Conditions: Chronic Idiopathic Urticaria Chronic Idiopathic Pruritus Lichen Planus Lichen Simplex Chronicus Plaque Psoriasis
Keywords: pruritus, chronic pruritus, moderate to severe
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
Participants with diseases characterized by chronic pruritus experiencing moderate to severe pruritus will be enrolled in this pilot Phase 2 study.

The diseases characterized by chronic pruritus investigated in this pilot study currently include chronic idiopathic urticaria (CIU), chronic idiopathic pruritus (CIP), lichen planus (LP), lichen simplex chronicus (LSC) and plaque psoriasis (PPs).

Detailed description:

Arms:
arm 1: Weekly for 8 weeks arm 2: Weekly for 8 weeks

Interventions: intervention 1: KPL-716 intervention 2: Placebo
Intervention descriptions: intervention 1: A loading dose of KPL-716 720 mg (2x maintenance dose) administered via 2 subcutaneous (SC) injections within 30 minutes on Day 1. All subsequent doses of KPL-716 (360 mg maintenance dose) administered via a single SC injection. intervention 2: Placebo dose administered via 2 SC injections within 30 minutes on Day 1. All subsequent doses of placebo administered via a single SC injection.

Protocol document:
Prot_000.pdf: 


 
Protocol KPL-716-C202 
 
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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 
 
 
 
 
 
 
 
 
 
 








 
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28 January 2019 (Version 1.0) 
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pruritus in diseases characterized by chronic pruritus.  The following chronic pruritic diseases will 
be studied. 
 
Each cohort will be enrolled and analyzed independently:   
• 
Cohort 1: Chronic Idiopathic Urticaria (CIU) 
• 
Cohort 2: Chronic Idiopathic Pruritus (CIP) 
• 
Cohort 3: Lichen Planus (LP) 
• 
Cohort 4: Lichen Simplex Chronicus (LSC) 
• 
Cohort 5: Plaque Psoriasis (PPs) 
 
Each cohort will enroll approximately 26 subjects and contain three periods: 
• 
Screening Period (Day-28 to Day-1, minimum 14 days and maximum 28 days) 
• 
Treatment Period (Day 1 [Baseline] to Week 8) 
• 
Follow-up Period (After week 8 to Week 18) 
 
Allowable window for Week 1 is ±1 day and from Week 2 to Week 18 visits is ± 2 days. 
In every cohort, a loading dose of KPL-716 at 720 mg SC (or matching placebo) will be followed 
by maintenance doses of 360 mg SC (or matching placebo) administered every week for 7 additional 
weekly doses in order to detect an early signal of efficacy on pruritus once exposures approach an 
expected steady state.  In addition, the impact of KPL-716 on sleep and quality of life will be 
assessed.  Furthermore, the impact of KPL-716 on urticaria in CIU (Cohort 1) will be investigated.   
Each cohort will utilize a washout design in which concomitant therapies that could impact pruritus 
will be prohibited from a designated timepoint prior to dosing through the End of Study (EOS) Visit, 
thus removing the confounding effect of these therapies on the assessment of KPL-716 efficacy. 
Subjects who use a moisturizer cream/emollient will be instructed to use the same moisturizer 
cream/emollient at the same frequency throughout the study.  Only subjects with CIU (Cohort 1) 
will be allowed to use H1 antihistamines at approved stable doses from 14 days prior to dosing to 
EOS Visit.  The permitted H1 antihistamines for CIU will be outlined in the Pharmacy Manual.  
Should subjects in any cohort experience an exacerbation of symptoms that is significant enough to 
warrant intervention, they will be provided with H1 antihistamines and/or topical corticosteroids 
(TCS) as rescue medication.  The permitted rescue medications for each cohort will be outlined in 
the Pharmacy Manual.   
Accountability for rescue medications will be maintained by the sites. The date, time, and the 
number of antihistamine tablets will be recorded and the weight of TCS tubes will be measured at 
dispensation, at every visit, and upon return.  
Screening Period: 
After the Informed Consent Form (ICF) is signed, subjects will enter the Screening Period for 
assessment of eligibility.   
During the Screening Visit, subject’s medical and surgical history will be reviewed including 
allergic history.  Review of medical history will include the specific cohort disease history and 
history of co-morbidities.  Prior and concomitant medications, therapies and procedures will be 
recorded. Subjects will be instructed on the required washout for specific excluded medications. 


 
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Vital signs and body weight 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 for study participation, subjects must have moderate to severe pruritus, defined as 
WI-NRS ≥ 7 at the Screening Visit and a mean weekly WI-NRS ≥ 5 for each of the 2 consecutive 
weeks immediately prior to randomization.  A minimum of 85% compliance with daily WI-NRS 
recording during the last 14 days of Screening Period prior to randomization is required for 
eligibility unless approved by the Sponsor.   
At the Screening Visit, subjects will be asked to rate their pruritus severity (WI-NRS) in the 
previous 24 hours on a numerical rating scale.  Subjects also will be instructed to record their daily 
rating of WI-NRS and two sleep parameters, difficulty falling asleep NRS and sleep quality NRS, 
from the beginning of screening to Day 1.  The daily recordings (WI-NRS, difficulty falling asleep 
NRS, and sleep quality NRS) will continue throughout the study for eligible subjects that proceed 
to dosing.   
Furthermore, subjects with CIU will be instructed to also complete on a daily basis the UAS7 
questionnaire (on itch and hives severity) from the beginning of screening to Day 1.  Daily 
completion of the UAS7 questionnaire will continue throughout the study for eligible CIU subjects 
that proceed to dosing. 
Additional assessments at the Screening Visit include those related to pruritus (Pruritus VAS, and 
5-D Pruritus), sleep (Sleep Loss VAS) and quality of life (DLQI and ItchyQoL).    
Collection of adverse events and concomitant medications will begin after signing the ICF and will 
continue until the EOS Visit.  For a Schedule of Activities, please see Appendix 1. 
Treatment Period: 
The treatment period will last 8 weeks. 
Pre-dose: 
Eligibility must be confirmed prior to dosing on Day 1. Subjects will have the following 
procedures performed prior to dosing on Day 1:  
• 
Review of medical and surgical history 
• 
Review of prior and concomitant medications 
• 
Review of adverse events 
• 
Review of compliance with recording of daily WI-NRS 
• 
Review of clinical laboratory results from the Screening Visit 
• 
Full physical examination 
• 
Vital signs and weight 
• 
ECG (if more than 30 days since screening ECG) 
• 
Subjects will record their Pruritus VAS, Sleep Loss VAS and complete the 5-D Pruritus, 
DLQI and ItchyQoL questionnaires. 
• 
Collection of laboratory blood tests 
• 
Collection of urine for urinalysis 
• 
Pregnancy test (if applicable) 
• 
Collection of
 PK
 blood samples 








 
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4. 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: 
 
hormonal contraceptives associated with inhibition of ovulation 
(stable dose for at least 4 weeks prior to first dose) 
 
intrauterine device (IUD) 
 
intrauterine system (IUS) 
 
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 
5. 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.   
6. 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.  
7. Female subjects of childbearing potential must have a negative serum β-hCG test at the 
Screening Visit and negative urine pregnancy test on Day 1.  
8. 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. 
 
Exclusion criteria: 
 
1. Has used the following medications within the indicated timeframe prior to Day 1 or does 
not agree to refrain from the use of the medications throughout the study treatment and 
Follow up Period: 
a. Systemic corticosteroids (IV/IM/oral):  8 weeks for IV/IM, 4 weeks for oral; Note: 
Intranasal corticosteroids, eye drops containing corticosteroids, and inhaled 
corticosteroids for stable medical conditions are allowed.  
b. Intralesional corticosteroids and intra-articular corticosteroids:  8 weeks 
c. Topical treatments including but not limited to corticosteroids, calcineurin 
inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, capsaicin, camphor, 
polidocanol or tars:  2 weeks   
d. Antihistamines: 1 week 


 
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• Subjects with CIU (Cohort 1) may use H1 antihistamine at approved and 
stable doses.  The acceptable H1 antihistamines will be defined in the 
Pharmacy Manual   
e. Immunomodulators (for example, cyclosporine, 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 (JAK) inhibitors:  3 months 
j. 
Dupilumab and ustekinumab:  6 months 
k. Any other marketed biologic:  3 months or until cell numbers return to normal in 
case of depleting antibodies such as rituximab 
l. 
Any investigational biologic drug:  6 months 
m. Any investigational non-biologic drug:  3 months 
n. Phototherapy involving Ultraviolet A (UVA), Ultraviolet B (UVB), or excimer:  4 
weeks 
o. Tanning salon use:  4 weeks 
2. Has received any investigational biologic or non-biologic drug that targets Oncostatin M, 
IL-31, or IL-31 receptor α, or Oncostatin M receptor β in the past. 
3. Is currently using medication known to cause pruritus (e.g., angiotensin converting enzyme 
inhibitors) unless timing of onset of pruritus and initiation of medication do not suggest 
that pruritus was caused by the medication.   
4. Has a diagnosis of LP and is currently using medication known to cause lichenoid reaction 
(e.g., angiotensin converting enzyme inhibitors and/or beta blockers) unless timing of 
onset of lichenoid skin changes and initiation of medication do not suggest that lichenoid 
reaction was caused by the medication.   
5. Has less than 85% compliance with the daily WI-NRS tool during the last 14 days of the 
Screening Period prior to randomization, unless approved by the Sponsor.  
6. Has had a significant flare of pruritus and/or skin eruption during the Screening Period 
(prior to the study drug administration) that requires a medical intervention. 
7. Has any inflammatory, pruritic, and/or fibrotic skin condition other than the diagnosis that 
defines the cohort unless approved by the Sponsor. For example:   
a. Has urticarial vasculitis, urticaria pigmentosa, systemic mastocytosis, familial cold 
urticaria or hereditary or acquired angioedema due to C1 inhibitor deficiency. 
b. Has a clear cause of urticaria including but not limited to cold, heat, solar, 
pressure, and delayed pressure.  Has contact urticaria, aquagenic urticaria or 
cholinergic urticaria.   
c. Has pustular psoriasis, erythrodermic/exfoliative psoriasis, drug-induced psoriasis, 
or psoriatic arthritis 
d. Has atopic dermatitis 
8. Has significant severe xerosis that persists despite the regular use of an emollient unless 
approved by the Sponsor. 


 
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9. Has uncontrolled hyperthyroidism or hypothyroidism.  Has insulin-dependent diabetes or 
uncontrolled diabetes defined as hemoglobin A1c >7.5%.   
10. Has had cancer or lymphoproliferative disease within 5 years prior to Day 1 
11. Has had any autoimmune disorder other those under investigation in this study 
12. Has had a severe allergic reaction to any foods or medications including anaphylactic 
reactions unless approved by the Sponsor.    
13. Has had systemic amyloidosis 
14. Has had immune deficiency, or opportunistic infections  
15. Has positive results for hepatitis B surface antigen (HbsAg) 
16. Has positive results for hepatitis B anti-core antibody (anti-HBc) but negative results for 
anti-surface antibody (anti-HBs) 
17. Has positive results for hepatitis C antibody 
18. Has human immunodeficiency virus (HIV) infection or positive HIV serology  
19. Has psychiatric illness other than stable mild to moderate anxiety and/or depression unless 
approved by the Sponsor   
20. Has been hospitalized for a psychiatric illness   
21. Has laboratory abnormalities that fall outside the windows below at the Screening Visit: 
a. Alanine aminotransferase > 1.5 x Upper limit of normal (ULN) 
b. Aspartate aminotransferase > 1.5 x ULN 
c. Gamma-glutamyl transferase > 1.5 x ULN 
d. Blood bilirubin > 1.25 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 <120,000/ µl  
g. Creatinine > 1.25 x ULN 
22. Has a body mass index (BMI) of <16 kg/m2 or >38 kg/m2 
23. Has systolic blood pressure above 150 mm Hg, diastolic blood pressure above 95 mm Hg 
at the Screening Visit or Day 1 (confirmed by repeat measurement).   
24. Has been hospitalized within 12 weeks prior to Day 1 
25. Has had major surgery within 12 weeks prior to Day 1 or has a major surgery planned 
during the study 
26. Has had an active infection including skin infection, requiring systemic treatment within 4 
weeks and/or topical treatment within 2 weeks of Day 1.  Has an active or chronic parasitic 
infection.  
27. Has any medical (heart, lung, kidney, liver, metabolic) 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.  
28. Has received a live attenuated vaccine within 12 weeks prior to Day 1 


 
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29. Has previously taken part in or withdrawn from this study or has previously received the 
study drug.  Screen failures may be rescreened at the discretion of the Investigator. 
30. Has a known hypersensitivity to KPL-716 or its excipients 
31. 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 
32. Has a positive urine drug screen for opiates, opioids, methadone, cocaine, phencyclidine, 
or amphetamines at the Screening Visit.  Exceptions may be made if a subject is on a 
Sponsor-approved medication for a stable concomitant condition that explains the positive 
drug screen result. 
33. Has received blood products within 8 weeks prior to Day 1 
34. Has donated blood within 12 weeks prior to Day 1, platelets within 10 weeks prior to Day 
1, or plasma within 6 weeks prior to Day 1 
Statistical Methods:  
All clinical study data will be presented in subject data listings.  Descriptive statistics will be 
presented for all endpoints and will include number of subjects (n), mean, standard deviation (SD), 
first quartile (Q1), median, third quartile (Q3), minimum and maximum for continuous variables, 
and frequency and percentage for categorical and ordinal variables.  
Statistical analyses of efficacy endpoints will be conducted separately for each cohort.   
 
Determination of Sample Size: 
This is a double-blind study.  Each cohort will be independently analyzed.  A total of 
approximately 26 subjects will be randomized in each cohort. The first 12 subjects will be 
randomized to the KPL-716 and the placebo arms in a 3:1 randomization ratio. The rest of the 14 
subjects will be randomized in a 1:1 randomization ratio.  There will be approximately 16 subjects 
and 10 subjects randomized to the KPL-716 arm and the placebo arm respectively. Based on a two-
sample t-test for the primary efficacy endpoint, change from baseline in weekly average of WI-
NRS at Week 8, assumed mean changes of 4 for the KPL-716 arm and 1.5 for the placebo arm, a 
total sample size of 26 subjects per cohort will provide about 80% power to detect a 2.5-point 
mean difference with a standard deviation of 2.8, given a two-sided alpha of 0.2.  Given the 
exploratory nature of this pilot study, the precision attained with the above cohort samples size is 
acceptable for early signal of efficacy assessments.  
 
Safety Analysis Set: 
All randomized subjects who take at least 1 dose of KPL-716 or placebo will be included in the 
Safety Analysis Set.  
 
Modified Intent-to-Treat (mITT) Analysis Set: 
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.   
 




 
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not involved with the conduct of the study.  Investigators and subjects will remain blinded to 
treatment assignment until after database lock and completion of clinical study report (CSR) as 
defined in the SAP. Details of the unblinded interim analysis plan will be specified in the SAP.   


 
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Figure 1 
Cohort Study Design Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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4.7 
Subject Number and Identification ................................................................. 43 
4.8 
Subject Withdrawal and Replacement ........................................................... 43 
4.9 
Study Termination or Temporary Suspension ............................................... 44 
5 
STUDY TREATMENTS ........................................................................................... 45 
5.1 
Description, Storage, Packaging, and Labeling .............................................. 45 
5.2 
Study Treatment Administration .................................................................... 45 
5.3 
Randomization ................................................................................................. 46 
5.4 
Blinding ............................................................................................................ 46 
5.5 
Study Treatment Compliance ......................................................................... 46 
5.6 
Study Drug Accountability .............................................................................. 47 
6 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ........................ 48 
6.1 
Concomitant Medications ................................................................................ 48 
6.2 
Blood Donation ................................................................................................ 49 
6.3 
Contraception .................................................................................................. 49 
7 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 50 
7.1 
Pharmacokinetic Assessments ......................................................................... 50 
7.1.1 
Pharmacokinetic Blood Sample Collection and Processing ....................... 50 
 
 
 
 
7.3 
Clinical Response Assessments ........................................................................ 50 
7.3.1 
Daily NRS Tool ....................................................................................... 50 
7.3.2 
Pruritus Visual Analog Scale (Pruritus VAS) ........................................... 51 
7.3.3 
Sleep loss Visual Analog Scale (Sleep Loss VAS).................................... 51 
7.3.4 
Weekly Urticaria Activity Score (UAS7).................................................. 51 
7.3.5 
5-D Pruritus Scale .................................................................................... 51 
7.3.6 
Dermatology Life Quality Index ............................................................... 51 
7.3.7 
ItchyQoL questionnaire ............................................................................ 52 
 
 
 
 
 
 
7.5 
Safety and Tolerability Assessments ............................................................... 52 
7.5.1 
Adverse Events ........................................................................................ 52 
7.5.2 
Clinical Laboratory Evaluations ............................................................... 56 
7.5.3 
Vital Signs ............................................................................................... 57 
7.5.4 
12-Lead Electrocardiogram ...................................................................... 57 
7.5.5 
Physical Examination ............................................................................... 57 
7.6 
Committees....................................................................................................... 58 
7.6.1 
Safety Review Committee (SRC) ............................................................. 58 
8 
SAMPLE SIZE AND DATA ANALYSES ............................................................... 59 
8.1 
Statistical Methods ........................................................................................... 59 




 
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12.3 
Finances and Insurance ................................................................................... 67 
13 REFERENCES .......................................................................................................... 68 
14 APPENDICES ........................................................................................................... 71 
14.1 
Appendix 1: Schedule of Activities .................................................................. 71 
14.2 
Appendix 2: Clinical Laboratory Tests ........................................................... 76 
14.3 
Appendix 3: Total Blood Volume .................................................................... 77 
 
 


 
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LIST OF IN-TEXT FIGURES  
Figure 1 
Cohort Study Design Diagram ................................................................ 17 
Figure 2 
Treatment Assignment Design Diagram ................................................. 46 
 
  
 
 
 
 
 
 




 
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Q 
Quartile 
QA 
Quality Assurance 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SOC 
System Organ Class 
TCS 
topical corticosteroids 
TEAE 
treatment-emergent adverse event 
UAS7 
Urticaria Activity Score/over 7 days 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WI-NRS 
Worst Itch Numeric Rating Scale 
  
 


 
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1 
INTRODUCTION 
1.1 
Background 
Chronic pruritus, defined as pruritus lasting for more than 6 weeks, is a common and often 
debilitating condition associated with a wide range of diagnoses.1   In chronic idiopathic 
urticaria (CIU), also called chronic spontaneous urticaria, chronic pruritus occurs in the 
context of recurrent hives that have no identifiable triggers.2  Chronic pruritus is the defining 
feature of chronic idiopathic pruritus (CIP), which disproportionately affects the elderly.3  
Patients with lichen planus (LP) experience chronic pruritus along with polygonal, flat-
topped, violaceous papules and plaques.4   Lichenified plaques develop on accessible body 
areas in response to constant rubbing from intense chronic pruritus in lichen simplex 
chronicus (LSC).5  Chronic pruritus affects up to 60-90% of patients with plaque psoriasis 
(PPs) who present with symmetrical, erythematous, silvery and scaly plaques commonly 
located on scalp, trunk, and extremities.6, 7    
Chronic pruritus is estimated to occur in approximately 20% (lifetime prevalence) of the 
population.1   Diagnoses associated with chronic pruritus are common diagnoses that affect a 
large number of patients.  The prevalence of CIU is estimated at up to 1%8, LP at 0.22 to 
5%9, LSC up to 12%10 and psoriasis up to 4% in Western Countries11. CIP is estimated to 
occur in 11.5 to 41% in the elderly.12 Chronic pruritus leads to lack of sleep, fatigue, 
diminished productivity, anxiety, depression and overall diminished quality of life.   
Inflammatory cell infiltration and hyperkeratosis are common features seen in skin biopsies 
of patients with chronic pruritus.  Histologic examination of skin biopsies from CIU patients 
demonstrates lymphocytes, eosinophils, neutrophils, basophils, mast cells (also increased in 
non-lesional skin), and activated macrophages.13  In patients with CIP, lymphocytic infiltrates 
are seen in the absence of inflammatory skin lesions.3   LP lesional biopsies show lysis of 
basal keratinocytes by CD8+ lymphocytes and IL-31 expression.14, 15  Epidermal hyperplasia, 
orthokeratosis, and hypergranulosis with lymphocytic perivascular infiltrates are common 
features of LSC.5  Psoriatic skin biopsies characteristically show perivascular and dermal 
inflammatory cell infiltration, parakeratosis, suprapapillary thinning, spongiform pustules, 
microabscess, and edema of the dermal papillae.16  
Chronic pruritus is treated with H1 non-sedating antihistamines as first line therapy.  In non-
responsive patients, sedating antihistamines such as hydroxyzine or doxepin, topical 
corticosteroid, and leukotriene receptor antagonists and topical calcineurin inhibitors may be 
tried.  In refractory disease, immunomodulatory agents such as cyclosporin and phototherapy 
are used.   Neuroactive medications such as gabapentin, anti-depressants, capsaicin, opioid 
agonists and antagonists are used in CIP with limited success. 17, 18, 19 Biologic therapy is 
available for the most severe patients with CIU (omalizumab) and psoriasis (adalimumab, 
etanercept, and infliximab,).7, 20   Despite the availability of a large range of medications with 
variety of mechanisms of action, chronic pruritus remains a significant unmet medical need 
due to poor response to treatment or unacceptable side effects.  Many patients with CIU, for 
example, remain symptomatic or are unwilling to tolerate or risk the adverse effects of 
cyclosporine (renal toxicity) and omalizumab (black box warning for omalizumab: 
anaphylaxis).   


 
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The primary objective of this study is to investigate the efficacy of KPL-716 in reducing 
pruritus in patients with chronic pruritic diseases experiencing moderate to severe pruritus.  
The secondary objectives are to investigate the impact of KPL-716 on sleep loss and quality 
of life.  Clinical response 
will be used to understand whether KPL-716 
responsiveness is limited to a specific subset of patients with chronic pruritus. 
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). 
1.2.1 
In Vivo 
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 final 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 M 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
, KPL-716 
simultaneously inhibits signaling of IL-31 and OSM, two (2) cytokine pathways important in 
pruritus, inflammation, hyperkeratosis and fibrosis.  KPL-716 does not inhibit signaling of 
OSM down the Leukemia Inhibitory Factor Receptor (LIFR) pathway, a pathway implicated 
in hematopoiesis and platelet synthesis.21  
KPL-716 via its dual pathway mechanism is predicted to reduce pruritus in chronic pruritic 
diseases and potentially modulate many aspects of disease pathology related to inflammation, 
hyperkeratosis and fibrosis.  A clinical effect on pruritus intensity is anticipated at therapeutic 
doses based on the Phase 1b study results (Protocol KPL-716-C001).  The targeted nature of 
the KPL-716 mechanism of action is expected to offer safety advantages compared to 
immunosuppressive therapies as well as systemic and topical corticosteroids.   


 
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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.22, 23  The published literature suggests 
that IL-31 plays a role in many chronic pruritic diseases.  Serum IL-31 levels are elevated in 
CIU patients compared to healthy controls and IL-31 levels decrease upon successful 
treatment of CIU.24   Similarly, serum IL-31 levels are increased in patients with psoriasis 
and levels decrease after UVB irradiation with treatment response.25   IL-31 levels are also 
elevated in patients with LP although pruritus intensity does not appear to correlate with IL-
31 levels in this disease.15   Despite absence of a primary dermatologic process in CIP, 
histologic analysis of CIP skin demonstrates lymphocytic and, in many cases, eosinophilic 
infiltration, accompanied by increased IgE and peripheral blood eosinophilia pointing to TH2 
polarization as a potential source of IL-31.3   Chronic scratching, disruption of epidermal 
barrier function, staphylococcal colonization and subsequent staphylococcal enterotoxin B 
production promote IL-31 production26 and may ultimately contribute to the itch-scratch 
cycle that underlies many chronic pruritic diseases such as atopic dermatitis and LSC.   
OSM, the other cytokine pathway inhibited by KPL-716, has been shown to play a role in 
inflammation, epidermal integrity and fibrosis, three (3) pathways important in many pruritic 
dermatologic disorders.  OSM increases the production of IL-4Rα and IL-13Rα. 27,  28, 29, 30, 31, 
32 OSM also increases IL-4 production and synergizes with IL-4 and IL-13 to upregulate 
downstream signaling events such as eotaxin production.27, 29, 30, 31, 32, 33  Similarly, OSM 
synergizes with IL-17 and increases CCL2 and IL-6 production.32  OSM impacts epidermal 
barrier function by modulating genes important in keratinocyte activation and 
differentiation.27, 28  Finally, OSM levels are increased in fibrotic diseases and OSM over 
expression in animal models has been shown to result in fibrotic changes.30, 34 
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 a variety of chronic pruritic conditions (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).   
This double-blind Phase 2 pilot study will utilize a washout design and enroll subjects with a 
physician-documented diagnosis of diseases characterized by chronic pruritus, including at 
this time CIU, CIP, LP, LSC, or PPs, of at least 6 months duration.  The study will enroll 
subjects with moderate to severe pruritus, defined as WI-NRS ≥ 7 at the Screening Visit and 
a mean weekly WI-NRS ≥ 5 for the 2 consecutive weeks immediately prior to randomization.  
Given the early stage of KPL-716 development, subjects will be excluded if they have co-
morbidities that would complicate interpretation of safety data such as infections, 
malignancies, and rheumatologic diseases.   
Ultimately, the data from this pilot study will help establish the range of chronic pruritic 
diseases responsive to KPL-716, so that future larger studies may then be conducted for 
further assessment of the impact of KPL-716 on pruritus and other disease manifestations.   










 
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4 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This Phase 2 pilot study is comprised of multiple cohorts each for a different study population.  
Each cohort is an independent randomized, double-blind, placebo-controlled sub-study to 
investigate the efficacy, safety, tolerability, PK and immunogenicity of KPL-716 administered 
SC in reducing pruritus in diseases characterized by chronic pruritus.  The following chronic 
pruritic diseases will be studied.  
• Cohort 1: Chronic Idiopathic Urticaria (CIU) 
• Cohort 2: Chronic Idiopathic Pruritus (CIP) 
• Cohort 3: Lichen Planus (LP) 
• Cohort 4: Lichen Simplex Chronicus (LSC) 
• Cohort 5: Plaque Psoriasis (PPs) 
Each cohort will be enrolled and analyzed independently.   
 
Each cohort will enroll up to 26 subjects and contain three periods: 
• Screening Period (Day-28 to Day-1, minimum 14 days and maximum 28 days) 
• Treatment Period (Day 1 [Baseline] to Week 8) 
• Follow-up Period (After week 8 to Week 18) 
 
Allowable window for Week 1 is ± 1 day and from Week 2 to Week 18 visits is ±2 days. 
In every cohort, a loading dose of KPL-716 at 720 mg SC (or matching placebo) will be 
followed by maintenance doses of 360 mg SC (or matching placebo) administered every week 
for 7 additional weekly doses in order to detect an early signal of efficacy on pruritus once 
exposures approach an expected steady state.  In addition, the impact of KPL-716 on sleep and 
quality of life will be assessed.  Furthermore, the impact of KPL-716 on urticaria in CIU 
(Cohort 1) will be investigated.   
Each cohort will utilize a washout design in which concomitant therapies that could impact 
pruritus will be prohibited from a designated timepoint prior to dosing through the End of Study 
(EOS) Visit, thus removing the confounding effect of these therapies on the assessment of 
KPL-716 efficacy. Subjects who use a moisturizer cream/emollient will be instructed to use 
the same moisturizer cream/emollient at the same frequency throughout the study.  Only 
subjects with CIU (Cohort 1) will be allowed to use H1 antihistamines at approved stable doses 
from 14 days prior to dosing to EOS Visit.  The permitted H1 antihistamines for CIU will be 
outlined in the Pharmacy Manual.  Should subjects in any cohort experience an exacerbation 
of symptoms that is significant enough to warrant intervention, they will be provided with H1 
antihistamines and/or topical corticosteroids (TCS) as rescue medication.  The permitted rescue 
medications for each cohort will be outlined in the Pharmacy Manual.   
Accountability for rescue medications will be maintained by the sites. The date, time, and the 
number of antihistamine tablets will be recorded and the weight of TCS tubes will be 
measured at dispensation, at every visit, and upon return.  


 
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4.1.1 
Screening Period  
After the informed consent form (ICF) is signed, subjects will enter the Screening Period for 
assessment of eligibility.   
During the Screening Visit, subject’s medical and surgical history will be reviewed including 
allergic history.  Review of medical history will include the specific cohort disease history and 
history of co-morbidities.  Prior and concomitant medications, therapies and procedures will 
be recorded.  Subjects will be instructed on the required washout for specific excluded 
medications. 
Vital signs and body weight 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 for study participation, subjects must have moderate to severe pruritus, defined 
as WI-NRS ≥ 7 at the Screening Visit and a mean weekly WI-NRS ≥ 5 for each of the two 
consecutive weeks immediately prior to randomization.  A minimum of 85% compliance with 
daily WI-NRS recording during the last 14 days of Screening Period prior to randomization is 
required for eligibility unless approved by the Sponsor.   
At the Screening Visit, subjects will be asked to rate their pruritus severity (WI-NRS) in the 
previous 24 hours on a numerical rating scale.  Subjects also will be instructed to record their 
daily rating of WI-NRS and two sleep parameters, difficulty falling asleep NRS and sleep 
quality NRS, from the beginning of screening to Day 1.  The daily recordings (WI-NRS, 
difficulty falling asleep NRS, and sleep quality NRS) will continue throughout the study for 
eligible subjects that proceed to dosing.   
Furthermore, subjects with CIU will also be instructed to complete on a daily basis the UAS7 
questionnaire (on itch and hives severity) from the beginning of screening to Day 1.  Daily 
completion of the UAS7 questionnaire will continue throughout the study for eligible CIU 
subjects that proceed to dosing. 
Additional assessments at the Screening Visit include those related to pruritus (Pruritus VAS, 
and 5-D Pruritus), sleep (Sleep Loss VAS), dermatology life quality index (DLQI) and Itchy 
quality of life (ItchyQoL).    
Collection of adverse events and concomitant medications will begin after signing the ICF and 
will continue until the EOS Visit.  For a Schedule of Activities, please see Appendix 1. 
 
4.1.2 
Treatment Period  
The treatment period will last 8 weeks. 
4.1.2.1 
Pre-dose  
Eligibility must be confirmed prior to dosing on Day 1. 
Subjects will have the following procedures performed prior to dosing on Day 1:  
• Review of medical and surgical history 
• Review of prior and concomitant medications 


 
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• Review of adverse events 
• Review of compliance with recording of daily WI-NRS 
• Review of clinical laboratory results from the Screening Visit 
• Full physical examination 
• Vital Signs and weight 
• ECG (if more than 30 days since screening ECG) 
• Subjects will record their Pruritus VAS, Sleep Loss VAS and complete the 5-D 
Pruritus, DLQI and ItchyQoL questionnaires 
• Collection of laboratory blood tests 
• Collection of urine for urinalysis 
• Pregnancy test (if applicable) 
 
 
 
 
Upon confirmation of subject eligibility and completion of required activities (Appendix 1), 
the subject will proceed to dosing.    
4.1.2.2 
Randomization and Dosing  
A loading dose of KPL-716 720 mg (2x maintenance dose) or matching placebo will be 
administered via two (2) SC injections within 30 minutes on Day 1 by the Investigator or 
qualified designee at the study sites.   
All subsequent doses of KPL-716 (360 mg maintenance dose) or matching placebo will be 
administered by the Investigator or qualified designee at the study sites via a single SC 
injection.   
All procedures assigned to dosing days are performed prior to study drug administration.  The 
following activities will take place prior to each maintenance dose: 
• Review of concomitant medications, therapies and procedures 
• Review of adverse events 
• Review of subject compliance 
• Vital signs (performed before and after dosing on each dosing day) 
• Completion of Pruritus VAS, Sleep Loss VAS 
• Blood collection for PK 
 
The following activities will take place prior to maintenance dosing at designated study visits 
as outlined in Appendix 1: 
• Physical examination  
• Collection of safety blood and urine samples 






 
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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 µg/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 two study populations. In both 
populations, as dose increased, half-life also increased consistent with a TMDD proﬁle.  
Furthermore, bioavailability between healthy volunteers and atopic dermatitis 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 other chronic pruritic conditions (such as CIU, CIP, 
LP, LSC and PPs) will also follow the same patterns.   
The weekly SC dosing regimen is proposed to ensure subsequent doses are administered 
before a significant decline in blood concentrations has occurred so as to reach initial KPL-
716 exposure levels similar to those achieved with 7.5 mg/kg IV as a single dose. A loading 
dose of 720 mg is administered in this Phase 2 pilot study in order to achieve blood 
concentrations that are likely to provide clinical benefit sooner in particular given the short 
treatment duration of this exploratory study.  720 mg was chosen for the loading dose since 
the peak concentration levels from this dose are anticipated to be less than those achieved by 
7.5 mg/kg IV, which showed acceptable safety and tolerability in the single dose study. A 
loading dose that is twice maintenance is typical, in particular to minimize risk of dosing 
errors.  Based on PK modeling, the expected Cmax and Ctrough from a loading dose of 720 mg 
SC followed by 7 weekly SC doses at 360 mg, the proposed regimen in this Phase 2 pilot 
study, are expected to be similar to those anticipated with 12 weekly doses of 360 mg SC, 
which has shown acceptable safety and tolerability to date in KPL-716-C001 Part 4.   
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 (total of 8) and the dose levels (720 mg loading dose and 
360 mg maintenance dose or 10 mg/kg and 5 mg/kg in a 72 kg adult, respectively) in this 
Phase 2a study fall well under 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 32 subjects with atopic dermatitis 
(Part 1) were exposed to single doses of KPL-716 or placebo IV or SC. There were no deaths, 
SAEs, or discontinuations due to AEs.  There were no infusion reactions or injection site 
reactions.  Drug-related or possibly related treatment-emergent AEs were infrequent.  In Part 
4 of KPL-716-C001 (repeated-single-dose study), subjects with moderate to severe atopic 
dermatitis experiencing moderate to severe pruritus are being randomized 1:1 and 
administered KPL-716 360 mg or placebo SC once weekly for a total of 12 doses. Based on 
PK modeling, steady state exposures should be achieved after approximately 5 doses of 360 
mg SC. To date, 30 subjects have been randomized in Part 4, 28 have received at least 1 dose 




 
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4.6 
Selection of Study Population 
4.6.1 
Inclusion Criteria 
1. Male or female, aged 18 to 75 years, inclusive, at the time of consent. 
2. Has a physician-documented diagnosis of the specified chronic pruritic disease.  
Duration of disease must be at least 6 months.  The study dermatologist or the study 
allergist/immunologist confirms the diagnosis of the specified chronic pruritic disease.  
The duration of disease (at least 6 months) can be documented as affirmed by the 
subject.  
• Pruritus associated with these diagnoses must be refractory to treatment with 
H1 antihistamines and must have been present for at least 6 weeks prior to 
Day 1   
• Subjects with CIU must have had pruritus and hives for at least 6 consecutive 
weeks prior to Day 1.  In subjects with CIU, urticarial eruptions must typically 
last less than 24 hours 
3. Has moderate to severe pruritus, defined as WI-NRS ≥ 7 at the Screening Visit and a 
mean weekly WI-NRS ≥ 5 for each of the two consecutive weeks immediately prior 
to randomization.  
4. 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: 
 hormonal contraceptives associated with inhibition of ovulation 
(stable dose for at least 4 weeks prior to first dose) 
 intrauterine device (IUD) 
 intrauterine system (IUS) 
 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 


 
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5. 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.   
6. 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.  
7. Female subjects of childbearing potential must have a negative serum β-hCG test at 
the Screening Visit and negative urine pregnancy test on Day 1.  
8. 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. 
4.6.2 
Exclusion Criteria 
1. Has used 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 
treatment and follow up period: 
a. Systemic corticosteroids (IV/IM/oral):  8 weeks for IV/IM, 4 weeks for oral; 
Note: Intranasal corticosteroids, eye drops containing corticosteroids, and 
inhaled corticosteroids for stable medical conditions are allowed.  
b. Intralesional corticosteroids and intra-articular corticosteroids:  8 weeks 
c. Topical treatments including but not limited to corticosteroids, calcineurin 
inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, capsaicin, 
camphor, polidocanol or tars:  2 weeks   
d. Antihistamines: 1 week 
• Subjects with CIU (Cohort 1) may use H1 antihistamine at approved 
and stable doses.  The acceptable H1 antihistamines will be defined in 
the Pharmacy Manual   
e. Immunomodulators (for example, cyclosporine, 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 (JAK) inhibitors:  3 months 
j. Dupilumab and ustekinumab:  6 months 
k. Any other marketed biologic:  3 months or until cell numbers return to normal 
in case of depleting antibodies such as rituximab 
l. Any investigational biologic drug:  6 months 


 
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m. Any investigational non-biologic drug:  3 months 
n. Phototherapy involving Ultraviolet A (UVA), Ultraviolet B (UVB), or 
excimer:  4 weeks 
o. Tanning salon use:  4 weeks 
2. Has received any investigational biologic or non-biologic drug that targets Oncostatin 
M, IL-31, or IL-31 receptor α, or Oncostatin M receptor β in the past. 
3. Is currently using medication known to cause pruritus (e.g., angiotensin converting 
enzyme inhibitors) unless timing of onset of pruritus and initiation of medication do 
not suggest that pruritus was caused by the medication.   
4. Has diagnosis of LP and is currently using medication known to cause lichenoid 
reaction (e.g., angiotensin converting enzyme inhibitors and/or beta blockers) unless 
timing of onset of lichenoid skin changes and initiation of medication do not suggest 
that lichenoid reaction was caused by the medication.   
5. Has less than 85% compliance with the daily WI-NRS tool during the last 14 days of 
the Screening Period prior to randomization, unless approved by the Sponsor.  
6. Has had a significant flare of pruritus and/or skin eruption during the Screening 
Period (prior to the study drug administration) that requires a medical intervention. 
7. Has any inflammatory, pruritic, and/or fibrotic skin condition other than the diagnosis 
that defines the cohort unless approved by the Sponsor.   
a. Has urticarial vasculitis, urticaria pigmentosa, systemic mastocytosis, familial 
cold urticaria or hereditary or acquired angioedema due to C1 inhibitor 
deficiency. 
b. Has a clear cause of urticaria including but not limited to cold, heat, solar, 
pressure, and delayed pressure.  Has contact urticaria, aquagenic urticaria or 
cholinergic urticaria.   
c. Has pustular psoriasis, erythrodermic/exfoliative psoriasis, drug-induced 
psoriasis, or psoriatic arthritis 
d. Has atopic dermatitis 
8. Has significant severe xerosis that persists despite the regular use of an emollient 
unless approved by the Sponsor. 
9. Has uncontrolled hyperthyroidism or hypothyroidism.  Has insulin dependent diabetes 
or uncontrolled diabetes defined as hemoglobin A1c >7.5%   
10. Has had cancer or lymphoproliferative disease within 5 years prior to Day 1 
11. Has had any autoimmune disorder other those under investigation in this study 
12.  Has had a severe allergic reaction to any foods or medications including anaphylactic 
reactions unless approved by the Sponsor 


 
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13. Has had systemic amyloidosis 
14. Has had immune deficiency, or opportunistic infections  
15. Has positive results for hepatitis B surface antigen (HbsAg) 
16. Has positive results for hepatitis B anti-core antibody (anti-HBc) but negative results 
for anti-surface antibody (anti-HBs) 
17. Has positive results for hepatitis C antibody 
18. Has human immunodeficiency virus (HIV) infection or positive HIV serology  
19. Has psychiatric illness other than stable mild to moderate anxiety and/or depression 
unless approved by the Sponsor   
20. Has been hospitalized for a psychiatric illness   
21. Has laboratory abnormalities that fall outside the windows below at the Screening 
Visit: 
a. Alanine aminotransferase > 1.5 x Upper limit of normal (ULN) 
b. Aspartate aminotransferase > 1.5 x ULN 
c. Gamma-glutamyl transferase > 1.5 x ULN 
d. Blood bilirubin > 1.25 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 <120,000/ µl  
g. Creatinine > 1.25 x ULN 
22. Has a body mass index (BMI) of <16 kg/m2 or >38 kg/m2 
23. Has systolic blood pressure above 150 mm Hg, diastolic blood pressure above 95 mm 
Hg at the Screening Visit or Day 1 (confirmed by repeat measurement).   
24. Has been hospitalized within 12 weeks prior to Day 1 
25. Has had major surgery within 12 weeks prior to Day 1 or has a major surgery planned 
during the study 
26. Has had an active infection including skin infection, requiring systemic treatment 
within 4 weeks and/or topical treatment within 2 weeks of Day 1.  Has an active or 
chronic parasitic infection.  
27. Has any medical (heart, lung, kidney, liver, metabolic) 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 


 
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assessments, affect compliance with study requirements, or complicate interpretation 
of study results.  
28. Has received a live attenuated vaccine within 12 weeks prior to Day 1 
29. Has previously taken part in or withdrawn from this study or has previously received 
the study drug.  Subjects may be rescreened if they have failed the Screening Period. 
30. Has a known hypersensitivity to KPL-716 or its excipients 
31. 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. 
32. Has a positive urine drug screen for opiates, opioids, methadone, cocaine, 
phencyclidine, or amphetamines at the Screening Visit.  Exceptions may be made if a 
subject is on a Sponsor-approved medication for a stable concomitant condition that 
explains the positive drug screen result. 
33. Has received blood products within 8 weeks prior to Day 1 
34. Has donated blood within 12 weeks prior to Day 1, platelets within 10 weeks prior to 
Day 1, or plasma within 6 weeks prior to Day 1 
4.7 
Subject Number and Identification 
Each subject that signs the ICF and enters the Screening Visit will be assigned a unique 
number.  The study sites 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 the study sites 
and included in the electronic Case Report Form (e-CRF).  
 
4.8 
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 study drug and withdraw subjects from the study for any of the 
following reasons: 
• Adverse event 
• Life threatening or other unacceptable toxicity 
• Subject requires use of a prohibited concomitant medication or therapy 
• General or specific changes in the subject’s condition unacceptable for further 
treatment within the study parameters, in the Investigator’s opinion 








 
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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 an 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 or until permission to destroy has been received by the 
Sponsor. 
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 study sites with drug destruction 
standard operating procedures and written Sponsor approval. 
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 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 including but not limited to corticosteroids, calcineurin 
inhibitors, phosphodiesterase inhibitors, retinoids, calcipotriol, capsaicin, 
camphor, polidocanol or tars  
d. Antihistamines 
• Subjects with CIU (Cohort 1) may use H1 antihistamine at approved 
and stable doses.  The acceptable H1 antihistamines will be defined in 
the Pharmacy Manual   
e. Immunomodulators (for example, cyclosporine, methotrexate, retinoids, 
azathioprine, mycophenolate, and thalidomide) 
f. Neuroactive drugs such as gabapentin and pregabalin 
g. Cannabinoids 
h. Opioid antagonists or agonists  
i. Janus Kinase (JAK) inhibitors 
j. Dupilumab and ustekinumab 
k. Any other marketed biologic 
l. Any investigational biologic drug 
m. Any investigational non-biologic drug 
n. Phototherapy involving UVA, UVB, or excimer 
o. Tanning salon use  
Topical corticosteroids and antihistamines may be provided in consultation with the Sponsor 
as rescue medications for an exacerbation of symptoms that is significant enough to warrant 
intervention.  


 
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For further details refer to the Pharmacy Manual. 
6.2 
Blood Donation 
Subjects are restricted from receiving blood or donating blood from Day 1 to the EOS Visit. 
6.3 
Contraception 
Nonpregnant, nonlactating sexually active women of child bearing 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 (IUD) 
o intrauterine system (IUS) 
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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and 10 indicating extremely difficult.  This NRS will be used to assess subjects’ level of 
difficulty falling asleep from the Screening Visit through EOS Visit (Week 18).  The 
difficulty falling asleep NRS is provided in the Daily NRS Tool Appendix 4. 
7.3.1.3 
Quality of Sleep Numerical Rating Scale 
Subjects will be asked to assign a numerical score to the quality of their sleep in the previous 
night using a scale from 0 to 10, with 0 indicating best possible sleep and 10 indicating worst 
possible sleep.  This NRS tool will be used to assess subjects’ quality of sleep from the 
Screening Visit through the EOS Visit (Week 18).  The sleep quality NRS is provided in the 
Daily NRS Tool Appendix 4. 
7.3.2 
Pruritus Visual Analog Scale (Pruritus VAS) 
Subjects will be asked to place a line perpendicular to the VAS line at the point that 
represents the intensity of their average pruritus experienced over the previous three days 
using a scale from 0 to 10, with 0 indicating no pruritus and 10 indication the worst 
imaginable pruritus.35  The Pruritus VAS is administered at every visit.  
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 three 
nights using a scale from 0 to 10, with 0 indicating no sleeplessness and 10 indicating the 
worst imaginable sleeplessness .35  The Sleep Loss VAS is administered at every visit.  
7.3.4 
Weekly Urticaria Activity Score (UAS7) 
The UAS is a daily self-assessment tool that evaluates the number of wheals and the intensity 
of subject’s pruritus.  It is graded from 0 to 3 for each parameter and is summed over seven 
consecutive days to obtain the UAS7 Score with a maximum score of 42.  The greater the 
severity of the disease the higher the score. The UAS7 tool will be completed only by 
subjects in the CIU Cohort.  The tool will be used from the Screening Visit through the EOS 
Visit (Week 18).36 
7.3.5 
5-D Pruritus Scale 
The 5-D Pruritus Scale evaluates pruritus in five domains: duration, degree, direction, 
disability and distribution.  Duration, degree and direction each consist of one item.  The 
disability domain contains four items and the distribution domain includes 16 items.  The first 
four domains are measured on a five-point Likert scale.  The scores from each domain are 
added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe 
pruritus).37  The 5-D Pruritus Scale is administered every two (2) visits. 
7.3.6 
Dermatology Life Quality Index   
The DLQI is a 10-question questionnaire that considers symptoms and feelings, daily 
activities, leisure, school, personal relationships, and treatment.  Each question is answered 
on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a lot, and 3 for very much) or with a 
yes or no, taking into account the previous week.  The scores are added with minimum of 0 




 
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An adverse event (AE) is any untoward medical occurrence in a 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 (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 and abnormal laboratory findings considered by the reporting investigator to be 
clinically significant. 
A 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 (Week 18). 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 (Week 
18). 
All non-serious AEs, whether volunteered, elicited, or noted on the physical examination, and 
serious adverse events (SAEs) will be recorded from the Screening Visit (signing the ICF) 
through the EOS Visit (Week 18).  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.  Instructions on recording and 
reporting of ISRs will be provided to study sites through the Study Manual.  
Any changes or additions to the subject’s concomitant medications will be entered into the 
e-CRF with appropriate start and stop dates.   
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. 
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 


 
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• 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 
 
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.   
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 sites.  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  


 
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• 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 
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 from the study or is lost to 
follow up.   
Serious Adverse Event Reporting 
Investigator Reporting Responsibilities to the Sponsor 
SAEs 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.  Report SAEs by fax, email, or telephone call to:  
Zamaneh Mikhak, MD 
Senior Director, Clinical Research and Development 
Kiniksa Pharmaceuticals Corp. 
100 Hayden Avenue 
Lexington, MA. 02421 
Tel: 781-430-8549 
Tel (after hours): 781-690-7633 
Email: zmikhak@kiniksa.com 
 
If the Investigator reports a SAE by telephone, then a completed SAE report form must 
follow within 1 business day and is to include a full description of the event and sequelae in 
the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE e-CRF.  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, lab reports, autopsy reports, and other 
documents when requested and applicable and if available. 
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 6.3) 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 6.3) 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. 
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 
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 2.  
At the Screening Visit and at any time during the study at the discretion of the Investigator 
and in consultation with the Sponsor, if needed, subjects will be asked to provide urine 
samples for a drugs abuse screening.   
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 


 
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timepoints in Appendix 1.  A serum pregnancy test will be performed if urine pregnancy is 
positive.   
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. 
7.5.3 
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 
(Week 18) as outlined in Appendix 1.  Subjects must be supine for at least 5 minutes before 
blood pressure and pulse rate measurements.   
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.  
7.5.4 
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 
>450 ms in men and >470 ms in 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. 
7.5.5 
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 (HEENT), 
lymph nodes, skin, respiratory, cardiovascular, gastrointestinal, musculoskeletal, and 


 
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neurological exams. Breast, anorectal, and genital examinations will be performed only if 
medically indicated.  
An abbreviated physical examination includes skin, cardiovascular, respiratory, and 
abdominal exams and as indicated based on subject’s symptoms. 
7.6 
Committees 
7.6.1 
Safety Review Committee (SRC) 
During KPL-716-C202, periodic reviews of safety and tolerability data will be conducted by 
a safety data review committee consisting of Investigators from active sites and a Sponsor 
physician representative.  In addition, the Sponsor will review internally emerging safety and 
tolerability data periodically.  
 
 
 
 


 
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8 
SAMPLE SIZE AND DATA ANALYSES 
8.1 
Statistical Methods 
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 (SD), first quartile (Q1), median, third quartile (Q3), minimum and 
maximum for continuous variables, and frequency and percentage for categorical and ordinal 
variables. Unless otherwise specified, all tests will be two-tailed using pre-specified levels of 
significance. Statistical analyses of efficacy endpoints will be conducted separately for each 
cohort. Details will be specified in the Statistical Analysis Plan (SAP).  
 
8.2 
Handling of Dropouts and Missing Data 
Criteria for removal of subjects from therapy or assessments are explained in Section 4.8. 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 
No Multiplicity adjustment is planned. 
8.4 
Determination of Sample Size 
This is a double-blind study.  Each cohort will be independently analyzed.  A total of 
approximately 26 subjects will be randomized in each cohort. The first 12 subjects will be 
randomized to the KPL-716 and the placebo arms in a 3:1 randomization ratio. The rest of the 
14 subjects will be randomized in a 1:1 randomization ratio.  There will be approximately 16 
subjects and 10 subjects randomized to the KPL-716 arm and the placebo arm respectively. 
Based on a two-sample t-test for the primary efficacy endpoint, change from baseline in 
weekly average of WI-NRS at Week 8, assumed mean changes of 4 for the KPL-716 arm and 
1.5 for the placebo arm, a total sample size of 26 subjects per cohort will provide about 80% 
power to detect a 2.5-point mean difference with a standard deviation of 2.8, given a two-
sided alpha of 0.2.   Given the exploratory nature of this pilot study, the precision attained 
with the above cohort samples size is acceptable for early signal of efficacy assessments.  
8.5 
Analysis Populations 
8.5.1 
Modified Intent-to-Treat Analysis Set 
All randomized subjects who receive at least one (1) dose of KPL-716 or placebo and have at 
least one (1) post-baseline efficacy assessment in the double-blind Treatment Period will be 
included in the modified intent-to-treat (mITT) analysis set. Efficacy analyses will be based 
on the mITT analysis sets. All mITT analyses will be based on each subject’s randomized 
treatment assignment.  
 




 
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8.7 
 Safety Analyses 
All safety analyses will be conducted based on the Safety Analysis Set. All safety data will be 
listed by subject.  Details for the analysis of safety data will be provided in the SAP. 
8.7.1 Extent of Exposure 
Statistical quantity of study drug administered will be summarized for each cohort. Number 
of subjects requiring dose interruption and treatment discontinuation with corresponding 
reasons will be summarized as well. 
8.7.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Any AEs not present before exposure to study drug or any event already present 
that worsens in either intensity or frequency after exposure to study drug are considered 
TEAEs. The number and percentage of subjects reporting TEAEs will be summarized by 
MedDRA System Organ Class (SOC) and preferred term (PT), by severity, and by 
relationship to study treatment. The number and percentage of subjects with SAEs, and the 
number and percentage of subjects with AEs leading to treatment discontinuation will also be 
summarized by MedDRA system organ class and preferred term.  
8.7.3 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. 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.  
8.7.4 ECG Analyses 
For repeated performance of 12-lead ECG, average values will be taken. Descriptive statistics 
of actual values and changes from baseline over time will be summarized by ECG parameter. 
For ECG overall interpretation of normal and abnormal, shift tables from baseline to each 
post baseline time points and worst post baseline will be presented. 
8.7.5 Vital Signs 
Vital signs will be summarized using descriptive statistics of actual values and changes from 
baseline over time. 
8.7.6 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.    
8.7.7 Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary. Frequencies and percentages of subjects using each concomitant medication will 




 
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9 
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
Auditing 
The study may be audited or reviewed by Kiniksa Quality Assurance (QA) department, 
IRB/IEC, and/or regulatory authority at any time.  The study sites are 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, e-CRF and source 
documentation completion and retention, and accurate study drug accountability.  To this 
end, the Study Monitor will visit the study sites at scheduled intervals per the Sponsor 
requirements and will be expected to be in frequent contact with the study sites 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 unblinded monitoring resource.   
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 Clinical Research Organization (CRO) will be responsible for data 
management of this study, including quality of the data.  The study sites will be responsible 
for data entry into the electronic data capture (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’s 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 Case 
Report Forms or EDC by staff at the study sites.  Following data entry, the e-CRF 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 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 sites 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 sites 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’s 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 sites.   


 
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11.4 
Subject Confidentiality 
The results from Screening and data collected during the study will be recorded in the CRF.  
To maintain confidentiality, the subjects will be identified only by a unique subject 
identification number. 
Subject medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the ICF signed by the subject, unless permitted or required by 
law. 
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 
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18. Powell R, Leech SC, Till S, et al. BSACI guideline for the management of chronic 
urticaria and angioedema.  Clinical & Experimental Allergy. 2015 Mar; 45(3):547-65 
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2017;139(5):1411-1421 
21. Qadi AA, Taberlay PC, Phillips JL, et al. The leukemia inhibitory factor receptor gene 
is a direct target of RUNX1. J of Cellular Biochem. 2016; 117:49-58  
22. Nemoto O, Furue M, Nakagawa H, et al. 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.  
23. Ruzicka T, Hanifin JM, Furue M, et al; XCIMA Study Group. Anti-Interleukin-31 
Receptor A Antibody for Atopic Dermatitis. N Engl J Med. 2017;376(9):826-835.  
24. Altricher S, Hawro T, Hanel K, et al. Successful omalizumab treatment in chronic 
spontaneous urticaria is associated with lowering of serum IL-31 levels. J Eur Acad 
Dermatol Venereol 2016;30:454-455 
25. Narbutt I, Olejncizak D, Sobolewska-Sztychny,et al. Narrow band ultraviolet B 
irraditatin cause alteration in interleukin-31 serum level in psoriatric patients. Arch 
Dermatol Res. 2013;305:191-195 
26.  Sonkoly E, Muller A, Lauerma AI, et al. IL-31: A new link between T cells and 
pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006; 117 (2): 411-417 
27. Gazel A, Rosdy M, Bertino B, et al. A characteristic subset of psoriasis-associated 
genes is induced by oncostatin-M in reconstituted epidermis. J Invest Dermatol. 
2006;126(12):2647-57.  
28. Boniface K, Diveu C, Morel F, et al. Oncostatin M secreted by skin infiltrating T 
lymphocytes is a potent keratinocyte activator involved in skin inflammation. J 
Immunol. 2007;178(7):4615-22. 
29. Fritz DK, Kerr C, Fattouh R, et al. 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.  
30. Mozaffarian A, Brewer AW, Trueblood ES, et al. Mechanisms of oncostatin M-induced 
pulmonary inflammation and fibrosis. J Immunol. 2008;181(10):7243-53. 
31. Fritz DK, Kerr C, Botelho F, et al. 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. 
32. Kwofie K, Scott M, Rodrigues R, et al. Regulation of IL-17A responses in human 
airway smooth muscle cells by Oncostatin M. Respir Res. 2015; 16:14.  


 
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28 January 2019 (Version 1.0) 
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33. Botelho FM, Rangel-Moreno J, Fritz D, et al. 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.  
34. Wong S, Botelho FM1, Rodrigues RM1, et al. Oncostatin M overexpression induces 
matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-
resistant BALB/c mice. Lab Invest. 2014;94(9):1-14. 
35. Kunz B, Oranje AP, Labrèze L, et al. Clinical validation and guidelines for the 
SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. 
Dermatology. 1997;195(1):10-9 
36. Hollis K, Proctor C, McBride D, et al. Comparison of Urticaria Activity Score Over 7 
Days (UAS7) Values Obtained from Once-Daily and Twice-Daily Versions; Results 
from the ASSURE-CSU Study. AM J Clin Dermatol. 2018 19:267-274. 
37. Elman S, Hynan LS, Gabriel V, et al. The 5-D itch scale: a new measure of pruritus. 
The British Journal of Dermatology. 2010;162(3):587-593. 
38. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994; 19: 210-216. 
39. Desai NS, Poindexter GB, Monthrope YM, et al. 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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28 January 2019 (Version 1.0)  
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4 Females of childbearing potential only.  A serum beta-human chorionic gonadotropin (βhCG) pregnancy test is performed at the Screening Visit.  A 
urine βhCG test is performed at all later time points.  A serum βhCG test is performed if urine βhCG test is positive. 
5Additional 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 On dosing days, all procedures will be performed prior to dosing.   
 
 


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28 January 2019 (Version 1.0)  
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14.2 
Appendix 2: Clinical Laboratory Tests 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase 
Blood urea nitrogen  
Calcium 
Carbon dioxide 
Chloride 
Cholesterol 
Creatinine 
Gamma-glutamyl 
transferase 
Glucose 
High-density lipoprotein 
Lactate dehydrogenase 
Low-density lipoprotein 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
 
Hematocrit  
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width  
White blood cell (WBC) count 
WBC differential (total and percentage): 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
Prothrombin time 
Partial thromboplastin time 
International normalized ratio 
Fibrinogen 
D-dimer (if abnormal fibrinogen levels) 
Bilirubin  
Blood 
Color and 
appearance  
Glucose 
Ketones 
Leukocyte esterase  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic 
examination (for 
cells, cellular 
debris, crystals and 
bacteria, 
completed only if 
abnormal findings 
upon macroscopic 
examination)  
Serologya: 
Drug screenb: 
Other: 
Hepatitis B surface 
antigen 
Hepatitis B core antibody 
Hepatitis B surface 
antibody 
Hepatitis C virus antibody 
Human 
immunodeficiency 
antibodies (type 1 and 2) 
 
Must include at least the following:  
Amphetamines/methamphetamines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Opioids 
Serum βhCG testc   
Urine βhCG testc 
    FSH 
    Total IgE 
 
 
 
 
a Analyzed only at the Screening Visit 
b Analyzed only at the Screening Visit; may be analyzed at later timepoints at the discretion of the Investigator. 
c A serum beta-human chorionic gonadotropin (βhCG) pregnancy test is performed at the Screening Visit for all 
females of childbearing potential.  A urine βhCG test is performed at all later time points.  A serum βhCG test is 
performed if urine βhCG test is positive. 
 
 





SAP_001.pdf: 
 
 
Kiniksa Pharmaceuticals, Ltd. 
Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
CONFIDENTIAL 
Page 1 of 42 
 
 
 
Kiniksa Pharmaceuticals, Ltd. 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to 
Investigate the Efficacy, Safety, and Tolerability of KPL-716 in Reducing 
Pruritus in Diseases Characterized by Chronic Pruritus 
Protocol Number: KPL-716-C202 
 
 
 
SAP Version: Version 1 
Date: April 13, 2020 
 
CONFIDENTIALITY STATEMENT 
The information in this document is the property of Kiniksa Pharmaceuticals, Ltd. and contains proprietary and confidential information to be 
held in strict confidence and not disclosed to any third party, without prior written consent of Kiniksa Pharmaceuticals, Ltd. Persons within your 
organization to whom any information herein is disclosed is on a need-to-know basis solely to carry out the purpose of this document, and be 
informed that such information is confidential and shall not be further disclosed by them without Kiniksa’s prior written 
consent.  Documentation, data, and all other information generated during the clinical study is proprietary and confidential information of Kiniksa 
Pharmaceuticals, Ltd. and shall not be disclosed to any third party, without prior written consent of Kiniksa Pharmaceuticals, Ltd. 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
CONFIDENTIAL 
Page 2 of 42 
 
DOCUMENT HISTORY  
  
Version 
Description 
Date 
1.0 
New 
April 13, 2020 
 
 
APPROVAL 
 
Electronic approvals are manifested in the final page of this document. 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
CONFIDENTIAL 
Page 3 of 42 
 
CONTENTS 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
2.1. 
Study Objectives ...........................................................................................................8 
2.1.1. 
Primary objective(s) ......................................................................................................8 
2.1.2. 
Secondary objective(s) ..................................................................................................8 
 
 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary endpoints .........................................................................................................9 
2.2.2. 
Secondary endpoints .....................................................................................................9 
 
 
2.2.4. 
Safety Parameters .......................................................................................................10 
 
 
2.3. 
Overall Study Design ..................................................................................................10 
3. 
DETERMINATION OF SAMPLE SIZE ...................................................................14 
4. 
STUDY ANALYSIS SETS ........................................................................................14 
4.1. 
Randomized Subjects ..................................................................................................14 
4.2. 
Modified Intent-to-Treat (mITT) Analysis Set ...........................................................14 
4.3. 
Per Protocol (PP) Analysis Set ...................................................................................14 
4.4. 
Safety Analysis Set .....................................................................................................14 
4.5. 
PK Analysis Set ..........................................................................................................14 
5. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................14 
5.1. 
General Methods .........................................................................................................14 
5.2. 
Baseline Value and Change from Baseline ................................................................15 
5.3. 
Study Day ...................................................................................................................15 
5.4. 
Analysis Visits ............................................................................................................15 
5.5. 
Time on study .............................................................................................................16 
5.6. 
Missing Data Handling ...............................................................................................16 
5.7. 
Multiple Comparisons/Multiplicity ............................................................................16 
6. 
STUDY SUBJECTS ...................................................................................................16 
6.1. 
Subject Disposition .....................................................................................................16 
6.2. 
Protocol Deviations ....................................................................................................16 


 
 
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7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................17 
7.1. 
Demographics .............................................................................................................17 
7.2. 
Screening and Baseline Disease Characteristics .........................................................17 
7.3. 
Medical History ..........................................................................................................18 
7.4. 
Prior and Concomitant Medications ...........................................................................18 
7.5. 
Prior and concomitant procedures ..............................................................................19 
8. 
EFFICACY ANALYSES ...........................................................................................19 
8.1. 
Analysis of primary efficacy endpoint .......................................................................19 
8.2. 
Analyses of other continuous efficacy endpoints .......................................................20 
8.3. 
Responder Analysis ....................................................................................................20 
8.4. 
Shift table for selected efficacy endpoints ..................................................................21 
 
 
9. 
SAFETY ANALYSES ...............................................................................................21 
9.1. 
Treatment Exposure ....................................................................................................21 
9.2. 
Adverse Events ...........................................................................................................22 
9.2.1. 
Overall Summary of Adverse Events .........................................................................22 
9.2.2. 
TEAEs .........................................................................................................................22 
9.2.3. 
Serious TEAEs ............................................................................................................23 
9.2.4. 
TEAEs Leading to Dose Interruption .........................................................................23 
9.2.5. 
TEAEs Leading to Treatment Discontinuation ..........................................................23 
9.2.6. 
TEAEs Leading to Study Discontinuation .................................................................23 
9.3. 
Laboratory Parameters ................................................................................................23 
9.4. 
Vital Signs and Weight ...............................................................................................23 
9.5. 
Electrocardiograms .....................................................................................................24 
9.6. 
Physical Examination .................................................................................................25 
10. 
PHARMACOKINETIC ANALYSIS .........................................................................25 
 
 
 
 
13. 
SUBGROUP ANALYSIS ..........................................................................................25 
14. 
INTERIM ANALYSES ..............................................................................................26 
15. 
DATA HANDLING CONVENTIONS ......................................................................26 
15.1. 
General Conventions ..................................................................................................26 


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Protocol: KPL-716-C202 
Version 1 April 13, 2020 
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16.
REFERENCES ...........................................................................................................27 
17.
APPENDICES ............................................................................................................28 
17.1. 
Study Schema and Schedule of Assessment ...............................................................28 
 
 
 
 
 
 
 
 
 
 
 
 
17.8. 
Clinical Laboratory Tests ...........................................................................................39 
17.9. 
Statistical Methods and SAS Codes ...........................................................................41 
LIST OF TABLES 
Table 1: 
Statistical Analyses for Change and Percent Change Endpoints ................................20 
Table 2: 
Statistical Analyses for Responders ............................................................................21 
Table 3: 
Criteria for Clinically Relevant Vital Signs Post-Baseline.........................................24 
Table 4: 
Subgroups Defined at Baseline ...................................................................................25 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
CONFIDENTIAL 
Page 6 of 42 
 
LIST OF ABBREVIATIONS 
Abbreviation  
Full Form  
  
 
AE  
Adverse event  
ANCOVA 
Analysis of covariance 
ATC  
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
CI 
Confidence interval 
CIU 
Chronic Idiopathic Urticaria 
CIP 
Chronic Idiopathic Pruritus 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
eCRF 
Electronic case report form 
EDC  
Electronic data capture  
EOT 
End of treatment 
EOS 
End of study  
DLQI 
Dermatology Life Quality Index  
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT  
Modified intent-to-treat  
  
  
PK  
Pharmacokinetic(s)  
PP 
Per protocol 
PT 
Preferred term 
QoL 
Quality of life 
QT  
Electrocardiographic interval from the beginning of the QRS 
complex to the end of the T wave  
QTcF  
QT interval corrected for heart rate using Fridericia’s method 
SAE  
serious adverse experience/event  
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 


 
 
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Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
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Abbreviation  
Full Form  
SE 
Standard error 
SOC 
System organ class 
TEAE  
Treatment-emergent adverse event  
UAS7 
Urticaria Activity Score/over 7 days 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug Dictionary 
WI-NRS 
Worst Itch Numeric Rating Scale 
 




 
 
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Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
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 To evaluate the immunogenicity of SC KPL-716 in subjects with chronic pruritus 
experiencing moderate to severe pruritus 
 
 
 
 
 
 
 
 
2.2. 
Study Endpoints 
2.2.1. 
Primary endpoints 
 Change from baseline in weekly average Worst Itch–Numeric Rating Scale (WI-
NRS) at Week 8  
2.2.2. 
Secondary endpoints 
Related to pruritus:  
 Change and percent change from baseline in weekly average of WI-NRS over time 
 Change and percent change from baseline in Pruritus Visual Analog Scale (VAS) 
over time 
 Change and percent change from baseline in 5-D Pruritus total score over time 
 Proportion of subjects achieving ≥4-point reduction from baseline in weekly average 
WI-NRS over time   
 Change and percent change from baseline in weekly itch severity score, a component 
of Urticaria Activity Score 7 (UAS7) (CIU only)   
Related to sleep:  
 Change and percent change from baseline in Sleep Loss VAS over time 
 Change and percent change from baseline in weekly average of difficulty falling 
asleep Numerical Rating Scale (NRS) over time 
 Change and percent change from baseline in weekly average of sleep quality NRS 
over time 
Related to quality of life: 
 Change and percent change from baseline in quality of life measures over time 
 
 
 
 
 
 
 


 
 
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Protocol: KPL-716-C202 
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2.2.4. 
Safety Parameters 
 Incidence rate and severity of treatment-emergent adverse events (TEAEs) and SAEs   
 Incidence rate and severity of study drug-related TEAEs and SAEs 
 Vital signs 
 Electrocardiogram (ECG) 
 Clinical laboratory test results  
 
 
 
 
 
 
2.3. 
Overall Study Design 
Study Design: 
This Phase 2 pilot study is comprised of multiple cohorts each for a different study population.  
Each cohort is an independent randomized, double-blind, placebo-controlled sub-study to 
investigate the efficacy, safety, tolerability, PK and immunogenicity of KPL-716 administered SC 
in reducing pruritus in diseases characterized by chronic pruritus. The following chronic pruritic 
diseases will be studied. Each cohort will be analyzed independently.  Pooled cohorts may be 
analyzed as well. 
 Cohort 1: Chronic Idiopathic Urticaria (CIU) 
 Cohort 2: Chronic Idiopathic Pruritus (CIP) 
 Cohort 3: Lichen Planus (LP) 
 Cohort 4: Lichen Simplex Chronicus (LSC) 
 Cohort 5: Plaque Psoriasis (PPs) 
Each cohort will enroll up to 26 subjects and contain three periods: 
 Screening Period (Day-28 to Day-1, minimum 14 days and maximum 28 days) 
 Treatment Period (Day 1 [Baseline] to Week 8) 
 Follow-up Period (After Week 8 to Week 18) 
 


 
 
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Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
CONFIDENTIAL 
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Figure 1: 
Cohort Study Design Diagram 
 
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 (Figure 2).  
The first 12 subjects of each cohort will be randomized to the KPL-716 and placebo arms in a 
3:1 randomization ratio.  The rest of the 14 subjects will be randomized in a 1:1 ratio. The 
randomization will be based on a computer-generated treatment randomization schedule 
prepared before the study by the Sponsor or designee.   
 
Figure 2: 
Treatment Assignment Design Diagram 
 
 
Efficacy assessments: 
Efficacy in reduction of pruritus will be assessed via daily recording of WI-NRS as well as on-
site assessment of Pruritus VAS and 5-D Pruritus.  Improvement in sleep will be assessed via 
daily recording of two NRS scales, one for difficulty falling asleep and the other for quality of 
sleep.  Impact on sleep will also be assessed via on-site Sleep Loss VAS.  Impact on quality of 
life will be assessed via on-site PROs: DLQI and ItchyQoL. Impact on pruritus and disease 
severity for subjects with CIU will be assessed via daily completion of UAS7 questionnaire. 
Schedules of these efficacy assessments are specified in Section 17.1.    
 WI-NRS score: Subjects will be asked daily to assign a numerical score to the intensity of 
their most severe (worst) pruritus in the past 24 hours using a scale from 0 to 10, with 0 
indicating no pruritus and 10 indicating the worst imaginable pruritus. The Worst-Itch 
NRS is provided in the Daily NRS Tool Section 17.2. 
 
Treatment Period D1 to W8 
Arm A 
KPL-716 qwk 
Screening Period 
D -28 to D-1 
Follow-up Period 
W8 to W18 
Arm B 
Placebo qwk 
 D1 
Randomization 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
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 The sleep quality NRS: Subjects will be asked daily to assign a numerical score to the 
quality of their sleep in the previous night using a scale from 0 to 10, with 0 indicating 
best possible sleep and 10 indicating worst possible sleep. The sleep quality NRS is 
provided in the Daily NRS Tool (Section 17.2). 
 
 The difficulty falling asleep NRS: Subjects will be asked daily to assign a numerical 
score to the intensity of their difficulty falling asleep last night due to itch using a scale 
from 0 to 10, with 0 indicating not difficult at all and 10 indicating extremely difficult. 
The difficulty falling asleep NRS is provided in the Daily NRS Tool (Section 17.2). 
 
 Pruritus VAS: Subjects will be asked to place a line perpendicular to the VAS line at the 
point that represents the intensity of their average pruritus experienced over the previous 
three days using a scale from 0 to 10, with 0 indicating no pruritus and 10 indicating the 
worst imaginable pruritus. Pruritus VAS scale is provided in Section 17.3. 
 
 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. The scale of Sleep Loss VAS 
can be found in Section 17.3.  
 
 The 5-D Pruritus Scale: This tool evaluates pruritus in five domains: duration, degree, 
direction, disability and distribution.  Duration, degree and direction each consist of one 
item.  The disability domain contains four items and the distribution domain includes 16 
items.  The first four domains are measured on a five-point Likert scale.  The scores from 
each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) 
and 25 (most severe pruritus) (Elman 2010).  The 5-D Pruritus Scale is administered 
every two (2) visits. The score of each of the 5 domains is obtained separately and 
summed together to get the total 5D-pruritus score.  
 For duration, degree and direction, use the number indicated below the response 
choice.    
 For disability, take the highest score for any of the 4 items (sleep, leisure/social, 
housework/errands, work/school).   
 For distribution, use the following scale: 
0-2 areas affected:  score 1 
3-5 areas affected:  score 2 
6-10 areas affected: score 3 
11-13 areas affected:  score 4 
14 to 16 areas affected:  score 5 
 
5-D Pruritus Scale is specified in Section 17.4. 
 
 DLQI: This tool is a 10-question questionnaire that considers symptoms and feelings, 
daily activities, leisure, school, personal relationships, and treatment. Each question, 


 
 
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Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
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except question 7, is answered on a scale of 0 to 3 (0 for not at all, 1 for a little, 2 for a 
lot, and 3 for very much), taking into account the previous week. For question 7: Subjects 
will be asked “Over the last week, has your skin prevented you from working or 
studying?” If answered yes, score=3; If no, a second question will be asked: “Over the 
last week how much has your skin been a problem at work or studying?” If further 
answered a lot, score=2; if a little, score=1; if not at all or not relevant, score=0.  The 
DLQI total score is defined as the sum of all 10-quesion scores with minimum of 0 
meaning no effect on quality of life and 30 meaning extremely large effect. DLQI 
questionnaire is provided in Section 17.5. 
 
 ItchyQoL: This tool 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. 
The ItchyQoL total score is defined as the sum of all 22-items scores. The ItchyQoL 
symptom subscale score is calculated as the sum of question 1-6. The ItchyQoL 
functional subscale score is calculated as the sum of question 7-13. The ItchyQoL 
emotional subscale score is calculated as the sum of question 14-22. If there is only 1 
item skipped in a subscale, the missing item value in the subscale will be imputed as the 
average of other non-missing item values. If 2 or more items are skipped in any given 
subscale, the subscale and total scores are set to missing. For other subscales that have 
less than 2 items skipped, those subscale scores need to be calculated. Total scores can be 
classified as little (0-30), mild (31-50), moderate (51-80), severe (81-110). ItchyQoL 
questionnaire is provided in Section 17.6 . 
 
 The UAS7: Subjects will be asked daily to self-assess the number of wheals and the 
intensity of the subject’s pruritus.  It is graded from 0 to 3 for each parameter and is 
averaged over seven consecutive days to obtain the UAS7 Score with a maximum score 
of 6.  The greater the severity of the disease the higher the score. The total score will be 
calculated from weekly average of subcomponents. The UAS7 tool will be completed 
only by subjects in the CIU Cohort.  UAS7 questions are can found in Section 17.7 . 
 
Safety Assessments:  
Safety will be assessed by monitoring of AEs, measurements of vital signs, physical 
examination, ECG evaluation, and clinical laboratory tests specified in Section 0. Assessments 
are specified in Section 17.1 . 
PK Assessment:  
PK blood samples will be collected according to Section 17.1.     
  
  
 
 


 
 
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Statistical Analysis Plan 
 
Protocol: KPL-716-C202 
Version 1 April 13, 2020          
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3. 
DETERMINATION OF SAMPLE SIZE 
This is a double-blind study.  Each cohort will be independently analyzed. A total of 
approximately 26 subjects will be randomized in each cohort. The first 12 subjects will be 
randomized to the KPL-716 and the placebo arms in a 3:1 randomization ratio. The rest of the 14 
subjects will be randomized in a 1:1 randomization ratio.  There will be approximately 16 
subjects and 10 subjects randomized to the KPL-716 arm and the placebo arm, respectively. 
Based on a two-sample t-test for the primary efficacy endpoint, change from baseline in weekly 
average of WI-NRS at Week 8, assumed mean changes of 4 for the KPL-716 arm and 1.5 for the 
placebo arm, a total sample size of 26 subjects per cohort will provide about 80% power to detect 
a 2.5-point mean difference with a standard deviation of 2.8, given a two-sided alpha of 0.2.   
Given the exploratory nature of this pilot study, the precision attained with the above cohort 
samples size is acceptable for early signal of efficacy assessments.   
4. 
STUDY ANALYSIS SETS 
4.1. 
Randomized Subjects 
Randomized subjects will include all subjects whose date of randomization is not missing.  
4.2. 
Modified Intent-to-Treat (mITT) Analysis Set 
All randomized subjects who receive at least one (1) dose of KPL-716 or placebo and have at 
least one (1) post-baseline efficacy assessment in the double-blind Treatment Period will be 
included in the modified intent-to-treat (mITT) analysis set. All mITT analyses will be based on 
each subject’s randomized treatment assignment. 
4.3. 
Per Protocol (PP) Analysis Set  
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. Protocol deviations that may potentially bias 
statistical analyses will be defined in the SAP before database lock. 
4.4. 
Safety Analysis Set 
All randomized subjects who take at least one (1) dose of KPL-716 or placebo will be included 
in the Safety Analysis Set. Safety analyses will be based on the actual treatment (KPL-716 or 
Placebo) that was administered to each subject.  
4.5. 
PK Analysis Set 
Subjects who received KPL-716 and who had at least one (1) PK sample will be included in the 
PK population. 
5. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
5.1. 
General Methods 
 All analyses and summaries will be produced using SAS® version 9.4 (or higher).  


 
 
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 Descriptive statistics in each cohort will be presented for all endpoints and will 
include number of subjects (n), mean, standard error (SE) and standard deviation 
(SD), first quartile (Q1), median, third quartile (Q3), minimum and maximum for 
continuous variables. Where specified, 80% and 95% Confidence Intervals (CI) of the 
mean will be calculated.  
 For categorical variables (including binary variables), counts and percentages will be 
presented. Where specified, 95% 2-sided CI for proportions and 80% and 95% for 
odds ratios will be presented. CI for proportions will be calculated based on exact 
binomial distribution.  
 For inferential statistical analyses in each cohort, the efficacy data will be analyzed 
and displayed by treatment group (KPL-716 and placebo) and visits. Unless otherwise 
specified, all tests will be two-tailed using pre-specified levels of significance. 
 Subject listings in all randomized subjects, except the listing for screen failures will 
be provided for all efficacy and safety data. In general, the subject listings will be 
sorted by treatment group, subject number and assessment date (and time, if 
applicable). 
 In general, 1 year will be defined as 365.25 days and 1 month will be defined as 
30.4375 days (365.25 days/12 months). 
5.2. 
Baseline Value and Change from Baseline 
In general, baseline is defined as the last non-missing value obtained immediately prior to the first 
SC injection otherwise specified.  
For daily collected efficacy endpoints (WI-NRS, difficulty falling asleep NRS, sleep quality NRS, 
UAS7), baseline is calculated as weekly average of non-missing scores from 7 days prior to Day 
1, which is the day when the first SC injection is administered. For those daily collected efficacy 
endpoints, weekly average will be calculated based on every 7 days starting on the day after the 
start of injection (Day 1). Change and percent change from baseline in weekly averages will be 
summarized and compared between KPL-716 and placebo. 
5.3. 
Study Day 
Study day is defined as the number of days from the first date of treatment to the event/visit date. 
It is calculated as follows: 
If the event date falls on the date of treatment, or after the date of treatment, 
 
 
Study Day = Event or Visit Date – 1st Treatment Date + 1 
If the event date falls before the date of 1st treatment,   
 
 
Study Day = Event or Visit Date – 1st Treatment Date 
5.4. 
Analysis Visits 
All data will be organized and analyzed according to the scheduled times as outlined in the 
protocol and by the visit denoted on the electronic case report form (eCRF), except for 
unscheduled and early termination (ET) visits. For unscheduled and early termination visits, 


 
 
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analysis visits will be assigned to closest visits based on event schedule table in Appendix 1. For 
multiple records on the same visit, CRF collected records will be used for the analysis. Summary 
by analysis visits will not include unscheduled analysis visits (after reassignment). However, 
unscheduled analysis visits will be included to define baseline, worst post baseline, or minimum, 
maximum post baseline and listings.   
5.5. 
Time on study 
Time on study will be defined as time from randomization date to the end of study. For ongoing 
subjects, cutoff dates will be used.  
 
5.6. 
Missing Data Handling 
No imputations will be performed for missing data for safety endpoints, unless otherwise 
specified. Missing data handling for efficacy endpoints is specified in Section 8 . 
 
5.7. 
Multiple Comparisons/Multiplicity  
No Multiplicity adjustment is planned. 
6. 
STUDY SUBJECTS 
6.1. 
Subject Disposition 
The subject disposition will be summarized by treatment and overall based on safety population. 
All information will be presented in numbers and percentages in a summary table. The following 
information will be presented in subject disposition table: 
 Screened subjects 
 Randomized subjects 
 Safety analysis set 
 mITT analysis set  
 Subjects who completed treatment and the primary reasons for treatment 
discontinuation 
 Subjects who complete study and the primary reasons for study discontinuation 
6.2. 
Protocol Deviations  
A protocol deviation can be defined as any deviation from the study protocol that does not 
materially affect the safety of the subjects and/or the conduct of the study and/or its evaluation. 
Important protocol deviations will be based upon the eCRF database and determined for all 
subjects by either medical review processes or programming based on the inclusion/exclusion 
criteria or other criteria presented in the protocol. 


 
 
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Current ICH GCP guidelines list the important protocol deviations that must be listed in the 
clinical report. Important protocol deviations are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of key study data or that may 
significantly affect a subject's rights, safety, or well-being. These may include: 
 Subjects that are dosed on the study despite not satisfying the inclusion criteria; 
 Subjects that develop withdrawal criteria whilst on the study but are not withdrawn; 
 Subjects that receive the wrong treatment or an incorrect dose; 
 Subjects that receive an excluded concomitant medication. 
A summary table will be provided as the number (%) of subjects with at least one important 
protocol deviation and the number (%) of subjects in each category. 
7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The demographics and baseline characteristics data will be summarized in mITT and safety 
populations. Descriptive statistics will be provided for continual variables. Numbers and 
percentages of subjects will be tabulated for categorical variables. 
7.1. 
Demographics  
The following demographic variables will be summarized. 
Age (years), calculated as the number of years between the date of birth and the date of signing 
the Informed Consent form. 
 Age (years) 
 Sex (Male or Female) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) = Weight(kg)/[Height(m)2] 
7.2. 
Screening and Baseline Disease Characteristics 
The following screening and baseline characteristics will be summarized. 
 Years since diagnosis (calculated relative to randomization date) 
 Screening visits and baseline efficacy endpoints 


 
 
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7.3. 
Medical History 
The medical history is coded using Medical Dictionary for Regulatory Activities (MedDRA 
version 21.1). The summary of medical history will be presented with number (%) by System 
Organ Class (SOC) and Preferred Term (PT). Each subject will be counted only once for each 
preferred term within a SOC per cohort. Similarly, for determination of MedDRA SOC 
incidences, subjects who experience multiple medical conditions under the same SOC will be 
counted only once for that SOC. 
7.4. 
Prior and Concomitant Medications  
All medications will be coded using the World Health Organization (WHO) drug dictionary. The 
WHO drug dictionary version B3 September 2018.  
Prior medications are defined as medications that started before the first dose of study drug.  
Concomitant medications are defined as medications that (1) started before the first dose of study 
drug and continued into the treatment period, or (2) started on or after the date of the first dose of 
study drug. The number (%) of subjects who took prior and concomitant medications will be 
summarized on the anatomical class (ATC level 3) and preferred term (PT) by treatment and 
overall subjects.  
For analysis purpose, topical corticosteroids [TCS], oral antihistamines [OH], and/or systemic 
corticosteroids which were used to treat pruritus or study skin conditions on or after first dose 
date, are defined as rescue medications. Transient use of TCS and systemic corticosteroids for 
non-study indications, are not considered as rescue medications. For example, transient use of 
TCS for injection site reactions, transient intranasal, or inhaled systemic corticosteroids for non-
study indications are not considered as rescue medications. Identification of rescue medications 
will be based on medical review. Number and percentage of subjects who used rescue 
medication will be summarized. Time to 1st use of any rescue medication, such as time to 1st use 
of TCS, or time to 1st use of oral antihistamine will be summarized descriptively as well.  
Prior TCS use regardless of indications, systemic corticosteroid, OH will be summarized as well, 
of which identification will be based on medical review. 
Prohibited medications include, but not limited to, Systemic corticosteroids (IV/IM/oral) , 
Intralesional corticosteroids and intra-articular corticosteroids, Topical treatments including but 
not limited to corticosteroids, calcineurin inhibitors, phosphodiesterase inhibitors, retinoids, 
calcipotriol, capsaicin, camphor, polidocanol or tars, Antihistamines, Immunomodulators (for 
example, cyclosporine, methotrexate, retinoids, azathioprine, mycophenolate, and thalidomide) , 
Neuroactive drugs such as gabapentin and pregabalin, Cannabinoids, Opioid antagonists or 
agonists,  Janus Kinase (JAK) inhibitors, Dupilumab and ustekinumab, Any other marketed 
biologic,  Any investigational biologic drug, Any investigational non-biologic drug, 
Phototherapy involving UVA, UVB, or excimer, Tanning salon use which are used after first 
dose date. Topical corticosteroids and antihistamines may be provided in consultation with the 
Sponsor as rescue medications for an exacerbation of symptoms that is significant enough to 
warrant intervention. Subjects with CIU (Cohort 1) may use H1 antihistamine at approved and 
stable doses. For further details refer to the Pharmacy Manual. Identification of prohibited 
medications will be based on medical review. Number and percentage of subjects who used 
prohibited medications will be summarized as well if any data available.  


 
 
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7.5. 
Prior and concomitant procedures  
The procedures are coded using Medical Dictionary for Regulatory Activities (MedDRA version 
21.1). The prior and concomitant procedures are defined similarly as the prior and concomitant 
medications. The summary of prior and concomitant procedures will be presented with number 
(%) by System Organ Class (SOC) and Preferred Term (PT). Each subject will be counted only 
once for each preferred term within a SOC per cohort. Similarly, for determination of MedDRA 
SOC incidences, subjects who experience multiple procedures under the same SOC will be 
counted only once for that SOC. 
8. 
EFFICACY ANALYSES 
All efficacy analyses will be performed in the mITT analysis set. The analysis of primary 
efficacy endpoint will be repeated in the PP population. Analysis based on the mITT set will be 
the primary analysis and the analyses based on other analysis sets will be considered as the 
supportive analyses. 
Line plots of LS Mean (SE) in percent change from baseline based on ANCOVA overtime will 
be presented and bar charts for responder analysis will be provided as well if needed for selected 
endpoints. 
8.1. 
Analysis of primary efficacy endpoint 
To minimize confounding impact on efficacy endpoints by rescue medications, efficacy 
assessments will be set to missing if collected in intervals:  
 Systemic corticosteroids: from first date and afterward. 
 TCS except for indication of injection site reactions from start date to end date plus 
2 days if duration is ≤2 days, plus 7 days if duration is ≥3 days. 
 Oral antihistamine, from start date to end date plus 1 day.  
 
Then, all missing post baseline values including those due to early discontinuation are imputed 
with last observation carried forward (LOCF) method up to the end of the period with last non-
missing CRF collected data or cutoff date whichever is first.   Then weekly average will be 
calculated and Analysis of Covariance (ANCOVA) model will be fitted with treatment as factor 
and corresponding baseline value as covariate. Least square (LS) mean and standard error (SE) 
with 80% and 95% confidence intervals (CI), and p-value for difference of the between-
treatment comparison of treatment with placebo will be provided. LS means (SE) and 80% and 
95% CIs will be reported for each treatment as well. 
 
As sensitivity analysis of primary endpoint, observed data will be used for ANCOVA model as 
well. If 50% or more data are missing for weekly average calculation at post baseline, the week 
will be set to missing. 
 
In addition, randomization ratio and sex may be considered for exploratory purpose.  


 
 
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8.2. 
Analyses of other continuous efficacy endpoints 
Other continuous efficacy endpoints will be analyzed with ANCOVA models based on data with 
LOCF imputation and observed data as primary efficacy endpoints described above. The detailed 
statistical analyses are specified and marked as ‘X’ in Table 1.  
 
Table 1: 
Statistical Analyses for Change and Percent Change Endpoints 
 
ANCOVA 
LOCF 
as 
Observed  
Primary efficacy endpoint: 
 Percent change from baseline in weekly average WI-NRS 
score at Week 8 
 
X 
 
X 
other continuous efficacy endpoints: Change and percent change from baseline endpoints 
 
 
Related 
to 
pruritus:  
 
- in weekly average of WI-NRS Pruritus over time 
-in Visual Analog Scale (VAS) over time 
- in 5-D Pruritus total score and subscales over time 
- in weekly itch severity score (a component of 
UAS7 (CIU only)) over time 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Related 
to sleep 
- in Sleep Loss VAS over time 
- in weekly average of difficulty falling asleep NRS 
over time  
- in weekly average of sleep quality NRS over time 
X 
X 
X 
X 
X 
X 
 
Related 
to 
quality 
of life 
- in DLQI total score over time 
- in ItchyQoL total score over time 
- in ItchyQoL symptom subscale score over time 
- in ItchyQoL functional subscale score over time 
-in ItchyQoL emotional subscale score over time 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8.3. 
Responder Analysis  
For primary efficacy endpoint and other selected efficacy endpoints, binary responder analyses 
will be conducted based on data with LOCF imputation or observed data described above. 
Proportions of responders will be summarized, and 95% confidence intervals will be calculated 
based on binomial exact distribution. For statistical inference, odds ratios and corresponding 
80% and 95% CIs will be calculated with Fisher exact tests.   


 
 
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Selected endpoints with responder analyses are listed in Table 2.  
Table 2: 
Statistical Analyses for Responders 
 
Fisher exact test 
Responder endpoints by visits 
LOCF 
As observed 
Related to pruritus: 
 Weekly average WI-NRS with a ≥4-point reduction  
 
X 
 
X 
Related to sleep: 
 Difficulty falling asleep NRS with a ≥4-point 
reduction 
 Sleep quality NRS with a ≥4-point reduction 
 
X 
X 
 
X 
X 
     Related to quality of life: 
 DLQI total score with a ≥4-point reduction 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
8.4. 
Shift table for selected efficacy endpoints 
Shift from baseline to post baseline visits in the categories of ItchyQoL total scores (little, mild, 
moderate, severe) will be presented based on data with LOCF and as observed.  
 
 
 
 
 
 
 
 
9. 
SAFETY ANALYSES 
Safety analyses will consist of data summaries for clinical and laboratory parameters, vital signs, 
and for adverse events (AEs). Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA v21.1). Laboratory parameters will be summarized using 
descriptive statistics, by post-treatment shifts relative to baseline. Vital signs and ECG data will 
be summarized using descriptive statistics. 
9.1. 
Treatment Exposure 
Descriptive statistics will be provided for the following. 


 
 
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 Duration of treatment calculated as [min(last dose date+6, end of study date)-first dose 
date +1]/7 
 Number and percentage of subjects will be tabulated by number of doses (1, 2, 3… and 
8). The loading dose is comprised of two injections of maintenance dose. 
 Treatment compliance calculated as (100 * number of study doses received/ total planned 
number of doses on treatment. For early discontinued subjects, total planned doses on 
treatment will be counted from first dose date to last dose date.  
9.2. 
Adverse Events 
Adverse events will be mapped to preferred term (PT) and system organ class (SOC) using the 
most up to date Medical Dictionary (MedDRA) version 21.1.  Treatment emergent AEs (TEAEs) 
are defined as all AEs started since the first dose date in the treatment period or all AEs occurred 
in the follow-up period. Furthermore, if an AE cannot be determined as treatment-emergent due 
to incomplete/missing data, conservatively, it will be considered as treatment emergent and 
included in the summary tables.  
9.2.1. 
Overall Summary of Adverse Events 
The following AE or TEAE summaries will be generated for the safety analysis set. 
 Overview of AEs, summarizing number (%) of subjects with any: 
o Any AEs 
o Any TEAEs 
o Drug-related TEAEs 
o Serious TEAEs 
o Drug related serious TEAEs 
o TEAEs leading to dose interruption 
o Drug-related TEAEs leading to dose interruption 
o TEAEs leading to treatment discontinuation 
o Drug-related TEAEs leading to treatment discontinuation 
o TEAEs leading to study discontinuation 
o Drug-related TEAEs leading to study discontinuation 
o Death 
9.2.2. 
TEAEs 
 Summary of TEAEs by primary SOC, PT 
 Summary of TEAEs by primary SOC, PT, and maximum severity (mild, moderate, or 
severe) 
 Summary of drug related TEAEs by primary SOC, PT 


 
 
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 Summaries of TEAEs presented by PT 
9.2.3. 
Serious TEAEs 
The following serious TEAE summaries will be generated: 
 Summary of serious TEAE by primary SOC, PT 
 Summary of drug related serious TEAE by primary SOC, PT  
9.2.4. 
TEAEs Leading to Dose Interruption 
 Summary of TEAEs leading to dose interruption by primary SOC, PT 
 Summary of drug related TEAEs leading to dose interruption by SOC, PT 
9.2.5. 
TEAEs Leading to Treatment Discontinuation 
 Summary of TEAEs leading to treatment discontinuation by primary SOC, PT 
 Summary of drug related TEAEs leading to treatment discontinuation by SOC, PT 
9.2.6. 
TEAEs Leading to Study Discontinuation 
 Summary of TEAEs leading to study discontinuation by primary SOC, PT 
 Summary of drug-related TEAEs leading to study discontinuation by SOC, PT 
9.3. 
Laboratory Parameters 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
chemistry, hematology, urinalysis, and serology) at the time points specified in Section 0. The 
data collected in different units will be converted in SI units (the International System of Units) 
for summary. The following summaries will be provided by laboratory category of chemistry, 
hematology, urinalysis, and serology. 
Laboratory values will be summarized as descriptive statistic for both actual value and change 
from baseline (post baseline minus baseline) by week. If lab values are recorded as <xx, the limits 
of xx will be used for summary. If lab values are recorded as TNTC (too many to count), 
correspondingly maximum values per confirmation by vendors will be used for summary.  
Shift table summarizing subject incidence of laboratory normal range (Low, Normal, High) at 
baseline contrasted with individual visits and minimum or maximum post baseline.  
 For parameters with bidirectional abnormality (low and high) will be presented by post baseline 
minimum and maximum.  
9.4. 
Vital Signs and Weight 
Vital signs (systolic and diastolic blood pressure, pulse, respiration, temperature) and weight will 
be summarized in descriptive manner by visit for both actual values and changes from baseline 
(post baseline minus baseline) for each visit. At any visit and timepoint, if the test is repeated, the 
average will be used for the analysis at this visit. 


 
 
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All vital signs including weight, pulse rate, body temperature, respiration rate, and systolic and 
diastolic blood pressure will be summarized. Descriptive statistics will be presented for the 
observed value and the change from baseline at each scheduled visit, and dose group (active 
versus pooled placebo). Incidence of clinically relevant vital signs noted post-baseline will also 
be summarized for each study part and treatment group (active versus pooled placebo). Clinical 
relevance is based on the following criteria (Table 3).  
Table 3: 
Criteria for Clinically Relevant Vital Signs Post-Baseline  
Parameter 
Clinically Relevant Criteria 
Systolic Blood Pressure (mmHg) 
 Hypertension: Any post-baseline value 
of 120-139, 140-159, ≥160  
 Hypotension: Any post-baseline value 
≤90 or post-baseline value ≥30 
decrease from baseline 
Pulse Rate (bpm) 
 Any post-baseline value >100 or ≥20 
increase from baseline 
 Any post-baseline value <60 or post-
baseline value ≥20 decrease from 
baseline 
Respiratory Rate (breaths/min) 
 Any post-baseline value >24 
 Any post-baseline value <10 
Body Temperature (°C) 
 Any post-baseline value ≥38 
 Any post-baseline value ≤36 
9.5. 
Electrocardiograms 
Numeric 12-lead ECG parameters will be summarized. Descriptive statistics will be presented 
for the observed value and the change from baseline at each scheduled visit, route of 
administration, and dose group (active versus pooled placebo). Incidence of a normal to 
abnormal shift for overall ECG interpretation will also be summarized as appropriate. Findings of 
other categorical parameters will be listed. For repeated assessment, if interpretations are the same, 
the last value will be taken for numerical assessment for summaries. If interpretations are different, 
the last value with the abnormal interpretation will be used for summary. 
For the assessment of QT interval changes from baseline, Fridericia’s method was used to 
correct for heart rate 
Below incidence of QTcF shifts from baseline will be summarized by category: 
 QTcF interval >450 msec  
 QTcF interval >470 msec  
 QTcF interval >500 msec 


 
 
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 QTcF change from the baseline (pre-dose) is >30 msec and  >60 msec 
9.6. 
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.  
10. 
PHARMACOKINETIC ANALYSIS 
The PK analysis plan and report will be done separately. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
13. 
SUBGROUP ANALYSIS 
The primary efficacy endpoints may be summarized as descriptive statistics by subgroups in 
Table 4 in the mITT analysis set.  
Table 4: 
Subgroups Defined at Baseline 
Subgroup 
Values 
Age group  
<65 years, ≥65 years 
Sex 
Female, Male 
Race 
White, Non-white (American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, Other) 


 
 
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14. 
INTERIM ANALYSES 
Unblinded efficacy data endpoint review and unblinded interim analyses may be performed for 
individual cohorts while enrollment is ongoing; one possible unblinded interim analysis for a 
given cohort may be conducted, for example, when approximately 12 subjects have been 
randomized in the cohort and treated for at least 8 weeks.  The purpose of the interim analysis is 
to assess for potential early signals of efficacy to inform updates of the clinical development 
plan. The interim analysis will be performed by an unblinded independent biostatistician; 
unblinded results will be communicated to selected Sponsor members who are not involved with 
the conduct of the study.  Investigators and subjects will remain blinded to treatment assignment 
until after database lock and completion of the clinical study report (CSR).  
15. 
DATA HANDLING CONVENTIONS 
15.1. 
General Conventions 
Imputation rules for the missing AE onset date 
For the partial date (missing day and/or month) of AE start date, the following imputation rules 
will be applied: 
 If AE Start Date year is equal to the year of the first dose and the AE end date is not 
before (<) the first dose, then the day and month will be imputed with the day and month 
of the first study dose date. Note: Partial missing / missing AE End date is considered as 
‘not before/on first dose’. Otherwise, the month and day is imputed as the first day of the 
year (01 Jan).  
 If only day is missing, and if the year and month are equal to the first dose date and AE 
end date is not before (<) the first dose, the AE start date will be imputed as the first dose 
date. Note: Partial missing / missing AE End date is considered as ‘not before/on first 
dose’. Otherwise, the day will be imputed as “01”. 
Imputation rules for the missing CM or MH onset date 
For partially missing CM or MH dates (missing day and/or month), the following imputation 
rules will be applied: 
 If CM or MH start date day and month are missing, the start date is imputed as the first 
day of the year (01 Jan) and impute the end date as the last day of the year (Dec 31).  
o If only day is missing, the start date is imputed as the first day of the month (01). 
Impute the end date as the last day of the month (28, 30 or 31 depending on month). Consider 
leap year.   
The imputed dates need to be capped by end of study dates, death dates, and cutoff dates when 
they are applicable.  
 


 
 
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16. 
REFERENCES 
 
 S. Elman, L.S. Hynan, V. Gabriel, and M.J. Mayo. The 5-Ditch scale: a new measure of 
pruritus.  Br J Dermatol. 2010 March; 162(3): 587-593. doi:10.1111/j.1365-
2133.2009.09586.x. 


 
 
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17. 
APPENDICES 
17.1. 
Study Schema and Schedule of Assessment  
Study Visits 
Screening 
Treatment Period 
Follow-up Period 
Week (W) 
W-4 to W0 
Baseline 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W10 
W12 
W14 
 
W16 
 
 
W18 
(EOS) 
Day (D) 
D -28 to -1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D71 
D85 
D99 
D113 
D127 
Study Procedures 
Windows 
(D) 
0 
1 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications, therapies, 
procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical examination1 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight, height, BMI2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
ECG (12-lead)3 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Adverse Events Monitoring 
From the Screening Visit through EOS Visit (Week 18) 


 
 
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Study Visits 
Screening 
Treatment Period 
Follow-up Period 
Week (W) 
W-4 to W0 
Baseline 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W10 
W12 
W14 
 
W16 
 
 
W18 
(EOS) 
Day (D) 
D -28 to -1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D71 
D85 
D99 
D113 
D127 
Study Procedures 
Windows 
(D) 
0 
1 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Concomitant 
meds/therapies/procedures 
monitoring 
 
From the Screening Visit through EOS Visit (Week 18) 
Subject Compliance assessment 
From the Screening Visit through EOS Visit (Week 18) 
Laboratory Tests 
Clinical laboratory blood tests 
          X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Pregnancy test4 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Serology (HIV, HBV, HCV)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing   
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration6  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Efficacy Measures  
Daily NRS Tool for assessment of 
pruritus and sleep 
Completed daily from the Screening Visit through EOS Visit (Week 18) 
Pruritus VAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep Loss VAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5-D Itch Scale 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
UAS7 
Completed daily from the Screening Visit through EOS Visit (Week 18) 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
SAP Version Draft 0.3 July 10, 2019            CONFIDENTIAL 
Page 30 of 42 
 
 
Study Visits 
Screening 
Treatment Period 
Follow-up Period 
Week (W) 
W-4 to W0 
Baseline 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W10 
W12 
W14 
 
W16 
 
 
W18 
(EOS) 
Day (D) 
D -28 to -1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D71 
D85 
D99 
D113 
D127 
Study Procedures 
Windows 
(D) 
0 
1 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
ItchyQoL 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
DLQI 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI=body mass index; DLQI=Dermatology Life Quality Index; ECG=electrocardiogram; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; ItchyQoL=Itchy Quality of Life; 
 PK=pharmacokinetic; 
UAS7=Urticaria Activity Score/over 7 days; VAS=Visual Analog Scale; WI-NRS=Worst itch numeric rating scale.   
1 At the Screening Visit and prior to dosing on Day 1, Week 8 and Week 18, a full physical examination will be performed including head/neck/thyroid, 
eyes/ears/nose/throat (EENT), skin, lymph nodes, respiratory, cardiovascular, gastrointestinal, musculoskeletal, and neurological exams.  Breast, 
anorectal, and genital examinations will be performed only if medically indicated.  At all other designated visits, an abbreviated physical examination 
will be performed including skin, cardiovascular, respiratory, and abdominal exams and as indicated based on subject’s symptoms.  A physical 
examination may be performed at any time if medically indicated per the Investigator’s medical judgment.  
2 Height will be measured, and BMI will be calculated only at the Screening Visit.  
3ECG and vital signs will be performed prior to blood draws, drug injections 
  ECG at Day 1 will be performed if it has been more than 
30 days since screening ECG. Vital signs will be measured every hour during the observation period on dosing days.   
4 Females of childbearing potential only.  A serum beta-human chorionic gonadotropin (βhCG) pregnancy test is performed at the Screening Visit.  A 
urine βhCG test is performed at all later time points.  A serum βhCG test is performed if urine βhCG test is positive. 
5Additional 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 On dosing days, all procedures will be performed prior to dosing.   
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
 
        
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
            
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
SAP Version Draft 0.3 July 10, 2019            CONFIDENTIAL 
Page 39 of 42 
 
 
17.8. 
Clinical Laboratory Tests 
Urinalysis 
Hematology 
Chemistry 
APPEARANCE 
ABS.BASOPHIL COUNT 
IGE 
BACTERIA 
ABS.EOSINOPHIL COUNT 
ALBUMIN 
BILIRUBIN 
ABS.LYMPHOCYTE COUNT 
ALKALINE PHOSPHATASE 
BLOOD 
ABS.MONOCYTE COUNT 
ALT 
CA OXALATE CRYSTALS 
ABS.NEUTROPHIL COUNT 
AST 
COLOR 
APTT 
BICARBONATE 
EPITHELIAL RENAL 
ATYPICAL LYMPHS 
BILIRUBIN, TOTAL 
EPITHELIAL SQUAMOUS 
BANDS 
BUN 
EPITHELIAL TRANSITIONAL 
BASOPHILS 
CALCIUM 
GLUCOSE 
BASOS 
CHLORIDE 
GRANULAR CAST 
BIZARRE PLATELETS 
CHOLESTEROL, TOTAL 
HYALINE CAST 
BLASTS 
CREATININE 
KETONE 
CALC.ABS.BASOPHIL COUNT 
GGT 
LEUKOCYTE ESTERASE 
CALC.ABS.EOSINOPHIL COUNT 
GLUCOSE, RANDOM 
NITRITE 
CALC.ABS.LYMPHOCYTE COUNT 
HDL-CHOLESTEROL 
PH 
CALC.ABS.MONOCYTE COUNT 
LDH 
PROTEIN 
CALC.ABS.NEUTROPHIL COUNT 
LDL-CHOLESTEROL 
RBC CAST 
DIFF COMMENT 
POTASSIUM 
RBCS 
EOS 
PROTEIN, TOTAL 
SPECIFIC GRAVITY 
EOSINOPHILS 
SODIUM 
TRI PHOSPHATE CRYSTALS 
FIBRINOGEN 
TRIGLYCERIDES 
URIC ACID CRYSTALS 
GIANT PLATELETS 
URIC ACID 
UROBILINOGEN 
HCT 
 
WAXY CAST 
HGB 
 
WBC CAST 
HYPERSEG.NEUTROPHILS 
Serology 
WBCS 
I.N.R. 
HEP B SURFACE AB 
YEAST 
LYMPHOCYTES 
HEP B SURFACE AG 
APPEARANCE 
LYMPHS 
HEP. C ANTIBODY 
BACTERIA 
MCH 
HEPATITIS B CORE AB 
 
MCHC 
HIV-1&2 AB SCREEN 
 
MCV 
 
Urine Drug Screen 
METAMYELOCYTES 
 
AMPHETAMINE 
MONOCYTES 
 
AMPHETAMINES 
MONOS 
 
COCAINE METAB CONF. 
MYELOCYTES 
 
COCAINE METABOLITES 
NEUTROPHILS 
 
METHADONE 
NUCLEATED RBCS 
 
METHAMPHETAMINE 
PLATELET COUNT 
Others 
OPIATES 
PLATELET ESTIMATE 
Hemoglobin A1c 
OXYCODONE 
PROMYELOCYTES 
FSH 
PHENCYCLIDINE 
PROTIME 
PREGNANCY, QUALITATIVE 
 
RBC 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
SAP Version Draft 0.3 July 10, 2019            CONFIDENTIAL 
Page 40 of 42 
 
 
 
RDW 
 
 
REACTIVE LYMPHS 
 
 
SEGS 
 
 
SMUDGE CELLS 
 
 
TOXIC GRANULATION 
 
 
UNCLASSIFIED 
 
 
WBC 
 
 
 
 
 
 
 
 
 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
SAP Version Draft 0.3 July 10, 2019            CONFIDENTIAL 
Page 41 of 42 
 
 
17.9. 
Statistical Methods and SAS Codes 
 
 Analysis of Covariance (ANCOVA)  
The primary and secondary endpoints of change and percent change from baseline value by week will be analyzed using ANCOVA. 
The ANCOVA model includes factors of treatment, sex, and baseline value as a covariate. The following is an example of the SAS 
codes used to perform the analysis. 
************************************************************************* 
* SAS Codes: ANCOVA model  
* Variables in the model:   
* chg = change from baseline in 
* trt = treatment group code 
* base = baseline value 
* week = visit  
************************************************************************; 
proc mixed data=eff; 
     by week; 
     class trt; 
     model chg = trt base; 
     lsmeans trt /pdiff cl; 
run; 
 
 Fisher’s Exact Test 
************************************************************************* 
* SAS Codes: Fisher’s Exact Test 
* Variables in the model:   
* resp = response variable (Y/N or 1/0) 
* trt = treatment group code 
* week = visit number 
*************************************************************************; 
proc freq data=dset order=data; 
     by week; 


 
 
Kiniksa Pharmaceuticals, Ltd. 
Protocol: KPL-716-C202 
 
SAP Version Draft 0.3 July 10, 2019            CONFIDENTIAL 
Page 42 of 42 
 
 
     table trt*resp / alpha=0.05; 
     exact relrisk fisher; 
     output out=outname exact;  
run; 
 




Signature Page for RIM-CLIN-001234 v1.0
Signature Page for RIM-CLIN-001234 v1.0
Approval
Aaron Young
Legal
01-Oct-2021 12:48:07 GMT+0000