid treatment, disease status, and Investigator discretion. The 
prednisone dose will then be tapered over the subsequent 26 weeks in accordance with the following 
tapering schedule shown in Table 3, with subjects entering the taper at different points, depending on their 
prednisone dose at Day 0.  
After subjects have completed the 26-week double-blind treatment period, they will discontinue and wash 
off blinded KPL-301 or placebo during a 12-week Washout Period.  During the Washout Safety Follow-
up Period, patients may be closely observed with no additional therapeutic or may receive prophylactic 
prednisone and tapered as per Investigator discretion.  After the Final Washout Safety Follow-up visit 
84 ± 3 days from the EOT Visit has been completed, subjects will exit the trial and should be transitioned 
to SoC per investigator judgement, regardless of what dose of prednisone subjects are on. 
Concomitant Medication: 
Subjects should receive concomitant medications in line with current SoC practices for GCA. Such 
medications may include but not limited to the equivalent of the following examples: low-dose aspirin 
(dose allowed per SoC), pantoprazole (40 mg daily), calcium (1000 mg daily), cholecalciferol (800 U 
daily), and IV ibandronate 3 mg every 3 months, for the duration of the study. 
Duration of Treatment: 
Subjects will receive SC KPL-301 or placebo as well as coadministered study-supplied oral prednisone, 
which will be tapered over a period of up to 26 weeks, unless the subject experiences a flare of GCA. 
Upon completion of the 26-week double-blind period subjects will discontinue KPL-301 or placebo and 
enter the 12-week Washout Safety Follow-up period in which they may receive study-supplied oral 
prednisone per the Investigator’s discretion.  Thus, the total study duration will be up to approximately 38-
44 weeks (including 6-week Screening Period). 
Efficacy Measures: 
• 
Clinical laboratory analyses (e.g., CRP, ESR, signs/symptoms) 
• 
Clinical GCA assessments, including, signs/symptom(s), 
 
 
• 
Imaging studies (as applicable), including ultrasound, MRI, CT/CTA, PET-CT, TAB (if 
applicable) 
• 
 


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Safety Measure(s): 
Safety measures include adverse events and clinical laboratory analyses (including chemistry, hematology, 
urinalysis, liver profiles, lipid panel, hemoglobin A1c [HbA1c], and anti-drug antibodies), vital sign 
measurements, electrocardiograms (ECGs), and physical examination findings. 
 
. 
Overview of Trial Design  
 
 
Statistical Methods: 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical study data will be 
presented in subject data listings. Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile (Q1), median, third quartile (Q3), 
minimum and maximum for continuous variables, and frequency and percentage for categorical and 
ordinal variables. The preliminary SAP is presented here, with the final SAP to be confirmed in a separate 
document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo and at least have 1 assessment 
in the double blind treatment period will be included in the modified intent-to-treat (mITT) analysis set. 
Efficacy analyses will be based on the mITT analysis set. All mITT analyses will be based on each 
subject’s randomized treatment assignment.  
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo will be included in the Safety 
Analysis Set. Safety analyses will be based on the medication that was actually administered to each 
subject. 
Per Protocol Analysis Set 


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All mITT subjects without important protocol deviations deemed to impact efficacy or ethical conduct 
will be included in the per-protocol (PP) analysis set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time from randomization to the first 
flare occurring within the treatment period. Detailed censoring rules will be provided in the SAP.  
The number and percentage of subjects who remain in remission (no flare), who flare, and who are lost to 
follow-up prior to a flare during the treatment period will be summarized for each treatment group.  Time 
to flare by Week 26 will be summarized by the 25th, 50th (median), and 75th percentiles calculated using 
the Kaplan-Meier method to estimate the survival functions for each treatment group. The 95% confidence 
interval (CI) for the percentiles will also be calculated. A log-rank test stratified by randomization strata 
will be used to compare KPL-301 and placebo with respect to time to flare by Week 26.  To describe the 
magnitude of treatment effect, the hazard ratio for KPL-301 compared to placebo and the corresponding 
95% CI will be calculated based on a Cox proportional-hazards model with treatment as a covariate and 
stratified by the randomization strata.  
The protocol definition of flare includes multiple components. Supportive analyses will be performed 
based on each individual component.  The details will be described in the SAP.  In addition, a sensitivity 
analysis will be performed using the same method described above for the per-protocol analysis set. 
Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared using the Kaplan-Meier method  
The following endpoints will be analysed using the Cochran-Mantel-Haenszel test, stratified by the 
randomized stratum: 
• 
Percentage of subjects who have completed the corticosteroid taper and who have a normal ESR 
by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have a normal CRP 
by Week 26 
• 
Percentage of subjects who have completed the corticosteroid taper and who have no 
signs/symptoms of GCA nor new or worsening vasculitis by imaging by Week 26 
The following time to event endpoints will be analyzed using the same methods used for the primary 
efficacy endpoint: 
• 
Time to elevated ESR by Week 26  
• 
Time to elevated CRP by Week 26  
• 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by Week 26 
The following continuous secondary efficacy endpoints will be analyzed. The analyses will include 
two-sided 95% CIs for the difference of treatment means, as appropriate. Details will be described in the 
SAP: 
• 
Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up period 
 
 
 
 
 
 




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Table 1: 
Schedule of Activities 
 
 
Screening 
Double – Blind Treatment Period (± 3 days) 
 
Washout Safety Follow-up 
(± 3 days) 
Assessment 
Up to 6 
weeks 
Baseline/ 
Day 0 
Wee
k 1 
Week 
2 
Week 
3 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 / 
EOTac 
UNSb 
Week 
30 
Week 
34 
Final Safety 
Follow-upc / 
Week 
38 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Chest X-ray 
Xg 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
Clinical GCA assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temporal biopsy 
Xf 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
 
 
Imaging (ultrasound)  
Xm 
Xn 
 
 
 
 
 
Xm 
 
 
 
Xm 
Xm 
 
 
Xm 
Imaging (MRI, CT/CTA, 
or PET-CT) 
Xm 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local CRP  
Xl 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Pulmonary function tests 
Xgh 
 
 
 
 
 
 
Xh 
 
 
 
Xh 
X 
 
 
Xh 
DLCO 
Xgh 
 
 
 
 
 
 
Xh 
 
 
 
Xh 
X 
 
 
Xh 
Dyspnea score and O2 
saturation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
Hematology 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Liver profile 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Fasting lipid panel and 
HbA1c 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 


Kiniksa Pharmaceuticals Ltd. 
 
30 March 2020 
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CONFIDENTIAL 
 
Screening 
Double – Blind Treatment Period (± 3 days) 
 
Washout Safety Follow-up 
(± 3 days) 
Assessment 
Up to 6 
weeks 
Baseline/ 
Day 0 
Wee
k 1 
Week 
2 
Week 
3 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 / 
EOTac 
UNSb 
Week 
30 
Week 
34 
Final Safety 
Follow-upc / 
Week 
38 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KPL-301 or PBO 
administration/dispensing 
 
Xde 
 
Xe 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
 
Prednisone dispensingk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CRP=C-reactive protein; CT=computed tomography; CTA=computed tomography angiography; DLCO= diffusing capacity for carbon monoxide; EOT=end of treatment; ESR= erythrocyte 
sedimentation rate; GCA= giant cell arteritis; Hb1Ac= haemoglobin A1c (glycolysed haemoglobin); IMP = KPL-301 or placebo; MRI=magnetic resonance imaging; 
 
O2=oxygen; PBO=placebo; PET=positron emission tomography; 
; TB=tuberculosis; UNS=unscheduled visit; 
a. 
EOT visit must be conducted in the event the subject permanently discontinues KPL-301 or placebo. After the EOT visit, subjects who discontinue treatment should continue attending their 
remaining scheduled visits for the duration of the study. 
b. 
In the event of an unscheduled visit, only the relevant assessments/activities pertaining to the visit need to be captured. Subjects reporting worsening of GCA symptoms or any safety issues may be 
brought in for an unscheduled visit at the study clinic at any time. This visit can be combined with the EOT visit in which all necessary EOT related assessments/activities should be completed. 
c. 
All subjects, including subjects who prematurely discontinue the study (i.e., withdraw consent), must complete at a minimum the Final Safety Follow up visit 84 ± 3 days after the EOT Visit.  
Additional follow up using public records may be captured if possible. 
d. 
At baseline, subject and/or caregiver should be trained on proper self-administration and handling and accountability of study drug. This training should be documented and can be repeated as 
necessary throughout the study. 
e. 
If a study site or clinic visit coincides with the subject’s scheduled dose, study treatment will be administered at the study site or clinic.  Study drug treatment should be dispensed as necessary to the 
subject for home administration to ensure dosing compliance.  Investigator staff may contact patients between visits to ensure compliance with protocol-specified treatment regimens. 
f. 
New-onset subjects can have an optional temporal artery biopsy taken at Screening (or otherwise available from diagnostic workup) and Week 26 as part of the study. For relapsing/refractory 
patients, if the subject has not had a prior a temporal biopsy an optional biopsy can be done at Screening and Week 26. If the subject has an existing biopsy sample available this can be submitted as 
the screening/predose sample and an optional biopsy can be performed at Week 26.  
g. 
Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at Screening, or existing documentation (if available) within 12 weeks of Day 0 can be used and reviewed by the Investigator or 
designee. 
h. 
PFTs and DLCO should be performed at Screening within 6 weeks prior to Day 0 (or documented report available from PFT &/or DLCO from within 12 weeks prior to Day 0). They should also be 
performed at Weeks 12 and 26 and 38 with a window of ±14 days. 
 
  
 
 
k. 
Subjects will be given prednisone as necessary and instructed to dose in alignment with their prednisone taper. Investigator staff may contact patients between visits to ensure compliance with 
protocol specified treatment regimens. 
l. 
Clinical decisions for determination of inclusion and flare will be based upon local laboratory values either ESR and/or CRP. 
m. 
The imaging technique used during screening to diagnose GCA should be repeated at week 26 for the study.  If ultrasound is available at screening for diagnosis of GCA this should be conducted 
again at weeks 12, 26 and 38, or in case of a suspected flare of GCA with no other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, CT/CTA or PET-CT was used at screening for diagnosis 
of GCA and no ultrasound is available, the same imaging technique used at screening should be repeated at week 26 or as necessary for diagnosis in case a suspected flare. 
n. 
Ultrasound imaging if clinically relevant should be performed at or before Day 0 to support clinical remission decision making unless there is no evidence of temporal artery inflammation and 
diagnosis of GCA is confined to large vessels (By MRI or CT). 
 


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Page 17 of 101 
 
 
CONFIDENTIAL 
4 Table of Contents 
1 
Protocol Approval ........................................................................................................ 2 
2 
Investigator and Administrative Structure ................................................................. 3 
3 
Synopsis ........................................................................................................................ 4 
4 
Table of Contents ....................................................................................................... 17 
5 
List of Abbreviations and Definition of Terms ......................................................... 22 
6 
Introduction ............................................................................................................... 24 
6.1 
Overview .................................................................................................................... 24 
6.2 
GM-CSF Biology ........................................................................................................ 26 
6.3 
Non-Clinical and Clinical Experience with KPL-301 ............................................... 28 
6.3.1 
Clinical Development Plan for KPL-301 in GCA ........................................ 29 
7 
Study Objectives ........................................................................................................ 29 
7.1 
Objectives ................................................................................................................... 29 
7.1.1 
Primary Objective........................................................................................ 29 
7.1.2 
Secondary Objective(s) ................................................................................ 29 
7.1.3 
Exploratory Objective.................................................................................. 30 
8 
Study Design............................................................................................................... 30 
8.1 
Rationale of Study Design .......................................................................................... 30 
8.2 
Selection of Doses in the Study .................................................................................. 31 
8.3 
Justification for Placebo ............................................................................................ 32 
8.4 
Methodology ............................................................................................................... 32 
8.4.1 
Main Study .................................................................................................. 32 
8.4.2 
Washout Safety Follow-up .......................................................................... 35 
8.5 
Study Duration ........................................................................................................... 35 
8.6 
Number of Planned Subjects ..................................................................................... 35 
8.7 
Eligibility Criteria ...................................................................................................... 35 
8.7.1 
Inclusion Criteria ......................................................................................... 35 
8.7.2 
Exclusion Criteria ........................................................................................ 37 
8.8 
Removal of Subjects from Therapy or Assessments ................................................. 38 
9 
Investigational Medicinal Products ........................................................................... 39 
9.1 
KPL-301 ..................................................................................................................... 39 
9.2 
Placebo ....................................................................................................................... 39 
9.3 
Prednisone .................................................................................................................. 40 
9.4 
Method of Assigning Subjects to Treatment Groups ............................................... 42 
9.5 
KPL-301 or Placebo Administration ......................................................................... 42 
9.6 
Blinding ...................................................................................................................... 43 
9.6.1 
Methods for Ensuring Blinding .................................................................... 43 
9.6.2 
Unblinding .................................................................................................. 43 
10 
Concomitant Therapy and Treatment Compliance.................................................. 43 




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CONFIDENTIAL 
13 
Safety Assessments ..................................................................................................... 50 
13.1 Adverse Events ........................................................................................................... 50 
13.1.1 
Adverse Event Definition ............................................................................ 50 
13.1.2 
Management of Specific Disease Related Events ......................................... 51 
13.1.3 
Adverse Events of Special Interest ............................................................... 51 
13.1.3.1 
Hepatic Function Abnormality ..................................................................... 51 
13.1.3.2 
Acute and Delayed Hypersensitivity Reactions ............................................ 51 
13.1.3.3 
Clinically Significant Pulmonary Abnormality ............................................ 51 
13.1.3.4 
Neutropenia ................................................................................................. 52 
13.1.3.5 
Serious Infection ......................................................................................... 52 
13.1.4 
Adverse Reactions ....................................................................................... 52 
13.1.5 
Unexpected Adverse Event .......................................................................... 52 
13.1.6 
Serious Adverse Event ................................................................................. 52 
13.1.7 
Suspected Unexpected Serious Adverse Reaction ........................................ 53 
13.2 Adverse Event Assessment ........................................................................................ 53 
13.2.1 
Relationship to Study Drug .......................................................................... 53 
13.2.2 
Intensity ...................................................................................................... 53 
13.3 Recording Adverse Events ......................................................................................... 54 
13.3.1 
Adverse Events Based on Signs and Symptoms ........................................... 54 
13.3.1 
Adverse Events Based on Examinations and Tests ....................................... 54 
13.4 Time Period for Collection of Adverse Events .......................................................... 54 
13.5 Follow-Up of Unresolved Adverse Events ................................................................. 54 
13.6 Reporting Serious Adverse Events ............................................................................ 54 
13.7 Pregnancy ................................................................................................................... 55 
14 
Statistical Methods ..................................................................................................... 55 
14.1 General Considerations ............................................................................................. 55 
14.1.1 
Handling Dropouts and Missing Data .......................................................... 56 
14.1.2 
Multiplicity Adjustment............................................................................... 56 
14.2 Determination of Sample Size ................................................................................... 56 
14.3 Analysis Sets ............................................................................................................... 56 
14.3.1 
Modified Intent-to-Treat Analysis Set .......................................................... 56 
14.3.2 
Safety Analysis Set ...................................................................................... 56 
14 3 3
Per Protocol (PP) Analysis Set 
 56
14.4 Endpoints ................................................................................................................... 57 
14.5 Analysis of Efficacy .................................................................................................... 57 
14.5.1 
Primary Efficacy Endpoint Analysis ............................................................ 58 
14 5 2 
Secondary Efficacy Endpoint Analysis 
 58 
14.6 Analysis of Safety ....................................................................................................... 59 
14.6.1 
Adverse Events ............................................................................................ 59 
14.6.2 
Clinical and Laboratory Events and Analyses .............................................. 59 


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CONFIDENTIAL 
14.6.3 
Vital Signs ................................................................................................... 59 
14.6.4 
Physical Examination .................................................................................. 59 
14 6 5 
Concomitant Medications 
 59 
14.8 Quality Assurance and Quality Control ................................................................... 60 
14.8.1 
Audit and Inspection .................................................................................... 60 
14.8.2 
Monitoring .................................................................................................. 60 
14.8.3 
Data Management and Coding ..................................................................... 60 
14.8.4 
Record Keeping ........................................................................................... 60 
15 
Records and Supplies ................................................................................................. 61 
15.1 Drug Accountability ................................................................................................... 61 
16 
Ethics .......................................................................................................................... 61 
16.1 Institutional Review Board ........................................................................................ 61 
16.2 Ethical Conduct of the Study ..................................................................................... 61 
16.3 Subject Information and Consent ............................................................................. 61 
16.4 Subject Confidentiality .............................................................................................. 62 
17 
Study Termination ..................................................................................................... 62 
17.1 Study Stopping Criteria ............................................................................................. 62 
18 
Reporting and Publication ......................................................................................... 63 
19 
References .................................................................................................................. 64 
20 
Appendices ................................................................................................................. 66 
20.1 Appendix 1: Investigator Signature Page ................................................................. 66 
20.3 Appendix 3: Summary of Changes ............................................................................ 68 
20.3.1 
Protocol Amendment v2.0 ........................................................................... 68 
20.3.2 
Protocol Amendment v3.0 ........................................................................... 85 
20.3.3 
Protocol Amendment v4.0 ........................................................................... 91 
 


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KPL-301-C001 (v 4.0) 
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Page 21 of 101 
 
 
CONFIDENTIAL 
List of Tables 
Table 1: 
Schedule of Activities ............................................................................................ 15 
Table 2:  
Overview of KPL-301 Clinical Trials in RA .......................................................... 28 
Table 3:  
Prednisone Tapering Schedule ............................................................................... 41 
 
List of Figures 
Figure 1:  Diagnosis Algorithm for GCA ............................................................................... 25 
Figure 2:  GCA Treatment Algorithm .................................................................................... 26 
Figure 3:  GM-CSF Biology and KPL -301 Mechanism of Action ......................................... 27 
Figure 4:  Reduction of Inflammatory Markers in RA Patients Treated with KPL-301 ........... 29 
Figure 5: 
Overview of Trial Design ...................................................................................... 30 
 


Kiniksa Pharmaceuticals Ltd. 
 
30 March 2020 
KPL-301-C001 (v 4.0) 
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Page 22 of 101 
 
 
CONFIDENTIAL 
5 List of Abbreviations and Definition of Terms 
ACR20 
American College of Rheumatology definition of improvement by 20% 
ADA 
antidrug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CDUS 
color Doppler ultrasound 
CI 
confidence interval 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CT 
computed tomography 
CTA 
computed tomography angiography 
DLCO 
diffusing capacity for carbon monoxide 
DMARD 
disease modifying anti-rheumatic drug 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End of Treatment 
ESR
erythrocyte sedimentation rate 
GCA 
giant cell arteritis 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte-macrophage colony growth factor 
HbA1c 
hemoglobin A1c (glycosylated hemoglobin) 
HbsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
Interactive Web Response System 
KPL-301 
Study Drug; nomenclature of mavrilimumab in this protocol 
mITT 
modified intent to treat 
MMF 
mycophenolate mofetil 
MoDC 
monocyte-derived dendritic cell 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
OLE 
open-label extension 


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30 March 2020 
KPL-301-C001 (v 4.0) 
Final 
Page 23 of 101 
CONFIDENTIAL 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PFT 
pulmonary function test 
PK 
pharmacokinetics 
PMR 
polymyalgia rheumatica 
POC 
proof of concept 
PP 
per protocol 
Q1 
first quartile 
Q3 
third quartile 
RA 
rheumatoid arthritis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD
standard deviation 
SoC 
standard of care 
TAB 
temporal artery biopsy 
TB 
tuberculosis 
TIA 
transient ischemic attack 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
US 
United States of America 


Kiniksa Pharmaceuticals Ltd. 
 
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KPL-301-C001 (v 4.0) 
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CONFIDENTIAL 
20.3 Appendix 3: Summary of Changes 
20.3.1 Protocol Amendment v2.0 
Rationale for Amendment – Protocol Amendment v2.0 was completed to clarify aspects of protocol 
version 1.0 as well as to incorporate feedback from global Regulatory and Ethical bodies.  Substantial 
changes to this version include: 
• 
Limiting the double-blind period to 26-weeks total, removing the extended exposure for patients 
who enroll earlier in the study. 
• 
Removal of the Open-Label Extension – Per Regulatory feedback, open-label KPL-301 should 
only be provided to patients after proof of efficacy has been established 
• 
Addition of 12-week Washout Safety Follow-up period to ensure patients have continued access 
to open-label study supplied prednisone and are adequately followed and weaned back to Standard 
of Care 
• 
Updated inclusion criteria regarding pregnancy and contraception methods to ensure highly 
effective methods of contraception are reflected 
• 
Provided clarification on sample size and event calculations 
• 
Addition of Serum Pregnancy test during screening, additional urine pregnancy tests, safety labs, 
 
• 
Addition of Definition of SUSAR and defined Study Termination criteria 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 




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CONFIDENTIAL 
Diagnostic criteria above > 6 weeks before Day 0; however, 
presence of Acute Phase Reactants and Signs/Symptoms as per 
above persists within 6 weeks of Day 0. 
 
8 
Synopsis (pg 6) 
Section 8.4.1 (pg 34) 
Subjects who complete screening procedures and are not considered 
eligible (screen failures) may be rescreened provided there is reason to 
believe that eligibility criteria will be met.  
 
Subjects who complete screening procedures and are not considered 
eligible (screen failures) may be rescreened one time provided there is 
reason to believe that eligibility criteria will be met.  
 
Clarified subjects should only 
be rescreened one time 
9 
Synopsis (pg 6) 
- 
Although either acute phase reactant (CRP or ESR) may be used 
during the study for eligibility and to determine remission or flares, 
it is advisable that the same acute phase reactant used to determine 
remission at screening also be used to determine flares during the 
treatment period. 
Additional text to provide 
guidance for interpretation of 
Acute Phase Reactants from 
remission 
in 
case 
of 
suspected 
flare 
during 
treatment period. 
10 
Synopsis (pg 7) 
Section 8.4.1 (pg 36) 
Section 8.8 (pg 40) 
Section 11.2 (pg 46) 
Any subject who prematurely discontinues the study drug treatment for 
safety or other reason will have an End-of-Treatment (EOT) visit and 
will be followed for the intended duration of study treatment (i.e., until 
the blind is broken) to address potential issues of informative censoring. 
Any subject who withdraws consent from the trial (i.e., all study 
procedures in addition to study drug) must complete a Safety Follow-up 
visit 28 ± 3 days from the last dose administered.  Additional follow up 
using public records may be captured where possible. 
An analysis of the study will be performed when the last subject reaches 
Week 26 according to the Statistical Analysis Plan (SAP). Based on the 
results of this analysis, all subjects will be offered open-label KPL-301 in 
the OLE portion of the trial, or the study will be discontinued. All 
subjects who do not proceed to the OLE must complete a Safety Follow-
up visit 28 ± 3 days from the last dose administered 
Any subject who prematurely discontinues the study drug treatment for 
safety or other reason will have an End-of-Treatment (EOT) visit and 
will be followed for the intended duration of study treatment (i.e., 
through Week 26 and Washout Safety Follow-up) to address 
potential issues of informative censoring. Any subject who withdraws 
consent from the trial (i.e., all study procedures in addition to study drug 
administration) must complete at a minimum the Final Washout 
Safety Follow-up visit 84 ± 3 days from the last dose administered.  
Additional follow-up using public records may be captured where 
possible. 
 
Removed 
and 
replaced 
language 
regarding 
the 
extension of the double-blind 
period past week 26 with 
language for the Washout 
Safety Follow-up Period 
11 
Synopsis (pg 7)  
Section 8.4.2 (pg 36) 
Section 11.3 (pg 46) 
 
Open-Label Extension: 
Depending on the results from the analysis of the 26-week placebo-
controlled base study, all subjects may be offered KPL-301 in an OLE. 
The OLE will continue for up to 6 months. During the OLE, subjects will 
be followed for safety information and will continue to follow study 
protocols from the double-blind period in the event of a flare and for 
steroid tapering procedures. During the OLE subjects may wean off 
KPL-301 onto SoC as determined by the Investigator. 
Washout Safety Follow-up: 
After subjects complete the 26-week double blind treatment period, 
they will discontinue and wash off of blinded KPL-301 or placebo 
during a 12-week Washout Safety Follow-up Period, which includes 
close safety follow-up and monitoring for potential GCA flares.  
During this time, it is recommended that subjects, regardless of 
remission status, receive SoC oral prednisone therapy, taking into 
consideration that they have just completed treatment with what 
may have been an efficacious therapy which supported the tapering 
off of standard of care concomitant oral corticosteroids.  Clinicians 
may choose to observe subjects closely during the washout period 
without any change in concomitant medications or may choose 
(consistent with current SoC guidelines) to increase the daily 
Removed 
open 
label 
extension 
per 
Regulatory 
Agency 
feedback 
and 
replaced with Washout Safety 
Follow-up period to ensure 
subjects 
are 
adequately 
followed and weaned back to 
Standard of Care. 


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Page 71 of 101 
 
 
CONFIDENTIAL 
corticosteroid dose prophylactically/empirically by approximately 
10 mg above the prednisone dose administered at Week 26.  The 
prednisone dose can then be tapered or maintained throughout the 
remainder of the 12-week Washout Safety Follow-up Period as per 
Investigator discretion.  After the Final Washout Safety Follow-up 
visit (Week 38) has been completed, the subjects will exit the trial 
and should be transitioned to SoC per investigator judgement.   It is 
not required that the steroid taper have been completed, (0 mg) 
prior to subjects exiting the trial at Week 38. 
 
12 
Synopsis (pg 8) 
For the primary endpoint analysis, the aim is to have approximately 36 
subjects assigned to KPL-301 and approximately 24 subjects assigned to 
placebo. Of the study population, the aim is to have 50% with new-onset 
disease and 50% with relapsing disease. 
Approximately 60 subjects will be randomized at a 3:2 allocation 
ratio.  Approximately 36 subjects will be assigned to KPL-301, and 
approximately 24 subjects will be assigned to placebo. Of the study 
population, the aim is to have 50% with new-onset disease and 50% 
with relapsing disease. 
Clarification 
13 
Inclusion Criteria 3 
Synopsis (pg 9)  
Section 8.7.1 (pg 37) 
…New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined 
as: … 
 
…Unequivocal cranial symptoms of GCA (new-onset localized 
headache, scalp or temporal artery tenderness, ischemia-related vision 
loss, or otherwise unexplained mouth or jaw pain upon mastication)… 
 
...Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND at least 
one of the following: 
Active GCA within 6 weeks of Day 0 defined as clinical 
sign/symptom(s) and Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/ 
dL  
OR 
No remission since the diagnosis of disease as per clinical expectations. 
(refractory nonremitting) 
…New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, 
defined as: … 
 
….Unequivocal cranial symptoms of GCA (new-onset localized 
headache, scalp or temporal artery pain or tenderness, ischemia-
related vision loss, or otherwise unexplained mouth or jaw pain upon 
mastication)… 
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND: 
Active GCA within 6 weeks of Day 0 defined as clinical 
sign/symptom(s) as per above and Westergren ESR > 30 mm/hour or 
CRP ≥ 1 mg/ dL 
 
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 
0 AND 
No remission since the diagnosis of disease as per clinical expectations. 
i.e. Presence of sign/symptoms as per above and Westergren 
ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks of Day 0.  
. 
Clarification and formatting 
for ease of understanding 
14 
Inclusion Criteria 4 
Synopsis (pg 9) 
Section 8.7.1 (pg 37) 
Remission of GCA at Day 0 (resolution of GCA symptom(s) and CRP < 
1.0 mg/dL or ESR < 20 mm in the first hour)... 
Remission of GCA at or before Day 0 (resolution of GCA symptom(s) 
and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour)… 
Clarification 


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CONFIDENTIAL 
15 
Inclusion Criteria 6 
Synopsis (pg 9) 
Section 8.7.1 (pg 37) 
If using methotrexate (MTX), oral or parenteral up to 25mg/week is 
permitted in screening if started more than 6 weeks prior to Day 0 and 
should be stable or decreasing with the intention to discontinue use by 
Day 0. 
 
If using methotrexate (MTX), oral or parenteral up to 25mg/week is 
permitted in screening if started more than 6 weeks prior to Day 0 and 
should be tapered to zero by Day 0. 
 
Clarification that MTX use is 
excluded during the study. 
16 
Inclusion Criteria 9 
Synopsis (pg 9,10) 
Section 8.7.1 (pg 38) 
Female subjects must be:..  
...c)  nonpregnant, nonlactating, and having agreed to use an effective 
method of contraception (i.e., hormonal contraceptives, intrauterine 
device (IUD), or double barrier methods such as condom plus 
diaphragm or diaphragm plus spermicide or condom plus spermicide) 
from Screening visit until 12 weeks after final study drug administration 
 
 
Female subjects must be:..  
...c)  nonpregnant, nonlactating, and if sexually active having agreed 
to use a highly effective method of contraception (i.e., hormonal 
contraceptives associated with inhibition of ovulation or intrauterine 
device [IUD], or intrauterine hormone-releasing system [IUS], or 
sexual abstinence) from Screening Visit until the Final Washout 
Safety Follow-up visit 84 ± 3 days from EOT Visit.   
 
Text added per regulatory 
feedback 
17 
Inclusion Criteria 10 
Synopsis (pg 10) 
Section 8.7.1 (pg 38) 
Male subjects must have documented vasectomy or must agree to use 
double barrier methods of contraception (such as condom plus 
diaphragm or diaphragm plus spermicide or condom plus spermicide) or 
use condom plus hormonal contraceptives or condom plus IUD with 
their partners of childbearing potential from Day 0 until the Safety 
Follow-up visit. Male subjects must agree to refrain from donating 
sperm from Day 0 until the Safety Follow-up visit. 
Male subjects must have documented vasectomy or if sexually active 
must agree to use a highly effective method of contraception with 
their partners of childbearing potential (i.e., hormonal contraceptives 
associated with the inhibition of ovulation or intrauterine device 
[IUD], or intrauterine hormone-releasing system [IUS], or sexual 
abstinence) from Day 0 until the Final Washout Safety Follow-up visit 
84± 3 days from EOT Visit. Male subjects must agree to refrain from 
donating sperm during this time period. 
 
18 
Exclusion Criteria 6 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Treatment with any investigational drug therapy within 4 weeks or 5 
half-lives of the study agent, whichever was longer, prior to Screening 
 
Treatment with any non-biologic investigational drug therapy within 4 
weeks or 5 half-lives of the study agent, whichever was longer, prior to 
Screening 
 
Text added for clarification 
19 
Exclusion Criteria 9 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Intramuscular, IV corticosteroids within 4 weeks prior to Screening 
 
Intramuscular, Intra-articular, or IV corticosteroids within 4 weeks 
prior to Screening 
 
Text added for clarification 
20 
Exclusion Criteria 11 
Synopsis (pg 10) 
Section 8.7.2 (pg 38) 
Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or 
mycophenolate mofetil (MMF) within 4 weeks of Screening 
 
Treatment with hydroxychloroquine, cyclosporine A, azathioprine, 
cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks 
of Screening 
 
Text added for clarification 
21 
Exclusion Criteria 15 
Synopsis (Pg 11) 
Active, untreated or partially treated latent tuberculosis (TB) 
Positive (or 2 indeterminate) QuantiFERON test results. 
Text changed for clarification 


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Section 8.7.2 (pg 39) 
22 
Exclusion Criteria 19 
Synopsis (pg 11) 
Section 8.7.2 (pg 39) 
History of cancer within the last 10 years (20 years for breast cancer) 
except for basal and squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix treated and considered cured 
 
History of cancer within the last 10 years - except for basal and 
squamous cell carcinoma of the skin or in situ carcinoma of the cervix 
treated and considered cured 
 
To allow for consistency of 
exclusion 
of 
all 
cancer 
including breast cancer within 
the last 10 years. 
23 
Exclusion Criteria 20 
Synopsis (pg 11) 
Section 8.7.2 (pg 39) 
Evidence of clinically uncontrolled respiratory disease. The 
Investigator should review the data from subjects’ respiratory 
assessments including chest x-ray and pulmonary function tests (PFTs) 
performed within 12 weeks prior to Day 0. The subjects must have had 
values ≥ 60% of predicted for measurements performed and no 
uncontrolled lung disease. A subject’s medical regimen should not 
have been significantly intensified to control lung disease within 12 
weeks prior to Day 0. 
 
Evidence of clinically uncontrolled respiratory disease. The 
Investigator should review the data from subjects’ respiratory 
assessments including chest x-ray and pulmonary function tests (PFTs)  
including DLCO performed during the screening period or within 
12 weeks prior to Day 0 if results of prior assessments are available. 
Available PFT and DLCO assessments must have had values ≥ 60% 
of predicted for measurements performed and no uncontrolled lung 
disease. A subject’s medical regimen should not have been 
significantly intensified to control lung disease within 12 weeks prior 
to Day 0. 
 
Text added for clarification 
24 
Test Products, Dosage 
and Mode of 
Administration 
Synopsis (pg 12) 
 
Cases of GCA flare should be treated according to the Investigator’s 
judgment and SoC to ensure the best possible care of the subject. In 
general, the subject should continue to receive the assigned KPL-301 or 
placebo and should also receive an increased dose of coadministered 
prednisone, as determined by the Investigator, generally of up to 60 
mg/day. The dosages of all concomitant medications used to treat the 
GCA flare must be documented. If a flare, particularly a major flare, 
should require a dose of corticosteroid higher than prednisone 60 mg/day, 
in the judgment of the Investigator, steroid escape therapy is allowed 
(i.e., doses of prednisone > 60 mg/day, or equivalent, or IV 
corticosteroids) until clinical remission is achieved. 
If the clinical response is positive, after an appropriate period of clinical 
stabilization, as determined by the Investigator, (usually 1-2 weeks) the 
subject may resume the protocol-defined steroid taper, starting at the 
dose at which remission was achieved or prednisone 60 mg/day, 
whichever is lower.  
Any subject who cannot adhere to the protocol-defined steroid taper due 
to flare/relapse will be allowed to receive a more gradual Investigator-
defined steroid taper and will continue to receive the assigned KPL-301 
or placebo.  
 
- 
Text deleted as it is duplicate 
of what is described in the 
Base 
Treatment 
Period 
section of the synopsis on pg 
7. 
25 
Test Products, Dosage 
and Mode of 
During the OLE, subjects will receive open-label KPL-301 150 mg every 
2 weeks for up to 6 additional months and may wean off KPL-301 onto 
After subjects have completed the 26-week double blind treatment 
period, they will discontinue and wash off blinded KPL-301 or 
Removed 
text 
regarding 
Open-label 
Extension 
and 




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30 
Overview 
of 
Trial 
Design 
Synopsis (pg 13)  
Figure 5 (pg 31) 
- 
- 
Design diagram replaced to 
reflect 26-week exposure and 
12-week 
Washout 
Safety 
Follow-up period. 
31 
Statistical Methods 
Synopsis (pg 14) 
Section 14.1 (pg 57) 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or 
higher. All clinical study data will be presented in subject data listings. 
Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile 
(Q1), median, third quartile (Q3), minimum and maximum for 
continuous variables, and frequency and percentage for categorical and 
ordinal variables. If there are missing values, the number missing will be 
presented, but without a percentage.  The preliminary SAP is presented 
here, with the final SAP to be confirmed in a separate document (SAP) 
prior to study unblinding. 
 
General Methods 
All statistical analyses will be performed using SAS® Version 9.3 or 
higher. All clinical study data will be presented in subject data listings. 
Descriptive statistics will be presented for all endpoints and will include 
number of subjects (n), mean, standard deviation (SD), first quartile 
(Q1), median, third quartile (Q3), minimum and maximum for 
continuous variables, and frequency and percentage for categorical and 
ordinal variables. The preliminary SAP is presented here, with the final 
SAP to be confirmed in a separate document (SAP) prior to study 
unblinding. 
 
Change of text to allow use 
of SAS Version 9.3 or higher 
32 
Statistical Methods 
Synopsis (pg 14) 
Section 14.3.1 (pg 58) 
 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or 
placebo and are assessed for at least 1 day in the double-blind treatment 
period will be included in the modified intent-to-treat (mITT) analysis 
set. Efficacy analyses will be based on the mITT analysis set. All mITT 
analyses will be based on each subject’s randomized treatment 
assignment.  
 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or 
placebo and at least have 1 assessment in the double-blind treatment 
period will be included in the modified intent-to-treat (mITT) analysis 
set. Efficacy analyses will be based on the mITT analysis set. All mITT 
analyses will be based on each subject’s randomized treatment 
assignment.  
 
Text changed for clarification 
33 
Statistical Methods 
Synopsis (pg 14) 
Section 14.3.3 (pg 58) 
Per Protocol Analysis Set 
All randomized subjects who complete Week 26 in the double blind 
period without protocol deviations deemed to impact efficacy or ethical 
conduct will be included in the per-protocol (PP) set. 
 
Per Protocol Analysis Set 
All mITT subjects without protocol deviations deemed to impact 
efficacy or ethical conduct will be included in the per-protocol (PP) set. 
 
Text changed to better reflect 
Per Protocol Analysis set 
after limiting the 26 week 
exposure. 
34 
Statistical Methods 
Synopsis (pg 14,15) 
Section 14.4 (pg 58- 59) 
Section 14.5.1 (pg 
59,60) 
Section 14.5.2 (pg 60) 
Primary Efficacy Endpoint Analysis 
The primary objective of this POC study is to evaluate the efficacy of 
KPL-301 versus placebo, coadministered with a 26 week steroid taper, 
for maintaining sustained remission for 26 weeks in subjects with new-
onset or relapsing/refractory GCA. Sustained remission is defined as the 
absence of flare (as defined above) from the start of double-blind 
treatment through Week 26. The primary efficacy analysis variable is 
time from start of double-blind treatment until the first flare occurring 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as 
time from randomization to the date of first flare occurring within the 
26-week period. Subjects who do not experience a flare during this 
period will be censored at the Week 26 visit. Subjects who drop out or 
are lost to follow-up prior to experiencing a flare during the 26-week 
double-blind period will be censored at the time of their last available 
visit. 
Text changed to provide 
clarification as well as to 
limit endpoint collection to 
the 26 Week exposure. 




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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
35 
Statistical Methods 
Synopsis (pg 15) 
Section 14.2 (pg 57,58) 
Sample Size Estimation 
With 36 subjects randomized to KPL-301 and 24 subjects randomized to 
placebo, a two-sided log-rank test for equality of survival curves with a 
0.05 significance level will have approximately 89% power to detect a 
37.5% difference (20% placebo vs 57.5% KPL-301) in the proportion of 
subjects who experience sustained remission during the 26-week 
double-blind base period. 
It is expected that the trial will have equal numbers of subjects in the two 
randomization strata. Assuming that the percentage of subjects 
experiencing sustained remission in the new onset stratum is 70% for 
KPL-301 and 30% for placebo. The percentage of subjects experiencing 
sustained remission in the relapsing/refractory stratum is 45% for KPL-
301 and 10% for placebo. A two-sided log-rank test with 0.1 significance 
level will have 75% power to detect a treatment difference within the 
stratum.   
Sample Size Estimation 
Assuming that time to flare follows an exponential distribution and 
the proportion of subjects without a flare by Week 26 will be 20% 
in placebo and 57 5% in KPL-301, the median time to flare would 
be estimated to be approximately 11.20 weeks in placebo and 32.57 
weeks in KPL-301.  The hazard ratio (KPL-301 vs. placebo) would 
be estimated to be approximately 0.3438.  With a 2-sided 
significance level of 0.05 and a 3:2 randomization ratio for KPL-301 
vs. placebo, it would require approximately 34 events to achieve 
86% power using a two- sided log rank test.   
Approximately 60 subjects will be randomized by disease stratum 
(new-onset or relapsing/refractory) to receive KPL-301 or placebo 
at a 3:2 allocation ratio. 
Subject disposition and the flare event accrual will be closely 
monitored during the study. The monitoring activities will be done 
in a blinded fashion. If there is a high dropout rate and/or the event 
accrual rate is significantly slower than anticipated, up to 10 
additional subjects may be randomized to obtain the target number 
of events required for the analysis of primary efficacy endpoint. 
 
Text changed to provide 
clarification 
36 
Schedule of Activities 
Synopsis (pg 16)  
Removed: 
Schedule of Assessments 
• Every 4 weeks thereafter visit and associated assessments 
• OLE visit and assessments 
• Fasting lipid panel and HbA1c during screening 
Added: 
Schedule of Activities 
• Week 30, Week 34, Week 38 Visits 
• Ultrasound at or before Day 0 and at Week 38 
• Pulmonary function tests including DLCO at Week 38 
• Serum pregnancy test during screening 
• Urine pregnancy test at Day 0, Week 12, Week 26 and Week 38 
• Safety Labs (Hematology, Chemistry & Liver profile) at Week 4 and 
Week 38 
• Fasting lipid panel and HbA1c at Day 0 
 
  
Activities removed to limit 
double-blind Period to 26 
Weeks.  Activities changed to 
remove Open-label extension 
and replace with Washout 
Safety 
Follow-up 
Period.  
Additional safety labs and 
procedures added per Ethic 
and Regulatory feedback. 


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CONFIDENTIAL 
 
37 
Schedule of Activities 
Footnotes 
Synopsis (pg 17)  
Footnotes 
a. Monthly visits are conducted until the last subject completes the 26-
week double-blind analysis period and the analysis is complete. 
 
e. Open-label extension visits occur monthly for up to 6 months. During 
the open-label extension subjects may wean off KPL-301 onto standard 
of care at the discretion of the investigator. 
 
f. During the open-label extension all subjects participating will receive 
open-label KPL-301. Any subjects on steroids at the end of the double-
blind period should taper steroids at the discretion of the investigator. 
 
m. Electrocardiogram or chest X-ray (or high res CT) are not required at 
an EOT visit but may be performed at a UNS visit 
- 
Footnotes 
removed 
per 
updated 
schedule 
of 
Activities 
38 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
c. In the event of an unscheduled visit, only the relevant assessments 
pertaining to the visit need to be captured. Subjects reporting worsening 
of GCA symptoms or any safety issues may be brought in for an 
unscheduled visit at the study clinic at any time. This visit can be 
combined with the EOT visit in which all necessary assessments should 
be completed. 
b. In the event of an unscheduled visit, only the relevant 
assessments/activities pertaining to the visit need to be captured. 
Subjects reporting worsening of GCA symptoms or any safety issues 
may be brought in for an unscheduled visit at the study clinic at any 
time. This visit can be combined with the EOT visit in which all 
necessary EOT related assessments/activities should be completed. 
 
Footnotes updated or added 
to provide clarity 
39 
Schedule of Activities 
Footnotes 
Synopsis 
(pg 
17) 
Section 8.8 (pg 40) 
d. All subjects, including subjects who prematurely discontinue the study 
(i.e., withdraw consent), must complete a safety follow up visit 28 ± 3 
days after the last dose of KPL-301 or placebo.  Additional follow up 
using public records may be captured if possible. 
 
c. All subjects, including subjects who prematurely discontinue the 
study (i.e., withdraw consent), must complete at a minimum the Final 
Safety Follow up visit 84 ± 3 days after the EOT Visit.  Additional 
follow up using public records may be captured if possible. 
Footnotes updated or added 
to provide clarity 
40 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
g. At baseline, subject and/or caregiver should be trained on proper self-
administration and handling and accountability of IMP. This training 
should be documented and can be repeated as necessary throughout the 
study. 
 
d. At baseline, subject and/or caregiver should be trained on proper self-
administration and handling and accountability of study drug. This 
training should be documented and can be repeated as necessary 
throughout the study. 
 
Footnotes updated or added 
to provide clarity 
41 
Schedule of Activities 
Footnotes 
h. If a study site or clinic visit coincides with the subject’s scheduled 
dose, study treatment will be administered at the study site or clinic.  
Study treatment should be dispensed as necessary to the subject for home 
e. If a study site or clinic visit coincides with the subject’s scheduled 
dose, study treatment will be administered at the study site or clinic.  
Study drug treatment should be dispensed as necessary to the subject 
Footnotes updated or added 
to provide clarity 


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CONFIDENTIAL 
Synopsis (pg 17) 
administration to ensure dosing compliance.  Investigator staff may 
contact patients between visits to ensure compliance with protocol 
specified treatment regimens. 
 
for home administration to ensure dosing compliance.  Investigator staff 
may contact patients between visits to ensure compliance with protocol-
specified treatment regimens. 
 
42 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
i. New-onset subjects can have an optional temporal artery biopsy taken 
at Screening and Week 26 as part of the study. For relapsing/refractory 
patients, if the subject has not had a prior a temporal biopsy an optional 
biopsy can be done at Screening and Week 26. If the subject has an 
existing biopsy sample available this can be submitted as the 
screening/predose sample and an optional biopsy can be performed at 
Week 26.  
 
f. New-onset subjects can have an optional temporal artery biopsy taken 
at Screening (or otherwise available from diagnostic workup) and 
Week 26 as part of the study. For relapsing/refractory patients, if the 
subject has not had a prior a temporal biopsy an optional biopsy can be 
done at Screening and Week 26. If the subject has an existing biopsy 
sample available this can be submitted as the screening/predose sample 
and an optional biopsy can be performed at Week 26.  
 
Footnotes updated or added 
to provide clarity 
43 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
j. Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at 
Screening, or existing documentation within 12 weeks of Day 0 can be 
used and reviewed by the Investigator or designee. 
 
g. Chest X-ray (or high res CT), DLCO, and PFTs should be obtained at 
Screening, or existing documentation (if available) within 12 weeks of 
Day 0 can be used and reviewed by the Investigator or designee. 
 
Footnotes updated or added 
to provide clarity 
44 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
k. PFTs and DLCO should be performed at Screening 6-12 weeks prior 
to Day 0. They should also be performed at Weeks 12 and 26 with a 
window of ±14 days; after Week 26 PFTs and DLCO should be 
performed every 6 months ± 14 days; if the EOT visit is > 3 months of 
the prior test, the assessment should be performed.  
  
h. PFTs and DLCO should be performed at Screening within 6 weeks 
prior to Day 0 (or documented report available from PFT &/or 
DLCO from within 12 weeks prior to Day 0). They should also be 
performed at Weeks 12 and 26 and 38 with a window of ±14 days;  
 
Footnotes updated or added 
to provide clarity 
45 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
p. Clinical decisions for determination of inclusion and flare will be 
based upon local laboratory values. 
 
l. Clinical decisions for determination of inclusion and flare will be 
based upon local laboratory values either ESR and/or CRP. 
 
Footnotes updated or added 
to provide clarity 
46 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
q. The imaging technique used during screening to diagnose GCA should 
be repeated throughout the study.  If ultrasound is available at screening 
for diagnosis of GCA this should be conducted again at weeks 12, 26 and 
then every 6 months thereafter, or in case of a suspected flare of GCA 
with no other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, 
CT/CTA or PET-CT was used at screening for diagnosis of GCA and no 
ultrasound is available this should be repeated at week 26 then every six 
months thereafter or in case a suspected flare as necessary in order to 
reduce the exposure of radiation to the subject. 
 
m. The imaging technique used during screening to diagnose GCA 
should be repeated at week 26 for the study.  If ultrasound is available 
at screening for diagnosis of GCA this should be conducted again at 
weeks 12, 26 and 38, or in case of a suspected flare of GCA with no 
other imaging (MRI, CT/CTA or PET-CT) required.  If MRI, CT/CTA 
or PET-CT was used at screening for diagnosis of GCA and no 
ultrasound is available, the same imaging technique used at screening 
should be repeated at week 26 or as necessary for diagnosis in case a 
suspected flare. 
 
Footnotes updated or added 
to provide clarity 


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CONFIDENTIAL 
47 
Schedule of Activities 
Footnotes 
Synopsis (pg 17) 
- 
n. Ultrasound imaging if clinically relevant should be performed at 
or before Day 0 to support clinical remission decision making unless 
there is no evidence of temporal artery inflammation and diagnosis 
of GCA is confined to large vessels (By MRI or CT). 
 
Footnote added to provide 
clarity 
48 
Section 9.1 (pg 40) 
…The investigational product is supplied as a sterile clear to opalescent, 
colorless to slightly brown-yellow liquid, free from visible particles, in a 
prefilled syringe at a nominal fill volume of 1.0 mL, stoppered with a 
Teflon-faced elastomeric stopper, and sealed with an aluminium 
overseal. Each syringe contains 150 mg (nominal) of active 
investigational product. 
 
…The investigational product is supplied as a sterile clear to opalescent, 
colorless to slightly brown-yellow liquid, free from visible particles, in a 
1mL prefilled syringe at a nominal fill volume of 1.0 mL, stoppered 
with a Teflon-faced elastomeric stopper, accessorized with a needle 
guard, and extended finger flange and a plunger rod. Each syringe 
contains 150 mg (nominal) of active investigational product. 
Text changed to provide 
clarity 
49 
Section 9.2 (pg 41) 
…The placebo is supplied as a sterile clear to slightly opalescent, 
colorless to slightly yellow liquid, free from visible particles, in a 
prefilled syringe at a nominal fill volume of 1.0 mL, stoppered with a 
Teflon-faced elastomeric stopper, and sealed with an aluminium 
overseal. 
…The placebo is supplied as a sterile clear to, colorless liquid, free from 
visible particles, in a 1 ml prefilled syringe at a nominal fill volume of 
1.0 mL, stoppered with a Teflon-faced elastomeric stopper, 
accessorized with a needle guard and extended finger flange and a 
plunger rod. 
Text changed to provide 
clarity 
50 
Section 9.3 (pg 42) 
… During the OLE, subjects will continue to follow study protocols from 
the double-blind period in the event of a flare and for steroid tapering 
procedures unless indicated otherwise as per the discretion of the 
Investigator. 
 
... During the Washout Safety Follow-up Period, the prednisone dose 
can then be tapered or maintained throughout the remainder of the 12-
week Washout Period as per the discretion of the Investigator.  After the 
Final Washout Safety Follow-up visit (Week 38) has been completed 
the subjects will exit the trial and should be transitioned to SoC per 
investigator judgement.    
 
Text added to replace OLE 
with Washout Safety Follow-
up Period 
51 
Section 9.4 (pg 42,43) 
Subjects who are candidates for enrollment will be evaluated for 
eligibility by the Investigator to ensure that the criteria given in Section 
8.7 have been satisfied and that the patients are eligible for 
randomization. 
Subjects will be randomized at a 3:2 ratio to receive either 150 mg KPL-
301 or placebo. Randomization will be stratified according to whether 
subjects have new-onset disease or relapsing disease.  Additional strata 
may be identified and described within the SAP. 
Subjects who are candidates for enrollment will be evaluated for 
eligibility by the Investigator to ensure that the criteria given in Section 
8.7 have been satisfied and that the subjects are eligible for 
randomization. 
Subjects will be randomized at a 3:2 ratio to receive either 150 mg KPL-
301 or placebo. Randomization will be stratified according to whether 
subjects have new-onset disease or relapsing disease.   
Text removed 
52 
Section 9.6.2 (pg 43,44) 
In the event of a medical emergency, the Investigator may unblind an 
individual subject’s treatment allocation in consultation with the Sponsor. 
In general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received 
active drug. In most cases, the management of a medical emergency 
would be the same whether or not active drug was received by the 
In the event of a medical emergency, the Investigator may unblind an 
individual subject’s treatment allocation and notify the Sponsor. In 
general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received 
active drug. In most cases, the management of a medical emergency 
would be the same whether or not active drug was being received by the 
Text removed and changed to 
provide clarity 


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CONFIDENTIAL 
subject. If this were to be the case, the treatment allocation should not be 
unblinded. 
Depending on the results of the Week 26 analysis, all subjects may be 
offered open-label KPL-301 in the OLE portion of the trial or the study 
will be discontinued after the double-blind period. If the study is 
discontinued after the double-blind period, subjects will not be unblinded 
(except for the reasons listed above) until the clinical database has been 
locked. 
subject. If this were to be the case, the treatment allocation should not 
be unblinded. 
 
53 
Section 12.2.1 (pg 47) 
- 
Ideally clinical assessments of GCA signs/symptoms should occur 
prior to the investigator reviewing subject imaging, lab or acute 
phase reactant results at any given visit to minimize potential for 
assessment bias. 
 
Text added for clarity 
54 
Section 12.2.3 (pg 47) 
In cases where ultrasound of temporal artery was captured during the 
diagnosis of GCA at Screening, this procedure should be repeated at 
Weeks 12, 26, EOT and every 6 months thereafter as well as any 
instances of suspected flare over the course of the study.  Imaging and 
relevant data should be included in any elements of the diagnostic work-
up pertinent to the Investigator diagnosis of GCA. 
In cases where ultrasound of temporal artery was captured during the 
diagnosis of GCA at Screening, this procedure should be repeated at 
Weeks 12, 26, EOT and Week 38 as well as any instances of suspected 
flare over the course of the study.  Imaging and relevant data should be 
included in any elements of the diagnostic work-up pertinent to the 
Investigator diagnosis of GCA. 
Text changed to incorporate 
Week 38 visit 
55 
Section 12.3.1 (pg 48) 
A complete physical examination as possible by local practice should 
include an evaluation of the head, eye, ear, nose, and throat as well as 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, 
genitourinary, 
and 
neurological 
systems. 
Any 
abnormality identified at baseline should be recorded on the Medical 
History and Physical Examination eCRFs. 
 
A complete physical examination as possible by local practice should 
include an evaluation of the head, eye, ear, nose, and throat as well as 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, 
genitourinary, 
and 
neurological 
systems. 
Any 
abnormality identified at baseline should be recorded on the Medical 
History and Physical Examination eCRFs. 
 
Text added for clarity 
56 
Section 12.4 (pg 48) 
The digital ECG recording must be obtained and reviewed by the 
Investigator or designee. For safety monitoring purposes, the Investigator 
or designee must sign and date all ECG tracings and place the paper copy 
as part of the subject’s permanent study file at the site. ECG 
characteristics, including heart rate, QS duration, and RR, PR, and QT 
intervals will be recorded on the eCRF. QTcB (Bazett’s correction) and 
QTcF (Fridericia’s corrections) will be calculated. Changes in T-wave 
and U-wave morphology and overall ECG interpretation will be 
documented in eCRF. 
 
The digital ECG recording must be obtained and reviewed by the 
Investigator or designee. For safety monitoring purposes, the 
Investigator or designee must sign and date all ECG tracings and place 
the paper copy as part of the subject’s permanent study file at the site 
and overall ECG interpretation will be documented in eCRF. 
Text removed for consistency 
with data collection 
57 
Section 12.5.1 (pg 49) 
PFTs and DLCO should be obtained at Screening 6 weeks prior to Day 0, 
or existing documentation within 12 weeks of day 0 can be used and 
reviewed by the Investigator or designee. During the course of the study 
PFTs and DLCO should be obtained at Screening 6 weeks prior to Day 
0, or existing documentation within 12 weeks of day 0 can be used and 
reviewed by the Investigator or designee. During the course of the study 
Text 
changed 
to 
reflect 
updated schedule of activities 




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CONFIDENTIAL 
 
64 
Section 13.1.3.3 (pg 52) 
…Any subject who has been referred for a specialist pulmonary 
evaluation should not receive the investigational product until the 
symptom(s) or sign(s) causing the referral have resolved. 
…Any subject who has been referred for a specialist pulmonary 
evaluation may be instructed to stop the investigational product until 
the symptom(s) or sign(s) causing the referral have resolved. 
Text changed for clarity 
65 
Section 13.1.7 (pg 54) 
- 
Suspected Unexpected Serious Adverse Reaction  
A Suspected Unexpected Serious Adverse Reaction is an adverse 
reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g. investigator’s brochure for an 
unauthorized 
investigational 
product 
or 
prescribing 
information/summary of product characteristics for an authorized 
product). All relevant information about suspected serious unexpected 
adverse reactions that are fatal or life-threatening will be recorded and 
reported to the competent authorities in all the applicable countries, and 
to the Ethics Committee/Institutional Review Boards in conjunction 
with Directive 2001/20/EC.  
Text 
added 
per 
Ethics/Regulatory request 
66 
Section 13.4 (Pg 55) 
AEs will be collected from the time of signing of informed consent 
through the final Safety Follow-up period (24 days ± 3days after the last 
dose of study drug). 
AEs will be collected from the time of signing of informed consent 
through the Final Washout Safety Follow-up period (84 days ± 3 days 
after the EOT visit). 
Text changed for consistency 
with schedule of activities 
67 
Section 14.1.2 (pg 57) 
The primary objective of this study is to evaluate the efficacy of KPL-
301 versus placebo, in combination with steroid taper, for maintaining 
sustained remission for 26 weeks. The primary efficacy analysis entails 
the inferential comparison of KPL-301 to placebo with respect to time 
from start of double-blind treatment until the first flare occurring within 
the first 26-weeks of the double-blind period. The key secondary efficacy 
analysis entails inferential comparison of KPL-301 to placebo with 
respect to time from start of double-blind treatment until the first flare 
anytime during the double-blind period.   
 
Multiplicity with respect to these two inferential efficacy analyses will be 
managed via the gated hierarchical testing procedure.  If and only if the 
primary comparison results in a statistically significant difference 
between KPL-301 and placebo at 0.05 level of significance, the key 
secondary comparison may be conducted at alpha 0.05 as well.   
 
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
Multiplicity with respect to the primary efficacy endpoint and the key 
secondary efficacy endpoints will be managed via the gated 
hierarchical testing procedure.  If and only if the primary comparison 
results in a statistically significant difference between KPL-301 and 
placebo at 0.05 level of significance, the key secondary comparison will 
be conducted at alpha 0.05 as well.   
 
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
 
Text updated for clarity 
68 
Section 16.2 (pg 63) 
This study will be conducted in compliance with the protocol, the ICH-
GCP guideline, the Declaration of Helsinki, and local regulations. 
This study will be conducted in compliance with the protocol, the ICH-
GCP guideline, the most recent version of the Declaration of Helsinki 
Text updated for clarity 


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CONFIDENTIAL 
 
in which the Sponsor intends to publish the results regardless of the 
study outcome, and local regulations. 
 
69 
Section 17 (pg 64) 
- 
Study Termination 
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  
Non-compliance that might significantly jeopardize the validity or 
integrity of the study  
Recommendation to suspend or terminate the study by independent 
body such as DMC or Health Authority 
Sponsor decision to terminate development  
 
Where required by applicable regulations, the investigator or head 
of the medical institution must inform the IRB/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. 
 
Text 
added 
per 
Ethics/Regulatory request 
 
 


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CONFIDENTIAL 
20.3.2 Protocol Amendment v3.0 
Rationale for Amendment – Protocol Amendment v3.0 was completed to clarify aspects of protocol 
version 2.0 as well as to incorporate feedback from global Regulatory bodies.  Substantial changes to this 
version include: 
• 
Discontinuation of study drug (KPL-301 or placebo) in the event of a GCA Flare 
 
 
• 
Clarification of individual patient and study stopping criteria 
• 
Correction of the US Safety contact number 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 
 


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CONFIDENTIAL 
Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
1 
Title Page (pg 1) 
Header throughout 
Date of Protocol: 15 Oct 2018 
Version of Protocol: 2.0 
Date of Protocol: 15 Nov 2018 
Version of Protocol: 3.0 
Administrative 
2 
Section 2 (pg 2)  
Section 13.6 (pg 55) 
US 24 Hour Safety Hotline: 1 888-483-77729 
US 24 Hour Safety Hotline: 1 888-483-7729 
Administrative correction 
3 
Synopsis (pg 7) 
Section 8.4.1 (pg 32) 
Cases of flare should be treated according to the Investigator’s judgment 
and standard of care (SoC) to ensure the best possible care of the subject. 
In general: 
• 
The subject should continue to receive the assigned KPL-301 or 
placebo and should also receive an increased dose of 
coadministered prednisone, as determined by the Investigator, 
generally of up to 60 mg/day. The dosages of all concomitant 
medications used to treat the GCA flare must be entered into the 
eCRF. 
• 
If a flare, particularly a major flare, should require a dose of 
corticosteroid higher than prednisone 60 mg/day, in the judgment 
of the Investigator, steroid escape therapy is allowed (i.e., doses 
of prednisone > 60 mg/day or equivalent, or intravenous (IV) 
corticosteroids) until clinical remission is achieved.  If the 
clinical response is positive, after an appropriate period of 
clinical stabilization, as determined by the Investigator, the 
subject may resume the protocol-defined steroid taper, starting at 
the dose at which remission was achieved or prednisone 60 
mg/day, whichever is lower.  Any subject who cannot adhere to 
the protocol-defined steroid taper due to flare/relapse will be 
allowed to receive a more gradual Investigator-defined steroid 
taper and will continue to receive the assigned KPL-301 or 
placebo. These subjects will be considered to have met the 
primary endpoint if a flare has occurred prior to Week 26.  
Subjects who experience a flare or subjects who cannot adhere to 
the protocol-defined steroid taper due to a flare should be managed 
to ensure the best possible care of the subject: 
• 
The subject must discontinue the assigned study drug (KPL-
301 or placebo) and should receive escape therapy in 
accordance with local SoC, as determined by the Investigator, 
which may include, for example, dose modifications of 
corticosteroids, other immunomodulatory agents, and/or 
approved therapies (e.g., tocilizumab). The dosages of all 
concomitant medications used to treat the GCA flare must be 
entered into the eCRF. 
• 
Escape corticosteroid therapy can be escalated immediately.  
Due to possible safety and pharmacologic effects resulting 
from overlapping exposures to immunomodulatory agents 
on top of co-administered corticosteroids, the investigator 
should consider a washout period of at least 35 days (based 
on elimination half-lives) after the last dose of study drug if 
deemed clinically appropriate. 
Text updated per regulatory 
feedback 




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8 
Section 8.8 (pgs 38-39) 
Subjects may withdraw from the study drug treatment or from the study 
as a whole at any time for any reason, without prejudice to their medical 
care. The Investigator also has the right to discontinue treatment with and 
withdraw subjects from the study for any of the following reasons: 
Adverse event 
Life threatening or other unacceptable toxicity 
Subject requires use of a prohibited concomitant medication or therapy 
General or specific changes in the subject’s condition unacceptable for 
further treatment within the study parameters, in the Investigator’s 
opinion 
Severe noncompliance 
Lost to follow-up 
Subject withdrawal of consent 
A decision to modify or discontinue development of the drug 
Subjects may withdraw from the study drug treatment or from the study 
as a whole at any time for any reason, without prejudice to their medical 
care. The Investigator also has the right to discontinue treatment with 
and withdraw subjects from the study for any of the following reasons: 
Adverse event or Life threatening or other unacceptable toxicity, for 
example: 
Hepatic function abnormality defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater 
than 2 × ULN, assessed as related to investigational product  
CTCAE Grade 4 (life-threatening) anaphylaxis or hypersensitivity 
reactions  
CTCAE Grade 4 (life-threatening) serious infection or opportunistic 
infection (including septic shock). In addition, subjects with a diagnosis 
or reactivation of TB, hepatitis B, or hepatitis C will not receive any 
further investigational product.  
CTCAE Grade 4 (life-threatening) neutropenia  
Adverse events of malignancy of any grade; except for basal and 
squamous cell carcinoma of the skin or in situ carcinoma of the cervix 
treated and considered cured.  
Subject requires use of a prohibited concomitant medication or therapy 
General or specific changes in the subject’s condition unacceptable for 
further treatment within the study parameters, in the Investigator’s 
opinion 
Severe noncompliance 
Lost to follow-up 
Pregnancy or a decision to become pregnant 
Subjects who request to be permanently discontinued from further 
receipt of investigational product, regardless of the reason (Subject 
withdrawal of consent) 
A decision to modify or discontinue development of the drug 
 
Text updated per regulatory 
feedback 
9 
Section 9.3 (pg 40) 
…Any subject who cannot adhere to the protocol-defined steroid taper 
due to flare/relapse will be allowed steroid escape therapy per the 
Investigator such as prednisone or similar > 60 mg/day or IV 
corticosteroids but will continue to receive the KPL-301 or placebo… 
…Any subject who cannot adhere to the protocol-defined steroid taper 
due to flare/relapse will be allowed escape therapy per the 
Investigator…. 
Text removed per regulatory 
feedback 


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CONFIDENTIAL 
10 
Section 10.2 (pg 43) 
The introduction of the following medications is not permitted from 
initiation of screening through the end of the study. 
The introduction of the following medications is not permitted from 
initiation of screening through the end of the study unless indicated for 
escape therapy. 
Text add for clarity 
11 
Section 10.3 (pg 43) 
Subject who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse will be allowed steroid escape therapy per the Investigator, 
such as prednisone or similar > 60mg/day or IV corticosteroids and will 
continue to receive the assigned study drug treatment (KPL-301 or 
placebo). These subjects are considered to have met the primary endpoint 
provided the flare occurs prior to Week 26. 
Subject who cannot adhere to the protocol-defined steroid taper due to 
flare/relapse must discontinue study drug (KPL-301 or placebo) and 
should receive escape therapy in accordance with local SoC per the 
Investigator.  Escape therapy may include, for example, prednisone or 
similar > 60mg/day,IV corticosteroids, other immunomodulatory agents,  
and/or approved therapies (e.g., tocilizumab). These subjects are 
considered to have met the primary endpoint provided the flare occurs 
prior to Week 26. 
Escape corticosteroid therapy can be escalated immediately. Due to 
unknown possible safety and pharmacological effects from overlapping 
exposures to immunomodulatory agents on top of co-administered 
corticosteroids, the investigator should consider a washout period of at 
least 35 days (based on elimination half-lives) after the last dose of 
study drug (KPL-301 or placebo) if deemed clinically appropriate.  
Text updated per regulatory 
feedback 
12 
Section 11.2 (pg 45) 
In cases of flare, the prednisone dose may be increased. Any subject who 
cannot adhere to the protocol-defined steroid taper due to flare/relapse 
will be allowed to receive a more gradual Investigator-defined steroid 
taper and will continue to receive the assigned KPL-301 or placebo. 
These subjects will be considered to have met the primary endpoint if a 
flare has occurred prior to Week 26.  
Subjects who experience a flare or who cannot adhere to the protocol-
defined steroid taper due to flare/relapse must discontinue the assigned 
study drug (KPL-301 or placebo) and should receive escape therapy 
in accordance with local SoC. These subjects will be considered to 
have met the primary endpoint if a flare has occurred prior to Week 26.  
Text updated per regulatory 
feedback 
13 
Section 12.6.7 (pg 49) 
For women of child bearing potential a serum pregnancy test should be 
performed prior to enrolment at the site. Urine pregnancy tests should be 
performed at Day 0, Week 12, Week 26 and the Final Washout Safety 
Follow-up Visit.  Abnormal laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours). 
 
For women of child bearing potential a serum pregnancy test should be 
performed prior to randomization at the site. Urine pregnancy tests 
should be performed at Day 0, Week 12, Week 26 and the Final 
Washout Safety Follow-up Visit.  Abnormal laboratory results should 
be repeated as soon as possible (preferably within 24 to 48 hours). 
 
Text changed for clarification 


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14 
Section 17.1 (pg 63) 
- 
17.1 Study Stopping Criteria 
If the sponsor receives a report of an event consistent with any one of 
the following, the medical monitor or designee will immediately assess 
the event by gathering all available information including, where 
possible, direct telephone contact with the reporter. A prompt review of 
the data will be initiated by the sponsor, and the information will be 
referred to the DMC within 1 business day of the receipt of the initial 
report by the Sponsor.  
Any CTCAE grade 5 (death) assessed as related to the investigational 
product  
Any CTCAE grade 4 (life-threatening) assessed as related to the 
investigational product  
Any CTCAE grade 4 (life-threatening) of anaphylaxis  
Hepatic function abnormality defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater 
than 2 × ULN, assessed as related to investigational product  
Any unforeseen events that, in the opinion of the DMC and the Sponsor, 
may contraindicate further dosing  
Clinically-significant pulmonary abnormalities that in the opinion of the 
DMC and the Sponsor may contraindicate further dosing  
If any above-listed events occur, the Sponsor will promptly conduct a 
cumulative review of safety data, including the DMC assessment of the 
event, and the circumstances of the event in question to determine 
whether the study should be modified, suspended or terminated. 
Text added per regulatory 
feedback 


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CONFIDENTIAL 
20.3.3 Protocol Amendment v4.0 
Rationale for Amendment – Protocol Amendment v4.0 was completed to clarify aspects of protocol 
version 3.0 as well as to incorporate feedback from global Regulatory bodies.  Substantial changes to this 
version include: 
• 
Updated secondary endpoints and analysis; and inserted study endpoints into the Synopsis 
Objective section. 
• 
The planned number of subjects to be enrolled in the study was updated from approximately 60 to 
approximately 70 subjects (42 subjects planned to be assigned to the KPL-301 arm and 
28 subjects planned to be assigned to the placebo arm) to align with the updated sample size 
estimation. 
• 
Added clarification that SAEs will be recorded in the eCRF within 24 hours of discovery. 
Please see the below summary of changes for more details on the changes incorporated into this version. 
Bold indicates addition, underline indicates removal. 
 
 






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CONFIDENTIAL 
Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
 
Safety Endpoints: 
• 
Incidence of treatment emergent adverse events 
• 
Change in physical exam results 
• 
Change in vital signs 
• 
Change in clinical laboratory parameters  
o 
Serum chemistry 
o 
Hematology 
o 
Urinalysis 
5 
Synopsis: Number of 
Subjects and  
Overview of Trial 
Design Figure 
Approximately 60 subjects will be randomized at a 3:2 allocation ratio.  
Approximately 36 subjects will be assigned to KPL-301, and approximately 
24 subjects will be assigned to placebo. Of the study population, the aim is 
to have 50% with new-onset disease and 50% with relapsing disease. 
Approximately 70 subjects will be randomized at a 3:2 allocation ratio.  
Approximately 42 subjects will be assigned to KPL-301, and approximately 
28 subjects will be assigned to placebo. Of the study population, the aim is 
to have 50% with new-onset disease and 50% with relapsing disease. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
6 
Synopsis: Statistical 
Methods 
General Methods 
All statistical analyses will be performed using SAS® Version 9.3 or higher. 
All clinical study data will be presented in subject data listings. Descriptive 
statistics will be presented for all endpoints and will include number of 
subjects (n), mean, standard deviation (SD), first quartile (Q1), median, 
third quartile (Q3), minimum and maximum for continuous variables, and 
frequency and percentage for categorical and ordinal variables. The 
preliminary SAP is presented here, with the final SAP to be confirmed in a 
separate document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo 
and at least have 1 assessment in the double blind treatment period will be 
included in the modified intent-to-treat (mITT) analysis set. Efficacy 
analyses will be based on the mITT analysis set. All mITT analyses will be 
based on each subject’s randomized treatment assignment. 
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo 
will be included in the Safety Analysis Set. Safety analyses will be based on 
the medication that was actually administered to each subject. 
General Methods 
All statistical analyses will be performed using SAS® Version 9.4 or higher. 
All clinical study data will be presented in subject data listings. Descriptive 
statistics will be presented for all endpoints and will include number of 
subjects (n), mean, standard deviation (SD), first quartile (Q1), median, third 
quartile (Q3), minimum and maximum for continuous variables, and 
frequency and percentage for categorical and ordinal variables. The 
preliminary SAP is presented here, with the final SAP to be confirmed in a 
separate document (SAP) prior to study unblinding. 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least 1 dose of KPL-301 or placebo 
and at least have 1 assessment in the double blind treatment period will be 
included in the modified intent-to-treat (mITT) analysis set. Efficacy 
analyses will be based on the mITT analysis set. All mITT analyses will be 
based on each subject’s randomized treatment assignment. 
Safety Analysis Set 
All randomized subjects who take at least 1 dose of KPL-301 or placebo will 
be included in the Safety Analysis Set. Safety analyses will be based on the 
medication that was actually administered to each subject. 
Updated text to allow use 
of SAS Version 9.4 or 
higher 
Updated text in Endpoint 
Analysis subsection for 
clarification and new 
statistical assumptions. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint. 
Time to elevated ESR 
and CRP by Week 26 
and time to 
sign/symptoms of GCA 
or new or worsening 
vasculitis by imaging by 
Week 26 were added as 
secondary efficacy 
endpoints in response to 
request from the FDA. 


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Current Text 
Revised Text 
Rationale 
Per Protocol Analysis Set 
All mITT subjects without protocol deviations deemed to impact efficacy or 
ethical conduct will be included in the per-protocol (PP) set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the date of first flare occurring within the 26-week 
period. Subjects who do not experience a flare during this period will be 
censored at the Week 26 visit. Subjects who drop out or are lost to follow-
up prior to experiencing a flare during the 26-week double-blind period will 
be censored at the time of their last available visit. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 26-week 
double-blind period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. Kaplan-Meier estimates of remission 
rate at 26 weeks will be presented with the corresponding 95% CI by 
treatment group. To describe the magnitude of treatment effect, the hazard 
ratio for KPL-301 compared to placebo and the corresponding 95% CI will 
be calculated based on a Cox proportional-hazards model with treatment as 
covariate. 
As a key secondary efficacy endpoint, time to flare by week 26 in the per 
protocol population will be analyzed using the same methods described 
above. Subjects who do not experience flare during double-blind treatment 
will be censored at their last visit of the double-blind treatment period. 
Subjects who drop out or are lost to follow-up prior to experiencing a flare 
at any time during double-blind treatment will be censored at the time of 
their last available visit. 
Additional secondary efficacy endpoints include the following endpoints 
that will be analyzed. Treatment comparisons will be performed using 
Cochran-Mantel-Haenszel test controlling for the randomized stratum. 
• 
Percentage of subjects who have completed the 26-week 
corticosteroid taper and who have a normal ESR 
• 
Percentage of subjects who have completed the 26-week 
corticosteroid taper and who have a normal CRP by Week 26 
Per Protocol Analysis Set 
All mITT subjects without important protocol deviations deemed to impact 
efficacy or ethical conduct will be included in the per-protocol (PP) analysis 
set. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the first flare occurring within the treatment period. 
Detailed censoring rules will be provided in the SAP.  
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 
treatment period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. To describe the magnitude of treatment 
effect, the hazard ratio for KPL-301 compared to placebo and the 
corresponding 95% CI will be calculated based on a Cox proportional-
hazards model with treatment as a covariate and stratified by the 
randomization strata. 
The protocol definition of flare includes multiple components. 
Supportive analyses will be performed based on each individual 
component.  The details will be described in the SAP.  In addition, a 
sensitivity analysis will be performed using the same method described 
above for the per-protocol analysis set. 
Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared 
using the Kaplan-Meier method  
The following endpoints will be analysed using the Cochran-Mantel-
Haenszel test, stratified by the randomized stratum: 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal ESR by Week 26 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal CRP by Week 26 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have neither signs/symptoms of GCA nor new or 
The key secondary 
endpoint time to flare by 
Week 26 in the Per 
Protocol population was 
deleted as it will be 
handled as a sensitivity 
analysis. 
Deleted time to 
corticosteroid dose of 
zero mg/day as a 
secondary efficacy 
endpoint because patients 
enter the study with 
varying doses of steroids. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
Updated statistical 
assumptions based on 
review of Phase 3 
Tocilizumab data. 




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Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
Approximately 60 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
Subject disposition and the flare event accrual will be closely monitored 
during the study. The monitoring activities will be done in a blinded 
fashion. If there is a high dropout rate and/or the event accrual rate is 
significantly slower than anticipated, up to 10 additional subjects may be 
randomized to obtain the target number of events required for the analysis 
of primary efficacy endpoint. 
approximately 26 weeks in placebo and 111 weeks in KPL-301.  The hazard 
ratio (KPL-301 vs. placebo) is estimated to be approximately 0.234.  With a 
2-sided significance level of 0.05 and a 3:2 randomization ratio for KPL-301 
vs. placebo, it would require approximately 20 events to achieve 87% power 
using a two-sided log rank test.   
Approximately 70 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
7 
Section 8.6 
Approximately 60 patients with GCA will be randomized as study subjects. 
For the primary endpoint analysis, the aim is to have 36 subjects assigned to 
KPL-301 and 24 subjects assigned to placebo, with balanced randomization 
in the two randomization cohorts. 
Approximately 70 patients with GCA will be randomized as study subjects. 
For the primary endpoint analysis, the aim is to have 42 subjects assigned to 
KPL-301 and 28 subjects assigned to placebo, with balanced randomization 
in the two randomization cohorts. 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
8 
Section 12.5.4 
The modified Borg scale (Borg, 1982) is a validated patient reported 
outcome and will be used to assess subjects’ perceived sensation of 
difficulty in breathing (dyspnea) while resting. This scale is a linear scale of 
numbers ranking the magnitude of difficulty in breathing, ranging from 0 
(nothing at all) to 10 (maximal). A validated version of the Borg scale in 
local language will be provided. 
The modified Borg scale (Borg and Borg, 2010) is a validated patient 
reported outcome and will be used to assess subjects’ perceived sensation of 
difficulty in breathing (dyspnea) while resting. This scale is a linear scale of 
numbers ranking the magnitude of difficulty in breathing, ranging from 0 
(nothing at all) to 10 (maximal). A validated version of the Borg scale in 
local language will be provided. 
Updated citation for 
modified Borg scale. 
9 
Section 13.6 
All SAEs, whether or not considered causally related to study drug or to the 
study procedure(s), have to be reported. All SAEs will be recorded in the 
eCRF. 
The Investigator must report all SAEs to the Safety Department and 
Sponsor within 24 hours of discovery via the SAE reporting form to: 
24 Hour Safety Hotline: +44 
1223 374 240 
 
24 Hour Safety Hotline Fax: +44 1223 374 102                  
US 24 Hour Safety Hotline: 1 888-483-7729 
US 24 Hour Safety Hotline Fax: 1 888-529-3580                 
All SAEs, whether or not considered causally related to study drug or to the 
study procedure(s), have to be reported. SAEs will be recorded in the eCRF 
within 24 hours of discovery. 
In case the eCRF is inaccessible, the Investigator must report all SAEs to 
the Safety Department and Sponsor within 24 hours of discovery via the 
SAE reporting form to: 
24 Hour Safety Hotline: +44 
1223 374 240 
 
24 Hour Safety Hotline Fax: +44 1223 374 102                  
US 24 Hour Safety Hotline: 1 888-483-7729 
US 24 Hour Safety Hotline Fax: 1 888-529-3580                 
Updated text upon 
request from Slovenian 
Inspection. 
10 
Section 14.1 
All statistical analyses will be performed using Statistical Analysis 
Software (SAS®) Version 9.3 or later. A statistical analysis plan (SAP) will 
be written and approved prior to performing the first review of the data. 
All statistical analyses will be performed using Statistical Analysis Software 
(SAS®) Version 9.4 or later. A statistical analysis plan (SAP) will be written 
and approved prior to performing the first review of the data. 
Updated text to allow use 
of SAS Version 9.4 or 
higher 


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Rationale 
11 
Section 14.1.2 
14.1.2 Multiple Comparisons/Multiplicity 
Multiplicity with respect to the primary efficacy endpoint and the key 
secondary efficacy endpoints will be managed via the gated hierarchical 
testing procedure.  If and only if the primary comparison results in a 
statistically significant difference between KPL-301 and placebo at 0.05 
level of significance, the key secondary comparison will be conducted at 
alpha 0.05 as well.   
All other secondary endpoints are considered exploratory, and no 
adjustment for multiple testing of secondary efficacy endpoints will be 
performed. 
 
14 1 2 Multiplicity Adjustment 
Multiplicity adjustment with respect to the primary efficacy and secondary 
efficacy endpoints will be performed using the gate-keeping hierarchical 
testing procedure. The order of the secondary endpoints will be described 
in the SAP. For each endpoint, the null hypothesis is that there is no 
treatment difference between KPL-301 and placebo. The alternative 
hypothesis is that KPL-301 is superior to placebo.  For each test, the 2-
sided Type I error rate is 0.05.  The primary endpoint will be tested 
first.  If the 2-sided p-value is ≤0.05 and the test statistic shows KPL-301 
is superior than placebo, statistical significance of the primary endpoint 
will be claimed, and the next hierarchical endpoint will be tested.  This 
process will continue until an endpoint is not statistically significant.    
Clarified language in 
response to request from 
the FDA. 
12 
Section 14.2 
Approximately 60 subjects will be randomized 3:2 by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo. 
Assuming that time to flare follows an exponential distribution and the 
proportion of subjects without a flare by week 26 will be 20% in placebo 
and 57.5% in KPL-301, the median time to flare would be estimated to be 
approximately 11.20 weeks in placebo and 32.57 weeks in KPL-301.  The 
hazard ratio (KPL-301 vs. placebo) would be estimated to be approximately 
0.3438.  With a 2-sided significance level of 0.05 and a 3:2 randomization 
ratio for KPL-301 vs. placebo, it would require approximately 34 events to 
achieve 86% power using a two- sided log rank test.  
Approximately 60 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
Subject disposition and the flare event accrual will be closely monitored 
during the study. The monitoring activities will be done in a blinded 
fashion. If there is a high dropout rate and/or the event accrual rate is 
significantly slower than anticipated, up to 10 additional subjects may be 
randomized to obtain the target number of events required for the analysis 
of primary efficacy endpoint. 
Assuming that time to flare follows an exponential distribution and the 
proportion of subjects without a flare by week 26 will be 50% in placebo and 
85% in KPL-301, the median time to flare would be approximately 26 weeks 
in placebo and 111 weeks in KPL-301 arm.  The hazard ratio (KPL-301 vs. 
placebo) would be approximately 0.234.  With a 2-sided significance level 
of 0.05 and a 3:2 randomization ratio for KPL-301 vs. placebo, it would 
require approximately 20 events to achieve 87% power using a two- sided 
log rank test.  
Approximately 70 subjects will be randomized by disease stratum (new-
onset or relapsing/refractory) to receive KPL-301 or placebo at a 3:2 
allocation ratio. 
 
Updated the planned 
number of subjects to 
address potential early 
dropout. 
Updated statistical 
assumptions based on 
review of Phase 3 
Tocilizumab data. 
13 
Section 14.4 
Efficacy Endpoints: 
Primary Endpoint:  
• 
Time to flare by Week 26 defined as time from randomization to 
the first flare occurring within the first 26-weeks of the double-
blind period 
Key secondary endpoint: 
Efficacy Endpoints: 
Primary Endpoint:  
• 
Time to flare by Week 26 defined as time from randomization to 
the first flare occurring within the treatment period 
Secondary Endpoints: 
Updated text in Efficacy 
Endpoints for 
clarification. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint.  




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KPL-301-C001 (v 4.0) 
Final 
Page 100 of 101 
 
 
CONFIDENTIAL 
Change 
ID 
Section(s) 
Current Text 
Revised Text 
Rationale 
o 
Urinalysis 
14 
Section 14.5 
14.5 Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  The 
primary and key secondary efficacy Analyses will be repeated using the PP 
set to assess the sensitivity of the results to major deviations/violations of 
the protocol.  All efficacy data including those collected during the open 
label extension will be listed by subject. 
14.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined in 14.1  
Subjects who do not experience a flare during this period will be censored 
at the Week 26 visit. Subjects who drop out or are lost to follow-up prior to 
experiencing a flare during the 26-week double-blind period will be 
censored at the time of their last available visit. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 26-week 
double-blind period will be summarized for each treatment group. Time to 
flare by week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare. The Kaplan-Meier estimates of remission rate at 26 
weeks will be presented with the corresponding 95% CI by treatment group. 
To describe the magnitude of treatment effect, the hazard ratio for KPL-301 
compared to placebo and the corresponding 95% CI will be calculated 
based on a Cox proportional-hazards model with treatment as covariate.  
14.5.2 Key Secondary Efficacy Analysis 
The key secondary efficacy endpoint is time to flare by week 26 in the per 
protocol population and will be analyzed using the same methods as 
described above. Subjects who do not experience flare during double blind 
treatment will be censored at their last visit of the double-blind treatment 
period.  Subjects who drop out or are lost to follow up prior to experiencing 
a flare at any time during double blind treatment will be censored at the 
time of their last available visit. 
14.5.3 Additional Secondary Efficacy Analysis 
The number and percentage of subjects with normal ESR at Week 26 as 
well as the number and percentage of subjects with normal CRP at Week 26 
will be analyzed.  Treatment groups will be compared using a Cochran-
Mantel-Haenszel test controlling for the randomized strata. Confidence 
14 5 Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  Analyses 
will be repeated using the PP set to assess the sensitivity of the results to 
important deviations of the protocol. 
14 5 1 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is time to flare by Week 26 defined as time 
from randomization to the first flare occurring within the treatment 
period. Detailed censoring rules will be provided in the SAP. 
The number and percentage of subjects who remain in remission (no flare), 
who flare, and who are lost to follow-up prior to a flare during the 
treatment period will be summarized for each treatment group. Time to 
flare by Week 26 will be summarized by the 25th, 50th (median), and 75th 
percentiles calculated using the Kaplan-Meier method to estimate the 
survival functions for each treatment group. The 95% confidence interval 
(CI) for the percentiles will also be calculated. A log-rank test stratified by 
randomization strata will be used to compare KPL-301 and placebo with 
respect to time to flare by Week 26. To describe the magnitude of treatment 
effect, the hazard ratio for KPL-301 compared to placebo and the 
corresponding 95% CI will be calculated based on a Cox proportional-
hazards model with treatment as a covariate and stratified by 
randomization strata.  
The protocol definition of flare includes multiple components. 
Supportive analyses will be performed based on each individual 
component.  The details will be described in the SAP.  In addition, a 
sensitivity analysis will be performed using the same method described 
above for the PP analysis set. 
14 5 2 Secondary Efficacy Endpoint Analysis 
Sustained remission rate at Week 26 will be estimated and compared 
using the Kaplan-Meier method. 
The following endpoints will be analyzed using the Cochran-Mantel-
Haenszel test stratified by the randomization strata. 
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal ESR by Week 26  
• 
Percentage of subjects who have completed the corticosteroid 
taper and who have a normal CRP by Week 26 
Updated text for 
clarification and new 
statistical assumptions. 
Sustained remission rate 
at Week 26 was added as 
a standalone secondary 
efficacy endpoint. 
Time to elevated ESR 
and CRP by Week 26 
and time to 
sign/symptoms of GCA 
or new or worsening 
vasculitis by imaging by 
Week 26 were added as 
secondary efficacy 
endpoints in response to 
request from the FDA. 
The key secondary 
endpoint time to flare by 
Week 26 in the Per 
Protocol population was 
deleted as it will be 
handled as a sensitivity 
analysis. 
Deleted time to 
corticosteroid dose of 
zero mg/day as a 
secondary efficacy 
endpoint because patients 
enter the study with 
varying doses of steroids. 
Updated the planned 
number of subjects to 
address potential early 
drop-out. 
Updated statistical 
assumptions based on 
review of Phase 3 



SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
STUDY KPL-301-C001 
 
 
 
A Phase 2, randomized, double-blind placebo-controlled study to test the efficacy and 
safety of KPL-301 in giant cell arteritis 
 
 
 
Sponsor: 
 
Kiniksa Pharmaceuticals, Ltd. 
Hamilton, Bermuda 
 
c/o Kiniksa Pharmaceuticals Corp. 
100 Hayden Ave 
Lexington, Massachusetts 02421 
Study Drug: 
KPL-301 
Protocol Number: 
KPL-301-C001 
Version: 
1.0 
Date:  
10SEP2020 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is the property of Kiniksa Pharmaceuticals, Ltd. and contains proprietary and 
confidential information to be held in strict confidence and not disclosed to any third party, without prior written consent 
of Kiniksa Pharmaceuticals, Ltd. 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 prior written consent from Kiniksa Pharmaceuticals, 
Ltd.  Documentation, data, and all other information generated during the clinical study is proprietary and confidential 
information of Kiniksa Pharmaceuticals, Ltd. and shall not be disclosed to any third party, without prior written consent 
of Kiniksa Pharmaceuticals, Ltd. 




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5.1.3. 
Baseline Values ..........................................................................................................11 
5.1.4. 
Last Contact ................................................................................................................11 
5.1.5. 
Duration Derivation ....................................................................................................11 
5.1.6. 
Randomization Strata ..................................................................................................12 
5.1.7. 
Week 26 ......................................................................................................................12 
5.2. 
Methods for Handling Missing Data ..........................................................................12 
5.3. 
Windowing of Visits ...................................................................................................12 
5.4. 
Protocol Deviations ....................................................................................................12 
6. 
STATISTICAL METHODOLOGY ...........................................................................13 
6.1. 
Study Populations .......................................................................................................13 
6.2. 
Subject Disposition .....................................................................................................13 
6.3. 
Demographics and Baseline Disease Characteristics and History .............................14 
6.4. 
Medical History ..........................................................................................................14 
6.5. 
Prior and Concomitant Medications ...........................................................................15 
6.6. 
Study Treatments and Extent of Exposure .................................................................15 
6.6.1. 
Treatment Duration .....................................................................................................15 
6.6.2. 
Cumulative Dose ........................................................................................................15 
6.6.3. 
Average Daily Dose ....................................................................................................15 
6.6.4. 
KPL301/Placebo Exposure .........................................................................................16 
6.6.5. 
Prednisone Exposure ..................................................................................................16 
6.6.6. 
Escape Therapy Exposure ...........................................................................................16 
6.6.7. 
Compliance .................................................................................................................16 
6.7. 
Efficacy Analysis ........................................................................................................16 
6.7.1. 
Multiplicity Adjustment..............................................................................................16 
6.7.2. 
Analysis of Primary Efficacy Endpoint ......................................................................17 
6.7.3. 
Analysis of Secondary Efficacy Endpoints ................................................................18 
6.7.3.1. 
Sustained remission rate at Week 26 ..........................................................................18 
6.7.3.2. 
Time to elevated ESR by week 26 ...............................................................................18 
6.7.3.3. 
Time to elevated CRP by week 26 ...............................................................................19 
6.7.3.4. 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by 
week 26 .......................................................................................................................19 
6.7.3.5. 
Cumulative steroid dose at Week 26 and at the End of the Washout Safety 
Follow-up Period ........................................................................................................19 
6.7.3.6. 
Percentage of subjects who have completed the corticosteroid taper and who 
have a normal ESR by week 26 ...................................................................................19 




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LIST OF ABBREVIATIONS  
Abbreviation 
Full Term 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST (SGOT) 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
AUC0-24 
Area under the plasma concentration curve from 0 to 24 hours 
CI 
Confidence interval 
Cmax 
Maximum concentration value 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTA 
Computed Tomography Angiography 
DILI 
Drug-induced liver injury 
DLCO 
Diffusing Capacity for Carbon monoxide  
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form  
EOT 
End of treatment 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCA 
Giant cell arteritis 
HR 
Hazard ratio 
ICH 
International Conference on Harmonization 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
modified Intent-to-treat analysis set 
MRI 
Magnetic Resonance Imaging 
NJS 
NJS Associates Company 


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Abbreviation 
Full Term 
PET-CT 
Positron Emission Tomography 
PFT 
Pulmonary Function Test  
POC 
Proof of Concept 
PP 
Per-Protocol  
PT 
Preferred term 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TEAESI 
TEAE of special interest  
TESAE 
Treatment emergent serious AEs  
TIA 
Transient ischemic attack 
TLG 
Table Listings and Graphs 
ULN 
Upper limit of normal 
 
 
 




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with corticosteroid taper, and a 12-week washout safety follow-up period during which subjects will 
discontinue and wash off blinded KPL-301 or placebo. 
Approximately 70 subjects with GCA will be randomized to receive KPL-301 or placebo at a 3:2 
allocation ratio stratified by disease status (new-onset or relapsing/refractory). Subjects randomized 
to KPL-301 will receive the drug 150mg every other week by subcutaneous (SC) injection co-
administered with a 26-week steroid taper. 
Subject who cannot adhere to the protocol-defined steroid taper due to flare/relapse must discontinue 
study drug (KPL-301 or placebo) and should receive escape therapy in accordance with local SoC 
per the Investigator. Escape therapy may include, for example, prednisone or similar > 60mg/day, IV 
corticosteroids, other immunomodulatory agents, and/or approved therapies (e.g., tocilizumab).  
1.3. 
Sample Size Justification  
The sample size calculation was based on the assumption that time to flare follows an exponential 
distribution and the proportion of subjects without a flare by week 26 will be 50% in placebo and 
85% in KPL-301, the median time to flare would be approximately 26 weeks in placebo arm and 111 
weeks in KPL-301 arm. The hazard ratio (KPL-301 vs. placebo) would be approximately 0.234. 
With a 2-sided significance level of 0.05 and a 3:2 randomization ratio for KPL-301 vs. placebo, it 
would require approximately 20 events to achieve 87% power using a two-sided log rank test. 
Approximately 70 subjects will be randomized by disease stratum (new-onset or relapsing/ 
refractory) to receive KPL-301 or placebo at a 3:2 allocation ratio. 
1.4. 
Randomization, Stratification, and Blinding 
An Interactive Web Response System (IWRS) will be used for assignment of the Subject 
Identification Number at enrolment, randomization to a treatment arm (KPL-301 or placebo), and 
assignment of blinded investigational product. 
The randomization is stratified by subjects’ disease status (new-onset or relapsing/refractory). 
Permutated block randomization will be employed with the block size specified in the randomization 
request.  
If a subject is randomized using incorrect baseline information from the stratification factor, that 
randomization will be accepted but the analysis will be based on the correct baseline information. 
To control bias during the study conduct and analyses, and to ensure proper type I error control, 
subject treatment assignments are blinded to study team members. An unblinded team will conduct 
analyses by treatment until the final database lock, upon which the study team will be unblinded. 
1.5. 
Data Cutoff 
There will be two data cutoffs. The first data cutoff is for the primary efficacy and safety analyses.  
It will occur after all randomized subjects have completed 26 weeks of treatment.  The second data 
cutoff will occur after all subjects have completed safety follow-up.  
1.6. 
Analysis Software 
Analyses will be performed using Statistical Analysis Software SAS® version 9.4 or higher. 


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2. 
DEFINITION OF ANALYSIS SETS 
2.1. 
Safety Analysis Set (SAF) 
All randomized subjects who take at least 1 dose of of study drug (KPL-301 or placebo) will be 
included in the Safety Analysis Set.  Safety analyses will be based on the medication that was 
actually administered to each subject.  
2.2. 
Modified Intent-to-Treat (mITT) Analysis Set  
All randomized subjects who receive at least 1 dose of study drug (KPL-301 or placebo) and have at 
least 1 assessment in the double-blind treatment period will be included in the mITT analysis set. 
Efficacy analyses will be primarly based on the mITT analysis set. All mITT analyses will be based 
on each subject’s randomized treatment assignment.  
2.3. 
Per Protocol (PP) Analysis Set  
All mITT subjects without important protocol deviations deemed to impact efficacy or ethical 
conduct will be included in the PP analysis set and will be determined before unblinding. Subjects 
who had steriod therapy increase for at least 5 mg/day for at least 1 week or took prohibited GCA 
medication duing the treatment period before a protocol-defined flare or end of treatment, whichever 
occurred first, will be excluded from the PP analysis set. 
In this study, subjects are at prednisone doses between 20 mg/day and 60 mg/day at time of 
randomization. For this dose range and under a tapering schedule of 6 months, which is shorter than 
what is considered standard of care (1 year or longer), a prednisone dose increase of 5mg or greater 
is considered a clinically significant change for the purposes of this SAP. Typical GCA 
corticosteroid taper protocols can be found in (Docken, 2020). 
3. 
EFFICACY PARAMETERS / ENDPOINTS 
3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to flare by week 26 defined as time from randomization to 
the first flare occurring within the treatment period. 
3.2. 
Secondary Efficacy Endpoints 
The hierarchical order of the secondary efficacy endpoints are as follows: 
• Sustained remission rate at Week 26 
• Time to elevated ESR by Week 26 
• Time to elevated CRP by Week 26 
• Time to signs/symptoms of GCA or new or worsening vasculitis on imaging by Week 26 
• Cumulative steroid dose at Week 26  
• Percentage of subjects who have completed the corticosteroid taper and who have a 
normal ESR by Week 26 
• Percentage of subjects who have completed the corticosteroid taper and who have a 
normal CRP by Week 26 


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• Percentage of subjects who completed the corticosteroid taper and who have neither 
signs/symptoms of GCA nor new or worsening vasculitis on imaging by Week 26 
• Cumulative steroid dose at the end of the Washout Safety Follow-up period 
4. 
SAFETY PARAMETERS / ENDPOINTS 
The following are safety endpoints: 
• Incidence of treatment emergent adverse events 
• Change in physical exam results 
• Change in vital signs 
• Change in clinical laboratory parameters  
• Change in ECGs 
• PFTs 
• DLCO 
• Dyspnea score 
• O2 saturation 
5. 
GENERAL STATISTICAL CONSIDERATIONS 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. In case of n<2, where n indicates the number 
of evaluable subjects at the particular time point, the standard deviation will be empty. The 
minimum and maximum statistics will be presented to the same number of decimal places as the 
original data. The mean and median will be presented to one more decimal place than the original 
data, whereas the standard deviation will be presented to two more decimal places than the original 
data.  
Frequencies and percentages will be displayed for categorical data. Percentages by categories will be 
based on the analysis set unless otherwise specified. The statistic “Missing” will also be presented as 
the number of missing entries/subjects, if any at that visit/timepoint, and presented as a summary 
statistic only when non-zero. 
Time to event data will be summarized using the Kaplan-Meier (KM) method, which will include 
the estimated median with 95% confidence interval (CI) and the 25th and 75th percentiles. 


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In by-visit summary tables, only scheduled visits/timepoints will be summarized. In listings all visits 
and timepoints with any data collected, including both scheduled and unscheduled visits, will be 
included. 
The change from baseline values will be derived for each subject as the post-baseline evaluation 
minus the baseline evaluation. 
Unless otherwise stated, any confidence interval computed will be derived using the SAS default 
method in the statistical procedure.  
All statistical comparisons will be made using two sided tests at the alpha=0.05 significance level 
unless specifically stated otherwise. All null hypotheses will be of no treatment difference.   
For stratified analyses, if there is no event for both arms, or all responses are the same within a 
stratification group, unstratified analyses will be conducted. This principal will be analogously 
applied to subgroups, but only to those subgroups for which lack of events/responses require it.  
Specifications for table, graphs, and data listing formats can be found in the TLF specifications for 
this study.   
5.1. 
Data Analysis General Informaiton and Definition  
5.1.1. 
Study Drug 
Study drug or study treatment refers to SC KPL-301 or placebo.   
5.1.2. 
Day 1 and Other Days 
Date of first dose of study treatment (or Day 1) is defined as the day of the first administration of 
study treatment after enrollment. First dose refers to first dose in study unless otherwise specified.  
Date of last dose of study drug is defined as the date of last administration of study treatment (last 
dose) in the study.  
5.1.3. 
Baseline Values 
For purpose of analyses, a baseline is defined as the last non-missing value obtained prior to the start 
of study treatment. For CRP and ESR, a baseline should be within 3 days of study treatment.  
5.1.4. 
Last Contact 
Last contact or last date known alive is defined as the last non-imputed date of any subject record 
prior to or on the data cutoff date in the clinical database. 
Calculations using dates will adhere to the following conventions: 
Study day for a date of interest (TARGET DATE) is calculated as 
STUDY DAY = TARGET DATE – Day 1 + 1 if TARGET DATE is on or after Day 1; 
STUDY DAY = TARGET DATE – Day 1 otherwise. 
Note that negative study days are reflective of observations obtained during the screening period. 
5.1.5. 
Duration Derivation 
Unless otherwise specified for a specific panel or variable, duration variables will be derived 
according to the following rules. Duration variables expressed in units greater than day will be 
rounded to 1 decimal place. 


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Duration (in days) = [end date – start date +1] 
Duration (in weeks) = [end date – start date +1] / 7 
Duration (in months) = [end date – start date +1] / 30.4375 
Duration (in years) = [end date – start date +1] / 365.25. 
5.1.6. 
Randomization Strata 
Randomization will be stratified by whether the disease is new or relapsing/refractory. The actual 
categorization of the randomization strata of disease status will be used in the analyses instead of 
what was entered in the IWRS.  The new-onset disease cohort includes subjects who have been 
diagnosed within 6 weeks of the first dose date using the Acute Phase Reactants, Signs/Symptoms 
and Diagnostic Criteria specified in the protocol. That is, a subject is considered new-onset if Day 1 
– first diagnosis date + 1 <= 42 days; and is relapsing/refractory otherwise. 
5.1.7. 
Week 26 
Week 26 in this document refers to the completion of the treatment period, which might not be 
exactly the 26th week, e.g. if due to treatment delay/use of + 3 days of out of window visit allowance 
more than 2 times. Efficacy assessments before the safety follow up will all be included in “at week 
26”, or “by week 26” analyses unless otherwise specified. 
5.2. 
Methods for Handling Missing Data 
Refer to Section 9 for detailed date imputation guidelines. 
5.3. 
Windowing of Visits 
Data will be summarized by visit week defined in the protocol when appropriate (e.g. lab 
parameters).  
5.4. 
 Protocol Deviations 
All protocol deviations will be entered into eTMS by site staff. The study team will have a blinded 
review of protocol deviations to determine their classification (important, not important) 
periodically.  Prior to the database lock, the study team will assess impact of all important protocol 
deviations on the efficacy or ethical conduct and whether they should be excluded from the per-
protocol analysis set.  
The number of important protocol deviations and the number of subjects with at least one important 
protocol deviation will be summarized by treatment group. Also, the number of subjects with at least 
one important protocol deviation with/without a potential impact on efficacy will be summarized by 
treatment group. The protocol deviation criteria types will also be summarized, with reference to the 
evaluabilitly document.  
All protocol deviations will be presented in by-subject listings, and subjects with protocol deviations 
that lead to exclusion from the per-protocol analysis set will be flagged.  


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6. 
STATISTICAL METHODOLOGY 
6.1. 
Study Populations 
A summary of analysis sets by treatment and overall will be presented along with percentages 
relative to all randomized subjects. 
• Subjects randomized 
• Subjects in the safety analysis set  
• Subjects in the mITT analysis set 
• Subjects in the PP analysis set 
6.2. 
Subject Disposition  
The number and percentage of subjects will be tabulated for the treatment discontinuation status for 
the safety analysis set by treatment and overall:   
• Subjects who completed study treatment 
• Subjects who discontinued early from study treatment 
Reasons for early treatment discontinuation will be summarized by the following categories 
collected on the electronic case report form (eCRF):  
• adverse event (AE)  
• death  
• lack of efficacy  
• lost to follow-up  
• non-compliance with study drug  
• physician decision  
• pregnancy  
• protocol deviations  
• sponsor decision to terminate study  
• withdrawal by subject and 
• other 
The number and percentage of subjects will be tabulated for the end of study status for the safety 
analysis set by treatment and overall:   
• Subjects who completed study 
• Subjects who are still on study 
• Subjects who terminated study early 
Reasons for early study termination will be summarized by the following categories collected on the 
eCRF:  
• adverse event 
• death  


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• lack of efficacy  
• lost to follow-up  
• non-compliance with study drug  
• physician decision  
• pregnancy   
• protocol deviation  
• study terminated by sponsor 
• withdrawal by subject  
• other 
In addition, time from randomization to last study assessment (weeks) will be summarized 
descriptively. 
By-subject listings will be provided for study disposition including days on study, eligibility, and 
discontinuation from treatment and study reasons. 
6.3. 
Demographics and Baseline Disease Characteristics and History 
Demographic and other baseline characteristics will be summarized by descriptive statistics for each 
treatment group and overall for the SAF. They will also be presented in by-subject listings. 
Descriptive statistics will be provided for the following: 
• age  
• weight (kg) 
• height (cm)  
• body mass index (BMI) (kg/m2)  
Frequency tabulations will be presented as collected in the eCRF for: 
• age (< 65 years or ≥ 65 years)  
• sex  
• race  
• ethnicity 
• substance use (tobacco) history (cigarettes, cigars, pipes, or chewing tobacco).  
 
Disease history such as disease status (new-onset or relapsing/refractory), prior GCA (yes/no), 
biopsy (yes/no), imaging (yes/no), and prior treatment will be summarized using frequencies and 
percentages and presented in by-subject listings. Time since diagnosis to randomization (month), 
ESR value for eligibility and at baseline, and CRP value for eligibility and at baseline (local and 
central separately) will be summarized by descriptive statistics.  
6.4. 
Medical History 
Medical history data will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 before database lock.  Medical history data will be summarized for the SAF 


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by treatment group and overall, by system organ class (SOC) and preferred term (PT) in descending 
frequency for overall. Subjects with multiple occurrences of the same medical condition will be 
counted once per each unique SOC and unique PT.    
All medical history data will be listed by subject. 
6.5. 
Prior and Concomitant Medications 
Prior medication is defined as medication with at least one dose taken before the date of the first 
dose of study drug.  
Concomitant medication is defined as medication with at least one dose taken between the date of 
first dose (inclusive) and the date of last dose date of study drug + 90 days (inclusive) of study drug.   
Post-treatment medication will be defined as medications taken after the last dose of study drug.  
Additionally, the medications will be considered concomitant if the start date of the medication is 
missing.  
A medication that started prior to the first dose of the study drug and continued after last dose date 
will be considered as prior, concomitant, and post treatment. 
Prior and concomitant medications will be coded using WHO Drug Dictionary WHODrug version 
Enhanced 01Mar2018 B3 and will be classified by Anatomical Therapeutic Class (ATC) level 2 and 
preferred term (PT) for the Safety Analysis Set. Frequencies and percentages of subjects using each 
concomitant medication will be presented by treatment group. Subjects taking the same medication 
multiple times will be counted once per medication. All medication use will be listed regardless of 
the timing of the start of the medication.  
6.6. 
Study Treatments and Extent of Exposure 
Study drug exposure, prednisone taper exposure, and escape therapy will be summarized 
descriptived for the SAF by treatment and for overall. Cumulative steroid dose combining 
information from both prednisone taper and escape therapy will be summarized as efficacy 
endpoints and be further discussed in Section 6.7.3.5. 
6.6.1. 
Treatment Duration  
Duration of treatment (weeks) = (last dose date of drug – first dose date of drug + 1) / 7. 
It will be calculated for study drug and corticosteroid taper respectively. 
6.6.2. 
Cumulative Dose 
Cumulative dose (mg) is defined as sum of all doses taken. The dosage will be counted as 0 for days 
when the drug is not taken/injected. It will be calculated for study drug, prednisone taper, and steroid 
respectively. Cumulative study drug and prednisone taper will be calculated during treatment period. 
Cumulative steroid doses will be calculated at the end of week 26 and at the end of the safety follow 
up. 
For the study drug, one partial injection is considered half of the full dosage. 
6.6.3. 
Average Daily Dose 
Average daily dose (mg) is defined as the cumulative dose divided by the number of days dosed. 
This will be summarized for cumulative steroid dose. 


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6.6.4. 
KPL-301/Placebo Exposure 
KPL-301 or placebo study drug exposure data will be summarized with descriptive statistics by 
treatment, and by treatment by randomization strata. 
Summary statistics of study drug for the treatment duration (weeks) and number of injections will be 
presented. Number of injections by category (<10, 10-13, 14, >14) will be summarized by frequency 
and percent of subjects.  
All KPL-301 exposure data will be listed. 
6.6.5. 
Prednisone Exposure 
Prednisone taper data will be summarized descriptively by treatment, and by treatment by 
randomization strata. 
Summary statistics of prednisone for the treatment duration (weeks) and cumulative dose by earlier 
of flare and week 26 will be presented. Categorical summaries for prednisone starting dose (20mg, 
25mg, 30mg, 35mg, 40mg, 50mg, 60mg) will be presented by treatment group. 
All prednisone exposure data will be listed.              
6.6.6. 
Escape Therapy Exposure 
The number and percent of subjects receiving escape therapy, type of escape therapy and initial dose 
received will be summarized by treatment, and by treatment by randomization strata.  
6.6.7. 
Compliance 
Compliance to KPL-301/Placebo = Actual total number of injections received / planned total number 
of injections. 
Compliance to prednisone will be measured by percentage of days in compliance = number of days 
in compliance / number of days on treatment. Descriptive summary will be presented for overall 
period and by week. 
6.7. 
Efficacy Analysis 
All efficacy analyses will be conducted by treatment for the mITT analysis set. Selected analyses 
may be in the PP analysis set. Endpoints involving flare will be based on adjudication primarily. 
Investigator assessment will only be used supportively. 
6.7.1. 
Multiplicity Adjustment 
Multiplicity adjustment with respect to the primary efficacy and secondary efficacy endpoints will 
be adjusted using the gate-keeping hierarchical testing procedure. The hierarchy order of the 
secondary endpoints is presented in Section 3.2. For each endpoint, the null hypothesis is that there 
is no treatment difference between KPL-301 and placebo.  The alternative hypothesis is that 
KPL-301 is superior to placebo. For each test, the 2-sided type I error rate is 0.05. The primary 
endpoint will be tested first. If the 2-sided p-value is ≤0.05, statistical significance of the primary 
endpoint will be claimed, and the next hierarchical endpoint will be tested. This process will 
continue until an endpoint is not statistically significant.   
There is no adjustment for other endpoints. 


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6.7.2. 
Analysis of Primary Efficacy Endpoint 
The primary endpoint of time to flare by Week 26, is defined as time from randomization to the first 
flare occurring within the treatment period.  Flare/relapse is defined as a C-reactive protein (CRP) of 
1 mg/dL or greater and/or erythrocyte sedimentation rate (ESR) of 30 mm/h or greater AND at least 
one of the following signs or symptoms attributed to GCA: 
• Cranial symptoms 
− New-onset localized headache  
− Scalp or temporal artery tenderness 
− Ischemic-related vision loss 
− Unexplained mouth or jaw pain upon mastication (i.e. claudication of tongue) 
− Transient ischemic aattach or stroke related to GCA 
• Extracranial symptoms 
− Claudication of the extremities 
− Symptoms of PMR (shoulder & hip girdle pain associated with inflammatory 
morning stiffness)  
• New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of 
the aorta or other great vessels or via ultrasound of the temporal arteries.  
Supportive findings could include other symptoms related to worsening GCA, such as sustained 
daily recurrent fever with a temperature over 38°C for more than 1week, chronic anemia, or 
unexplained weight loss. 
Subjects who do not experience a flare during this period will be censored according to Table 1 End 
of treatment (EOT) in the table refers to early discontinuation of treatment. 
Table 1:   
Censoring Rules for Time to Flare by Week 26 
 
Scenario 
Event or 
Censoring 
Censoring Reason 
Date of Event or Censoring 
1 Flare occurrence on or prior to 
week 26  
Event 
No censoring 
Date of flare 
2 No flare occurrence on or prior 
to week 26 
Censored 
No flare occurrence 
Date of last assessment by 
week 26 
3 No flare occurrence on or prior 
to EOT  
Censored 
No flare occurrence 
by EOT 
Date of last assessment by 
EOT 
4 No post baseline assessment 
Censored 
No assessment 
Date of randomization 
Time to flare by week 26 will be summarized by the 25th, 50th (median), and 75th percentiles 
calculated using the Kaplan-Meier (KM) method to estimate the survival functions for each 
treatment group. The 95% confidence interval (CI) for the percentiles will be calculated using a log-
log transformation. Plots of survival curves by treatment using the KM method will be presented. 
Additional survival plots will be provided by treatment for the stratification factor. 
A log-rank test stratified by the stratification factor (disease status) will be used as the primary 
treatment comparison between KPL-301 and placebo. To describe the magnitude of treatment effect, 
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calculated based on a Cox proportional-hazards model with treatment as a covariate and stratified by 
the stratification factor. 
If subjects were randomized based on incorrect stratum, then the corrected stratum will be used for 
stratified analyses rather than the incorrect stratum recorded at randomization. 
The primary analysis of time to flare will be based on the adjudication outcome. Time to flare per 
investigator’s assessment will be used a supportive analysis of the primary endpoint. A 2x2 table of 
concordance will be used to assess the agreement between adjudicated and investigator assessments.  
As a sensitivity analysis, the stratified analyses of time to flare based on adjudication will be 
repeated for the per protocol analysis set defined in Section 2.3 .  
The stratified analyses of time to flare based on adjudication will also be repeated for the mITT 
analysis set by censoring subjects without flare before EOT at the last assessment date by week 26. 
That is, the censoring does not take into consideration of the early treatment discontinuation. The 
scenario 3 in the censoring table follows scenario 2 rule. 
Subgroup analyses of the primary efficacy endpoint may be performed with age group, sex, race, and 
stratification factor.  
6.7.3. 
Analysis of Secondary Efficacy Endpoints 
All analyses of secondary efficacy endpoints will use the mITT population. Sustained remission rate 
will be based on the adjudication outcome. Local assessments of ESR, CRP, and imaging will be 
used for other secondary efficacy endpoints. 
6.7.3.1. 
Sustained remission rate at Week 26 
Subjects who complete the treatment period without a flare by week 26 will be consideted to have 
sustained remission. The sustained remission rate at week 26 can be obtained from the estimates of 
time to flare at week 26 by using the Kaplan-Meier method, along with their standard errors using 
Greenwood’s formula. Comparison with p-value will be conducted between the treatment groups. 
Two-sided p-value and 95% CI calculated using normal approximation.               
6.7.3.2. 
Time to elevated ESR by week 26  
Time to elevated ESR will be defined as the time from randomization to earliest date of an ESR 
value of ≥30 mm/hr. All subjects who do not have an elevated ESR by week 26/ EOT will be 
censored at last assessment date or the randomization date, whichever is later.  
Table 2: 
Censoring Rules for Time to Elevated ESR by Week 26 
 
Scenario 
Event or 
Censoring 
Date of Event or Censoring 
1 
Elevated ESR on or prior to week 26  
Event 
Date of elevated ESR 
2 
No elevated ESR on or prior to week 
26 
Censored 
Date of last assessment with no elevated 
ESR by week 26 
3 
No elevated ESR on or prior to EOT 
Censored 
Date of last assessment with no elevated 
ESR by EOT 
4 
No post baseline assessment 
Censored 
Date of randomization 
Analysis and presentation will be the same as that of the primary efficacy endpoint. The KM method 
to estimate the survival functions for each treatment group (overall and by stratification factor). The 
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CI will be estimated using a stratified Cox model with treatment as the explanatory variable and 
strata as the stratification factor.  
6.7.3.3. 
Time to elevated CRP by week 26  
Time to elevated CRP will be defined as the time from randomization to earliest date of a CRP value 
of ≥1.0 mg/dL. All subjects who do not have an elevated CRP by week 26/ EOT will be censored at 
last assessment date or the randomization date, whichever is later.  Detailed censoring rule follows 
that for ESR. Subjects with elevated CRP at baseline will be excluded from the analysis. 
Analysis and presentation will be the same as that of the primary efficacy endpoint. The KM method 
to estimate the survival functions for each treatment group (overall and by stratification factor). The 
treatment comparison will be based on a stratified log-rank test. The HR and its 95% CI will be 
estimated using a stratified Cox model with treatment as the explanatory variable and strata as the 
stratification factor.  
6.7.3.4. 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging by week 26 
Time to signs/symptoms of GCA or new or worsening vasculitis by imaging will be defined as the 
time from randomization to earliest date of subjects experiencing signs/symptoms of GCA, or new 
or worsening vasculitis by imaging. All subjects who do not have an event by week 26/ EOT will be 
censored at last assessment date and/or randomization date, whichever is later. Detailed censoring 
rule follows that for ESR.  
Analysis and presentation will be the same as that of the primary efficacy endpoint. The KM method 
to estimate the survival functions for each treatment group (overall and by stratification factor). The 
treatment comparison will be based on a stratified log-rank test. The HR and its 95% CI will be 
estimated using a stratified Cox model with treatment as the explanatory variable and strata as the 
stratification factor.  
6.7.3.5. 
Cumulative steroid dose at Week 26 and at the End of the Washout Safety Follow-up 
Period 
The cumulative corticosteroid dose from first dose date of study drug to Week 26 will be compared 
between the treatment descriptively, and analytically using analysis of covariance (ANCOVA). The 
stratification factor and the corticosteroid starting dose will be the covariates in the model for 
treatment comparisons. The analyses will include 95% CIs for the difference of the mean cumulative 
steroid doses between the treatment groups.  
Similar analysis will be conducted for cumulative steroid dose from first dose date to the end of the 
washout safety follow up period. 
The average daily dose during the same periods will be summarized descriptively. 
6.7.3.6. 
Percentage of subjects who have completed the corticosteroid taper and who have a 
normal ESR by week 26  
The number and percentage of subjects who completed the corticosteroid taper per schedule and 
have normal ESR (<30 mm/hr) by week 26 will be presented by treatment. Subjects will be 
considered to have completed the corticosteroid taper if receiving 1 mg/day for those start at 60 
mg/day starting dose, or 0 mg/day for those start with doses less than 60 mg/day by week 26 and 
maintain through week 26. Having normal ESR by week 26 requires all assessments of ESR from 
the completion of corticosteroid taper through week 26 being normal. If there is no assessment after 
completion of taper, the subject will not be counted in the numerator. 




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6.8. 
Safety Analysis 
All safety analyses will be conducted based on the Safety Analysis Set. All safety data including 
those collected during the Washout Safety Follow-up will be listed by subject. 
6.8.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product. An AE does not necessarily have a causal 
relationship with this treatment. Drug-related AEs will be considered those to be at least possibly 
related to investigational product based on the investigator’s assessment. 
Treatment emergent AEs (TEAEs) is defined as AEs that begin after the first administration of 
investigational products or existing AEs that worsen after the first dose of study medication through 
the 90 days after the last dose date. 
TEAEs will be coded using MedDRA version 21.0. A summary of the frequency (number and 
percentage of subjects) of TEAEs will be presented by system organ class (SOC) and preferred term 
(PT) by treatment, in descreasing frequency of SOC and PT in the KPL-301 arm. The TEAE will 
also be analyzed by their severity (mild, moderate or severe), relationship to study drug, leading to 
death, resulting in dose interruption, leading to withdrawal of study treatment.  Treatment emergent 
serious AEs (TESAE), drug related TESAEs, TEAE of special interest (TEAESI) will also be 
tabulated.  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and requires close monitoring and rapid communication 
by the investigator to the sponsor. An AESI may be serious or non-serious. AESI are defined in 
Section 13.1.3 of the protocol. 


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A subject experiencing the same AE multiple times will be counted only once for that preferred 
term. Similarly, if a subject experiences multiple AEs (preferred terms) within the same system 
organ class, then that subject will be counted only once for that system organ class. When 
summarizing by severity and relationship, only event with highest severity or relationship will be 
counted. 
Tables will include the following details: 
• Overview of TEAEs (summary from all the subsequent tables) 
• TEAEs by severity 
• Drug related TEAEs 
• TESAEs 
• Drug related TESAEs 
• Non-serious TEAEs 
• TEAESI 
• TEAEs leading to permanent discontinuation of study drug 
• TEAEs leading to dose interruption  
• TEAEs resulting in deaths. 
All AEs and SAEs occurring throughout the conduct of the study, including all-cause deaths, will be 
displayed in listings.   
6.8.2. 
Clinical Laboratory Parameters 
Laboratory assessments should be collected as per the schedule of assessments, starting at Screening, 
Baseline, Week 4, Week 12, Week 20, Week 26/EOT, and Final Safety Follow-up/Week 38.  
Unscheduled laboratory assessments for safety issues are permitted as deemed necessary by the 
Investigator. Local laboratory tests and values may be used by the Investigator as necessary to 
support clinical decisions. 
Clinical laboratory assessments are listed in Table 3.  


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Table 3: 
Clinical Laboratory Assessments 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Apolipoprotein A 
Apolipoprotein B 
Aspartate aminotransferase 
(AST) 
C3 
C4 
Calcium 
Chloride 
Creatinine 
Creatinine phosphokinase 
Glucose 
HbA1c 
High-density lipoprotein 
Low-density lipoprotein 
Phosphorus 
Potassium  
Sodium  
Total bilirubin (direct and 
indirect will be performed if 
total bilirubin is greater than 
the ULN) 
Total Cholesterol 
Total protein 
Triglycerides 
Urea 
Uric acid 
Hemoglobin  
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count  
WBC differential (total and percentage): 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Bilirubin  
Blood 
Creatinine 
Glucose 
Ketones 
Leukocyte esterase  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
 
 
Other: 
Serum pregnancy test prior to randomization 
Urine pregnancy test at Day 0, Week 12, Week 26 and the Final Washout Safety Follow-up Visit. 
 
Continuous laboratory data will be examined for trends using descriptive statistics of actual values 
and changes from baseline over time in each treatment group. These data will also be categorized as 
low, normal or high based on the reference ranges of the central laboratory. Shift tables from 
baseline to worst post baseline time point will be presented. In shift tables from baseline to worst 


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post-baseline value, the worst value post baseline within a subject will include both scheduled and 
unscheduled visits. In each shift table, the denominator of the percentage in a cell within a baseline 
category (e.g., normal) will be the total number of subjects in each treatment group in the category at 
baseline. 
Biochemistry and hematology lab tests will be assessed relative to laboratory normal ranges (low, 
normal, high). Shift from baseline to the worst grade on study, and from baseline to by visit 
reference will be presented. Shifts from baseline to worst value on study will be presented for 
categorical or ordinal lab parameters. Incidence of subjects with laboratory values outside laboratory 
supplied normal range will also be presented.  
All biochemistry and hematology results will be presented in by-subject listings. Urinalysis results 
will be summarized by categoricals and will also presented in the listing.  
6.8.3. 
Vital Signs 
Vital signs including measurements of weight, respiratory rate, pulse rate, systolic and diastolic 
blood pressure, and temperature will be measured at each scheduled study visit starting from 
Screening. Blood pressure measurements should be obtained after the subject has been seated for at 
least 5 minutes. Body weight and BMI will also be included.  
Vital signs will be summarized using descriptive statistics of actual values and changes from 
baseline over time and by treatment group.  
All vital signs assessments will be listed appropriately.  
6.8.4. 
Electrocardiogram 
ECG variables will be summarized using descriptive statistics for each treatment group at Screening 
and post-baseline visit (unscheduled) for the following:  
• QT  
• RR  
• PR  
• QRS 
• Heart Rate  
Number and percent of subjects with normal, not clinically significant abnormal, and clinically 
significant abnormal results for the 12 lead ECG will be tabulated by treatment group at Screening. 
ECG assessments will be performed only at Screening, with the exception of unscheduled 
assessments. 
All ECG data will be listed in by-subject listings.    
6.8.5. 
Physical Examination Findings 
A complete physical examination includes at minimum evaluation of vital signs, head, eye, ear, nose, 
and throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems. Physical examination assessments will be measured at 
Screening and Week 26/EOT.  
Physical examination findings will be summarized by visit. The number and percentage of subjects 
with normal, abnormal not clinically significant and abnormal clinically significant findings will be 
presented for each body system. 


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New or worsened physical examination abnormalities following treatment will be recorded as AEs 
and will be reflected in the summary of AEs.  
All physical examination findings will be presented in by-subject listings.  
6.8.6. 
Respiratory Evaluations 
Pulmonary Function Test (PFT) and Diffusing Capacity for Carbon monoxide (DLCO) will be 
assessed at Screening, Week 12, Week 26/EOT, and Final Safety Follow-up /Week 38 with a 
window of ±14 days.  
PFTs, DLCO, and oxygen saturation will be summarized using descriptive statistics of actual values, 
change from baseline, percent change from baseline over time and by treatment group.  
Percent of subjects meeting certain threshold values will be summarized over time and by treatment 
group for PFTs (<20%, ≥20% reduction from a previous value), and DLCO (<20%, ≥20% reduction 
from a previous value). 
Dyspnea score will be summarized using descriptive statistics of actual values and change from 
baseline over time, and by minimum and maximum post-baseline value. Percent of subjects meeting 
threshold values of <3, 3-4, ≥5 will be summarized over time by treatment group. 
Boxplots of actual results and change from baseline will be produced for PFTs, DLCO, oxygen 
saturation, and dyspnea score at each scheduled study visit. 
The modified Borg scale (Borg, 2010) is a validated patient reported outcome and will be used to 
assess subjects’ perceived sensation of difficulty in breathing (dyspnea) while resting. This scale is a 
linear scale of numbers ranking the magnitude of difficulty in breathing, ranging from 0 (nothing at 
all) to 12 (absolute maximum/highest possible). 
Oxygen saturation will be assessed as part of respiratory system assessment. Pulse oximetry must be 
performed before PFTs and should be done with the subject in a seated position after a 10-minute 
period of rest. Dypsnea and oxygen saturation assessments will be conducted at every study visit 
with the exception of Baseline.  
All respiratory evaluation data will be presented in by-subject listings. 
7. 
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL 
7.1. 
Changes from Protocol 
• The protocol stated the first administration of subcutaneous KPL-301/placebo and oral 
prednisone taper will take place at the study site on Day 0. In this SAP, we defined the 
first administration of subcutaneous KPL-301/placebo as Day 1. The start date of the oral 
prednisome taper is not included the definition of Day 1 since not all patients took the 
first dose of subcutaneous KPL-301/placebo and oral prednisone taper on the same day. 
• TEAE definition was updated to include AE through last dose + 90 days. 
• CM definition was updated to include medications through last dose + 90 days. 
• Included PFTs, DLCO, Dyspnea score, O2 saturation in safety endpoints. 
• The protocol described the categories of cranial symptoms as follows. Section 6.7.2  of 
this SAP adopts the abbreviated categories from the eCRF. 
− New or recurrent headache or pain or tenderness of the scalp or the temporal artery 


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− Visual signs/symptoms such as ischemic retinopathy, optic neuropathy, diplopia, 
amaurosis fugax, etc. 
− New or recurrent claudication of the tongue, masseter muscle, or worsening temporal 
artery signs and symptoms  
− Transient ischemic attack (TIA) or stroke related to GCA in the opinion of the 
Investigator  
• The protocol described the categories of extracranial symptoms as follows. Section 6.7.2  
of this SAP adopts the abbreviated categories from the eCRF. 
− Classic PMR-like symptoms, defined as shoulder and/or hip girdle pain associated 
with inflammatory morning stiffness 
− New or recurrent claudication in the peripheral circulation (i.e., in one of the 
extremities)  
7.2. 
Impact of Covid-19 pandemic 
The impact of the pandemic to the study conduct is expected to be limited as assessed by the amount 
missing data due to lack of office visits or other COVID-19 related issues with the conduct of the 
trial. Therefore there are no special data handling rules and analyses implemented for COVID-19 
related protocol deviations. A separate document will be prepared to summarize any protocol 
deviations which occurred as a result of the pandemic.  
8. 
REFERENCES 
Borg GAJ. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14:37781. 
Docken WP. Treatment of Giant Cell Arteritis. UpToDate Aug 2020 
https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations. Pain. 2005 Jan;113(1-2):9-19. 
Mannion AF, Balagué F, Pellisé F, Cedraschi C. Pain measurement in patients with low back pain. 
Nature Clinical Practice Rheumatology 2007;3(11):610-18. 
SAS Institute Inc. (2001): The SAS System, Version 8.2. Cary, NC. SAS Institute Inc. 


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9. 
APPENDICES 
9.1. 
Handling of Missing Safety Data 
No imputation will be made for completely missing date unless otherwise specified. General 
imputation rules mentioned below apply to partially missing or impossible dates: 
• If the stop date is not missing, and the imputed start date is after the stop date, the start 
date will be imputed by the stop date 
• If the start date is not missing, and the imputed stop date is before the start date, then the 
imputed stop date will be equal to the start date 
• Any imputed dates need to be logical. For example, last dose date should not be later than 
death date. 
When imputation rules in subsequent sections contradicts the general rule, always follow the general 
rule.  
9.1.1. 
Adverse Event Date Imputation 
Follow the general rule specified in Section 9.1. 
Incomplete Start Date: 
Missing day, month, and year 
No imputation will be made; the corresponding AE will be included.  
Missing day and month 
• If the year is the same as the year of the first dose date, then impute day and month as the day 
and month of the first dose 
• If the year is prior to the year of the first dose date, then impute day and month as 31 Dec 
• If the year is after the year of the first dose date, then impute day and month as 01 Jan. 
Missing day only 
• If the month and year are the same as those of the first dose date, then impute day as the day 
of the first dose date 
• If either the year of partial date is before the year of the first dose date, or the years are the 
same, but the month of partial date is before the month of the first dose date then impute day 
as last day of the month 
• If either the year of partial date is after the year of the first dose date, or the years are the 
same, but the month of partial date is after the month of the first dose date, then impute day 
as first day of the month.  
Incomplete Stop Date: 
Missing day, month, and year 
• No imputation will be made. 
Missing day and month 


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• If the year is the same as the year of the last dose date, then impute day and month as the day 
and month of the last dose date 
• If the year is prior to the year of the last dose date, then impute day and month as 31 Dec 
• If the year is after the year of last dose date, then impute day and month as 01 Jan. 
Missing day only 
• If the month and year are the same as those of the last dose date, then impute day as the day 
of the last dose date; 
• If either the year of partial date is not the same as the year of the last dose date, or the years 
are the same, but the month of partial date is not the same as the month of the last dose date, 
then impute day as last day of the month.  
9.1.2. 
Concomitant Medication Date Imputation 
Follow the general rules specified in Section 9.1 and rules in Section 9.1.1 . 


Kiniksa Pharmaceuticals, Ltd. 
 
KPL-301-C001 
 
         Statistical Analysis Plan 
Version 1.0, [10SEP2020] 
 
Confidential 
Page 30 of 31 
 
 
 


Kiniksa Pharmaceuticals, Ltd. 
 
KPL-301-C001 
 
         Statistical Analysis Plan 
Version 1.0, [10SEP2020] 
 
Confidential 
Page 31 of 31 
 
 
 


Signature Page for RIM-CLIN-000608 v2.0
Signature Page for RIM-CLIN-000608 v2.0
Approval
11-Sep-2020 02:14:52 GMT+0000
Approval
11-Sep-2020 02:21:19 GMT+0000
Approval
11-Sep-2020 11:24:56 GMT+0000
Approval
11-Sep-2020 11:38:01 GMT+0000