A Phase 2a/b, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects With Prurigo Nodularis
Phase: PHASE2
Conditions: Prurigo Nodularis, Pruritis
Sponsor: Genentech, Inc.

Official Title:  KPL-716-C201: A Phase 2a/b, Randomized, Double-Blind, Placebo-
Controlled Study to Investigate the Efficacy, Safety, Tolerability and
Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects with
Prurigo Nodularis
NCT Number: 
NCT03816891
Document & Date: 
Protocol Version 6: 19-July-2021 

PROTOCOL 
KPL-716-C201: A Phase 2a/b, Randomized, Double-Blind, 
Placebo-Controlled Study to Investigate the Efficacy, Safety, Tolerability 
and Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects with 
Prurigo Nodularis   
 
Protocol Status: Final 
Protocol Version 6, 19 July 2021 
Protocol Version 5, 21 December 2020 
Replaces, Protocol Version 4, 4 September 2020 
Replaces Protocol Version 3, 13 May 2019 
Replaces Protocol Version 2, 01 February 2019 
Replaces Version 1.1, 06 November 2018 
 
Study Drug: KPL-716 
Protocol Number: KPL-716-C201 
IND Number: 132912  
Sponsor: 
Kiniksa Pharmaceuticals, Ltd. 
 
Sponsor Medical Contact: 
 MD, PhD 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property of Kiniksa Pharmaceuticals, 
Ltd., and is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, 
members of your staff who have a need to know the information, and an applicable Institutional Review Board or 
Independent Ethics Committee.  You agree that the information contained herein is only to be used by you and your 
staff as necessary to conduct the authorized clinical studies of the investigational drug described in the protocol.  You 
further agree to not publish or otherwise disclose any of the information to others without written authorization from 
Kiniksa Pharmaceuticals, Ltd., except to the extent necessary to obtain informed consent from those persons to whom 
the study drug may be administered. 

 
Protocol KPL-716-C201 
 
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INVESTIGATOR AGREEMENT  
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
Investigator’s Name (Print) 
 
 
 
 
 
Investigator’s Signature 
 
                          Date 
 
 
 
 
 
 
 
 
 
 

 
Protocol KPL-716-C201 
 
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PROTOCOL CLARIFICATION FOR VERSIONS 4.0 AND LATER 
For the purpose of maintaining protocol simplicity and to prevent misinterpretations or mistakes in 
the Phase 2b portion of the study, all Phase 2a study specifics have been removed, (starting from 
Version 4.0 of the protocol), as they are no longer applicable to investigational sites participating in 
the Phase 2b study.   
Please refer to Version 3.0 of the protocol for specific Phase 2a study design details. 

 
Protocol KPL-716-C201 
 
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PROTOCOL SYNOPSIS 
Title of Study:  
A Phase 2a/b, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, 
Safety, Tolerability and Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects with 
Prurigo Nodularis 
Phase of Clinical Development:  
Phase 2a/b  
Study Population: 
Subjects with prurigo nodularis (PN) experiencing severe pruritus will be enrolled in this Phase 2b 
study.   
Study Centers:   
Approximately 75 study centers are planned in North America, Europe, and Asia-Pacific  
Number of Subjects (planned): 
Approximately 180 subjects 
Primary Objective 
• 
To evaluate the efficacy of subcutaneous (SC) KPL-716 vs. placebo in reducing pruritus in 
PN subjects experiencing severe pruritus 
Secondary Objectives 
• 
To evaluate the effect of SC KPL-716 vs. placebo in improving sleep in PN subjects 
experiencing severe pruritus 
• 
To evaluate the effect of SC KPL-716 vs. placebo in improving quality of life in PN 
subjects experiencing severe pruritus 
• 
To evaluate the effect of SC KPL-716 vs. placebo in reducing disease severity in PN 
subjects experiencing severe pruritus 
• 
To evaluate the safety and tolerability of SC KPL-716 vs. placebo in PN subjects 
experiencing severe pruritus 
• 
To evaluate the pharmacokinetics (PK) of SC KPL-716 in PN subjects experiencing severe 
pruritus 
Exploratory Objectives 
• 
To evaluate the immunogenicity of SC KPL-716 in PN subjects experiencing severe 
pruritus 
• 
To evaluate the effect of KPL-716 vs. placebo on skin and blood biomarkers 
• 
To evaluate the correlation between KPL-716 responsiveness and co-morbidities in PN 

 
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Primary Efficacy Endpoint for Phase 2b 
• 
Percent change from baseline in weekly average Worst Itch–Numeric Rating Scale (WI-
NRS) at Week 16 
Key Secondary Efficacy Endpoints for Phase 2b  
• 
Proportion of subjects achieving at least a 6-point reduction from baseline in weekly 
average WI-NRS at Week 16 
• 
Proportion of subjects achieving at least a 4-point reduction from baseline in weekly 
average WI-NRS at Week 16   
• 
Proportion of subjects achieving 0 or 1 in PN-IGA at Week 16 
Other Secondary Efficacy Endpoints for Phase 2b 
Related to pruritus: 
• 
Change and percent change from baseline in weekly average of WI-NRS over time 
• 
Proportion of subjects achieving at least a 6-point reduction from baseline in weekly 
average WI-NRS over time.   
• 
Proportion of subjects achieving at least a 4-point reduction from baseline in weekly 
average WI-NRS over time.   
Related to disease severity:  
• 
Proportion of subjects achieving 0 or 1 in PN-IGA over time 
• 
Proportion of subjects with at least 2-point improvement from baseline in PN-IGA 
over time 
• 
Proportion of subjects achieving 0 or 1 in Investigator’s Global Assessment for Prurigo 
Nodularis-Stage (IGA-CNPG-S) over time 
• 
Proportion of subjects with at least 2-point improvement from baseline in IGA-CNPG-
S over time 
Related to sleep:  
• 
Change and percent change from baseline in weekly average of Sleep Loss Visual 
Analog Scale (VAS) over time 
Related to quality of life: 
• 
Change and percent change from baseline in ItchyQoL over time  
Exploratory Efficacy Measures for Phase 2b: 
• 
Proportion of subjects achieving 0 or 1 in IGA-CNPG-Activity (IGA-CNPG-A) over 
time 
• 
Change from baseline in Prurigo Nodularis Nodule Assessment Tool (PN-NAT) over 
time 
• 
Change from baseline in the total score of Patient Health Questionnaire (PHQ-9) over 
time 
• 
Change from baseline in the total score of General Anxiety Disorder (GAD-7) over 
time  
• 
Days and proportion of subjects using rescue medication over time 

 
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• 
Patient Global Impression of Prurigo Nodularis Severity (PGI-PN-S) over time 
• 
Patient Global Impression of Change (PGIC) over time  
• 
Change from baseline in skin and blood biomarkers over time 
Safety Parameters for Phase 2b: 
• 
Incidence rate and severity of treatment-emergent adverse events (TEAEs)  
• 
Incidence rate and severity of study drug-related TEAEs  
• 
Vital signs, electrocardiogram (ECG), and clinical laboratory test results  
Other Parameters for Phase 2b: 
• 
PK: Measurement of plasma concentrations of KPL-716 
• 
Immunogenicity: Measurement of anti-drug (anti-KPL-716) antibodies (ADA) 
Study Design for Phase 2b: 
This is a randomized, double-blind, placebo-controlled study to investigate the efficacy, safety, 
tolerability, PK, and immunogenicity of KPL-716 administered SC in PN subjects experiencing 
severe pruritus.   
The Phase 2b study (Figure 1) will consist of a 4-week Screening Period and a 16-week Double-
Blind Period, followed by a 36-week Open-Label-Extension (OLE) Period. Approximately 180 PN 
subjects experiencing severe pruritus, will be randomized (at 1:1:1:1 ratio) into one of the 
following 4 arms:  KPL-716 540 mg SC, once every 4 weeks (Q4W); KPL-716 360 mg SC, Q4W; 
KPL-716 120 mg SC, Q4W; or placebo SC, Q4W.  A total of 4 doses of study drug will be 
administered during the Double-Blind Period to measure the efficacy, safety, and PK of KPL-716.  
The Phase 2b will utilize a washout monotherapy design in which concomitant therapies that could 
impact pruritus or disease severity will be prohibited from designated windows through the end of 
the OLE Period, thus removing the confounding effect of these therapies on the assessment of 
KPL-716 efficacy.  Should subjects experience an exacerbation of symptoms that is significant 
enough to warrant intervention, oral antihistamines and/or topical corticosteroids may be provided 
4 weeks post-randomization, as outlined in the Pharmacy Manual.  The days of rescue medication 
use will be recorded by subjects in an e-Diary and types and duration of rescue medications used 
will be recorded as a concomitant medication.    
After the Double-Blind Period, all subjects will have the option to receive KPL-716 360 mg SC, 
Q2W during the OLE Period to evaluate the long-term safety and PK.  For subjects who complete 
the Double-Blind Period but choose not to participate in OLE, or who terminate earlier, an End of 
Study (EOS) Visit will be required 4 weeks following the date of last study drug dose. 
An interim analysis may be performed after at least 50% of subjects have completed the Week 16 
Visit.  Additional details regarding the interim analysis, if performed, will be provided in the 
Statistical Analysis Plan (SAP) along with other analysis plan(s). 
Subjects will follow the schedule below: 
• 
Screening Period (minimum 7 days and maximum 28 days) 
• 
Double-Blind Period (Day 1 [Baseline] to Week 16)  
• 
Open-Label-Extension Period (End of Week 16 to Week 52)  
The allowable visit window from Week 4 to Week 16 is ± 2 days and thereafter to Week 52 is ± 3 
days.  

 
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At any point following randomization, home health nursing or telemedicine services may be 
applied to accommodate COVID-19 limitations to in-person visits and dosing.   
Screening Period for Phase 2b: 
After the informed consent form (ICF) is signed, subjects will enter the Screening Period for 
assessment of eligibility.   
During the Screening Period, subjects’ medical and surgical history will be reviewed including 
allergic history.  Review of medical history will include PN disease history (year of first PN nodule 
and year of diagnosis) and history of co-morbidities.  Prior and concomitant medications, therapies 
and procedures will be recorded for PN and any other medical condition.  Vital signs will be 
measured, and subjects will undergo a full physical examination.  Clinical laboratory tests and an 
ECG will be performed.  Urine drug screen and pregnancy test (if applicable) will also be 
performed.   
To be eligible, subjects must have a physician-documented diagnosis of PN with at least 20 
nodules of approximately 0.5 to 2 cm.  The nodules must be pruritic and present on at least 2 
different anatomical locations (not be localized), involve the extremities, with extensor extremity 
involvement greater than the flexor extremity involvement.  Nodules on the head (face and scalp) 
are not counted as an anatomical location for eligibility criteria. Each arm, each leg, and the trunk 
are considered different anatomical locations.  The minimum required duration of disease is at least 
6 months from the time of first PN nodule to Day 1, as affirmed by the subject.   
At the Screening Visit, subjects will be asked to rate their pruritus severity (worst itch) over the last 
24 hours on the WI-NRS.  In addition, subjects will record their WI-NRS on a daily basis during 
the Screening Period.  Subjects will be given training on Accurate Symptom Reporting and 
Placebo Response Reduction during the Screening Visit, Baseline Visit, and Visits of Weeks 4, 8 
and 12, or as needed.  The daily recordings can begin any time after the Screening Visit.  Subjects 
will use internet connected devices for daily electronic recordings.  To be eligible for study 
participation, subjects must have severe pruritus, defined as WI-NRS ≥7 at the Screening Visit and 
a mean weekly WI-NRS ≥7 for the week (7 consecutive days) immediately prior to randomization 
(at least 5 days recordings) on e-Diary.     
During the Screening Period, whole-body medical photographs will be taken (upper front, lower 
front, upper back, and lower back) without the face and with the genitals covered.  In addition, a 
representative area of disease will be determined by the PI at the Screening Visit, and medical 
photographs of this area will be taken and followed throughout the study.  Medical photographs 
will be used for confirmation of diagnosis of PN as defined in the Study Manual and for 
assessment of disease severity over time.  Subjects may be asked to return to the study site during 
the Screening Period for unscheduled visits for repeat screening procedures if needed. 
Additional assessments during the Screening Period include those related to pruritus, sleep, quality 
of life, anxiety and depression and disease severity, etc. (see Schedule of Activities for details).  
Subjects will be instructed on the required washout for specific excluded medications.  The subject 
reported daily recordings (WI-NRS and rescue medication use) will continue throughout the study 
for eligible subjects that proceed to dosing.   
Collection of AEs and concomitant medications will begin after signing the ICF and will continue 
until the EOS Visit.  For Schedule of Activities, please see Appendix 1.  
In an effort to minimize subject burden and/or risk during the COVID-19 pandemic, sites may 
offer to split the Screening Visit into two parts; a virtual preliminary Screening Visit in which 
some assessments may be performed [e.g. ICF, medical history, concomitant medications, subject 
questionnaires (completed electronically) and some eligibility criteria], followed by an in-person 
visit in which all remaining eligibility assessments may be performed that require subjects to be 

 
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physically present (e.g. blood collection for clinical laboratories, ECG, medical photography, vital 
signs, and disease severity assessments).  
Treatment Period for Phase 2b: 
Pre-dose: 
Prior to dosing on Day 1, subjects will undergo an additional review of eligibility, medical and 
surgical history, prior and concomitant medications, therapies, procedures, and AEs.  Clinical 
laboratory results from the Screening Visit will be reviewed.  Compliance with recording of daily 
WI-NRS for the 7 days immediately prior to dosing will also be reviewed.  Urine drug screen and 
pregnancy test (if applicable) will be performed.  Vital signs will be measured.  ECG and a full 
physical examination will be performed. 
Eligible subjects will undergo collection of safety blood and urine samples as well as blood 
samples for PK, ADA, and potential blood biomarkers.  Medical photographs will be taken of the 
representative area of disease identified during the Screening Period.  Whole-body photographs 
(upper front, lower front, upper back, and lower back) without the face and with genitals covered 
will also be captured prior to the first dose.   
For subjects who provide additional consent for the collection of skin biopsies (optional), the 
biopsies (one lesional and one non-lesional) will be performed, along with medical photographs of 
the biopsy areas prior to biopsy collection.     
Upon confirmation of subject eligibility and completion of required activities (Appendix 1), 
subjects will be randomized and proceed to dosing.    
Randomization and Dosing: 
Subjects will be randomized 1:1:1:1 to receive different dosing regimens of KPL-716 or placebo.  
At the end of the Double-Blind Period, all subjects will have the option to enter the OLE Period to 
receive KPL-716 360 mg SC Q2W.  Stratification will be performed based on sex and years since 
the first nodule observed (i.e., ≥10 years vs. <10 years).  
Subjects will be observed for 1-hour post-dosing with vital signs monitored.  All doses of KPL-716 
or matching placebo will be administered by the Investigator, a qualified investigational site 
designee, or home health nurse (in case of COVID-19 disruption) via SC injection during the 
Double-Blind Period.   
Phase 2b:   
• 
Arm A:  KPL-716, 540 mg, SC, every 4 weeks 
• 
Arm B:  KPL-716, 360 mg, SC, every 4 weeks 
• 
Arm C:  KPL-716, 120 mg, SC, every 4 weeks 
• 
Arm D:  Placebo, SC, every 4 weeks  
The dose levels and dosing intervals for Phase 2b have been chosen based on Phase 2a results so as 
not to exceed exposures observed in Phase 2a.   
All procedures assigned to dosing days will be performed prior to study drug administration.  The 
following activities will take place prior to each dose during the Double-Blind Period: 
• 
Review of concomitant medications, therapies, and procedures 
• 
Review of AEs 
• 
Review of subject e-Diary compliance 
• 
Vital signs (performed before and after dosing on each dosing day) 

 
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• 
Collection of blood for PK 
• 
Completion of Sleep Loss VAS 
The following activities will take place prior to dosing at designated study visits as outlined in 
Appendix 1: 
• 
Physical examination and ECG 
• 
Collection of safety blood and urine samples 
• 
Pregnancy test (if applicable) 
• 
Collection of PK and/or blood biomarker samples 
• 
Medical photography 
• 
Completion of patient questionnaires (ItchyQoL PHQ-9, GAD-7, PGI-PN-S, PGIC) 
• 
Assessment of disease severity (PN-NAT, PN-IGA, IGA-CNPG-S, IGA-CNPG-A) 
• 
Skin biopsies (optional)  
AEs and concomitant medications will be collected throughout the study.  Subjects will continue to 
complete their daily questionnaire on pruritus (WI-NRS) and rescue medication use until the EOS 
Visit.   
In case of study drug discontinuation, subjects will continue to follow the schedule of activities for 
each visit minus study drug administration.  Under these circumstances, the second set of biopsies 
(optional) will be performed at the earliest possible visit following early Double-Blind Period drug 
discontinuation, if applicable.  In case of study drug interruption or missed dosing visits, subjects 
will resume the schedule of activities in accordance with their study day.  In case of early 
withdrawal from the entire study, subjects will complete an EOS Visit 4 weeks after the last dose.  
In addition, if early termination occurs prior to the end of treatment period, biopsies should be 
collected at the EOS visit, if applicable.    
Open-Label Extension Period for Phase 2b: 
During the OLE Period, subjects will be administered KPL-716, 360 mg, SC, Q2W with the last 
dosing at Week 48 Visit.  Subjects may be permitted to self-administer KPL-716 as an outpatient 
during the OLE provided the Safety Review Team (SRT) determines that the available safety and 
tolerability data support outpatient self-administration, the Investigator and the Medical Monitor 
approve the individual case, and the subject receives adequate training and successfully performs 3 
KPL-716 self-administrations (e.g., Weeks 16, 18, and 20) under the supervision of study site 
personnel.  If self-administration is not authorized by the SRT, the Investigator, or the Medical 
Monitor, or if an individual subject is unable/unwilling to perform self-administration, KPL-716 
will continue to be administered by the Investigator, a qualified investigational site designee or 
home health nurse.  During the OLE Period, subjects will also undergo vital signs measurement, 
review of concomitant medications, therapies and procedures, review of AEs, monitoring of 
compliance, and PK blood sample collection at visits according to the Schedule of Activities.  
Sleep Loss VAS, physical examination, clinical laboratory tests (including pregnancy testing if 
applicable), quality of life assessment, and evaluation of disease severity will be performed at 
designated visits.  Subjects will continue to complete their daily questionnaires on pruritus and 
rescue medication use throughout the OLE Period.  Should subjects self-administer drug, collection 
of AEs, concomitant medication use, and NRS compliance assessments at visits as outlined in 
Appendix 1 may be completed remotely by study staff.    
The EOS Visit will include vital signs, full physical examination, ECG, clinical laboratory blood 
tests, urinalysis, and urine pregnancy test (if applicable) as well as PK, ADA, and biomarker blood 
sampling.  Biopsies for biomarker assessment will be collected from subjects who provide 

 
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additional consent.  All efficacy assessments for pruritus, sleep, quality of life and disease severity 
will also be completed at this visit.  Medical photography of the whole body and the representative 
area (identified during the Screening Period and followed throughout the study) will be obtained.  
All subjects will complete an EOS Visit.  
Duration of Phase 2b:  
The planned study duration per subject for Phase 2b will be approximately 56 weeks including a 
maximum of 4 weeks for the Screening Period, 16 weeks for the Double-Blind Period, and 36 
weeks for the OLE Period. 
The minimum duration for the Screening Period will be 7 days.  
Study Drug: 
Study Drug: KPL-716 or matching placebo 
Active Substance: KPL-716 
Strength, Formulation, and Route of Administration: 180 mg/mL solution 
 
, 
subcutaneous administration.   
Matching placebo:  
 
, subcutaneous administration. 
Study Treatment:  
For Phase 2b, subjects will be randomized to receive KPL-716 or matching placebo on Day 1 and 
will remain in the same treatment arm throughout the Double-Blind Period, then all subjects will 
have the option to participate in the OLE Period, starting dosing at the End of Week 16 Visit. 
Phase 2b: 
• 
Arm A:  KPL-716 at 540 mg SC on Day 1 and at Weeks 4, 8, and 12 during the Double-
Blind Period 
• 
Arm B:  KPL-716 at 360 mg SC on Day 1 and at Weeks 4, 8 and 12 during the Double-
Blind Period 
• 
Arm C:  KPL-716 at 120 mg (see Pharmacy Manual for formulation instructions) SC on 
Day 1 and at Weeks 4, 8 and 12 during the Double-Blind Period 
• 
Arm D:  Placebo SC on Day 1 and at Weeks 4, 8, and 12 during the Double-Blind Period 
Study Assessments: 
Efficacy Assessment:  
Efficacy in reduction of pruritus will be assessed via daily recording of WI-NRS.  Efficacy in 
improvement of sleep will be assessed via Sleep Loss VAS.  Impact on quality of life will be 
assessed via ItchyQoL, PHQ-9, and GAD-7.  Impact on disease severity will be followed by PN-
IGA, PN-NAT, IGA-CNPG-S, IGA-CNPG-A, PGI-PN-S, and PGIC.  See Schedule of Activities 
Appendix 1.  
An area representative of the subject’s disease will be chosen at the Screening Visit and followed 
over time through medical photography at designated time points.  Whole-body photographs and/or 
images of biopsy locations (prior to collection of biopsies), if applicable, will be taken at indicated 
study visits.   
Skin biopsies will be collected pre- and post-treatment during this study.  Skin biopsies are 
encouraged but optional.  Two individual punch biopsies (one from lesional skin and one from 
adjacent non-lesional skin) will be collected prior to dosing at Day 1, and post-treatment biopsies 

 
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will be collected at Week 16 or EOS.  Biopsy collection procedures and processing will be outlined 
in a separate manual.  
Safety Assessments: 
Safety will be assessed by monitoring of AEs, measurements of vital signs, physical examination, 
ECG evaluation, and clinical laboratory tests. 
PK Assessment: 
PK blood samples will be collected from all subjects as specified in the Schedule of Activities.  PK 
samples will be collected pre-dose on dosing days.  
Biomarker Assessment:  
Blood samples will be collected from all subjects for biomarkers analysis.  Biomarker samples will 
be collected pre-dose on dosing days as specified in the Schedule of Activities. 
Immunogenicity Assessment:  
Blood samples for ADA assessment will be collected from all subjects pre-dose on dosing days as 
specified in the Schedule of Activities. 
Selection of Phase 2b Study Population: 
Inclusion Criteria: 
1. Male or female aged 18 to 80 years, inclusive, at the time of consent. 
2. Have a physician-documented diagnosis of PN that is confirmed by review of medical 
photography (as outlined in the Study Manual) during the Screening Period.  Duration of 
PN (since the time of first PN nodule) must be at least 6 months from the time of first PN 
nodule to Day 1, as affirmed by the subject.  
3. Have at least 20 nodules of approximately 0.5 to 2 cm at the Screening Visit and Day 1.  
The nodules must be pruritic and present on at least 2 different anatomical locations (not 
be localized), involve the extremities, with extensor extremity involvement greater than the 
flexor extremity involvement.  Nodules on the head (face and scalp) are not counted as an 
anatomical location for eligibility criteria.  Each arm, each leg, and trunk are considered 
different anatomical locations.   
4. Subject has severe pruritus, defined as WI-NRS ≥7 at the Screening Visit and a mean 
weekly WI-NRS ≥7 for the week (7 consecutive days) immediately prior to randomization 
(at least 5 days of recordings) on eDiary.  
5. PN-IGA score of ≥3 (on a scale of 0-4, in which 3 is moderate and 4 is severe) at 
Screening and Baseline Visits 
6. Sexually active female subjects must be:  
• 
postmenopausal, defined as at least 12 consecutive months post cessation of menses 
(without an alternative medical cause) and confirmed by a follicular stimulating hormone 
(FSH) test, or  
• 
surgically sterile following documented hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy or  
• 
nonpregnant, nonlactating, and having agreed to use a highly effective method of 
contraception from the Screening Visit until 16 weeks after final study drug 
administration.   
o Note:  highly effective methods of contraception include: 

 
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▪ 
hormonal contraceptives associated with inhibition of ovulation (stable 
dose for at least 4 weeks prior to first dose) 
▪ 
intrauterine device 
▪ 
intrauterine system 
▪ 
double barrier methods of contraception (barrier methods include male 
condom, female condom, cervical cap, diaphragm, contraceptive 
sponge) in conjunction with spermicide. 
▪ 
tubal ligation 
▪ 
vasectomized male partner 
7. Sexually active male subjects must have documented vasectomy or must agree to use a 
highly effective method of contraception as defined above with their partners of 
childbearing potential from first dose until 16 weeks after final study drug administration.   
8. Male subjects must agree to refrain from donating sperm from first dose until 16 weeks 
after the last study drug administration.  Female subjects must agree to refrain from 
donating eggs from first dose until 16 weeks after the last study drug administration.  
9. Female of childbearing potential must have a negative serum β-hCG test at the Screening 
Visit and negative urine pregnancy test on Day 1.  
10. Able to comprehend and willing to sign an Informed Consent Form and able to abide by 
the study restrictions and comply with all study procedures for the duration of the study. 
11. Subjects must be on optimized and stable treatment for co-morbidities for at least 28 days 
prior to Day 1.  
Exclusion Criteria: 
 
1. Use of the following medications within the indicated timeframe prior to Day 1 and does 
not agree to refrain from the use of the medications throughout the study (except those 
specified in the Pharmacy Manual): 
a. Systemic corticosteroids (IV/IM/oral):  4 weeks; Note: Intranasal corticosteroids, 
eye drops containing corticosteroids, and inhaled corticosteroids for stable medical 
conditions are allowed.  
b. Intralesional corticosteroids and intra-articular corticosteroids:  6 weeks 
c. Topical treatments for PN including but not limited to corticosteroids, calcineurin 
inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, capsaicin, camphor, 
polidocanol, cannabinoids, gabapentin, or tars:  2 weeks 
d. Antihistamines:  2 weeks 
e. Immunomodulators (for example, cyclosporin, methotrexate, retinoids, 
azathioprine, mycophenolate, and thalidomide):  4 weeks 
f. Neuroactive drugs such as gabapentin and pregabalin:  4 weeks 
g. Cannabinoids:  2 weeks 
h. Opioid antagonists or agonists:  5 half-lives if known or 4 weeks  
i. 
Janus kinase inhibitors:  5 half-lives if known or 4 weeks 
j. 
Dupilumab:  8 weeks  
k. Any other marketed biologic:  5 half-lives or within 4 months of using rituximab 

 
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l. 
Any investigational drug:  5 half-lives 
m. Phototherapy involving UVA, UVB, or excimer:  4 weeks 
n. Tanning salon use:  4 weeks  
o. Live attenuated vaccine: 12 weeks 
2. Has received any investigational biologic or non-biologic drug that targets Oncostatin M, 
IL-31, IL-31 receptor , or Oncostatin M receptor  in the past 3 months.  
3. Required rescue therapy for PN during the Screening Period or expected to require rescue 
therapy within 4 weeks following the Baseline Visit. 
4. Has a significant exacerbation and/or skin eruption during the Screening Period (prior to 
the study drug administration) that requires medical intervention. 
5. Presence of scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, 
habitual picking, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis 
herpetiformis, sporotrichosis, bullous disease, and/or skin condition other than PN or 
atopic dermatitis unless approved by the Sponsor. 
6. Plan to change emollients or moisturizers, or to have bath oil treatment for relief of 
pruritus during the course of the trial.   
7. Presence of psychogenic pruritus or neuropathic pruritus at the Screening Visit.  
8. Presence of severe depression as indicated by PHQ-9 total score of ≥20 or item 9 score >0 
at the Screening Visit or Day 1. 
9. Presence of severe anxiety as indicated by GAD-7 score of ≥15 at the Screening Visit or 
Day 1. 
10. Presence of severe chronic pain (e.g., back pain, migraine, osteoarthritis, etc., defined as 
≥7.0 on 0 to 10 NRS scale with 0 being no pain and 10 being the worst pain possible) at 
the Screening Visit. 
11. Presence of uncontrolled hyperthyroidism or hypothyroidism or uncontrolled diabetes 
defined as hemoglobin A1c >7.5%.  
12. Presence or history of cancer or lymphoproliferative disease within 5 years prior to the 
Screening Visit, with the exception of basal and squamous cell carcinoma of the skin or in 
situ carcinoma of the cervix successfully treated and considered controlled. 
13. Presence or history of immune deficiency, or opportunistic infections.  
14. Positive results for hepatitis B surface antigen (HbsAg) and/or hepatitis B anti-core 
antibody (anti-HBc) but negative results for anti-surface antibody (anti-HBs) at the 
Screening Visit. 
15. Positive results for hepatitis C antibody unless patient received curative therapy and a 
negative viral load is documented. 
16. Human immunodeficiency virus (HIV) infection or positive HIV serology at the Screening 
Visit.  
17. Positive COVID-19 viral test at the Screening Visit or suspected COVID-19 infection at 
the Baseline Visit. 
18. Subject is on hemodialysis or peritoneal dialysis. 
19. Latent or active TB, as determined by a positive Quantiferon-based TB test result at the 
Screening visit. 

 
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20. Laboratory abnormalities that fall outside the windows below at the Screening Visit: 
a. Alanine aminotransferase >3 x upper limit of normal (ULN) 
b. Aspartate aminotransferase >3 x ULN 
c. Gamma-glutamyl transferase >3 x ULN 
d. Blood bilirubin >2 x ULN 
e. Hemoglobin more than 1g/dL below the lower limit of normal for sex per the 
laboratory in which screening lab is performed.   
f. Platelet count <150,000/ µL  
g. Neutrophil count < 1,500/L 
21. Major surgery within 12 weeks prior to Day 1 or has a major surgery planned during the 
study. 
22. Has an active infection, including skin infection, requiring systemic treatment within 4 
weeks and/or topical treatment within 2 weeks of Day 1.  Subject has an active or chronic 
parasitic infection.  
23. Any medical or psychiatric condition which, in the opinion of the Investigator or the 
Sponsor, may place the subject at increased risk as a result of study participation, interfere 
with study participation or study assessments, affect compliance with study requirements, 
or complicate interpretation of study results.  
24. Has a known hypersensitivity to KPL-716 or its excipients. 
25. Has a known history of drug or alcohol abuse in the last 2 years prior to Day 1.  Has more 
than eight drinks (5 ounces of wine, 12 ounces of beer or 1.5 ounces of liquor) weekly for 
females and 15 drinks weekly for males. 
26. Has a positive urine drug screen for opiates, opioids, methadone, cocaine, phencyclidine, 
or amphetamines at the Screening Visit or Day 1.  Exceptions may be made if a subject is 
on a medication for a stable concomitant condition that explains the positive drug screen 
result. 
27. Has had a severe allergic reaction to any foods or medications including anaphylactic 
reactions, unless approved by the Sponsor.    
28. For subject providing consent for the optional skin biopsy, presence or history of 
coagulation disorders, hypertrophic scar, or keloid, or currently under treatments with 
chronic anti-coagulants (aspirin ≤ 325mg/day is acceptable). 
Statistical Methods for Phase 2b:  
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, first 
quartile, median, third quartile, minimum and maximum for continuous variables, and frequency 
and percentage for categorical and ordinal variables.  
Statistical analyses for the Phase 2a and Phase 2b portions of the study will be conducted 
separately.  An integrated analysis of the pooled data may be performed at the end of the study 
depending on the results of these individual analyses.  The primary efficacy endpoint in Phase 2b 
will be analyzed with ANCOVA including treatment as fixed effect, baseline WI-NRS, and 
randomization stratification factor as covariates.  
For key secondary efficacy endpoints, the difference of proportions and the corresponding 95% CI 
for the difference of proportions will be displayed.  Treatment groups will be compared using a 

 
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Cochran-Mantel-Haenszel test controlling for the randomization stratification variables.  Details 
for the analyses including handling subjects randomized to different treatment durations and dose 
levels will be specified in the SAP. 
Multiple comparison/Multiplicity: 
As this is a dose finding study, there is no multiplicity adjustment planned for the comparisons of 
multiple doses of KPL-716 versus placebo. 
Determination of Sample Size: 
The Phase 2b sample size calculation is based on the primary efficacy endpoint (percentage change 
from baseline of WI-NRS at Week 16) using a two-sample t-test.  
Approximately 180 subjects in total will be equally randomized to the 4 arms of Phase 2b.  At 
Week 16, 53% and 30% reduction in weekly average of WI-NRS are assumed for KPL-716 and 
placebo arms, respectively.  For each comparison, assuming treatment effect of 23% difference in 
weekly average WI-NRS reduction from baseline at Week 16 and standard deviation of 35%, and 
two-sided alpha of 0.05, 38 subjects in each arm will guarantee 80% power to the treatment effect.  
Approximately 45 patients in each arm are required after adjusting for 15% lost follow up.  
Randomization Strata:  
• 
Sex: Male vs Female 
• 
Years since first nodule observation: ≥10 years vs <10 years 
Analysis Sets: 
Modified Intent-to-Treat Analysis Sets:  
All randomized subjects who receive at least 1 dose of KPL-716 or placebo and have at least 1 
post-baseline efficacy assessment in the double-blind Treatment Period will be included in the 
modified intent-to-treat (mITT) analysis set.   
Safety Analysis Sets: 
All randomized subjects who take at least 1 dose of KPL-716 or placebo will be included in the 
Safety Analysis Set.  
Per Protocol (PP) Analysis Sets: 
All mITT subjects who have no important protocol deviations that may potentially bias efficacy 
analyses of the study will be included in the PP set. 
Pharmacokinetic (PK) Analysis Sets: 
Subjects who received KPL-716 and who had at least one PK sample will be included in the PK 
population. 
Analysis of Efficacy:  
The primary efficacy endpoint in Phase 2b will be analyzed with ANCOVA including treatment as 
fixed effect, baseline WI-NRS, and randomization as covariates.  Details will be specified in the 
Phase 2b SAP. 
Analysis of Safety: 
All safety analyses will be conducted based on the Safety Analysis Set.  Summary tables will be 
done for safety endpoints (treatment emergent AEs, labs, vital signs, etc.).  All safety data will be 
listed by subject.  Details for the analysis of safety data will be provided in the SAP. 
PK Analyses: 

 
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For all subjects, serum samples will be collected before each dose at time points shown in 
Appendix 1 in order to quantify concentrations of KPL-716.  Descriptive statistics will be 
calculated for the serum concentrations of KPL-716 by visit.  Individual listings of plasma 
concentrations will be provided. 
Biomarker Analyses: 
Skin and blood biomarker levels will be analyzed.  
Immunogenicity Analyses: 
Serum ADA will be listed and summarized by treatment group and overall using descriptive 
statistics. 
Interim Analysis: 
An interim analysis for Phase 2b portion may be conducted after at least 50% subjects complete 
Week 16 Visit.  If the interim analysis is conducted in the Phase 2b part, a two-sided alpha of 
0.0001 will be spent.  The two-sided alpha level for the final Phase 2b efficacy analysis will be 
0.05. Additional details regarding the interim analysis, if performed, will be provided in the SAP 
along with other analysis plans. 

 
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Figure 1 
Phase 2b Study Design Diagram 
Double-Blind Period D1 to W16 
 
Arm A 
KPL-716 540 mg, 
q4wk 
Arm B 
KPL-716 360 mg, 
q4wk 
Screening Period 
D -28 to D -1 
 D1 
Open-Label Extension Period 
W16 to W52 
Arm C 
KPL-716 120 mg, 
q4wk 
Randomization 
Arm D 
Placebo q4wk 

 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT .........................................................................................2 
SPONSOR’S SIGNATURE PAGE ........................................................................................3 
PROTOCOL CLARIFICATION FOR VERSIONS 4.0 AND LATER .............................4 
PROTOCOL SYNOPSIS ........................................................................................................5 
TABLE OF CONTENTS ......................................................................................................19 
LIST OF IN-TEXT TABLES ...............................................................................................23 
LIST OF IN-TEXT FIGURES .............................................................................................23 
LIST OF ABBREVIATIONS ...............................................................................................24 
1 
INTRODUCTION ..........................................................................................................26 
1.1 
Background ..........................................................................................................26 
1.2 
Summary of Nonclinical Pharmacology ............................................................27 
1.3 
Study Rationale ....................................................................................................27 
1.4 
Justification for Using a Placebo Control Arm .................................................29 
1.5 
Benefit-risk Assessment .......................................................................................29 
2 
OBJECTIVES ................................................................................................................31 
2.1 
Primary Objective ................................................................................................31 
2.2 
Secondary Objectives...........................................................................................31 
2.3 
Exploratory Objectives ........................................................................................31 
3 
ENDPOINTS ..................................................................................................................32 
3.1 
Primary Efficacy Endpoint for 2b ......................................................................32 
3.2 
Key Secondary Efficacy Endpoints for 2b .........................................................32 
3.3 
Other Secondary Efficacy Endpoints for Phase 2b ..........................................32 
3.4 
Safety Parameters for Phase 2b ..........................................................................33 
3.5 
Other Parameters for 2b .....................................................................................33 
4 
INVESTIGATIONAL PLAN .......................................................................................34 
4.1 
Study Design .........................................................................................................34 
4.1.1 
Screening Period for Phase 2b ..................................................................34 
4.1.2 
Treatment Period .......................................................................................36 
4.1.2.1 
Pre-dose .............................................................................................36 
4.1.2.2 
Randomization and Dosing .............................................................36 
4.1.3 
OLE for Phase 2b .......................................................................................37 
4.2 
Duration of Phase 2b ...........................................................................................38 
4.3 
Study Drug ............................................................................................................38 
4.4 
Study Treatment ..................................................................................................38 
4.5 
Selection of Doses in the Study ...........................................................................39 
4.6 
Study Assessments ...............................................................................................41 
4.6.1 
Efficacy Assessment ...................................................................................41 
4.6.2 
Safety Assessments .....................................................................................42 
4.6.3 
PK Assessments ..........................................................................................42 

 
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4.6.4 
Biomarker Assessment ..............................................................................42 
4.6.5 
Immunogenicity Assessments ...................................................................42 
4.7 
Selection of Study Population .............................................................................42 
4.7.1 
Inclusion Criteria .......................................................................................42 
4.7.2 
Exclusion Criteria ......................................................................................43 
4.8 
Subject Number and Identification ....................................................................46 
4.9 
Subject Withdrawal and Replacement ..............................................................46 
4.10 
Study Termination or Temporary Suspension..................................................47 
5 
STUDY TREATMENTS ...............................................................................................49 
5.1 
Description, Storage, Packaging, and Labeling ................................................49 
5.2 
Study Treatment Administration .......................................................................49 
5.3 
Randomization .....................................................................................................50 
5.4 
Blinding .................................................................................................................50 
5.5 
Study Treatment Compliance .............................................................................51 
5.6 
Study Drug Accountability..................................................................................51 
6 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ..........................52 
6.1 
Concomitant Medications ...................................................................................52 
6.2 
Diet ........................................................................................................................52 
6.3 
Smoking ................................................................................................................53 
6.4 
Blood Donation .....................................................................................................53 
6.5 
Contraception .......................................................................................................53 
7 
STUDY ASSESSMENTS AND PROCEDURES ........................................................54 
7.1 
Pharmacokinetic Assessments ............................................................................54 
7.2 
Immunogenicity Assessment ...............................................................................54 
7.3 
Clinical Response Assessments ...........................................................................54 
7.3.1 
Daily NRS Tool ...........................................................................................54 
7.3.2 
Worst Itch Numerical Rating Scale..........................................................54 
7.3.3 
Sleep loss Visual Analog Scale (Sleep Loss VAS) ....................................54 
7.3.4 
Prurigo Nodularis Nodule Assessment Tool (PN-NAT) .........................54 
7.3.5 
Prurigo Nodularis Investigator’s Global Assessment (PN-IGA) ...........55 
7.3.6 
Investigator’s Global Assessment of Prurigo Nodularis-Stage 
(IGA-CNPG-S) ...........................................................................................55 
7.3.7 
Investigator’s Global Assessment of Prurigo Nodularis-Activity 
(IGA-CNPG-A) ..........................................................................................55 
7.3.8 
Medical Photographs .................................................................................55 
7.3.9 
ItchyQoL questionnaire.............................................................................56 
7.3.10 
Patient Health Questionnaire (PHQ-9) ....................................................56 
7.3.11 
General Anxiety Disorder (GAD-7) .........................................................56 
7.3.12 
Patient Global Impression of Prurigo Nodularis Severity 
(PGI-PN-S)..................................................................................................56 
7.3.13 
Patient Global Impression of Change (PGIC).........................................56 

 
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7.4 
Biomarker Assessments .......................................................................................57 
7.4.1 
Blood Sample Collection and Processing .................................................57 
7.4.2 
Skin Biopsy Collection and Processing ....................................................57 
7.5 
Safety and Tolerability Assessments ..................................................................57 
7.5.1 
Adverse Events ...........................................................................................57 
7.5.1.1 
Adverse Event Definition and Categorization ...............................57 
7.5.1.2 
Adverse Drug Reactions ..................................................................59 
7.5.1.3 
Adverse Event of Special Interest ...................................................59 
7.5.1.4 
Serious Adverse Events ...................................................................59 
7.5.2 
Pregnancy ...................................................................................................60 
7.5.3 
Clinical Laboratory Evaluations ..............................................................61 
7.5.4 
Vital Signs ...................................................................................................61 
7.5.5 
12-Lead Electrocardiogram ......................................................................62 
7.5.6 
Physical Examination ................................................................................62 
7.5.7 
Safety Data Review ....................................................................................62 
8 
SAMPLE SIZE AND DATA ANALYSES ..................................................................63 
8.1 
General Considerations .......................................................................................63 
8.2 
Handling of Dropouts and Missing Data ...........................................................63 
8.3 
Multiple Comparisons/Multiplicity ....................................................................63 
8.4 
Determination of Sample Size .............................................................................63 
8.5 
Analysis Populations ............................................................................................63 
8.5.1 
Modified Intent-to-Treat Analysis Sets ....................................................63 
8.5.2 
Safety Analysis Sets....................................................................................64 
8.5.3 
Per Protocol (PP) Analysis Sets ................................................................64 
8.5.4 
Pharmacokinetic Analysis Sets .................................................................64 
8.6 
Analysis of Efficacy ..............................................................................................64 
8.7 
Analysis of Safety .................................................................................................64 
8.7.1 
Adverse Events ...........................................................................................64 
8.7.2 
Clinical and Laboratory Events and Analyses ........................................65 
8.7.3 
Vital Signs ...................................................................................................65 
8.7.4 
Physical Examination ................................................................................65 
8.7.5 
Concomitant Medications .........................................................................65 
8.8 
Pharmacokinetic Analyses ..................................................................................65 
8.9 
Biomarker Analyses .............................................................................................65 
8.10 
Immunogenicity Analyses ...................................................................................65 
8.11 
Gene Expression Analyses ...................................................................................65 
8.12 
Interim Analyses ..................................................................................................66 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................67 
9.1 
Auditing ................................................................................................................67 
9.2 
Monitoring ............................................................................................................67 

 
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10 DATA HANDLING AND RECORD KEEPING ........................................................68 
10.1 
Data Handling ......................................................................................................68 
10.2 
Case Report Form ................................................................................................68 
10.3 
Records..................................................................................................................68 
11 ETHICAL AND REGULATORY CONSIDERATIONS ..........................................69 
11.1 
Ethics Committee or Institutional Review Board .............................................69 
11.2 
Regulatory Considerations ..................................................................................69 
11.3 
Informed Consent ................................................................................................69 
11.4 
Subject Confidentiality ........................................................................................70 
11.5 
Protocol Amendments .........................................................................................70 
12 ADMINISTRATIVE ASPECTS ...................................................................................71 
12.1 
Disclosure ..............................................................................................................71 
12.2 
Reports and Publications ....................................................................................71 
12.3 
Finances and Insurance .......................................................................................71 
13 REFERENCES ...............................................................................................................72 
14 APPENDICES ................................................................................................................74 
14.1 
Appendix 1: Schedule of Activities .....................................................................74 
14.2 
Appendix 2:  Daily NRS Tool for Phase 2b .......................................................79 
14.3 
Appendix 3:  Prurigo Nodularis Nodule Assessment Tool (PN-NAT) ............80 
14.4 
Appendix 4: Prurigo Nodularis Investigator’s Global Assessment 
(PN-IGA) ...............................................................................................................82 
14.5 
Appendix 5: Sleep Loss Assessment (average during the past 3 nights) .........83 
14.6 
Appendix 6: Patient Global Impression of Change (PGIC).............................84 
14.7 
Appendix 7: Investigator’s Global Assessment for Prurigo Nodularis-
Stage (IGA-CNPG-S) ...........................................................................................85 
14.8 
Appendix 8: Investigator’s Global Assessment for Prurigo Nodularis-
Activity (IGA-CNPG-A) ......................................................................................86 
14.9 
Appendix 9: Patient Health Questionnaire (PHQ-9) ........................................87 
14.10 Appendix 10: Generalized Anxiety Disorder (GAD-7).....................................88 
14.11 Appendix 11: ItchyQoL Questionnaire ..............................................................89 
14.12 Appendix 12: Patient Global Impression of Prurigo Nodularis Severity 
(PGI-PN-S)............................................................................................................91 
14.13 Appendix 13: Summary of Changes (Version 6 compared to Version 5) .......92 

 
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LIST OF IN-TEXT TABLES  
Table 1 
Schedule of Activities for Phase 2b ...........................................................75 
 
 
LIST OF IN-TEXT FIGURES  
Figure 1 
Phase 2b Study Design Diagram................................................................18 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation 
or Specialist 
Term 
Explanation 
ADA 
anti-drug antibodies (anti-KPL-716 antibodies) 
AE 
adverse event 
AESI 
AE of special interest 
Anti-HBc 
hepatitis B core antibody 
Anti-HBs 
hepatitis B surface antibody 
ASR 
Accurate Symptom Reporting  
ATC 
Anatomical Therapeutic Chemical 
AUC0-∞ 
Area under the concentration-time curve from time zero to infinity 
β-hCG 
β-human chorionic gonadotropin 
BMI 
body mass index 
Cmax 
maximum concentration 
CRO 
Clinical Research Organization 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
end of study 
FSH 
Follicle-stimulating hormone 
GAD-7 
General Anxiety Disorder 
HBV 
hepatitis B virus 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonization 
IEC 
International Ethics Committee 
IGA-CNPG-A 
Investigator’s Global Assessment for Prurigo Nodularis-Activity 
IGA-CNPG-S 
Investigator’s Global Assessment for Prurigo Nodularis-Stage 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IWRS 
interactive web response system 
LIFR 
leukemia inhibitory factor receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effect level 
NRS 
Numerical Rating Scale 
OSM 
oncostatin M 
OSMR 
oncostatin M Receptor beta 
PD 
pharmacodynamic(s) 
PGI-PN-S 
Patient Global Impression of Prurigo Nodularis Severity 
PGIC 
Patient Global Impression of Change 
PHQ-9 
Patient Health Questionnaire 

 
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Abbreviation 
or Specialist 
Term 
Explanation 
PK 
pharmacokinetic(s) 
PN 
prurigo nodularis 
PN-IGA 
Prurigo Nodularis Investigator Global Assessment 
PP 
per-protocol 
PRR 
Placebo Response Reduction 
PT 
preferred term 
Q 
quartile 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SOC 
System Organ Class 
SRT 
Safety Review Team  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WI-NRS 
Worst Itch Numeric Rating Scale 
  
 

 
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1 
INTRODUCTION 
1.1 
Background 
Prurigo nodularis (PN) is a chronic skin disease characterized by symmetrically distributed, 
intensely pruritic hyperkeratotic nodules most frequently affecting extensor extremities and 
the trunk (1, 2).  PN is recognized as the nodular subtype of a recently described umbrella 
condition called Chronic Prurigo, which encompasses a larger variety of lesions ranging from 
papule to umblicated ulcers to plaques (1).  
There are no approved therapies for PN.  Topical therapies such as topical corticosteroids, 
calcineurin inhibitors, calcipotriol, and capsaicin, systemic corticosteroids, thalidomide, 
systemic immunomodulatory drugs such as methotrexate and cyclosporin, antiepileptics and 
antidepressants, phototherapy and photochemotherapy are often tried with limited success 
and in some cases with unfavorable risk benefit ratio (3). As a result, PN carries a significant 
unmet medical need as the intractable itching, the intense scratching and the ensuing skin 
lesions lead to sleep loss, embarrassment, anxiety, and depression and overall diminish 
quality of life (4).  
Histologically, PN is characterized by thick compact orthohyperkeratosis, irregular epidermal 
hyperplasia, increased capillaries, an inﬂammatory inﬁltrate consisting of mainly 
lymphocytes and macrophages and to a lesser degree eosinophils and neutrophils, increased 
fibroblasts, and vertical fibrosis of the papillary dermis (5). Although the exact etiology of 
PN is unknown, the symptomatology of the disease implicates pruritic pathways and its 
histologic features point to epidermal activation, inflammation, and fibrosis.   
PN is associated with a number of co-morbidities including infections (HIV and hepatitis C), 
chronic kidney disease, malignancies, endocrine, hematologic, gastrointestinal, 
cardiovascular, pulmonary, dermatologic and psychiatric conditions (6, 7).  Chronic pruritus 
is a feature of many of these co-morbidities.  In a subset of patients with chronic pruritus, 
whether idiopathic in origin or in association with a co-morbidity, chronic pruritus and 
chronic scratching lead to neuronal sensitization and the onset of a vicious itch-scratch cycle 
that ultimately results in the development of nodules.  Although chronic pruritus in the 
context of an underlying condition can trigger PN, once PN develops its clinical course and 
severity appear to be independent of the original underlying condition such that treatment of 
the underlying condition is not sufficient to treat PN (1).  
In addition to published studies describing cohorts of PN patients (6, 7, 8, 9) , Kiniksa 
undertook an observational study, which enrolled 54 PN patients in the United States and 
Europe, to understand better the clinical manifestations, standard of care management, natural 
history and pathogenesis of the disease (Data on file at Kiniksa).  In approximately 13% to 
50% of patients, no underlying condition was identified as the trigger for the chronic pruritus 
that led to PN suggesting that some patients may have an idiopathic form of the disease 
(7 and Data on file at Kiniksa). The two largest published studies, with 108 patients in 
Germany and 909 patients in the US, found atopic dermatitis in association with PN in only 
7 and 10.7% of PN patients, respectively (6, 7).  Although atopic dermatitis is not a common 
underlying condition in PN, atopic disposition is believed to be prevalent with 46% and 65% 
of patients described to have atopic diathesis in 2 separate studies (7 and 9).  Whether 
presence of atopy impacts the pathogenesis of PN and/or its clinical course and whether it 
defines a specific subset of patients remains to be seen.  In a broader sense, it also remains to 

 
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be seen whether the presence or absence of an underlying condition or the type of underlying 
condition impacts the mechanism of disease in PN or whether all circumstances lead to a 
common pathway of chronic pruritis that drives disease pathogenesis in PN.   
The primary objective of this study is to investigate the efficacy of KPL-716 in reducing 
pruritus in PN.  The secondary objectives are to investigate the impact of KPL-716 on sleep 
loss, quality of life and disease severity.  Clinical response and/or biomarker studies will be 
used to understand whether KPL-716 responsiveness is limited to a specific subset of patients 
with PN.  For the rationale of the study, please see Section 1.3.  
1.2 
Summary of Nonclinical Pharmacology 
A series of in vitro studies have been conducted with KPL-716 to characterize its binding 
properties and biologic activity.  For details on the in vitro profiles, refer to the Investigator’s 
Brochure (IB). 
KPL-716 was well tolerated in multi-dose 7-week and 26-week primate toxicity studies.  In 
the 7-week toxicity study, cynomolgus monkeys were dosed once every other week with 
either an intravenous (IV) bolus injection of up to 500 mg/kg KPL-716 or a subcutaneous 
(SC) injection of 300 mg/kg KPL-716, for a total of 3 doses.  The multi-dose, 7-week, 
preclinical toxicology study in cynomolgus monkeys revealed no specific toxicities, and the 
no observed adverse effect levels (NOAELs) for systemic toxicity were 500 mg/kg for IV 
administration and 300 mg/kg for SC administration.  For further details, refer to the IB.   
In the chronic toxicology study, weekly administration of KPL-716 by IV bolus injection or 
SC at doses up to 200 mg/kg IV/SC for 26 weeks (27 total doses) was well tolerated in 
cynomolgus monkeys.  Based on these results under the conditions and duration of the study 
provided in the preliminary report, the NOAEL was considered to be 200 mg/kg IV/SC, the 
highest dose tested.  A low level of anti-drug antibody (ADA) response was noted in the 
toxicity study, which was not unexpected because KPL-716 is a fully human antibody.  The 
magnitude of the ADA response was judged to be insufficient to impact toxicokinetic 
evaluations  
1.3 
Study Rationale 
KPL-716 is a first-in-class, fully human monoclonal antibody against oncostatin receptor beta 
(OSMRβ).  OSMRβ is a cell surface receptor that heterodimerizes with IL-31 receptor alpha 
(IL-31Rα) to mediate signaling of IL-31.  It also heterodimerizes with gp130 to mediate 
signaling of oncostatin (OSM).  By targeting a single epitope (OSMRβ), KPL-716 is 
designed to simultaneously inhibit signaling of IL-31 and OSM, 2 cytokine pathways, which 
are important in pruritus, inflammation, hyperkeratosis, and fibrosis.  In contrast, KPL-716 
does not inhibit signaling of OSM down the leukemia inhibitory factor receptor (LIFR) 
pathway, a pathway implicated in hematopoiesis and platelet synthesis (10).  
PN is a disease characterized by intractable pruritus and hyperkeratotic nodules.  In addition 
to hyperkeratosis and epidermal hyperplasia, typical histologic abnormalities include 
lymphocytic, monocytic and to a lesser degree granulocytic inflammation and dermal 
papillary fibrosis (5). KPL-716 via its dual pathway mechanism is predicted to reduce 
pruritus and potentially modulate these other aspects of disease pathology in PN.  A clinical 
relief on pruritus intensity was observed at therapeutic doses based on the Phase 1b study 

 
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results in atopic dermatitis patients (Protocol KPL-716-C001 and data on file).  It is also 
anticipated that inhibition of signaling of two pathways critical in pruritus, inflammation, 
hyperkeratosis, and fibrosis ultimately may improve severity of disease from the baseline and 
may offer additional advantages beyond current therapies.  The targeted nature of the 
KPL-716 mechanism of action is also expected to offer safety advantages compared to 
immunosuppressive therapies as well as systemic and topical corticosteroids.   
The role of IL-31 in pruritus is well established, as IL-31 receptor inhibition has been shown 
to decrease pruritus in subjects with atopic dermatitis (11, 12).  The published literature 
suggests that IL-31 plays a role in PN.  Two studies have shown increased IL-31 mRNA 
expression levels in the lesional skin of PN patients compared to healthy volunteers and 
patients with psoriasis (13, 14).  Another study showed IL-31 and IL-31Rα protein expression 
in a subset of inflammatory cells in PN skin though to a lesser extent than that seen in atopic 
dermatitis (15).  In a Phase 1b study, KPL-716-C001, KPL-716 demonstrated OSMRβ target 
engagement and an early signal of efficacy by reducing pruritus in subjects with atopic 
dermatitis.  Please see IB.  KPL-716 is therefore being investigated in this Phase 2 study for 
its efficacy in reducing pruritus in patients with PN (primary endpoint).  The reduction in 
pruritus is anticipated to improve sleep and quality of life.  Therefore, this study will 
investigate the impact of KPL-716 on sleep and quality of life (secondary endpoints).   
OSM, the other cytokine pathway inhibited by KPL-716, has been shown to play a role in 
inflammation, epidermal integrity, and fibrosis, 3 pathways important in PN pathogenesis.  
OSM increases the production of IL-4Rα and IL-13Rα (16-21).  OSM also increases IL-4 
production and synergizes with IL-4 and IL-13 to upregulate downstream signaling events 
such as eotaxin production (16, 18, 19, 20, 21, and 22).  Similarly, OSM synergizes with 
IL-17A and increases CCL2 and IL-6 production (21).  OSM impacts epidermal barrier 
function by modulating genes important in keratinocyte activation and differentiation (16 17).  
Finally, OSM levels are increased in fibrotic diseases and OSM over expression in animal 
models has been shown to result in fibrotic changes (19, 23).  The interplay between OSM 
and multiple pathologic processes in PN, from hyperkeratosis to inflammation to fibrosis, 
suggests that KPL-716 may modulate disease severity.  Therefore, the impact of KPL-716 in 
disease severity will be investigated in this study (secondary endpoints).  Clinical effect on 
pruritus, sleep, quality of life and disease severity will be measured using existing and novel 
patient reported outcomes and disease scoring tools.   
This Phase 2 study will utilize a wash out monotherapy design and enroll subjects with a 
physician-documented diagnosis of PN of at least 6 months duration from the time of first PN 
nodule as affirmed by the subject.  There are currently no established diagnostic criteria for 
PN.  In order to differentiate PN from other pruritic inflammatory skin conditions and to 
ensure uniformity of diagnosis across the study, certain disease characteristic features are 
included under eligibility criteria.  As an exploratory objective, clinical response may be 
correlated with biomarker changes if collected to understand whether KPL-716 
responsiveness is broad or limited to a specific subset of PN patients.  
Ultimately, the data from this Phase 2 study will help establish the therapeutic dose and 
regimen of KPL-716 for treatment of pruritus and potentially for disease modification in PN 
and inform the study population for Phase 3.   
 

 
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1.4 
Justification for Using a Placebo Control Arm 
Currently there are no approved therapeutics for PN.  Some conventional therapeutics (such 
as, topical corticosteroids, immunosuppressants, phototherapy) have been used off-label in 
clinical practice with mild to moderate efficacy at best.  These treatments are often associated 
with severe adverse effects.  Given the average duration of the disease (over 9 years in the 
KPL-716-C201 Phase 2a trial), many patients have exhausted these conventional off-label 
therapeutics without satisfactory results.  Thus, it is not reasonable or ethical to compare with 
or add-on to any of those off-label therapeutics. 
The efficacy measures on pruritus, sleep and quality of life are subjective assessments; 
therefore, they are not suitable for use in an open-label trial because subjects are likely to be 
biased due to expectations of improvement.  Thus, a placebo-controlled, double-blind, and 
randomized study is the best setting to assess the therapeutic effects and safety of KPL-716.  
It has been a common practice to use placebo-control for pruritus trials in the scientific 
community.  The placebo in this trial consists of commonly approved excipients, with well-
established safety profiles.  
1.5 
Benefit-risk Assessment 
KPL-716 is anticipated to offer a therapeutic benefit to patients with chronic pruritic 
inflammatory skin diseases through its dual inhibition of IL-31 and OSM, 2 cytokine 
pathways important in pruritus, inflammation, hyperkeratosis, and fibrosis.  In the first-in-
human study of KPL-716, Part 1 and 4 of KPL-716-C001, KPL-716 demonstrated OSMRß 
target engagement and an early signal of efficacy by reducing pruritus in subjects with atopic 
dermatitis.  For a summary of clinical pharmacodynamic (PD) data from KPL-716-C001, 
please see the IB. KPL-716-C201 phase 2a primary efficacy endpoint analysis showed 
clinical benefits in both pruritus reduction and skin lesion improvement. 
PN is a debilitating disease in which patients suffer from intractable pruritus and disfiguring 
skin nodules for which there are no approved therapies.  KPL-716 is being tested in this 
Phase 2 study for its potential efficacy in reducing pruritus in patients with PN (primary 
endpoint) through inhibition of IL-31 signaling.  A reduction in pruritus is anticipated to 
improve sleep and quality of life in subjects with PN (secondary endpoint), as was seen in the 
Phase 1b study in subjects with atopic dermatitis and in Phase 2a PN patients.  Given the 
potential impact of OSM on pathologic processes important in PN, hyperkeratosis, 
inflammation and fibrosis, the inhibition of OSM signaling by KPL-716 may also provide 
benefit in reducing disease severity.  At a minimum, it is anticipated that subjects in this 
study would benefit from the assessment of their medical status and routine interactions with 
investigative dermatologists.  For Phase 2b, all subjects (including the placebo arm) will have 
the option of being dosed with KPL-716 360 mg, SC, Q2W during the OLE Period to 
maximize potential benefits but not exceed the doses tested previously (i.e., 720 mg SC or 
7.5 mg/kg IV, or 360 mg SC weekly). 
As described previously, in the first-in-human study (KPL-716-C001), 50 healthy volunteers 
(Part 3) and 75 subjects with atopic dermatitis (Part 1 and 4) were exposed to single or repeat 
doses of KPL-716 up to 7.5 mg/kg IV or 12 weekly 360 mg SC or placebo.  In the 
KPL-716-C201 Phase 2a, 49 PN patients (n = 23 in KPL-716, n = 26 in placebo) were given 
720 mg SC loading dose and followed by up to 15 weekly dosing of 360 mg SC or placebo.  
In the KPL-716-C202 Phase 2 trial on a basket of chronic pruritus conditions (chronic 

 
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idiopathic pruritis, plaque psoriasis, chronic idiopathic urticaria, lichen simplex chronicus, 
and lichen planus, n = 58), subjects were treated with 720 mg loading dose and 7 weekly 
dosing of 360 mg SC or placebo.  Among all the studies, one serious adverse event (SAE) of 
angioedema was reported (KPL-716-C202, blinded), rated as possibly related.  After 
treatment with oral antihistamine and corticosteroids, the subject recovered without the need 
for hospitalization.  There were no deaths, or dose-limitation events.  Drug-related or possibly 
related treatment-emergent AEs were infrequent.  For additional information, please see the 
IB. 
The available toxicology and prior human data support the dose level and duration of 
treatment in this study.  No specific safety concerns are anticipated with inhibition of 
signaling through OSMRβ in PN subjects experiencing severe pruritus as KPL-716 does not 
inhibit constitutive signaling of OSM down the LIFR pathway, a pathway implicated in 
hematopoiesis and platelet synthesis (10).  New and unknown adverse events (AEs) may 
emerge in a new study as the drug is investigated under chronic use with prolonged exposure 
in a new disease population.   
There may be some discomfort from collection of blood samples, subcutaneous study drug 
injections and other procedures.  Subcutaneous injections and skin biopsies can infrequently 
lead to skin irritation, local inflammation, secondary skin infection, as well as vasovagal 
reactions.  There is no theoretic base or evidence that KPL-716 treatment may interfere with 
immune system.  For mitigating risks during COVID-19 pandemic, we will exclude any 
subjects with active SARS-CoV-2 virus infection.  The subjects will undergo supervised 
study procedures and will be closely monitored for adverse experiences during their 
participation in the study. 
Overall, the benefit-risk assessment favors the continuation of the Phase 2b portion of the 
study.  
 

 
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2 
OBJECTIVES 
2.1 
Primary Objective  
• To evaluate the efficacy of SC KPL-716 vs. placebo in reducing pruritus in PN 
subjects experiencing severe pruritus 
2.2 
Secondary Objectives 
• To evaluate the effect of SC KPL-716 vs. placebo in improving sleep in PN subjects 
experiencing severe pruritus 
• To evaluate the efficacy of SC KPL-716 vs. placebo in improving quality of life in PN 
subjects experiencing severe pruritus 
• To evaluate the effect of SC KPL-716 vs. placebo in reducing disease severity in PN 
subjects experiencing severe pruritus 
• To evaluate the safety and tolerability of SC KPL-716 vs. placebo in PN subjects 
experiencing severe pruritus 
• To evaluate the pharmacokinetics (PK) of SC KPL-716 in PN subjects experiencing 
severe pruritus 
2.3 
Exploratory Objectives 
• To evaluate the immunogenicity of SC KPL-716 in PN subjects experiencing severe 
pruritus 
• To evaluate the effect of KPL-716 vs. placebo on skin and blood biomarkers 
• To evaluate the correlation between KPL-716 responsiveness and co-morbidities in 
PN 

 
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3 
ENDPOINTS 
3.1 
Primary Efficacy Endpoint for 2b 
• Percent change from baseline in weekly average Worst Itch–Numeric Rating Scale 
(WI-NRS) at Week 16 
3.2 
Key Secondary Efficacy Endpoints for 2b 
• Proportion of subjects achieving at least a 6-point reduction from baseline in weekly 
average WI-NRS at Week 16 
• Proportion of subjects achieving at least a 4-point reduction from baseline in weekly 
average WI-NRS at Week 16   
• Proportion of subjects achieving 0 or 1 in PN-IGA at Week 16 
3.3 
Other Secondary Efficacy Endpoints for Phase 2b 
Related to pruritus: 
• Change and percent change from baseline in weekly average of WI-NRS over 
time 
• Proportion of subjects achieving at least a 6-point reduction from baseline in 
weekly average WI-NRS over time.   
• Proportion of subjects achieving at least a 4-point reduction from baseline in 
weekly average WI-NRS over time.   
Related to disease severity:  
• Proportion of subjects achieving 0 or 1 in PN-IGA over time 
• Proportion of subjects with at least 2-point improvement from baseline in PN-IGA 
over time 
• Proportion of subjects achieving 0 or 1 in Investigator’s Global Assessment for 
Prurigo Nodularis-Stage (IGA-CNPG-S) over time 
• Proportion of subjects with at least 2-point improvement from baseline in 
IGA-CNPG-S over time 
Related to sleep:  
• Change and percent change from baseline in weekly average of Sleep Loss Visual 
Analog Scale (VAS) over time 
Related to quality of life: 
• Change and percent change from baseline in ItchyQoL over time  
     Exploratory Efficacy Measures: 
• Proportion of subjects achieving 0 or 1 in IGA-CNPG-Activity (IGA-CNPG-A) 
over time 
• Change from baseline in Prurigo Nodularis Nodule Assessment Tool (PN-NAT) 
over time 

 
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• Change from baseline in the total score of Patient Health Questionnaire (PHQ-9) 
over time 
• Change from baseline in the total score of General Anxiety Disorder (GAD-7) 
over time  
• Days and proportion of subjects using rescue medication over time 
• Patient Global Impression of Prurigo Nodularis Severity (PGI-PN-S) over time 
• Patient Global Impression of Change (PGIC) over time  
• Change from baseline in skin and blood biomarkers over time 
3.4 
Safety Parameters for Phase 2b 
• Incidence rate and severity of treatment-emergent AEs (TEAEs)   
• Incidence rate and severity of study drug-related TEAEs  
• 
Vital signs, electrocardiogram (ECG), and clinical laboratory test results  
3.5 
Other Parameters for 2b 
• PK: Measurement of plasma concentrations of KPL-716 
• Immunogenicity: Measurement of anti-KPL-716 ADA 

 
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4 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This is a randomized, double-blind, placebo-controlled study to investigate the efficacy, 
safety, tolerability, PK, and immunogenicity of KPL-716 administered SC in PN subjects 
experiencing severe pruritus.  
The Phase 2b (Figure 1) portion of the study will consist of a 4-week Screening Period and a 
16-week Double-Blind Period followed by a 36-week Open-Label-Extension (OLE) Period. 
Approximately 180 PN subjects experiencing severe pruritus will be randomized (at 1:1:1:1 
ratio) into one of the following 4 arms:  KPL-716 540 mg SC, once every 4 weeks (Q4W); 
KPL-716 360 mg SC, Q4W; KPL-716 120 mg SC, Q4W; or placebo SC, Q4W.  A total of 
4 doses of study drug will be administered during the Double-Blind Period to measure the 
efficacy, safety, and PK of KPL-716.  The Phase 2b portion of the study will utilize a 
washout monotherapy design in which concomitant therapies that could impact pruritus or 
disease severity will be prohibited from designated windows through the end of the OLE 
Period, thus removing the confounding effect of these therapies on the assessment of 
KPL-716 efficacy.  Should subjects experience an exacerbation of symptoms that is 
significant enough to warrant intervention, oral antihistamines and/or topical corticosteroids 
may be provided 4 weeks post-randomization, as outlined in the Pharmacy Manual.  The days 
of rescue medication use will be recorded in an e-Diary and types and duration of rescue 
medications used will be recorded as a concomitant medication.  
After the Double-Blind Period, all subjects will have the option to receive KPL-716 360 mg 
SC, Q2W during the OLE Period to evaluate long-term safety and PK.  For subjects who 
complete the Double-Blind Period but choose not to participate in OLE, or who terminate 
earlier, an End of Study (EOS) Visit will be required 4 weeks following the date of last study 
drug dose. 
An interim analysis may be performed after at least 50% of subjects have completed the 
Week 16 Visit.  Additional details regarding the interim analysis, if performed, will be 
provided in the Statistical Analysis Plan (SAP) along with other analysis plan(s). 
Subjects will follow the schedule below: 
• Screening Period (minimum 7 days and maximum 28 days) 
• Double-Blind Period (Day 1 [Baseline] to Week 16)   
• Open-Label-Extension Period (End of Week 16 to Week 52)  
The allowable visit window from Week 4 to Week 16 is ± 2 days and thereafter to Week 52 
is ± 3 days.  
At any point following randomization, home health nursing or telemedicine services may be 
applied to accommodate COVID-19 limitations to in-person visits and dosing.   
4.1.1 
Screening Period for Phase 2b 
After the informed consent form (ICF) is signed, subjects will enter the Screening Period for 
assessment of eligibility.   

 
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During the Screening Period, subject’s medical and surgical history will be reviewed 
including allergic history.  Review of medical history will include PN disease history (year of 
first PN nodule and year of diagnosis) and history of co-morbidities.  Prior and concomitant 
medications, therapies and procedures will be recorded for PN and any other medical 
condition.  Vital signs will be measured, and subjects will undergo a full physical 
examination.  Clinical laboratory tests and an ECG will be performed.  Urine drug screen and 
pregnancy test (if applicable) will also be performed.   
To be eligible, subjects must have a physician-documented diagnosis of PN with at least 20 
nodules of approximately 0.5 to 2 cm.  The nodules must be pruritic and present on at least 2 
different anatomical locations (not be localized), involve the extremities, with extensor 
extremity involvement greater than the flexor extremity involvement.  Nodules on the head 
(face and scalp) are not counted as an anatomical location for eligibility criteria.  Each arm, 
each leg, and the trunk are considered different anatomical locations.  The minimum required 
duration of disease is at least 6 months from the time of first PN nodule to Day 1, as affirmed 
by the subject.   
At the Screening Visit, subjects will be asked to rate their pruritus severity (worst itch) over 
the past 24 hours on the WI-NRS.  In addition, subjects will record their WI-NRS on a daily 
basis during the Screening Period.  Subjects will be given training on Accurate Symptom 
Reporting (ASR) and Placebo Response Reduction (PRR) during the Screening Visit, 
Baseline Visit, and Weeks 4, 8 and 12, or as needed.  The daily recordings can begin any time 
after the Screening Visit.  Subjects will use internet-connected devices for daily electronic 
recordings.  To be eligible for study participation, subjects must have severe pruritus, defined 
as WI-NRS ≥7 at the Screening Visit and a mean weekly WI-NRS ≥7 for the week (7 
consecutive days) immediately prior to randomization (at least 5 days of recordings) on e-
Diary.   
During the Screening Period, whole-body medical photographs will be taken (upper front, 
lower front, upper back, and lower back) without the face and with the genitals covered.  In 
addition, a representative area of the disease will be determined by the PI at the Screening 
Visit, and medical photographs of this area will be taken and followed throughout the study.  
Medical photographs will be used for confirmation of diagnosis of PN as defined in the Study 
Manual and for assessment of disease severity over time.  Subjects may be asked to return to 
the study site during the Screening Period for unscheduled visits for repeat screening 
procedures if needed. 
Additional assessments at the Screening Visit may include those related to pruritus, sleep, 
quality of life, anxiety and depression, disease severity, etc.  Subjects will be instructed on 
the required washout for specific excluded medications.  The daily recordings (WI-NRS and 
rescue medication) will continue throughout the study for eligible subjects that proceed to 
dosing.   
Collection of AEs and concomitant medications will begin after signing the ICF and will 
continue until the EOS Visit.  For Schedule of Activities, please see Appendix 1.  
In an effort to minimize subject burden and/or risk during the COVID-19 pandemic, sites 
may offer to split the Screening Visit into two parts; a virtual preliminary Screening Visit in 
which some assessments may be performed [e.g. ICF, medical history, concomitant 
medications, subject questionnaires (completed electronically) and some eligibility criteria], 

 
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followed by an in-person visit in which all remaining eligibility assessments may be 
performed that require subjects to be physically present (e.g. blood collection for clinical 
laboratories, ECG, medical photography, vital signs, and disease severity assessments). 
4.1.2 
Treatment Period  
4.1.2.1 
Pre-dose  
Prior to dosing on Day 1, subjects will undergo review of eligibility, medical and surgical 
history, prior and concomitant medications, therapies and procedures and AEs.  Clinical 
laboratory results from the Screening Visit will be reviewed.  Compliance with recording of 
daily WI-NRS for the 7 days immediately prior to dosing will also be reviewed.  Urine drug 
screen and pregnancy test (if applicable) will be performed.  Vital signs will be measured.  
ECG and a full physical examination will be performed. 
Eligible subjects will undergo collection of safety blood and urine samples as well as blood 
samples for PK, ADA, and potential blood biomarkers.  Medical photographs will be taken of 
the representative area of disease identified during the Screening Period.  Whole-body 
photographs (upper front, lower front, upper back, and lower back) without the face and with 
genitals covered will also be captured prior to the first dose.  For subjects who provide 
additional consent for the collection of skin biopsies (optional), the biopsies (one lesional and 
one non-lesional) will be performed along with medical photographs of the biopsy areas prior 
to biopsy collection.  Skin biopsies are optional.  Upon confirmation of subject eligibility and 
completion of required activities (Appendix 1), subjects will be randomized and proceed to 
dosing.    
4.1.2.2 
Randomization and Dosing  
Subjects will be randomized 1:1:1:1 to receive different dosing regimens of KPL-716 or 
placebo.  At the end of the Double-Blind Period, all subjects will have the option to enter the 
OLE Period to receive KPL-716 360 mg SC Q2W.    Stratification will be performed based 
on sex and years since the first nodule observed (i.e., ≥10 years vs. <10 years).  
Phase 2b:  Figure 1 
• Arm A:  KPL-716, 540 mg, SC, every 4 weeks 
• Arm B:  KPL-716, 360 mg, SC, every 4 weeks 
• Arm C:  KPL-716, 120 mg, SC, every 4 weeks 
• Arm D:  Placebo, SC, every 4 weeks 
The dose levels and dosing intervals for Phase 2b have been chosen based on Phase 2a results 
so as not to exceed exposures observed in Phase 2a.   
All procedures assigned to dosing days will be performed prior to study drug administration.  
The following activities will take place prior to each dose during the Double-Blind Period: 
• Review of concomitant medications, therapies, and procedures 

 
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• Review of AEs 
• Review of subject compliance 
• Vital signs (performed before and after dosing on each dosing day) 
• Collection of blood for PK 
• Completion of Sleep Loss VAS 
The following activities will take place prior to dosing at designated study visits if applicable 
as outlined in Appendix 1: 
• Physical examination and ECG 
• Collection of safety blood and urine samples 
• Pregnancy test (if applicable)  
• Collection of PK and/or blood biomarker samples 
• Medical photography 
• Completion of patient questionnaires (ItchyQoL, PHQ-9, GAD-7, PGI-PN-S, PGIC)  
• Assessment of disease severity (PN-NAT, PN-IGA, IGA-CNPG-S, IGA-CNPG-A) 
• Skin biopsies (Skin biopsies are optional)  
AEs and concomitant medications will be collected throughout the study.  Subjects will 
continue to complete their daily questionnaire on pruritus (WI-NRS) and sleep until the EOS 
Visit.   
In case of study drug discontinuation, subjects will continue to follow the schedule of 
activities for each visit minus study drug administration.  Under these circumstances, the 
second set of biopsies (optional) will be performed at the earliest possible visit following 
early Double-Blind Period drug discontinuation, if applicable.  In case of study drug 
interruption or missed dosing visits, subjects will resume the schedule of activities in 
accordance with their study day.  In case of early withdrawal from the entire study, subjects 
will complete an EOS Visit 4 weeks after the last dose.  In addition, if the early termination 
occurs prior to the end of the treatment period, biopsies should be collected at the EOS visit, 
if applicable. 
4.1.3 
OLE for Phase 2b    
During the OLE Period, subjects will be administered KPL-716, 360 mg, SC, Q2W with the 
last dosing at the Week 48 Visit.  In the OLE portion of the study subjects may be permitted 
to self-administer KPL-716 as outpatients provided all of the following conditions are met: 
• Safety Review Team (SRT) determines that the available safety and tolerability data 
support outpatient self-administration.   

 
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• Study subjects receive adequate training and successfully performs 3 KPL-716 self-
administrations (e.g., Weeks 16, 18, and 20) under the supervision of study site 
personnel.   
• Study Investigator and Study Medical Monitor approve individual subject to self-
administer drug. 
If self-administration is not authorized by the SRT, the Investigator, Medical Monitor, or an 
individual subject is unable/unwilling to perform self-administration, KPL-716 will continue 
to be administered by the Investigator, a qualified investigational site designee or home 
health nurse.  During the OLE Period, subjects will also undergo vital signs measurement, 
review of concomitant medications, therapies and procedure, review of AEs, monitoring of 
compliance, and PK blood sample collection at visits according to the Schedule of Activities.  
Sleep Loss VAS, physical examination, clinical laboratory tests (including pregnancy testing 
if applicable), quality of life assessment, and evaluation of disease severity will be performed 
at designated visits.  Subjects will continue to complete their daily questionnaires on pruritus 
and rescue medication use throughout the OLE Period.  Should subjects self-administer drug, 
collection of AEs, concomitant medication use, and NRS compliance assessments ,as 
outlined in Appendix 1, may be completed remotely by study staff.      
The EOS Visit will include vital signs, full physical examination, ECG, clinical laboratory 
blood tests, urinalysis, and urine pregnancy test (if applicable) as well as PK, ADA, and 
biomarker blood sampling.  Biopsies for biomarker assessment will be collected from 
subjects who provide additional consent.  All efficacy assessments for pruritus, sleep, quality 
of life and disease severity will also be completed at this visit.  Medical photography of the 
whole body and the representative area (identified during the Screening Period and followed 
throughout the study) will be obtained.  All subjects will complete an EOS Visit.  
4.2 
Duration of Phase 2b 
The planned study duration per subject for Phase 2b will be approximately 56 weeks 
including a maximum of 4 weeks for the Screening Period, 16 weeks for the Double-Blind 
Period, and 36 weeks for the OLE Period. 
The minimum duration for the Screening Period will be 7 days. 
4.3 
Study Drug 
Study Drug: KPL-716 or matching placebo 
Active Substance: KPL-716 
Strength, Formulation and Route of Administration: 180 mg/mL solution 
 
, subcutaneous administration.   
Matching placebo: 
 
, subcutaneous administration. 
4.4 
Study Treatment 

 
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For Phase 2b, subjects will be randomized to receive KPL-716 or matching placebo on Day 1 
and will remain in the same treatment arm throughout the Double-Blind Period, then all 
subjects will have the option to participate in the OLE Period, starting dosing at the End of 
Week 16 Visit. 
Phase 2b: Figure 1 
• Arm A:  KPL-716 at 540 mg SC on Day 1 and at Weeks 4, 8, and 12 during the 
Double-Blind Period 
• Arm B:  KPL-716 at 360 mg SC on Day 1 and at Weeks 4, 8, and 12 during the 
Double-Blind Period  
• Arm C:  KPL-716 at 120 mg (see Pharmacy Manual for formulation instructions) SC 
on Day 1 and at Weeks 4, 8, and 12 during the Double-Blind Period 
• Arm D:  Placebo SC on Day 1 and at Weeks 4, 8, and 12 during the Double-Blind 
Period 
4.5 
Selection of Doses in the Study 
In the first-in-human study of KPL-716, Part 1 of KPL-716-C001, KPL-716 demonstrated 
OSMRß target engagement and an early signal of efficacy by reducing pruritus in subjects 
with atopic dermatitis.  In that study, a single IV dose of KPL-716 was given to subjects with 
atopic dermatitis at escalating doses of 0.3 mg/kg, 1.5 mg/kg, and 7.5 mg/kg.  The decrease 
from baseline in pruritus intensity was compared between KPL-716 recipients at the top IV 
dose of 7.5 mg/kg (n = 10) and pooled IV placebo recipients (n = 10).  Target engagement 
was established, as a single dose of KPL-716 7.5 mg/kg IV reduced pruritus rapidly, within 
the first week of study drug exposure, compared to placebo.  For a summary of clinical PD 
data from Part 1 of KPL-716-C001, please see IB.  
Conclusive PK/PD correlation to determine Ceff following single dose administration of KPL-
716 in subjects with atopic dermatitis was not feasible due to the small sample size in lower 
dose groups in the Phase 1b study.  Nonetheless, an anti-pruritic effect was evident after 
KPL-716 administration at 7.5 mg/kg as a single IV dose, which resulted in a maximum 
concentration (Cmax) of 217 g/mL and area under the concentration-time curve (AUC)0-∞ of 
59,700 g•hr/mL.  The anti-pruritic effect of KPL-716 was still evident 28 days after the 
single IV dose of 7.5 mg/kg, which corresponded to blood concentration levels of 
approximately 30 g/mL at Day 28.  Although it was not possible to ascertain the precise 
magnitude of the antipruritic effect after 4 weeks because of topical corticosteroid 
coadministration, data suggested that efficacy persisted to approximately 6 weeks.  There is 
also uncertainty around the Ceff for the anti-inflammatory effect via OSM axis inhibition.  To 
establish proof of concept in patients with PN, a new study population, the SC dosing 
regimen for this Phase 2a study was chosen to mimic and extend into chronic dosing the PK 
parameters achieved with the 7.5 mg/kg IV administered as a single dose, given that it had 
previously demonstrated a prolonged anti-pruritic effect.  Chronic dosing via the SC route 
was selected for this study rather than IV administration as a more practical and patient-
friendly route of administration.   

 
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PK analysis of a single SC dose of KPL-716 at 360 mg administered to healthy volunteers 
demonstrated that peak blood concentrations of 31 g/mL were achieved slowly in 125 hours 
and declined with a half-life of 168 hours (7 days).  Comparison of PK parameters across 
dose levels and routes of administration in healthy volunteers and subjects with atopic 
dermatitis showed that exposures were similar in the 2 study populations.  In both 
populations, as dose increased, half-life also increased consistent with a TMDD proﬁle.  
Furthermore, bioavailability between healthy volunteers and AD subjects at the evaluated 
dose levels was generally comparable (42% vs. 65%); the number of subjects in these 
analyses were small.  Based on the similarities in PK parameters between healthy volunteers 
and atopic dermatitis subjects despite anticipated differences in target expression levels, it is 
likely that PK parameters in PN patients will also follow the same patterns.   
The Phase 2a in PN patients, under the regimen of 720 mg loading dose with up to 15 weekly 
360 mg SC doses, demonstrated clinical efficacy and an acceptable safety profile.  The Cmax 
and Ctrough were 235 and 220 g/mL at week 16, respectively, in the 16-week dosing cohort.  
Clinical efficacy persisted when drug concentration dropped to approximately 30 g/mL 
among responders 9 weeks after last dosing.  However, it is not certain if Ceff is 30 g/mL or 
lower as the follow-up period may be insufficient.  Additionally, the observed exposure 
metrics from interim PK samples were largely comparable with predicted concentration-time 
profiles using the updated PK model (including all subjects from KPL-716-C001).  This 
model was thus used to conduct regimen simulation for Phase 2b.  Four repeated doses of 540 
mg Q4W could reach a steady status with Ctrough ≥ 10, 20, or 30 g/mL in 95%, 77%, or 51% 
of subjects, respectively; therefore, this regimen could be efficacious if Ceff is 30 g/mL or 
lower.  Four repeated doses of 360 mg Q4W SC could reach a steady status with Ctrough ≥ 5 
g/mL in 88% of subjects and Ctrough ≥ 10 g/mL in 68% of subjects.  This regimen could 
provide a reasonable coverage for an estimated Ceff of 5-8 g/mL concluded from the 
cynomolgus monkey itch model study.  Four repeated doses of 120 mg Q4W SC could reach 
a steady status with Ctrough above 5 or 10 g/mL in 1.6% or 0.1% of subjects, respectively.  
Thus, 120 mg Q4W SC is chosen as a subtherapeutic dose.  A 16-week treatment/observation 
is used to allow for at least 4 repeated doses of each regimen to reach steady status.  No 
loading dose is planned to avoid masking onset of efficacy and efficacy differentiation among 
the different dose regimens.  Per the PK simulation, continuous treatment in OLE with 360 
mg, SC, Q2W results in at least 96% or 82% of subjects with Ctrough ≥ 10 or 20 g/mL and 
Cmax and Ctrough (i.e., < 100 g/mL) is below the level achieved in the Phase 2a QW dose but 
higher than the Q4W doses in the blinded portion of the study.  If follows that the proposed 
Q2W OLE dose provides a more robust drug coverage than the Q4W doses while assumed at 
least as safe as higher Phase 2a QW exposures, thus complementing the exploration for an 
efficacious and safe dose overall. 
The available pre-clinical toxicology data support the selection of the above doses.  The 
multi-dose, 7-week, preclinical toxicology study in cynomolgus monkeys revealed no 
specific toxicities, and the highest administered dose (500 mg/kg IV) was identified as the 
NOAEL.  In a chronic toxicology study, weekly administration of KPL-716 by IV bolus 
injection or SC at doses up to 200 mg/kg for 26 weeks (27 total doses) was well tolerated in 
cynomolgus monkeys.  Based on these results under the conditions and duration of the study 
provided in the study report, the NOAEL was considered to be 200 mg/kg IV/SC, the highest 
dose tested.  The number of doses and the dose levels in this Phase 2b study are well 

 
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supported by the number of doses (total of 27) and the NOAEL (200 mg/kg) in the chronic 
toxicology study.   
The available safety data support the selection of above dose levels.  In the first-in-human 
study (KPL-716-C001), 50 healthy volunteers (Part 3) and 75 subjects with atopic dermatitis 
(Part 1 and 4) were exposed to single or repeat doses of KPL-716 or placebo.  In the KPL-
716-C201 Phase 2a, 49 PN patients (n = 23 in KPL-716, n = 26 in placebo) were weekly 
dosed at 360 mg SC (with 720 mg loading dose) or placebo for 8 or 16 weeks.  In the KPL-
716-C202 Phase 2 trial on a basket of chronic pruritus conditions (chronic idiopathic pruritis, 
plaque psoriasis, chronic idiopathic urticaria, lichen simplex chronicus, and lichen planus, n = 
58), subjects were treated with active drug (720 mg loading dose followed by 360 mg weekly 
SC dosing) or placebo for 8 weeks.  Among all the studies, one SAE of angioedema was 
reported (KPL-716-C202, blinded), rated as possibly related to study drug.  After treatment 
with oral antihistamine and corticosteroids, the subject recovered without the need for 
hospitalization.  There were no deaths or dose-limitation events.  Drug-related or possibly 
related treatment-emergent AEs were infrequent.  For additional information, please see the 
IB. 
The objective of the Phase 2b study is to define the minimally efficacious dose by exploring 
the clinical response to varying Ctrough levels.  Another objective is to identify a likely 
practical dosing regimen to carry forward into subsequent confirmatory studies.  In the Phase 
2b study, subjects will be randomized 1:1:1:1 to receive 4 different dosing regimens of KPL-
716 or placebo SC: KPL-716 540 mg SC, Q4W; KPL-716 360 mg SC, Q4W; KPL-716 120 
mg SC, Q4W; or placebo SC, Q4W, during the Double-Blind Period.  After the Double-Blind 
Period, all subjects will have the option to receive KPL-716 360 mg SC, Q2W during the 
OLE Period to evaluate the long-term safety and PK, and to maximize potential benefits but 
not exceed the doses tested previously (i.e., 720 mg SC or 7.5 mg/kg IV or 360 mg SC 
weekly).   
4.6 
Study Assessments  
4.6.1 
Efficacy Assessment   
Efficacy in reduction of pruritus will be assessed via daily recording of WI-NRS.  Efficacy in 
improvement in sleep will be assessed via Sleep Loss VAS.  Impact on quality of life will be 
assessed via ItchyQoL, PHQ-9, and GAD-7.  Impact on disease severity will be followed by 
PN-IGA, PN-NAT, IGA-CNPG-S, IGA-CNPG-A, PGI-PN-S, and PGIC.  See Schedule of 
Activities Appendix 1.  
An area representative of the subject’s disease will be chosen at the Screening Visit and 
followed over time through medical photography at designated time points.  Whole-body 
photographs and images of biopsy locations (prior to collection of biopsies), if applicable, 
will be taken at indicated study visits.   
Skin biopsies will be collected pre- and post-treatment during this study.  Skin biopsies are 
encouraged but optional.  Two individual punch biopsies (one from lesional skin and one 
from adjacent non-lesional skin) will be collected prior to dosing at Day 1 and post-treatment 
biopsies will be collected at Week 16 or EOS.  Biopsy collection procedures and processing 
will be outlined in a separate manual.  

 
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4.6.2 
Safety Assessments  
Safety will be assessed by monitoring of AEs, measurements of vital signs, physical 
examination, ECG evaluation, and clinical laboratory tests. 
4.6.3 
PK Assessments 
PK blood samples will be collected from all subjects as specified in the Schedule of 
Activities.  PK samples will be collected pre-dose on dosing days.  
4.6.4 
Biomarker Assessment 
Blood samples will be collected from all subjects for biomarker analysis.  Blood samples will 
be collected pre-dose on dosing days as specified in the Schedule of Activities. 
4.6.5 
Immunogenicity Assessments  
Blood samples for ADA assessment will be collected from all subjects pre-dose on dosing 
days as specified in the Schedule of Activities. 
 
4.7 
Selection of Study Population 
4.7.1 
Inclusion Criteria 
1. Male or female aged 18 to 80 years, inclusive, at the time of consent. 
2. Have a physician-documented diagnosis of PN that is confirmed by review of medical 
photography (as outlined in the Study Manual) during the Screening Period.  Duration 
of PN (since the time of first PN nodule) must be at least 6 months from the time of 
first PN nodule to Day 1, as affirmed by the subject.  
3. Have at least 20 nodules of approximately 0.5 to 2 cm at the Screening Visit and Day 
1.  The nodules must be pruritic and present on at least 2 different anatomical 
locations (not be localized), involve the extremities, with extensor extremity 
involvement greater than the flexor extremity involvement.  Nodules on the head 
(face and scalp) are not counted as an anatomical location for eligibility criteria.  Each 
arm, each leg, and trunk are considered different anatomical locations.   
4. Subject has severe pruritus, defined as WI-NRS ≥7 at the Screening Visit and a mean 
weekly WI-NRS ≥7 for the week (7 consecutive days) immediately prior to 
randomization (at least 5 days of recordings) on eDiary. 
5. PN-IGA score of ≥3 (on a scale of 0-4, in which 3 is moderate and 4 is severe) at 
Screening and Baseline Visits.  
6. Sexually active female subjects must be:  
• postmenopausal, defined as at least 12 consecutive months post cessation of 
menses (without an alternative medical cause) and confirmed by a follicular 
stimulating hormone (FSH) test, or  

 
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• surgically sterile following documented hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy or  
• nonpregnant, nonlactating, and having agreed to use a highly effective method 
of contraception from the Screening Visit until 16 weeks after final study drug 
administration.   
o Note:  highly effective methods of contraception include: 
▪ hormonal contraceptives associated with inhibition of ovulation 
(stable dose for at least 4 weeks prior to first dose) 
▪ intrauterine device 
▪ intrauterine system 
▪ double barrier methods of contraception (barrier methods 
include male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge) in conjunction with 
spermicide. 
▪ tubal ligation 
▪ vasectomized male partner 
7. Sexually active male subjects must have documented vasectomy or must agree to use 
a highly effective method of contraception as defined above with their partners of 
childbearing potential from first dose until 16 weeks after final study drug 
administration.   
8. Male subjects must agree to refrain from donating sperm from first dose until 16 
weeks after the last study drug administration.  Female subjects must agree to refrain 
from donating eggs from first dose until 16 weeks after the last study drug 
administration.  
9. Female of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) test at the Screening Visit and negative urine pregnancy test on 
Day 1.  
10. Able to comprehend and willing to sign an Informed Consent Form and able to abide 
by the study restrictions and comply with all study procedures for the duration of the 
study. 
11. Subjects must be on optimized and stable treatment for co-morbidities for at least 28 
days prior to Day 1.  
4.7.2 
Exclusion Criteria 
1. Use of the following medications within the indicated timeframe prior to Day 1 and 
does not agree to refrain from the use of the medications throughout the study (except 
these specified in the Pharmacy Manual): 

 
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a. Systemic corticosteroids (IV/IM/oral):  4 weeks; Note: Intranasal 
corticosteroids, eye drops containing corticosteroids, and inhaled 
corticosteroids for stable medical conditions are allowed.  
b. Intralesional corticosteroids and intra-articular corticosteroids:  6 weeks 
c. Topical treatments for PN including but not limited to corticosteroids, 
calcineurin inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, 
capsaicin, camphor, polidocanol, cannabinoids, gabapentin, or tars:  2 weeks 
d. Antihistamines:  2 weeks 
e. Immunomodulators (for example, cyclosporin, methotrexate, retinoids, 
azathioprine, mycophenolate, and thalidomide):  4 weeks 
f. Neuroactive drugs such as gabapentin and pregabalin:  4 weeks 
g. Cannabinoids:  2 weeks 
h. Opioid antagonists or agonists:  5 half-lives if known or 4 weeks  
i. Janus inase inhibitors:  5 half-lives if known or 4 weeks 
j. Dupilumab:  8 weeks 
k. Any other marketed biologic:  5 half-lives or within 4 months of using 
rituximab 
l. Any investigational drug:  5 half-lives 
m. Phototherapy involving UVA, UVB, or excimer:  4 weeks 
n. Tanning salon use:  4 weeks 
o. Live attenuated vaccine: 12 weeks 
2. Has received any investigational biologic or non-biologic drug that targets Oncostatin 
M, IL-31, IL-31 receptor  or Oncostatin M receptor  in the past 3 months. 
3. Required rescue therapy for PN during the Screening Period or expected to require 
rescue therapy within 4 weeks following the Baseline Visit. 
4. Has a significant exacerbation and/or skin eruption during the Screening Period (prior 
to the study drug administration) that requires a medical intervention. 
5. Presence of scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, 
habitual picking, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis 
herpetiformis, sporotrichosis, bullous disease and/or skin condition other than PN or 
atopic dermatitis unless approved by the Sponsor.  
6. Plan to change emollients or moisturizers, or to have bath oil treatment for relief of 
pruritus during the course of the trial.    

 
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7. Presence of psychogenic pruritus or neuropathic pruritus at the Screening Visit.  
8. Presence of severe depression as indicated by PHQ-9 total score of ≥20 or item 9 score 
> 0 at the Screening Visit or Day 1. 
9. Presence of severe anxiety as indicated by GAD-7 score of ≥15 at the Screening Visit 
or Day 1. 
10. Presence of severe chronic pain (e.g., back pain, migraine, osteoarthritis, etc., defined 
as ≥7.0 on 0 to 10 NRS scale with 0 being no pain and 10 being the worst pain possible) at 
the Screening Visit. 
11. Presence of uncontrolled hyperthyroidism or hypothyroidism or uncontrolled diabetes 
defined as hemoglobin A1c >7.5%.  
12. Presence or history of cancer or lymphoproliferative disease within 5 years prior to 
Screening Visit, with the exception of basal and squamous cell carcinoma of the skin or in 
situ carcinoma of the cervix successfully treated and considered controlled. 
13. Presence or history of immune deficiency, or opportunistic infections.  
14. Positive results for hepatitis B surface antigen (HbsAg) and/or hepatitis B anti-core 
antibody (anti-HBc) but negative results for anti-surface antibody (anti-HBs) at the 
Screening Visit. 
15. Positive results for hepatitis C antibody unless patient received curative therapy and a 
negative viral load is documented. 
16. Human immunodeficiency virus (HIV) infection or positive HIV serology at the 
Screening Visit.  
17. Positive COVID-19 viral test at Screening Visit or suspected COVID-19 infection at 
Baseline Visit. 
18. Subject is on hemodialysis or peritoneal dialysis. 
19. Latent or active TB, as determined by a positive Quantiferon-based TB test result at 
Screening Visit. 
20. Laboratory abnormalities that fall outside the windows below at the Screening Visit: 
a. Alanine aminotransferase >3 x upper limit of normal (ULN) 
b. Aspartate aminotransferase >3 x ULN 
c. Gamma-glutamyl transferase >3 x ULN 
d. Blood bilirubin >2 x ULN 
e. Hemoglobin more than 1g/dL below the lower limit of normal for sex per the 
laboratory in which screening lab is performed 
f. Platelet count <150,000/ µL 

 
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g. Neutrophil count <1,500/µL  
21. Major surgery within 12 weeks prior to Day 1 or has a major surgery planned during 
the study. 
22. Has an active infection, including skin infection, requiring systemic treatment within 
4 weeks and/or topical treatment within 2 weeks of Day 1.  Subject has an active or 
chronic parasitic infection.  
23. Any medical or psychiatric condition which, in the opinion of the Investigator or the 
Sponsor, may place the subject at increased risk as a result of study participation, 
interfere with study participation or study assessments, affect compliance with study 
requirements, or complicate interpretation of study results.  
24. Has a known hypersensitivity to KPL-716 or its excipients. 
25. Has a known history of drug or alcohol abuse in the last 2 years prior to Day 1.  Has 
more than eight drinks (5 ounces of wine, 12 ounces of beer or 1.5 ounces of liquor) 
weekly for females and 15 drinks weekly for males. 
26. Has a positive urine drug screen for opiates, opioids, methadone, cocaine, 
phencyclidine, or amphetamines at the Screening Visit or Day 1.  Exceptions may be 
made if a subject is on a medication for a stable concomitant condition that explains 
the positive drug screen result. 
27. Has had a severe allergic reaction to any foods or medications including anaphylactic 
reactions, unless approved by the Sponsor. 
28. For subject providing consent for the optional skin biopsy, presence or history of 
coagulation disorders, hypertrophic scar, or keloid, or currently under treatments with 
chronic anti-coagulants (aspirin ≤ 325mg/day is acceptable).    
4.8 
Subject Number and Identification 
Each subject that signs the ICF and enters the Screening Visit will be assigned a unique 
screening number.  The study site will record these numbers on a screening log, document 
reasons for screening failure or eligibility, whichever is applicable.   
Once a subject qualifies for randomization, a unique treatment code will be obtained from a 
designated center via the interactive web response system (IWRS), which will assign the 
treatment for the subject.  The randomization number will be kept on-file at study site and 
included in the electronic case report form (eCRF).  
4.9 
Subject Withdrawal and Replacement 
Subjects may withdraw from the study drug treatment or from the entire study 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 

 
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• 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 (Subjects will be defined as lost to follow up if they have not 
responded to 3 phone calls and one certified letter) 
• Subject withdrawal of consent 
• A decision to modify or discontinue development of the drug 
In case of study drug interruption or missed dosing visits, subjects will resume the schedule 
of activities in accordance with their study day.   
In case of study drug discontinuation, subjects will continue to follow the schedule of 
activities for each visit minus dosing.  Under these circumstances, the second set of biopsies 
will be performed at the earliest possible visit.  Skin biopsies are optional.   
If a subject withdraws from the entire study, the subject must complete the EOS Visit.  In 
addition, if the early termination occurs prior to the last week of treatment, biopsies should be 
collected at the EOS visit. 
If the subject withdraws from study treatment and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should 
be collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal or consent. 
Subjects will not be replaced. 
4.10 
Study Termination or Temporary Suspension 
The Sponsor reserves the right to temporarily suspend or terminate this study in part or whole 
at any time.  The reasons for temporarily suspending or terminating the study may include but 
are not limited to: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
• Subject enrollment is unsatisfactory 
• 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 a 
Health Authority 

 
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• Sponsor decision to terminate development 
Where required by applicable regulations, the investigator or head of the medical institution 
must inform the Institutional Review Board (IRB)/International Ethics Committee (IEC) 
promptly and provide the reason(s) for the suspension/termination.  If the study is suspended 
for safety reasons and it is deemed appropriate by the sponsor to resume the study, approval 
from the relevant regulatory authorities (and IECs when applicable) will be obtained prior to 
resuming the study. 

 
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5 
STUDY TREATMENTS 
5.1 
Description, Storage, Packaging, and Labeling  
The study drug will be supplied by the Sponsor, along with the batch/lot numbers and 
Certificates of Analysis (CoA).  Study drug refers to KPL-716 and the matching placebo. 
• Active Ingredient: KPL-716 
• Strength, Formulation Form and Route of Administration: 180 mg/mL solution  
 
 for subcutaneous administration. 
KPL-716 drug product is a sterile solution formulation, supplied as a single-use vial for SC 
injection.  The 3 mL Schott vials are filled with 2.3 mL to allow for a delivered volume up to 
2 mL, and an extractable dose up to 360 mg/vial.     
Refer to Pharmacy Manual on reconstitution of 120 mg dose with the above KPL-716 drug 
product. 
The placebo is also a sterile solution formulation, supplied as a single-use vial for SC 
injection.  The same 3 mL Schott vials are used for the placebo with each vial filled with 
2.3 mL to allow for a delivered volume up to 2 mL. 
Study drug labeling will be in compliance with applicable, local, and national regulations.  
Study drug may be dispensed only under the supervision of the Investigator or an authorized 
designee and only for administration to the study subjects.  
Study drug must be stored in a secure area with limited access and allows for required storage 
conditions.  The Investigator, or an authorized designee, will ensure that all study drug is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements.  To ensure adequate records, all study drugs will be 
accounted for using drug accountability forms as instructed by the Sponsor. 
The study drug and placebo will be prepared in such a way as to preserve the study blind 
across dose levels.  Storage conditions and study drug handling procedures will be detailed in 
the Pharmacy Manual.   
5.2 
Study Treatment Administration 
Investigators participating in this study will assume responsibility for complying with all 
procedures and guidelines for the use of KPL-716 as outlined in the study protocol, the 
Investigator’s Brochure, and other study-related materials provided by the Sponsor and/or 
designee. 
In Phase 2b, subjects will be randomized 1:1:1:1 to receive 4 different dosing regimens of 
KPL-716 or placebo during the Double-Blind study period.   
Phase 2b:  Figure 1 

 
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• Arm A:  KPL-716, 540 mg, SC, every 4 weeks 
• Arm B:  KPL-716, 360 mg, SC, every 4 weeks 
• Arm C:  KPL-716, 120 mg, SC, every 4 weeks 
• Arm D:  Placebo, SC, every 4 weeks. 
In the OLE, subjects will be administered KPL-716, 360 mg, SC, Q2W with the last dosing at 
the Week 48 Visit.  Subjects may be permitted to self-administer KPL-716 as outpatients 
during the OLE, provided the SRT determines that the available safety and tolerability data 
support outpatient self-administration, the Investigator and Medical Monitor approve the 
individual case, and the subject receives adequate training and successfully performs 3 KPL-
716 self-administrations (e.g., Weeks 16, 18, and 20) under the supervision of study site 
personnel.  If self-administration is not authorized by the SRT the Investigator, or Medical 
Monitor, or if an individual subject is unable/unwilling to perform self-administration, KPL-
716 will continue to be administered by the Investigator, a qualified investigational site 
designee or home health nurse.  
5.3 
Randomization 
All subjects who are eligible for study participation will be randomized prior to study drug 
administration.  Eligible subjects will be randomized to receive KPL-716 or placebo.  The 
randomization will be based on a computer-generated treatment randomization schedule 
prepared before the study by the Sponsor or designee.  Randomization will be stratified on 
the basis of sex and years since first nodule observation (≥ 10 years vs <10 years).  
An IWRS will issue a unique treatment code to each subject, which will assign the treatment 
for the subject.  Prior to each dosing, the medical ID number of the vial to be administered 
will be obtained from the IWRS based on the computer-generated treatment randomization 
schedule.  The study drug will be prepared and administered according to instructions in the 
Pharmacy Manual.  An unblinded pharmacist, or unblinded authorized designee, will be 
required to prepare drug for administration, in accordance with the Pharmacy Manual, to 
uphold study blinding. 
5.4 
Blinding 
This will be a double-blind, placebo-controlled study.  As such, the Investigator, the subjects, 
the Sponsor, and remaining clinical site staff will be blinded to treatment.  Only unblinded 
pharmacists and/or unblinded clinical site staff, for the purpose of preparing of study drug 
doses, will be aware of subject treatment arm assignments. 
The unblinded treatment assignment for each individual subject may be made available to the 
Investigator through the IWRS only in the event of a medical emergency or an adverse 
reaction that necessitates identification of the study drug for the medical management or 
welfare of that subject.  Except in a medical emergency, the Investigator and blinded clinical 
site staff will remain blinded during the conduct of the study.  The process and requirements 
for unblinding will be detailed in an Unblinding Plan.  The date/initials and reason for the 
Investigator and/or clinical staff removing the study blind will be documented.   

 
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5.5 
Study Treatment Compliance 
The following measures will be employed to ensure study treatment and procedures 
compliance: 
• All doses will be administered under the supervision of the Investigator or an 
authorized designee.  Subjects may be permitted to self-administer KPL-716 as an 
outpatient during the OLE provided the SRT determines that the available safety and 
tolerability data support outpatient self-administration, the Investigator and Medical 
Monitor approve the individual case, and the subject receives adequate training and 
successfully performs 3 KPL-716 self-administrations (e.g., Weeks 16, 18, and 20) 
under the supervision of study site personnel.  If self-administration is not authorized 
by the SRT, the Investigator, or the Medical Monitor, or if a subject is 
unable/unwilling to perform self-administration, KPL-716 will continue to be 
administered by the Investigator, a qualified investigational site designee or home 
health nurse. 
• At each dosing occasion, accountability of study drug will be performed. 
5.6 
Study Drug Accountability 
The accurate record of the medical ID number of the study drug administered will be 
maintained including the exact volume and the date and time of dispensing.  This study drug 
accountability record will be available for inspection at any time by the unblinded study 
monitor.  At the completion of the study, the original drug accountability record will be 
available for review by the Sponsor upon request.  Used vials and containers will be 
destroyed upon satisfactory completion of the treatment compliance and study drug 
accountability procedures.  Any unused unit doses will be retained until completion of the 
study. 
At the completion of the study, unused study drug remaining at the sites (if applicable) will 
be returned to the Sponsor or designee or disposed of by the study sites that have appropriate 
drug destruction standard operating procedures and per the Sponsor’s written instructions. 
For further details refer to the Pharmacy Manual. 

 
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6 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1 
Concomitant Medications 
All subjects enrolled in this study must agree to follow the study protocol with respect to 
concomitant medications from the Screening Visit through the EOS Visit.  The following 
medications are prohibited from designated timepoints before Day 1 (as noted in the 
exclusion criteria) and throughout the study.   
a. Systemic corticosteroids (IV/IM/oral).  Note: Intranasal corticosteroids, eye 
drops containing corticosteroids, and inhaled corticosteroids for stable medical 
conditions are allowed.  
b. Intralesional corticosteroids and intra-articular corticosteroids   
c. Topical treatments for PN including but not limited to corticosteroids, 
calcineurin inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, 
capsaicin, camphor, polidocanol, cannabinoids, gabapentin, or tars  
d. Antihistamines   
e. Immunomodulators (for example, cyclosporin, methotrexate, retinoids, 
azathioprine, mycophenolate, and thalidomide)   
f. Neuroactive drugs such as gabapentin and pregabalin  
g. Cannabinoids (other routes)  
h. Opioid antagonists or agonists  
i. Janus kinase inhibitors 
j. Dupilumab  
k. Any other marketed biologic 
l. Any investigational drug  
m. Phototherapy involving UVA, UVB, or excimer   
n. Tanning salon use 
o. Live attenuated vaccine   
Topical corticosteroids and antihistamines may be provided 4 weeks after randomization as 
rescue medications for an exacerbation of symptoms that is significant enough to warrant 
intervention.  
For further details refer to the Pharmacy Manual. 
6.2 
Diet 

 
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History of drug or alcohol abuse in the last 2 years prior to Day 1 is an exclusion criterion.  
Screening for drugs of abuse may be performed at the discretion of the Investigator and in 
consultation with the Sponsor at any time during the study. 
6.3 
Smoking 
Current users of nicotine >3 packs per day or nicotine equivalent/day is exclusionary for this 
study.  Should subjects become non-compliant with these restrictions during the study, 
premature discontinuation may be considered by the Investigator, in consultation with the 
Sponsor, according to the terms stipulated in Section 4.10.  
6.4 
Blood Donation 
Subjects are restricted from receiving blood or donating blood from Day 1 to the EOS Visit. 
6.5 
Contraception 
Nonpregnant, nonlactating sexually active women of childbearing potential must agree to use 
a highly effective method of contraception from the Screening Visit until 16 weeks after final 
study drug administration.   
• Note:  highly effective methods of contraception include: 
o hormonal contraceptives associated with inhibition of ovulation (stable 
dose for at least 4 weeks prior to first dose) 
o intrauterine device 
o intrauterine system 
o double barrier methods of contraception (barrier methods include male 
condom, female condom, cervical cap, diaphragm, contraceptive 
sponge) in conjunction with spermicide. 
o tubal ligation 
o vasectomized male partner 
Sexually active male subjects must have documented vasectomy or must agree to use a highly 
effective method of contraception as defined above with their partners of childbearing 
potential from first dose until 16 weeks after final study drug administration.   
 

 
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7 
STUDY ASSESSMENTS AND PROCEDURES 
Every effort should be made to schedule and perform study visits on the nominal day as 
outlined in Appendix 1. 
7.1 
Pharmacokinetic Assessments 
PK blood samples will be collected by venipuncture at the times shown in Appendix 1.  
Procedures for collection, processing, and shipping of PK blood samples will be detailed in 
the Laboratory Manual.   
7.2 
Immunogenicity Assessment 
ADA blood samples for immunogenicity will be collected by venipuncture at the times 
indicated in Appendix 1. Procedures for collection, processing, and shipping of 
immunogenicity blood samples will be detailed in the Laboratory Manual.   
7.3 
Clinical Response Assessments 
Clinical response assessments will be conducted at times specified in Appendix 1. Pruritus 
will be assessed using daily recording of WI-NRS.  Sleep will be assessed using Sleep Loss 
VAS at each study visit.  Quality of life will be followed via ItchyQoL, PHQ-9, and GAD-7.  
Disease severity will be evaluated using PN-NAT, PN-IGA, IGA-CNPG-S, IGA-CNPG-A, 
PGI-PN-S, PGIC, as well as medical photography.  Biomarkers will be assessed in the blood 
and the skin to understand the mechanism of clinical response to KPL-716.  
7.3.1 
Daily NRS Tool 
The Daily NRS Tool (provided in Appendix 2:  Daily NRS Tool for Phase 2b) contains one 
numerical rating scale to assess subjects’ pruritus (WI-NRS) and one Yes/No question 
regarding the use of rescue medication for itch relief. The Daily NRS Tool will be used daily 
during the Screening Period through the EOS Visit. 
7.3.2 
Worst Itch Numerical Rating Scale   
Subjects will be asked to assign a numerical score to the intensity of their most severe (worst) 
pruritus using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the worst 
imaginable pruritus.  This pruritus NRS will be used to assess subjects’ daily level of worst 
pruritus during the Screening Period through the EOS Visit.  The WI- NRS is provided in the 
Daily NRS Tool Appendix 2:  Daily NRS Tool for Phase 2b. 
7.3.3 
Sleep loss Visual Analog Scale (Sleep Loss VAS) 
Subjects will be asked to place a line perpendicular to the VAS line at the point that 
represents the intensity of their average sleeplessness experienced over the previous 3 nights 
using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the worst 
imaginable sleeplessness at every visit (24).  The Sleep Loss VAS (Appendix 5: Sleep Loss 
Assessment (average during the past 3 nights) is administered per the Schedule of Activities.  
7.3.4 
Prurigo Nodularis Nodule Assessment Tool (PN-NAT) 

 
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PN-NAT is a novel exploratory tool for the evaluation of disease severity based on estimate 
of the number of nodules over the whole body, estimate of hardness of nodules in 
representative area, estimate of extent of excoriation over the whole body, distribution of 
nodules, exact number of nodules in the representative area. There are 5 components to PN-
NAT.  Patients may present with smaller papular lesions, scarring, or post-inflammatory 
hyper- or hypo-pigmentation of the skin, which are not considered as part of this assessment.  
A score is assigned to each component based on the appearance of the disease at the time of 
the evaluation without referring to the baseline state.  PN-NAT is provided in Appendix 3:  
Prurigo Nodularis Nodule Assessment Tool (PN-NAT). The PN-NAT tool is administered at 
designated visits.   
7.3.5 
Prurigo Nodularis Investigator’s Global Assessment (PN-IGA)   
PN-IGA is a novel exploratory tool for the overall assessment of PN disease severity based 
on the elevation of the nodules and number of elevated nodules.  The IGA will be performed 
by the Investigator.  The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe 
disease).  Patients may present with smaller papular lesions, scarring, or post-inflammatory 
hyper- or hypo-pigmentation of the skin, which are not considered as part of this assessment.  
An IGA score is assigned based on the appearance of the disease at the time of the evaluation 
without referring to the baseline state.  Every effort will be made for the same Investigator to 
assess PN-IGA over time.  PN-IGA is provided in Appendix 4: Prurigo Nodularis 
Investigator’s Global Assessment (PN-IGA). The PN-IGA tool is administered at designated 
visits. 
7.3.6 
Investigator’s Global Assessment of Prurigo Nodularis-Stage (IGA-CNPG-S)   
IGA-CNPG-S is a novel tool for the assessment of PN disease severity based on the number 
of palpable nodules.  The IGA will be performed by the Investigator.  The IGA utilizes a 5-
point scale that ranges from 0 (clear) to 4 (severe).  A score is assigned based on the 
appearance of the disease at the time of the evaluation without referring to the baseline state.  
Every effort will be made for the same Investigator to assess IGA-CNPG-S over time.  The 
IGA-CNPG-S is provided in Appendix 7: Investigator’s Global Assessment for Prurigo 
Nodularis-Stage (IGA-CNPG-S). The IGA-CNPG-S tool is administered at designated visits. 
7.3.7 
Investigator’s Global Assessment of Prurigo Nodularis-Activity 
(IGA-CNPG-A)   
IGA-CNPG-A is a novel tool for the assessment of PN disease activity based on the 
proportion of nodules with excoriations and crusts.  The IGA will be performed by the 
Investigator.  The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe).  A 
score is assigned based on the appearance of the disease at the time of the evaluation without 
referring to the baseline state.  Every effort will be made for the same Investigator to assess 
IGA-CNPG-A over time.  The IGA-CNPG-A is provided in Appendix 8: Investigator’s 
Global Assessment for Prurigo Nodularis-Activity (IGA-CNPG-A). The IGA-CNPG-A tool 
is administered at designated visits.  
7.3.8 
Medical Photographs  
Standardized medical photographs will include photographs of the whole body, of the 
representative area (as the same area identified in the PN-NAT assessment) and biopsy areas.  

 
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Photographs will be collected pre-dose on dosing days.  Whole body photographs will be 
taken of the upper front, lower front, upper back and lower back at 4 timepoints: Screening 
Visit, prior to dosing at Day 1, End of Double-Blind Period (Week 16), and the EOS Visits.  
The representative areas of the subject’s disease will be photographed as detailed in Schedule 
of Activities.  Sites of lesional and non-lesional biopsies will be photographed before dosing 
at Day 1 and at End of Double-Blind Period, prior to performing biopsies.  Medical 
photographs will be used for confirmation of diagnosis of PN as outlined in the Study Manual 
and to follow response to therapy over time.  Medical photographs will also be used to link 
skin biomarker data with the gross morphology of the skin.   
Photographs will not include the face or genitals.  Subject-identifiable information will be 
removed.  In case of early termination or early withdrawal, medical photographs will be 
performed during subject’s EOS Visit.   
Instructions on taking the medical photographs are provided in study manuals. 
7.3.9 
ItchyQoL questionnaire 
The ItchyQoL tool (Appendix 11: ItchyQoL Questionnaire 
) focuses on impact of pruritus on daily activities and on the level of psychological stress. It 
contains 22 items.  The frequency items are scored using a 5-point Likert scale ranging from 
“never” to “all the time”.  The bother items are scored from 1 (not bothered) to 5 (severely 
bothered).  The recall period in ItchyQoL is the past week.  There is a total score and 3 
subscale scores: Symptom subscale, Functional subscale, and Emotional subscale (25).  The 
ItchyQoL will be administered at designated visits.  
7.3.10 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9 (Appendix 9: Patient Health Questionnaire (PHQ-9) is a patient-reported measure 
that assesses the subject’s general mental health. The PHQ-9 contains 9 items scored on a 
Likert scale ranging from 0: “not at all” to 3: “every day.” The recall period is the past 2 
weeks.  Question 10 asks the subject to rate the impact of these problems on work, daily 
activities, and relationships.  The PHQ-9 will be administered at designated visits. 
7.3.11 
General Anxiety Disorder (GAD-7) 
The GAD-7 (Appendix 10: Generalized Anxiety Disorder (GAD-7) is a patient-reported 
survey that assesses the subject’s level of anxiety. The GAD-7 contains 7 items scored on a 
Likert scale ranging from 0: “not at all” to 3: “nearly every day.” The recall period is the past 
2 weeks.  The GAD-7 will be administered at designated visits. 
7.3.12 
Patient Global Impression of Prurigo Nodularis Severity (PGI-PN-S) 
The PGI-PN-S (Appendix 12: Patient Global Impression of Prurigo Nodularis Severity 
(PGI-PN-S) is a patient-reported questionnaire that assesses the subject’s impression of PN 
disease severity at the time of evaluation. It is scored from 0: “absent” to 4: “severe.” 
7.3.13 
Patient Global Impression of Change (PGIC) 

 
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The PGIC (Appendix 6: Patient Global Impression of Change (PGIC) is a patient-reported 
survey that assesses the subject’s impression of change on prurigo nodularis since the 
beginning of the study. Scoring ranges from -1: “very much improved” to 7: “very much 
worse.” 
7.4 
Biomarker Assessments  
7.4.1 
Blood Sample Collection and Processing 
Blood samples will be collected by venipuncture at the times indicated in Appendix 1.  Blood 
biomarker profiles will be analyzed.  Skin biomarker analyses will be performed and may 
include markers related to pruritus, inflammation, and/or fibrosis.   
7.4.2 
Skin Biopsy Collection and Processing 
Subjects will undergo skin biopsy sampling for biomarker analysis at the times indicated in 
Appendix 1.  Skin biopsies are optional.  Skin biopsies will be collected pre- and post-
treatment during the study.   
Specific instructions will be provided in a separate manual.   
7.5 
Safety and Tolerability Assessments  
7.5.1 
Adverse Events 
7.5.1.1 
Adverse Event Definition and Categorization 
The investigator is responsible for collecting all AEs that are observed or reported during the 
study from the time the subject signs the ICF through the EOS Visit, regardless of their 
relationship to study drug or their clinical significance.  
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
AEs also include: any worsening compared to baseline (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. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug.  
The condition of subjects will be monitored from time of signing the ICF through the EOS 
Visit.  In addition, subjects will be observed for any signs or symptoms and asked about their 
condition by open questioning, such as “How have you been feeling since you were last 
asked?”, at every study visit from the Screening Visit through the EOS Visit. 

 
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All non-serious AEs, whether volunteered, elicited, or noted on the physical examination, and 
SAEs will be recorded from the Screening Visit (signing the ICF) through the EOS Visit.  
The AE information collected during the period from the Screening Visit until study drug 
administration on Day 1 is intended only for establishing a baseline status for subjects and for 
recording any screening procedure-related AEs.  The nature, time of onset, duration, and 
severity of all AEs, both serious and non-serious, will be documented, together with an 
Investigator’s opinion of the relationship to study drug administration.   
Identification and reporting of injection site reactions (ISRs) will be performed in the context 
of safety surveillance for Adverse Events as outlined above.  KPL-716 will be administered 
subcutaneously into an area of normal skin unaffected by PN, recording and reporting of 
ISRs will be provided to study sites.  
Any changes or additions to the subject’s concomitant medications will be entered into the 
eCRF with appropriate start and stop dates.   
AEs or laboratory anomalies that are critical to safety evaluations and must be reported by the 
investigator to the sponsor and/or Clinical Research Organization (CRO) medical monitor. 
All AEs and SAEs will be followed until resolution, until the Investigator and Sponsor agree 
that follow-up is no longer necessary, or the subject withdraws consent from the study or is 
lost to follow up.  Any SAEs that are ongoing after completion of the last study visit or early 
termination should be followed up until the outcome has been determined. 
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 underlying 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.   
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 may be 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 the EOS Visit will be followed, where possible, until resolution.   
7.5.1.2 
Adverse Drug Reactions 
All noxious and unintended responses to an investigational medicinal product (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.   
7.5.1.3 
Adverse Event of Special Interest 
An adverse event of special interest (AESI) is an adverse event (serious or nonserious) of 
scientific and medical concern, specific to the IMP or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor may be appropriate.  
Such events may require further investigation on site in a timely manner by the investigator 
or designee in order to characterize and understand them.  AESIs may be added or removed 
during a study by protocol amendment.  Angioedema is considered as an AESI for detailed 
reporting and timely processing.  
7.5.1.4 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence 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.  An AE is life-threatening if the subject was at immediate risk 
of death from the event as it occurred (i.e., does not include a reaction that might 
have caused death if it had occurred in a more serious form).  For instance, drug-
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization signifies that the subject has been admitted to the hospital or short-
stay-type unit, or an emergency room stay for longer than 24 hours for observation 
and/or treatment at a level of care which would not have been appropriate at the 
study site.  Hospitalization for elective treatment of a pre-existing non-worsening 
condition or, which is not the result of an AE, are not considered an AE.  The 
details of such hospitalizations must be recorded on the medical history or 
physical examination page of the eCRF.  Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization or meet other criteria that define SAEs.  
• results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.  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 

 
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• 
Any suspected transmission via a medicinal product of an infectious agent 
reaction. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
All SAEs will be followed until resolution, until the Investigator and the Sponsor agree that 
follow-up is no longer necessary, or the subject withdraws consent or is lost to follow-up.   
Serious Adverse Event and AESI Reporting 
Investigator Reporting Responsibilities to the Sponsor 
SAEs and/or AESI due to any cause, whether or not related to the study drug, must be 
reported to the Sponsor or designee within 24 hours of occurrence or when the Investigator 
becomes aware of the event.  A completed SAE report form must be submitted including a 
full description of the event and sequelae in the format detailed in the SAE reporting form.  
The following contact information is to be used for SAE reporting:  
                  
The event must also be recorded on the standard AE eCRF.  Preliminary reports of SAEs 
must be followed by detailed descriptions as soon as possible including clear and redacted 
photocopies of hospital case reports, consultant reports, autopsy reports, and other documents 
when requested and applicable and if available.   
Investigator Reporting Responsibilities to IRB 
Unanticipated problems posing risks to study subjects will be reported to the IRB/IEC per 
their institutional policy.  Copies of each report and documentation of IRB/IEC notification 
and acknowledgement of receipt will be kept in the Investigator’s study file. 
Sponsor Reporting Responsibilities to Participating Investigators 
It is the responsibility of the Sponsor or designee to immediately notify all participating 
Investigators of any AE associated with the use of the study drug that is both serious and 
unexpected, as well as any finding from tests in laboratory animals that suggest a significant 
risk for human subjects.  
7.5.2 
Pregnancy 
Formal reproduction toxicology testing of KPL-716 has not yet been performed. 
Female subjects of childbearing potential must therefore agree to use a highly effective and 
protocol approved contraceptive method (Section 6.5) for the duration of the study and until 

 
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16 weeks after last study drug administration under this protocol.  Regular pregnancy tests 
will be performed for female subjects of childbearing potential, as defined in Appendix 1.    
Male subjects who have a female partner of childbearing potential must agree to use a highly 
effective and protocol approved contraceptive method (Section 6.5) for the duration of the 
study and until 16 weeks after last study drug administration under this protocol. 
If a subject becomes pregnant while participating in the study, study drug dosing must be 
discontinued immediately.  
A female subject must immediately inform the Investigator if she becomes pregnant during 
the study.  A male subject must inform the Investigator if his female partner becomes 
pregnant during the study.  Pregnancies occurring up to 16 weeks after last study drug 
administration must be reported to the Investigator.  The Investigator must report all 
pregnancies to the Sponsor or designee immediately and no later than 24 hours of their first 
knowledge of the pregnancy.  The Investigator should counsel the subject that it is unknown 
what effects study drug might have on a fetus.  Monitoring of the subject should continue 
until conclusion of the pregnancy. 
Instances of fetal death or congenital abnormality, if brought to the attention of the 
Investigator at any time after cessation of the study treatment and considered by the 
Investigator to be possibly related to the study treatment, must be reported to the Sponsor as 
an SAE. 
7.5.3 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the time points specified in 
Appendix 1. 
Subjects will be asked to provide urine samples for a drugs of abuse screen at the Screening 
Visit and Day 1 prior to dosing and at any time during the study at the discretion of the 
Investigator and in consultation with the Sponsor, if needed.  
For all female subjects of childbearing potential, the serum pregnancy test will be performed 
at the Screening Visit and the urine pregnancy test will be performed at the designated 
timepoints in Appendix 1.  Dosing should not proceed if urine pregnancy test is positive, until 
a negative serum pregnancy test is confirmed. Postmenopausal status will be confirmed via 
FSH testing at Screening.     
An Investigator will perform a clinical assessment of all clinical laboratory test results. 
After Screening, any clinically significant abnormal findings should be reported as AEs. 
7.5.4 
Vital Signs 
Supine blood pressure (systolic and diastolic), pulse rate, respiratory rate, and body 
temperature will be assessed at every visit from the Screening Visit through the EOS Visit as 
outlined in Appendix 1.  Subjects must be supine for at least 5 minutes before blood pressure 
and pulse rate measurements.   

 
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Vital signs may also be performed at other times if judged to be clinically appropriate by the 
Investigator or if the ongoing review of the safety data suggests a more detailed assessment 
of vital signs is required.  All measurements will be performed singly and may be repeated if 
outside the relevant clinical reference range.  Additional vital sign assessments may be 
performed if clinically indicated, in the opinion of the Investigator.  
7.5.5 
12-Lead Electrocardiogram 
The 12-lead ECG recording will be performed at the designated time points as outlined 
Appendix 1.  
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes.  
Single 12-lead ECGs will be repeated twice if either of the following criteria apply: 
• QT interval corrected for heart rate using Fridericia’s method - QTcF interval 
>500 ms in men and women 
• QTcF change from the baseline (pre-dose) is >60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required.  The Investigator or designee will perform a clinical assessment of each 12-lead 
ECG. 
Any new clinically significant ECG abnormalities occurring during the study will be recorded 
as AEs. 
7.5.6 
Physical Examination 
A full physical examination or an abbreviated physical examination will be performed at the 
timepoints specified in Appendix 1. 
A full physical examination includes head/neck/thyroid; eyes/ears/nose/throat (EENT); 
respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological.  
Breast, anorectal, and genital examinations will be performed only if medically indicated.  
An abbreviated physical examination includes cardiovascular, respiratory, abdominal exams 
and as indicated based on subject’s symptoms. 
7.5.7 
Safety Data Review 
A SRT including 2 physicians from the Sponsor, 1 CRO medical monitor (if needed) and 
critical cross-functional team members from the Sponsor will meet periodically to review 
AEs/SAEs, reasons for study discontinuations, and key clinical and laboratory assessments.  
SRT members will be blinded to subject treatment assignment.  The SRT will operate under 
the SOPs of the sponsor SRT. 
The study may be terminated if unexpected, significant, or unacceptable safety risks to 
enrolled subjects arise, or if recommended by applicable board(s) after review of safety and 
efficacy data. 

 
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8 
SAMPLE SIZE AND DATA ANALYSES 
8.1 
General Considerations 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 
9.4 or later.  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, 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 pre-specified levels of 
significance. 
Statistical analyses for the Phase 2b portion of the study will be conducted separately.  An 
integrated analysis of the pooled data may be performed at the end of the study depending on 
the results of these individual analyses.  Details for the analyses will be specified in the SAP. 
8.2 
Handling of Dropouts and Missing Data 
Criteria for removal of subjects from therapy or assessments are explained in Section 4.10. 
To the extent possible, attempts will be made to minimize the amount of missing data through 
measures planned in the study conduct.  Details for handling missing values will be specified 
in the SAP.  
8.3 
Multiple Comparisons/Multiplicity 
As this is a dose finding study, there is no multiplicity adjustment planned for the 
comparisons of multiple doses of KPL-716 versus placebo. 
8.4 
Determination of Sample Size 
The Phase 2b sample size calculation is based on the primary efficacy endpoint percentage 
change from baseline of WI-NRS at Week 16 using a two-sample t-test.  
Approximately 180 subjects in total will be equally randomized to the 4 arms of Phase 2b.  At 
Week 16, 53% and 30% reduction in weekly average of WI-NRS are assumed for KPL-716 and 
placebo arms, respectively.  For each comparison, assuming treatment effect of 23% difference 
in weekly average WI-NRS reduction from baseline at Week 16 and standard deviation of 
35%, and two-sided alpha of 0.05, 38 subjects in each arm will guarantee 80% power to the 
treatment effect.  Approximately 45 patients in each arm are required after adjusting for 15% 
lost follow up.  
8.5 
Analysis Populations 
The following analysis sets will be defined for the Phase 2b portion of the study. 
8.5.1 
Modified Intent-to-Treat Analysis Sets 
All randomized subjects who receive at least 1 dose of KPL-716 or placebo and have at least 
1 daily WI-NRS score in the double-blind Treatment Period will be included in the modified 

 
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intent-to-treat (mITT) analysis set.  Efficacy analyses will be based on the mITT analysis 
sets.  All mITT analyses will be based on each subject’s randomized treatment assignment.  
8.5.2 
Safety Analysis Sets 
All randomized subjects who take at least 1 dose of KPL-716 or placebo will be included in 
the Safety Analysis Set.  Safety analyses will be based on the treatment (KPL-716 or 
Placebo) that was administered to each subject. 
8.5.3 
Per Protocol (PP) Analysis Sets 
All mITT subjects who have no important protocol deviations that may potentially bias 
efficacy analyses of the study will be included in the PP set. 
8.5.4 
Pharmacokinetic Analysis Sets 
Subjects who received KPL-716 and who had at least one PK sample will be included in the 
PK population. 
8.6 
Analysis of Efficacy 
All efficacy analyses will be performed on the mITT analysis set.  The primary efficacy 
endpoint in Phase 2b will be analyzed with ANCOVA including treatment as fixed effect, 
baseline WI-NRS, and randomization stratification factors as covariates.  
For key secondary efficacy endpoints, the difference of proportions and the corresponding 
95% CI for the difference of proportions will be displayed.  Treatment groups will be 
compared using a Cochran-Mantel-Haenszel test controlling for the randomization 
stratification variables. 
The analyses of primary and key secondary efficacy endpoints will be repeated using the PP 
set to assess the sensitivity of the results to important protocol deviations that could 
potentially bias the analysis.  All efficacy data will be listed by subject.  
Details will be specified in the Phase 2b SAP. 
8.7 
Analysis of Safety 
All safety analyses will be conducted based on the Safety Analysis Set.  Summary tables will 
be done for safety endpoints (treatment emergent AEs, labs, vital signs, etc.).  All safety data 
will be listed by subject.  Details for the analysis of safety data will be provided in the SAP. 
8.7.1 
Adverse Events 
Adverse events will be mapped to preferred term (PT) and system organ class (SOC) using 
the most up to date Medical Dictionary for Regulatory Activities (MedDRA).  AEs that begin 
after the first administration of study drug or existing AEs that worsen after the first dose of 
study medication are considered TEAEs.  The number and percentage of subjects reporting 
TEAEs will be summarized for each treatment group by MedDRA SOC and PT, by severity, 
and by relationship to study treatment.  The number and percentage of subjects with serious 
AEs, and the number and percentage of subjects with AEs leading to treatment 

 
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discontinuation will also be summarized for each treatment group by MedDRA system organ 
class and preferred term.  
8.7.2 
Clinical and Laboratory Events and Analyses 
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 each post baseline time point will be presented.  
8.7.3 
Vital Signs 
Vital signs will be summarized using descriptive statistics of actual values and changes from 
baseline over time.  The incidence of clinically notable vital signs will be summarized by 
treatment group. 
8.7.4 
Physical Examination 
Clinically significant new or worsened physical examination abnormalities following 
treatment will be recorded as AEs and will be reflected in the summary of AEs.    
8.7.5 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary and will be classified 
by Anatomical Therapeutic Chemical (ATC) classification level 4 and PT for the Safety 
Analysis Set.  Frequencies and percentages of subjects using each concomitant medication 
will be presented for the Safety Analysis Set overall, and by treatment group.  All medication 
use will be listed regardless of the timing of the start of the medication. 
8.8 
Pharmacokinetic Analyses 
For all subjects, serum samples will be collected before each dose at time points shown in 
Appendix 1 to quantify concentrations of KPL-716.  Descriptive statistics will be calculated 
for the serum concentrations of KPL-716 by visit.  Individual listings of plasma 
concentrations will be provided. 
Pharmacokinetic data may be used in a subsequent population pharmacokinetic evaluation 
that will be conducted outside of this study and described in a separate report. 
8.9 
Biomarker Analyses 
Skin and blood biomarkers levels will be analyzed and summarized in a separate report 
8.10 
Immunogenicity Analyses 
Serum ADA will be listed and summarized by treatment group and overall using descriptive 
statistics.   
8.11 
Gene Expression Analyses 

 
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Biomarker profiles (eg, potentially cytokines, chemokines, and other inflammatory markers) 
will be analyzed from blood samples.  Gene expression will also be analyzed from skin 
biopsy specimens.  Other gene expression analyses may be performed for target genes related 
to pruritus, inflammation, and/or fibrosis as determined by the Sponsor and summarized in a 
separate report.   
Descriptive statistics and changes from baseline, as applicable, will be calculated for gene 
expression.  No inferential statistical analyses are planned. 
8.12 
Interim Analyses 
An interim analysis for Phase 2b portion may be conducted after at least 50% subjects 
complete Week 16 Visit.  If the interim analysis is conducted in the Phase 2b part, a two-
sided alpha of 0.0001 will be spent.  The two-sided alpha level for the final Phase 2b efficacy 
analysis will be 0.05.  Additional details regarding the interim analysis, if performed, will be 
provided in the SAP along with other analysis plans. 
 

 
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9 
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
Auditing 
The study may be audited or reviewed by Kiniksa Quality Assurance department, IRB/IEC, 
and/or regulatory authority at any time.  The study site is required to allow for study-related 
monitoring, audits, IRB review, and regulatory inspections by providing direct access to the 
study source data and documents. 
Measures will be undertaken to protect the confidentiality of records that could identify 
subjects, ensuring the privacy and confidentiality rules are followed in accordance with 
applicable regulatory requirements. 
9.2 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this 
clinical trial.  The Study Monitor will monitor the study conduct, eCRF and source 
documentation completion and retention, and accurate study drug accountability.  To this 
end, the Study Monitor will visit the study site at scheduled intervals per the Sponsor 
requirements and will be expected to be in frequent contact with the study site through verbal 
and written communication.  It is essential that the Study Monitor has access to all 
documents, related to the study and the individual subjects, at any time these are requested.  
In turn, the Study Monitor will adhere to all requirements for subject confidentiality as 
outlined in the ICF.  The Investigator and Investigator’s staff will be expected to cooperate 
with the Study Monitor, to be available during a portion of the monitoring visit to answer 
questions, and to provide any missing information. 
Monitoring to review study drug receipt, inventory, storage, documentation, and handling 
will be conducted by the study monitor.  In Part 2b this activity may be performed by 
separate unblinded study monitor.  
Specific details will be outlined in the Clinical Monitoring Plan. 
 

 
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10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Data Handling 
The Sponsor’s CRO will be responsible for data management of this study, including quality 
of the data.  The study site will be responsible for data entry into the electronic data capture 
system (EDC) system.  A comprehensive validation check program will verify the data.  
Discrepancies will be generated automatically in the system at the point of entry or added 
manually for resolution by the study site staff. 
The Data Management Plan will outline the quality checks to be performed on the data.  
Study data transfers will be outlined in Data Transfer Agreements.  
10.2 
Case Report Form 
Data will be captured in source documentation at study sites and then entered into the eCRFs 
or EDC by staff at the study site.  Following data entry, the eCRF pages and the data entry 
will undergo quality control checks in accordance with written procedures.  Any 
discrepancies will be resolved in the database.   
Following all data validation steps, the Investigator will sign the completed electronic data 
prior to any planned interim data analysis snapshots and/or a final database lock. 
10.3 
Records 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the study site in accordance with 21 Code of Federal Regulations 312.62(c).  No 
records may be destroyed during the retention period without the written approval of the 
Sponsor.  No records should be transferred to another location or a third-party vendor without 
a written notification to the Sponsor.   
Study records will be maintained by the Sponsor or Designee.  Record and document keeping 
will be detailed in a separate plan.   
 

 
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11 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
Ethics Committee or Institutional Review Board 
Prior to the start of the study, the following documents will be reviewed and approved by the 
participating IRB/IEC according to local procedures: 
• protocol 
• ICF 
• subject recruitment procedures (e.g., advertisements) 
• any other written information to be provided to subjects. 
The IRB will be informed by the Investigator of any changes to the approved protocol.   
Any amendments to the protocol will require IRB/IEC approval.  Any administrative 
amendments to the protocol will be provided to IRBs/IECs according to IRB/IEC procedures.   
The IRB/IEC will be informed by the Investigator of serious and unexpected SAEs in 
accordance with the IRB/IEC reporting requirements.  The Investigator will provide the 
IRB/IEC with progress reports per IEB/IEC procedures. 
11.2 
Regulatory Considerations 
The study will be conducted in accordance with the protocol and with: 
• consensus ethical principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International Organizations 
of Medical Sciences Ethical Guidelines 
• International Conference on Harmonization (ICH) E6 Guideline for Good Clinical 
Practice 
• applicable local laws and regulations. 
The Investigator will be responsible for the overall conduct at the study site and adherence to 
the requirements of the ICH guidelines and all other applicable local regulations. 
11.3 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF that includes all required elements of informed consent per ICH and local regulations.  
The ICF will give details of the study drug, procedures, and potential risks of the study.  
Subjects will be instructed that they are free to obtain further information from the 
Investigator and that their participation is voluntary, and they have the right to voluntarily 
withdraw from the study at any time. 
Following discussion of the study with the study site personnel, subjects will sign and date 
the ICF in the presence of a qualified staff member to indicate that they are voluntarily giving 
their informed consent.  One copy will be given to the subject, and the original signed ICF 
will be maintained in the subject’s records at the study site.   

 
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Skin biopsies are optional in this study.  
11.4 
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 and 
security according to national and/or local laws and regulations on personal data protection.   
Sponsor and study vendor databases will similarly be managed and maintained according to 
national and/or local laws and regulations to prevent unauthorized access, disclosure, 
dissemination, alteration or loss of information and personal data.  In the event of any such 
data security breach, immediate action will be taken by sponsor and/or study vendor to 
remedy the breach, assess the extent of data exposure, and implement appropriate measures 
to limit possible adverse effects.   
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 secured 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. 
11.5 
Protocol Amendments 
Protocol amendments will be submitted to the IRB/IEC and to regulatory authorities in 
accordance with local regulatory requirements.  Approval must be obtained from the 
IRB/IEC and regulatory authorities (as locally required) before implementation of any 
changes, except for changes necessary to eliminate an immediate hazard to subjects, as 
defined by regulatory requirements. 

 
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12 
ADMINISTRATIVE ASPECTS 
12.1 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the study, shall be regarded as confidential of the Sponsor.  The 
Investigator (and/or designee) agrees to use such information solely for carrying out the study 
and to not disclose such information in any way without a prior written permission from the 
Sponsor.  Study information from this protocol will be posted on publicly available clinical 
trial registers according to local regulations. 
12.2 
Reports and Publications 
The Sponsor shall have the sole and exclusive right to publish information obtained from the 
study, including any data, results, and conclusions.  Investigators participating in the study 
execution may be invited to participate in the authorship of a potential publication in a 
manner commensurate with their participation in the study execution and in accordance with 
International Committee of Medicinal Journal Editors standards. 
12.3 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 

 
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13 
REFERENCES 
1. Pereira MP, Steinke S, Zeidler C, et al. European academy of dermatology and 
venereology European prurigo project: expert consensus on the definition, classification 
and terminology of chronic prurigo. J Eur Acad Dermatol Venereol. 2018;32(7):1059-
1065.  
2. Fostini AC, Girolomoni G, Tessari G. Prurigo nodularis: an update on etiopathogenesis 
and therapy. J Dermatol Treat. 2013;24(6):458-462.  
3. Qureshi AA, Abate LE, Yosipovitch G, Friedman AJ. A Systematic Review of Evidence-
Based Treatments for Prurigo Nodularis. J Am Acad Dermatol. 2018; pii: S0190-
9622(18)32628-8.  
4. Pereira MP, Ständer S. Assessment of severity and burden of pruritus. Allergol Int. 
2017;66(1):3-7.  
5. Weigelt N, Metze D, Ständer S. Prurigo nodularis: systematic analysis of 58 histological 
criteria in 136 patients. J Cutan Pathol. 2010;37(5):578-86.  
6. Boozalis E, Tang O, Patel S, Semenov YR, Pereira MP, Stander S, Kang S, Kwatra SG. 
Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad 
Dermatol. 2018 Oct;79(4):714-719.e3.  
7. Iking A, Grundmann S, Chatzigeorgakidis E, Phan NQ, Klein D, Ständer S. Prurigo as a 
symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 
108 patients. J Eur Acad Dermatol Venereol. 2013;27(5):550-557.  
8. Winhoven SM, Gawkrodger DJ. Nodular prurigo: metabolic diseases are a common 
association. Clin Exp Dermatol. 2007;32(2):224-225.  
9. Tanaka M, Aiba S, Matsumura N, Aoyama H, et al. Prurigo nodularis consists of two 
distinct forms: early-onset atopic and late-onset nonatopic. Dermatology 1995;190: 269–
276.  
10. Qadi AA, Taberlay PC, Phillips JL, Young A, West AC, Brettingham-Moore K, 
Dickinson JL, Holloway AF. The leukemia inhibitory factor receptor gene is a direct 
target of RUNX1. J of Cellular Biochem. 2016; 117:49-58  
11. Nemoto O, Furue M, Nakagawa H, Shiramoto M, Hanada R, Matsuki S, Imayama S, 
Kato M, Hasebe I, Taira K, Yamamoto M, Mihara R, Kabashima K, Ruzicka T, Hanifin 
J, Kumagai Y. The first trial of CIM331, a humanized antihuman interleukin-31 receptor 
A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, 
tolerability and pharmacokinetics of a single dose in a randomized, double-blind, 
placebo-controlled study. Br J Dermatol. 2016;174(2):296-304.  
12. Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, Galus R, Etoh 
T, Mihara R, Yoshida H, Stewart J, Kabashima K; XCIMA Study Group. Anti-
Interleukin-31 Receptor A Antibody for Atopic Dermatitis.  N Engl J Med. 
2017;376(9):826-835.  
13. Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, Alenius H, Dieu-
Nosjean MC, Meller S, Rieker J, Steinhoff M, Hoffmann TK, Ruzicka T, Zlotnik A, 
Homey B. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J 
Allergy Clin Immunol. 2006;117(2):411-7.  

 
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14. Park K, Mori T, Nakamura M, Tokura Y. Increased expression of mRNAs for IL-4, IL-
17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur J 
Dermatol. 2011;21(1):135-6.  
15. Nobbe S, Dziunycz P, Mühleisen B, Bilsborough J, Dillon SR, French LE, Hofbauer GF. 
IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. 
Acta Derm Venereol. 2012;92(1):24-8.  
16. Gazel A, Rosdy M, Bertino B, Tornier C, Sahuc F, Blumenberg M. A characteristic 
subset of psoriasis-associated genes is induced by oncostatin-M in reconstituted 
epidermis. J Invest Dermatol. 2006;126(12):2647-57.  
17. Boniface K, Diveu C, Morel F, Pedretti N, Froger J, Ravon E, Garcia M, Venereau E, 
Preisser L, Guignouard E, Guillet G, Dagregorio G, Pène J, Moles JP, Yssel H, Chevalier 
S, Bernard FX, Gascan H, Lecron JC. Oncostatin M secreted by skin infiltrating T 
lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol. 
2007;178(7):4615-22. 
18. Fritz DK, Kerr C, Fattouh R, Llop-Guevara A, Khan WI, Jordana M, Richards CD. A 
mouse model of airway disease: oncostatin M-induced pulmonary eosinophilia, goblet 
cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial 
pulmonary fibrosis is STAT6 independent. J Immunol. 2011;186(2):1107-18.  
19. Mozaffarian A, Brewer AW, Trueblood ES, Luzina IG, Todd NW, Atamas SP, Arnett 
HA. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J 
Immunol. 2008;181(10):7243-53. 
20. Fritz DK, Kerr C, Botelho F, Stampfli M, Richards CD. Oncostatin M (OSM) primes IL-
13- and IL-4-induced eotaxin responses in fibroblasts: regulation of the type-II IL-4 
receptor chains IL-4Ralpha and IL-13Ralpha1. Exp Cell Res. 2009;315(20):3486-99.  
21. Kwofie K, Scott M, Rodrigues R, Guerette J, Radford K, Nair P, Richards CD. 
Regulation of IL-17A responses in human airway smooth muscle cells by Oncostatin M. 
Respir Res. 2015;16:14.  
22. Botelho FM, Rangel-Moreno J, Fritz D, Randall TD, Xing Z, Richards CD. Pulmonary 
expression of oncostatin M (OSM) promotes inducible BALT formation independently of 
IL-6, despite a role for IL-6 in OSM-driven pulmonary inflammation. J Immunol. 
2013;191(3):1453-64.  
23. Wong S, Botelho FM1, Rodrigues RM1, Richards CD1. Oncostatin M overexpression 
induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of 
fibrosis-resistant BALB/c mice. Lab Invest. 2014;94(9):1003-16.  
24. Kunz B, Oranje AP, Labrèze L, Stalder JF, Ring J, Taïeb A. Clinical validation and 
guidelines for the SCORAD index: consensus report of the European Task Force on 
Atopic Dermatitis. Dermatology. 1997;195(1):10-9. 
25. Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Swerlick RA, Chen SC. A pilot 
quality-of-life instrument for pruritus. J Am Acad Dermatol. 2008; 59(2):234-44. 
 

 
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14 
APPENDICES 
14.1 
Appendix 1: Schedule of Activities 
 

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19 July 2021 (Version 6) 
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Table 1 
Schedule of Activities for Phase 2b 
Study Visits 
Screen-
ing 
Double-Blind Period 
Open-Label Extension Period14 
Week (W) 
W-4 to 
W0 
Base-
line 
W2 
W4 
W8 
W12 W16/E
OT 
W18 
W20 
W2215 
W2415 
W2615 
W2815 
W3015 
W32 
W3415 
W3615 
W3815 
W4015 
W4215 
W4415 
W4615 
W48 
W52/ 
EOS 
Day (D) 
D -28 to -
1 
D1 
D15 D29 D57 
D85 
D113 
D127 D141 
D155 
D169 
D183 
D197 
D211 
D225 
D239 
D253 
D267 
D281 
D295 
D309 
D323 
D337 D365 
Study Procedures Windows 
(Days) 
0 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
surgical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications, 
therapies, 
procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASR and PRR 
training8 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Vital signs3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Body weight, 
height, BMI2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ECG (12-lead)3 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Quantiferon-based 
TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
monitoring 
From the Screening Visit through the EOS Visit (Week 52) 
Concomitant 
meds/therapies/ 
procedures 
From the Screening Visit through the EOS Visit (Week 52) 
Compliance 
assessment 
From the Screening Visit through the EOS Visit (Week 52) 

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19 July 2021 (Version 6) 
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Study Visits 
Screen-
ing 
Double-Blind Period 
Open-Label Extension Period14 
Week (W) 
W-4 to 
W0 
Base-
line 
W2 
W4 
W8 
W12 W16/E
OT 
W18 
W20 
W2215 
W2415 
W2615 
W2815 
W3015 
W32 
W3415 
W3615 
W3815 
W4015 
W4215 
W4415 
W4615 
W48 
W52/ 
EOS 
Day (D) 
D -28 to -
1 
D1 
D15 D29 D57 
D85 
D113 
D127 D141 
D155 
D169 
D183 
D197 
D211 
D225 
D239 
D253 
D267 
D281 
D295 
D309 
D323 
D337 D365 
Study Procedures Windows 
(Days) 
0 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
blood tests  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Pregnancy test4 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Serology (HIV, 
HBV, HCV)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 test 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug of 
Abuse screen6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 7,14 
 
X 
 
X 
X 
X 
X13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug 
accountability 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy and PD 
Measures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily NRS Tool 
for assessment of 
pruritus and 
rescue medication 
use8 
From the Screening Visit through the EOS Visit (Week 52) 
Sleep Loss VAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
IGA-CNPG-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
IGA-CNPG-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
PN-NAT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
PN-IGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 

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19 July 2021 (Version 6) 
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Study Visits 
Screen-
ing 
Double-Blind Period 
Open-Label Extension Period14 
Week (W) 
W-4 to 
W0 
Base-
line 
W2 
W4 
W8 
W12 W16/E
OT 
W18 
W20 
W2215 
W2415 
W2615 
W2815 
W3015 
W32 
W3415 
W3615 
W3815 
W4015 
W4215 
W4415 
W4615 
W48 
W52/ 
EOS 
Day (D) 
D -28 to -
1 
D1 
D15 D29 D57 
D85 
D113 
D127 D141 
D155 
D169 
D183 
D197 
D211 
D225 
D239 
D253 
D267 
D281 
D295 
D309 
D323 
D337 D365 
Study Procedures Windows 
(Days) 
0 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
PGI-PN-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ItchyQoL 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
PHQ-9 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
GAD-7 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
PGIC 
 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Medical 
photographs – 
representative 
areas9 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Medical 
photographs – 
whole body9 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical 
photographs – 
prior to biopsies10 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin biopsies10  
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biomarker 
samples11  
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK and 
Immunogenicity 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples12 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ADA samples 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies;  ASR = accurate symptom reporting; β hCG = β-human chorionic gonadotropin; BMI = body mass index; ECG = electrocardiogram;  EOS 
= end of study; EOT = end of treatment; GAD-7 = General Anxiety Disorder-7; HBV = hepatitis B virus;  HCV = hepatitis C virus; HIV = human immunodeficiency 
virus;  WI-NRS = Worst itch numeric rating scale;  PD = pharmacodynamic;  PHQ-9= Patient Health Questionnaire-9; PK = pharmacokinetics;  PN-NAT = Prurigo 
Nodularis Nodule Assessment Tool;  PN-IGA = Prurigo Nodularis Investigator Global Assessment;  PRR = placebo response reduction; ItchyQoL = Itchy Quality of 
Life; VAS=Visual Analog Scale; IGA-CNPG-S = Investigator’s Global Assessment for Prurigo Nodularis-Stage; IGA-CNPG-A = Investigator’s Global Assessment for 

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Prurigo Nodularis-Activity; PGIC = Patient Global Impression of Change; PGI-PN-S = Patient Global Impression of Prurigo Nodularis Severity.  Subjects may be 
asked to return to the study site if needed to complete eligibility assessment.  At prescreening, potentially eligible subjects may be matched with the closest study site. 
1 At the Screening Visit, prior to dosing on Day 1, Week 16 and at the EOS Visit (Week 52), a full physical examination will be performed to assess the following 
systems: head/neck/thyroid; eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological.  Breast, 
anorectal, and genital examinations will be performed only if medically indicated.  At all other designated visits, a focused examination on skin condition and an 
abbreviated physical examination will be performed consisting of cardiovascular, respiratory, and abdominal systems and as indicated based on subjects’ symptoms.  
Additional physical examinations may be performed at any time if medically indicated per the Investigator’s medical judgement.  
2 Height will be measured, and BMI will be calculated only at the Screening Visit.  Weight will be measured at all designated study visits. 
3 Blood draws and ECG (12-lead ECG) will be recorded within 2 hours of dosing. ECG and vital signs will be performed prior to blood draws, skin biopsies and 
medical photography.   
4 Females of childbearing potential only.  A serum βhCG pregnancy test is performed at the Screening Visit.  A urine βhCG test is performed at all later time points and 
a serum βhCG test is performed if urine βhCG test is positive at these timepoints.  Dosing should not proceed if urine pregnancy test is positive, until a negative serum 
pregnancy test is confirmed. 
5 Baseline COVID results not required to proceed with randomization dosing.   
6 Additional screening for drugs of abuse may be performed at the discretion of the Investigator and in consultation with the Sponsor at any time during the study. 
7 On dosing days, all blood samples (safety, PK, ADA,  biomarkers, serum pregnancy if indicated, etc.), all urine samples (urinalysis, pregnancy, urine drug screen if 
indicated), all efficacy assessments (Sleep Loss VAS, PN-NAT, PN-IGA, etc.), all patient reported outcomes (ItchyQoL, PHQ-9, GAD-7), all medical photography, 
ECG and/or skin biopsies will be performed prior to dosing.  Subjects will be randomized to receive KPL-716 or placebo on Day 1.  Subjects will be observed for 1 
hour after each dosing.  Vital signs will be measured at the end of the 1-hour observation period and adverse events will be recorded if any.  In case study drug 
treatment is interrupted or discontinued, subjects should continue with study visits as outlined in the Schedule of Activities, minus dosing.  In case of early withdrawal, 
subjects will follow the schedule of activities for the EOS Visit (Week 52). 
8 At the Screening Visit, subjects will be instructed through ASR and PRR training to evaluate the intensity of their WI-NRSon a daily basis.  The ASR and PRR 
training should be repeated monthly until Week 12 or as needed.  The daily recordings can begin any time after the Screening Visit.  Eligible subjects will continue 
daily recording of WI-NRS and rescue medication use from Day 1 through the EOS Visit. 
9 At the Screening Visit, medical photographs will be taken of the representative area of subject’s disease as determined by the PI.  The same representative area will be 
followed over time.  In addition, whole body medical photographs will be captured (upper front and lower front, upper back, and lower back) without the face and with 
the genitals covered.  Confirmation of diagnosis of PN will be performed by review of medical photographs (Refer to Study Manual) prior to each subject’s 
randomization.      
10 Skin biopsies will be collected pre- and post-treatment during the study, Skin biopsies are optional.  A medical photograph of the location of the biopsies (prior to 
biopsies) will be taken. 
11 Blood samples for biomarkers include serum sample(s) and whole blood sample(s) for each individual patient. 
12 PK blood samples will be collected prior to study drug administration on dosing days.  
13 This study drug administration (which is part of the OLE) will only occur if subjects elect to be in the OLE. 
14 All subjects will have the option to receive KPL-716 360 mg SC, Q2W during the OLE Period to evaluate long-term safety and PK.  
15 Should subjects self-administer drug, collection of AEs, concomitant medication use, and NRS compliance assessments may be completed remotely by study staff.    

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14.2 
Appendix 2:  Daily NRS Tool for Phase 2b 
Daily Assessment of Itch and Rescue Medications in Prurigo Nodularis 
Instructions: Please select the box that best describes your experience with prurigo nodularis over the past 24 hours.   
1. Over the past 24 hours, 
how would you rate your 
most severe itch? 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No  
itch 
 
 
 
 
 
 
 
Worst 
imaginable 
itch 
Instructions: The next question is about your rescue medication use for itch over the past 24 hours. 
2. Please mark below if you 
used any medication to 
reduce itch other than the 
study drug. 
Yes  
          No  
 
 
 

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14.3 
Appendix 3:  Prurigo Nodularis Nodule Assessment Tool (PN-NAT)  
Instructions:  The purpose of this tool is to assess the severity of nodule burden and guide the 
physician’s assessment of a patient’s prurigo nodularis.  Patients may present with smaller papular 
lesions, scarring, or post-inflammatory hyper- or hypo-pigmentation of the skin, which are not 
considered as part of this assessment.  Using your clinical judgment and the guidelines provided 
below, please select a score for each item that best describes the patient’s prurigo nodularis right 
now.  
Please refer to the following definitions to guide the assessment: 
• 
“Nodule” is defined as a raised hard lesion of approximately 0.5 cm to 2 cm in diameter 
• 
“Smaller papular lesion” is defined as a raised lesion of less than 0.5 cm in diameter 
• 
“Scarring” is defined as fibrous tissue that has replaced normal skin after damage by injury 
or disease  
• 
“Post-inflammatory hyperpigmentation” is defined as increased pigmentation in the location 
where there used to be inflammation  
• 
“Post-inflammatory hypopigmentation” is defined as decreased pigmentation in an area 
where there used to be inflammation 
• 
“Excoriation” is defined as a scratch mark or a linear break in the skin that that could be open 
or covered with blood or crust 
Estimate of the Number of Nodules Over the Whole Body 
Score 
 
0 
0 nodules 
1 
1-9 nodules  
2 
10-19 nodules  
3 
20-49 nodules 
4 
≥50 nodules  
Estimate of Extent of Excoriations Over the Whole Body 
Score 
0 
0 nodules are excoriated 
1 
<25% of nodules are excoriated 
2 
25%-75% of nodules are excoriated 
3 
>75% of nodules are excoriated 
Distribution of Nodules 
Select all body parts with nodules 
Upper arm (from the elbow to the shoulder) 
• 
right 
• 
left 
Lower arm (from the elbow to the hand) 
• 
right 
• 
left 
Trunk including chest, abdomen, groin, or buttocks 
• 
front trunk 
• 
back trunk 
• 
groin 

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• 
buttocks 
Upper leg (from the knee to the upper thigh) 
• 
right 
• 
left 
Lower leg (from the knee to the foot) 
• 
right 
• 
left 
Number of body parts with nodules 
Exact nodule count in representative area 
Select the Representative Area 
Please refer to the user manual for 
instructions to select a 
representative area. 
Upper arm (from the elbow to the shoulder) 
• 
right 
• 
left 
Lower arm (from the elbow to the hand) 
• 
right 
• 
left 
Trunk including chest, abdomen, groin, or buttocks 
• 
front trunk 
• 
back trunk 
• 
groin 
• 
buttocks 
Upper leg (from the knee to the upper thigh) 
• 
right 
• 
left 
Lower leg (from the knee to the foot) 
• 
right 
• 
left 
Exact number of nodules in 
representative area 
 
 
Estimate of Hardness of Nodules in Representative Area 
Score 
 
0 
0 nodules are hard 
1 
<25% of nodules are hard 
2 
25%-75% of nodules are hard 
3 
>75% of nodules are hard 
 
 

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14.4 
Appendix 4: Prurigo Nodularis Investigator’s Global Assessment 
(PN-IGA) 
 
 
Instructions:  The purpose of this tool is to assess the severity of nodule burden and guide the 
physician’s global assessment of a patient’s prurigo nodularis based on (a) the presence /absence of 
nodules and (b) the size of nodules as defined by their elevation.  Patients may present with smaller 
papular lesions, scarring, or post-inflammatory hyper- or hypo-pigmentation of the skin, which are 
not considered as part of this assessment.  Using your clinical judgment and the guidelines provided 
below, please select a score for each item that best describes the patient’s prurigo nodularis right 
now.  
 
Please refer to the following definitions to guide the assessment: 
1. “Nodule” is defined as a raised hard lesion of approximately 0.5 cm to 2 cm in diameter 
2. “Smaller papular lesion” is defined as a raised lesion of less than 0.5 cm in diameter 
3. “Scarring” is defined as fibrous tissue that has replaced normal skin after damage by injury or 
disease  
4. “Post-inflammatory hyperpigmentation” is defined as increased pigmentation in the location 
where there used to be inflammation  
5. “Post-inflammatory hypopigmentation” is defined as decreased pigmentation in an area 
where there used to be inflammation 
Estimate of the Number of Nodules Over the Whole Body 
Grade (select one) 
Morphological Descriptor 
 Clear 
No nodules 
 Almost Clear 
 
Nodules are present, none (0%) are severely elevated (> 0.5 
cm in elevation) 
 
 Mild 
 
Nodules are present, few (less than 25%) are severely 
elevated (> 0.5 cm in elevation) 
 
 Moderate 
 
Nodules are present, some (25%-75%) are severely elevated 
(> 0.5 cm in elevation) 
 
 Severe 
 
Nodules are present, most (greater than 75%) are severely 
elevated (> 0.5 cm in elevation) 
 

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14.5 
Appendix 5: Sleep Loss Assessment (average during the past 3 nights) 
 
 
 

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14.6 
Appendix 6: Patient Global Impression of Change (PGIC) 
Since the start of the study, my prurigo nodularis is: 
  
✓ one box only: 
 
(1) 
 Very Much Improved 
(2) 
 Much Improved 
(3) 
 Minimally Improved 
(4) 
 No Change 
(5) 
 Minimally Worse 
(6) 
 Much Worse 
(7) 
 Very Much Worse 
 
 

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14.7 
Appendix 7: Investigator’s Global Assessment for Prurigo Nodularis-
Stage (IGA-CNPG-S) 
 

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14.8 
Appendix 8: Investigator’s Global Assessment for Prurigo Nodularis-
Activity (IGA-CNPG-A) 
 
 
 

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14.9 
Appendix 9: Patient Health Questionnaire (PHQ-9) 
 
 
 

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14.10 
Appendix 10: Generalized Anxiety Disorder (GAD-7) 
 
 
 
 

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14.11 
Appendix 11: ItchyQoL Questionnaire 
 
 

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14.12 
Appendix 12: Patient Global Impression of Prurigo Nodularis Severity 
(PGI-PN-S) 
Instructions: Please select the box that best describes the severity of your prurigo nodularis 
right now. 
Right now, my prurigo nodularis is: 
0 
Absent (No sign or symptom of prurigo nodularis) 
1 
Minimal 
2 
Mild 
3 
Moderate 
  4 
Severe  
 
 
 

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14.13 
Appendix 13: Summary of Changes (Version 6 compared to Version 5) 
The following are changes to the KPL-716-C201 protocol (version 6 versus Version 5), which 
summarizes major changes to the protocol.  Additional minor changes were also made with respect to 
typos, minor edits for clarification, adding new abbreviations to the list of abbreviations, and updating 
the table of contents. 
Protocol Section  
Modification 
Rationale 
First page + footer 
Added/changed to Protocol Version 6, 19 July 2021 and 
included
to the Sponsor 
New protocol version. 
Synopsis  
Removed Latin America 
Removed as Sponsor 
will not be enrolling 
subjects in this region.   
Synopsis, and 
Section 3.2  
Proportion of subjects achieving 0 or 1 from baseline in PN-
IGA at Week 16 
Clarified the PN-IGA 
measures the overall 
assessment at Week 16.   
Synopsis and Section 
4.7.2 
8. Presence of moderately severe depression as indicated by 
PHQ-9 total score of ≥1520 or item 9 score >0 at the Screening 
Visit or Day 1. 
Revised to reduce 
screen failures.  Some 
screen-failed subjects 
by PHQ-9 cut-off score 
of 15 from activated 
North America sites 
were confirmed to be 
non-depressive by 
psychiatrists.  Currently 
revised to only exclude 
subjects who scored 
severe depression by 
PHQ-9. 
Synopsis and Section 
8.3  
Multiple comparison/Multiplicity 
There is a multiplicity adjustment planned for efficacy 
endpoints in Phase 2b. Details will be specified in the SAP. 
As this is a dose finding study, there is no multiplicity 
adjustment planned for the comparisons of multiple doses of 
KPL-716 versus placebo. 
As this is a dose-
ranging study and not 
intended to make label 
claims out of it, so 
multiplicity is not 
planned. 
Synopsis 
An interim analysis for Phase 2b portion may be conducted 
after at least 50% subjects complete Week 16 Visit.  If the 
interim analysis is conducted in the Phase 2b part, a two-sided 
alpha of 0.0001 will be spent.  The two-sided alpha level for 
the final Phase 2b efficacy analysis will be 0.05.  Additional 
details regarding the interim analysis, if performed, will be 
provided in the SAP along with other analysis plans. 
Added to align with 
Section 8.12. 
Section 7.3.4 
PN-NAT is a novel exploratory tool for the evaluation of 
disease severity based on estimate of the number of nodules 
over the whole body, estimate of hardness of nodules over the 
whole body in representative area, estimate of extent of 
excoriation over the whole body, distribution of nodules, exact 
number of nodules in the representative area.  There are 5 
components to PN-NAT.   
Editorial alignment 
with Appendix 3.  

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Protocol Section  
Modification 
Rationale 
Section 7.3.13 
The PGIC (Appendix 6: Patient Global Impression of Change 
(PGIC) is a patient-reported survey that assesses the subject’s 
impression of change in on prurigo nodularis since the 
beginning of the study. Scoring ranges from 13: “very much 
improved” to 73: “very much improved worse.” 
Editorial alignment 
with Appendix 6. 
 

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