Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Ixekizumab in Patients From 6 to Less Than 18 Years of Age With Moderate-to-Severe Plaque Psoriasis
Phase: PHASE3
Conditions: Plaque Psoriasis
Sponsor: Eli Lilly and Company

 
I1F-MC-RHCD(2.1) Clinical Protocol Addendum 
 
 
Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, 
Tolerability, and Efficacy of Ixekizumab in Patients from 6 to Less than 18 Years of Age with 
Moderate-to-Severe Plaque Psoriasis. 
 
NCT03073200 
 
Approval Date: 20-Jul-2017 
 
 

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1. Protocol Addendum I1F-MC-RHCD(2.1)
Multicenter, Double-Blind, Randomized, 
Placebo-Controlled Study to Evaluate Safety, Tolerability, 
and Efficacy of Ixekizumab in Patients from 6 to Less than 
18 Years of Age with Moderate-to-Severe Plaque Psoriasis
Confidential Information
The information contained in this protocol addendum is confidential and is 
intended for the use of clinical investigators.  It is the property of Eli Lilly and Company or 
its subsidiaries and should not be copied by or distributed to persons not involved in the 
clinical investigation of ixekizumab (LY2439821), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  This document and 
its associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4.
Ixekizumab (LY2439821)
This addendum is to be performed in addition to all procedures required by 
protocol I1F-MC-RHCD or any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum (2) Electronically Signed and Approved by Lilly:  
30 November 2016
Revised Protocol Addendum (2.1) Electronically Signed and Approved by Lilly
on date provided below.
Approval Date: 20-Jul-2017 GMT

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2. Table of Contents
Protocol Addendum I1F-MC-RHCD(2.1)
Multicenter, Double-Blind, Randomized, Placebo-Controlled 
Study to Evaluate Safety, Tolerability, and Efficacy of 
Ixekizumab in Patients from 6 to Less than 18 Years of Age 
with Moderate-to-Severe Plaque Psoriasis
Section
Page
1.
Protocol Addendum I1F-MC-RHCD(2.1) Multicenter, Double-Blind, 
Randomized, Placebo-Controlled Study to Evaluate Safety, 
Tolerability, and Efficacy of Ixekizumab in Patients from 6 to Less 
than 18 Years of Age with Moderate-to-Severe Plaque Psoriasis.........................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................4
4.
Protocol Additions ..............................................................................................................5
4.1.
Use of Etanercept during the Double-Blind Treatment Period 
(Period 2).......................................................................................................................5
4.2.
Double-Blind Randomized Withdrawal Period in Subjects in 
EU Countries .................................................................................................................8
5.
References ........................................................................................................................11

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List of Attachments
Attachment
Page
Attachment 1.
Protocol Addendum RHCD(2.1)
Schedule of Activities....................................................................................12
Attachment 2.
Protocol Addendum RHCD(2.1)
Study Design .................................................................................................19

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3. Rationale for Addendum
The following addition is being made to Protocol I1F-MC-RHCD (RHCD) for pediatric subjects 
with plaque psoriasis (Ps). This addendum is to be performed in addition to all procedures 
required by Protocol RHCD or any subsequent amendments to that protocol.
The following addition will apply in countries where etanercept is approved for severe pediatric 
psoriasis treatment only (emerging markets and European countries) and where subjects may be 
randomized to etanercept:

Period 2:  Double-Blind Treatment Period:  Where applicable, 30 subjects will be 
randomized to etanercept (Enbrel®), an open-label reference arm. Placebo will not be 
given to match etanercept. Subjects will only receive placebo to match ixekizumab.  To 
maintain statistical validity, a blinded assessor will conduct the efficacy assessments in 
countries where etanercept will be administered.  Subjects randomized to etanercept 
during the Double-Blind Treatment Period (Period 2) will begin treatment with 
ixekizumab during the 48-Week Open-Label Maintenance Period (Period 3) after an 
8-week washout period (to avoid increased risks with concurrent etanercept and 
ixekizumab exposures).
The following addition will also apply for subjects from European (EU) countries:

Period 4: 48-Week Double-Blind, Randomized Withdrawal Period:  Subjects from 
EU countries who meet the response criterion (defined as static Physician’s Global 
Assessment [sPGA] [0,1]) at Week 60 will be rerandomized to ixekizumab or placebo 
(1:1 ratio). Subjects who are rerandomized to ixekizumab will receive ixekizumab 20, 
40, or 80 mg every 4 weeks (Q4W) according to their weight at the time of 
rerandomization.  Upon disease relapse to Ps (sPGA ≥2), subjects will receive 
ixekizumab 20, 40, or 80 mg Q4W according to their weight.
The parent or legal guardian will sign the informed consent form (ICF), and the subject will sign 
the assent form prior to any study assessments, examinations, or procedures being performed.

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4. Protocol Additions
The underlined and strikethrough text in the following sections show the additions and deletions 
applicable to subjects participating in this addendum.  Additionally, the revised Schedule of 
Activities and study design figure are presented in Attachment 1 and Attachment 2, respectively.
4.1.
Use of Etanercept during the Double-Blind Treatment Period 
(Period 2)
4.
Objectives and Endpoints
Objectives
Endpoints
Other Secondary
to compare the efficacy of ixekizumab Q4W and
etanercept at Week 12 (Visit 7) as measured by PASI 75 
and by sPGA (0,1) in countries where etanercept is 
approved

proportion of subjects achieving PASI 75 at 
Week 12

proportion of subjects achieving sPGA (0,1) at 
Week 12
Abbreviations:  PASI 75 = at least a 75% improvement from baseline in Psoriasis Area and Severity Index score; 
Q4W = every 4 weeks; sPGA = static Physician’s Global Assessment.
5.1.
Overall Design

Period 2:  Double-Blind Treatment Period (Induction Period) will occur from 
Week 0 (baseline; Visit 2) to Week 12 (Visit 7) comparing ixekizumab to placebo
in a double-blind fashion and to etanercept (as a reference arm).

Period 3:  48-Week Open-Label Maintenance Period will occur from Week 12 
(Visit 7) to Week 60 (Visit 19).  Subjects randomized to etanercept during 
Period 2 will receive ixekizumab at doses of 20, 40, or 80 mg according to their 
weight after an etanercept 8-week washout period is complete. The etanercept 
washout period will be from Week 12 through Week 20.

Period 4:  Extension Period will occur from Week 60 (Visit 19) to Week 108 
(Visit 31).  Subjects from countries outside of the EU, irrespective of response,
and nonresponders from the EU will continue with open-label treatment with the 
ixekizumab dose received during the previous period (Period 3).  Subjects from 
the EU who meet response criteria (defined as those with sPGA [0,1]) will be 
rerandomized to ixekizumab or placebo in the Double-Blind, Randomized 
Withdrawal Period.  
(See Section 4.2 of this protocol addendum for details on the Double-Blind,
Randomized Withdrawal Period.)
5.1.2. 12-Week Double-Blind Treatment Period (Period 2)
Subjects randomized to etanercept will be administered etanercept 0.8 mg/kg, not exceeding 
50 mg per dose, every week from Week 0 through Week 11.

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7.1.
Treatments Administered
This study involves a comparison of ixekizumab administered by subcutaneous (SC) injection 
with placebo and with etanercept (as a reference arm).  The investigational product (Ixekizumab, 
etanercept, and placebo should be at room temperature when injected.  Possible injection sites 
include the abdomen, thigh, and upper arm (using the arm contralateral for blood samples for
PK).  The injection site should not be in a psoriatic lesion and should be rotated to another area 
for subsequent doses at the same visit.  Placebo will not be given to match etanercept.  To 
maintain statistical validity, a blinded assessor will conduct the efficacy assessments in countries 
where etanercept will be administered.
After training by the clinical staff, injections of etanercept will be self-administered by the 
subject or caregiver.
Training:  For training purposes, the proper procedures for preparation of the needed dose of 
etanercept and administration of the initial injection will be performed by clinical staff at Week 0 
(Visit 2).  Each subject must return to the clinical site for all injections and be trained to 
self-inject etanercept under the supervision of the investigator until the investigator judges the 
subject sufficiently competent to perform the self-injections independently.  After this time, the 
subject will be allowed to self-inject at home.
Administration:  If the subject is unable to perform the injection, a caregiver may inject 
etanercept to the subject.  In this case, the caregiver will also be trained to inject etanercept to the 
subject at the study site until the investigator judges the caregiver sufficiently competent to inject.  
All subsequent injections will be administered by the subject or caregiver.
Table RHCD.3 shows the etanercept treatment regimen.
Table RHCD.3.
Etanercept Treatment Regimen
Regimen
Dose
Week 0 through Week 11
Week 12 through Week 20
Etanercept
0.8 mg/kg, not exceeding 50 mg per 
dose
No injections because of the washout 
period
7.1.1. Packaging and Labeling
Etanercept (Enbrel®) will be supplied by the sponsor or its designee in accordance with cGMP.  
Etanercept will be supplied in 2 presentations to be administered based on subject weight: 

Powder for solution for injection in a single-dose vial and diluent for reconstitution.  
Each vial contains 25 mg of etanercept.

Solution for injection in a single-dose, prefilled, disposable manual syringe. Each 
syringe of etanercept is designed to deliver 50 mg of etanercept.

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7.2.
Method of Treatment Assignment
Subjects from countries where etanercept is approved for severe pediatric psoriasis treatment 
only (emerging markets and European countries) who meet all criteria for enrollment at Visit 1 
and Visit 2 will be randomized to double-blind treatment at Week 0 (Visit 2) in a 2:2:1 ratio to 
ixekizumab, etanercept, or placebo until approximately 75 subjects with severe psoriasis from 
etanercept-approved countries are randomized to ixekizumab (30 subjects), etanercept 
(30 subjects), and placebo (15 subjects).
7.3.
Blinding
Etanercept will be administered open label during Period 2 and a blinded assessor will be used 
(see Section 7.1).
7.5.
Preparation/Handling/Storage/Accountability
Instructions for the preparation of etanercept will be provided by the sponsor.
7.6.
Treatment Compliance
Etanercept:  The subject or caregiver will record information in a Study Drug Administration 
Log, including the date, time, and anatomical location of administration of etanercept (for 
treatment compliance); carton number; who prepared and administered the investigational 
product; and the reason if investigational product was not fully administered.
10.3.1. General Statistical Considerations
During the Double-Blind Treatment Period, approximately 75 subjects with severe psoriasis 
from etanercept-approved countries will be randomized to ixekizumab (30 subjects), etanercept 
(30 subjects), and placebo (15 subjects) in a 2:2:1 ratio.
Study RHCD (2) will have approximately 85% power to test the superiority of ixekizumab to 
etanercept for sPGA (0,1) and at least a 75% improvement from baseline in Psoriasis Area and 
Severity Index score (PASI 75) at Week 12 based on the 2-sided Fisher exact test at significance 
level of 0.05. The study will have approximately 45% power to test the superiority of etanercept
to placebo for PASI 75 at Week 12 based on the 2-sided Fisher exact test at significance level of 
0.05.  The following assumptions were used for the power calculations for both sPGA (0,1) and 
PASI 75 response rates based on ixekizumab clinical studies in adult subjects with 
moderate-to-severe plaque psoriasis (Ps) efficacy data (Griffiths et al. 2015; Gordon et al. 2016):  
80% responders for ixekizumab, 40% responders for etanercept, and 10% for placebo.

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Subjects with severe psoriasis in countries where etanercept is used as a reference arm will be 
included in the treatment comparisons of ixekizumab and etanercept for the Double-Blind 
Treatment Period.
For subjects with severe psoriasis in countries where etanercept is used as a reference arm, 
treatment comparisons in the proportion of subjects achieving PASI 75 or sPGA (0,1) at 
Week 12 will be analyzed using Fisher’s exact test.  Missing data will be imputed using the 
nonresponder imputation method (NRI).
Further details will be described in the SAP.
4.2.
Double-Blind Randomized Withdrawal Period in Subjects in 
EU Countries
4.
Objectives and Endpoints
Objectives
Endpoints
to assess whether ixekizumab Q4W is superior to 
placebo for EU subjects during the Double-Blind 
Randomized Withdrawal Period

time to relapse to moderate severity (sPGA ≥2) 
during the Double-Blind, Randomized Withdrawal 
Period

proportion of subjects achieving sPGA (0,1) at 
Week 108 (Visit 31)
Abbreviations:  Q4W = every 4 weeks; sPGA = static Physician’s Global Assessment.
5.1.
Overall Design

Period 4:
Extension Period will occur from Week 60 (Visit 19) to Week 108 (Visit 31).  
Subjects from countries outside of the EU, irrespective of response, and 
nonresponders from the EU will continue with open-label treatment with the 
ixekizumab dose received during the previous period.
OR
48-Week Double-Blind, Randomized Withdrawal Period will occur from Week 60
(Visit 19) to Week 108 (Visit 31) for subjects in the EU who meet the response 
criterion at Week 60 (defined as sPGA [0,1]). Subjects will be rerandomized to 
ixekizumab or placebo (1:1 ratio).
5.1.4. 48-Week Extension Period or Double-Blind, Randomized Withdrawal Period
(Period 4)
Subjects from EU countries who meet the response criterion at Week 60 (defined as sPGA [0,1]) 
will be rerandomized to ixekizumab or placebo (1:1 ratio) at Visit 19 (Week 60).  Subjects who 

I1F-MC-RHCD(2.1) Clinical Protocol Addendum
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are rerandomized to ixekizumab will receive ixekizumab 20, 40, or 80 mg every 4 weeks (Q4W) 
according to their weight at the time of rerandomization.  Upon disease relapse to Ps (sPGA ≥2), 
subjects will receive ixekizumab 20, 40, or 80 mg Q4W according to their weight.  Subjects from 
EU countries who do not meet the response criterion at Week 60 will continue with open-label 
treatment with ixekizumab.
7.2.
Method of Treatment Assignment
Subjects who meet response criteria (sPGA [0,1]) from EU countries will enter the Double-Blind 
Randomized Withdrawal Period and will be rerandomized to double-blind treatment at Week 60 
(Visit 19) in a 1:1 ratio to ixekizumab or placebo.  Subjects who are rerandomized to ixekizumab 
will receive ixekizumab 20, 40, or 80 mg Q4W according to their weight at the time of 
rerandomization.  Subjects from EU countries who relapse (sPGA ≥2) during the Double-Blind 
Randomized Withdrawal Period will receive open-label treatment with ixekizumab according to 
their weight at the time of relapse.
7.3.
Blinding
During the 48-Week Double-Blind, Randomized Withdrawal Period, subjects from EU countries
who meet the response criterion at Week 60 (defined as sPGA [0,1]) will be rerandomized to 
double-blind ixekizumab or placebo (1:1 ratio).
10.3.1. General Statistical Considerations
During the Double-Blind, Randomized Withdrawal Period (Period 4), approximately 40 subjects 
from EU countries will be rerandomized to ixekizumab (20 subjects) and placebo (20 subjects) in
a 1:1 ratio.  The response criterion for rerandomization is sPGA (0,1) at Week 60.
The study will have approximately 95% power to test the superiority of ixekizumab to placebo in 
time to relapse (sPGA ≥2) based on the 2-sided log-rank test at a significance level of 0.05.  The 
following assumptions were used for the power calculations:  20% relapse for ixekizumab and 
85% relapse for placebo. Relapse rates were estimated based on ixekizumab clinical studies in 
adult subjects with moderate-to-severe Ps efficacy data (Griffiths et al. 2015; Gordon et al. 
2016).
Unless otherwise specified, efficacy, health outcomes, and safety analyses for the Double-Blind, 
Randomized Withdrawal Period will be conducted on the Double-Blind, Randomized 
Withdrawal Period Population, defined as all rerandomized patients (i.e., subjects from countries 
in the EU who were rerandomized at Week 60) who received at least 1 dose of study treatment 
during Double-Blind, Randomized Withdrawal Period.  Patients will be analyzed according to 
the treatment to which they were rerandomized.

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Treatment comparisons of ixekizumab and placebo during the Double-Blind, Randomized 
Withdrawal Period will be performed for the Double-Blind, Randomized Withdrawal Period
Population.
The time to relapse (loss of response; sPGA ≥2) during Double-Blind, Randomized Withdrawal 
Period (Period 4) is defined as:
Time to relapse (days) = date of first sPGA ≥ 2 during Period 4 –
date of Week 60 rerandomization + 1.
If a patient has not experienced relapse (sPGA ≥2) by completion or early discontinuation of 
Period 4, the patient will be censored at the date of their last visit during Period 4.
The number of patients at risk and experiencing a relapse event by each scheduled visit during 
Period 4 will be presented by treatment group.  The Kaplan–Meier estimate of the proportion of 
patients relapsing will be presented for each visit.  Treatment group comparisons will be 
performed using the log-rank test.  For each treatment group, a Kaplan–Meier plot of the time to 
relapse will be provided.
Treatment comparisons in the proportion of subjects achieving sPGA (0,1) at Week 108 will be 
analyzed using Fisher’s exact test.  Missing data will be imputed using the NRI.
Further details will be described in the SAP.

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5. References
Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, Reich K, Amato D, Ball 
SG, Braun DK, Cameron GS, Erickson J, Konrad RJ, Muram TM, Nickoloff BJ, Osuntokun 
OO, Secrest RJ, Zhao F, Mallbris L, Leonardi CL; UNCOVER-1 Study Group; UNCOVER-2 
Study Group; UNCOVER-3 Study Group. Phase 3 trials of ixekizumab in moderate-to-severe 
plaque psoriasis. N Engl J Med. 2016;375(4):345-356.
Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, Cameron GS, Erickson
J, Zhang L, Secrest RJ, Ball S, Braun DK, Osuntokun OO, Heffernan MP, Nickoloff BJ, Papp 
K; UNCOVER-2 and UNCOVER-3 investigators. Comparison of ixekizumab with etanercept 
or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from 
two phase 3 randomised trials. Lancet. 2015;386(9993):541-551.

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Attachment 1.Protocol Addendum RHCD(2.1)
Schedule of Activities

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Screening (Period 1) and Double-Blind Treatment Period (Period 2)
Screening 
(Period 1)
Double-Blind Treatment Period (Period 2)
Randomization
Visit No (V)
V1
V2
V3
V4
Study Week
W0
W1
W2
W3
W4
W5
Study Days
(Approximately)
-30 to -7 d
0
7 ± 2d
14 ± 2d
21 ± 2d
28 ± 2d
35 ± 2d
Informed consent and assenta
X
Randomization
X
Dispense study drugi
X
X
X
Administer study drugj,k
Group 1:  IXE
40, 80, or 160 mg 
or placebo
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  IXE
20, 40, or
80 mg or 
placebo 
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Double-Blind Treatment Period (Period 2)
Double-Blind Treatment Period (Period 2)
Visit No (V)
V5
V6
V7
Study Week
W6
W7
W8
W9
W10
W11
W12
Study Days
(Approximately)
42 
± 2d
49
± 2d
56 ± 2d
63 ± 2d
70 ± 2d
77 ± 2d
84 ± 2d
Dispense IPi
X
X
Administer IPj,k
Group 1:  
no injections
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  IXE
20, 40, or 80 mg
or placebo
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  no 
injections
Group 2:  
etanercept
Group 1:  IXE
20, 40, 80, or 160 
mg or placebo
Group 2:  no 
injections

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Maintenance Period (Period 3)
Maintenance Period 
(Period 3)
Visit No (V)
V8
V9
V10
V11
V12
V13
V14
Study Week
W16
W20
W24
W28
W32
W36
W40
Study Days
(Approximately)
112 ± 7d
140 ± 7d
168± 7d
196± 7d
224± 7d
252± 7d
280± 7d
Dispense IPi
X
X
X
X
X
X
X
Administer IP
Group 1: IXE
20, 40, or 80 mg
Group 2:  no 
injections
Group 1:  IXE
20, 40, or
80 mg
Group 2:  IXE
40, 80, or 
160 mg
All subjects:
IXE 20, 40, or 80 mg

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Maintenance Period (Period 3) and Extension Period or Double-Blind, Randomized Withdrawal Period (Period 4)
Maintenance Period
(Period 3)
Extension Period or Double-Blind, Randomized Withdrawal Period
(Period 4)
Visit No (V)
V15
V16
V17
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
Study Week
W44
W48
W52
W56
W60
W64
W68
W72
W76
W80
W84
W88
W92
W96
Study Days
(Approximately)
308 ± 
7d
336 ± 
7d
364 ± 
7d
392 ± 
7d
420 ± 
7d
448 ± 
7d
476 ± 
7d
504 ± 
7d
532 ± 
7d
560 ± 
7d
588 ± 
7d
616 ± 
7d
644 ± 
7d
672 ± 
7d
Randomization
X
Dispense IPi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer IP
All subjects:  IXE 20, 40, or 80 mg
Group 1 (EU nonresponders and all OEU subjects):  Open-label IXE 20, 40, or 80 mgw
Group 2 (responders from EU countries):  Double-blind IXE 20, 40, or 80 mg or 
placebow

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Extension Period (Period 4) and Post-Treatment Follow-Up (Period 5)
Extension Period 
(Period 4)
Post-Treatment Follow-Up Period 
(Period 5)v
Visit No (V)
V29
V30
V31/ ETV
V801
V802
V803w
Study Week
W100
W104
W108
LV + 4W
LV + 12W
LV + 24W
Study Days
(Approximately)
700 ± 7d
728 ± 7d
756 ± 7d
± 4d
± 4d
± 4d
Telephone Visit
X
X
Dispense IPi
X
X
Administer IP
Group 1 (nonresponders and 
OEU subjects):  Open-label 
IXE 20, 40, or 80 mgw
Group 2 (responders from 
EU countries):  Double-blind
IXE 20, 40, 80 mg or placebow

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Schedule of Activities, Protocol I1F-MC-RHCD(2.1)
Abbreviations:  d = day; ETV = early termination visit; EU = European Union; IP = investigational product; IXE = ixekizumab; LV= date of last visit; 
OEU = outside the European Union; V = study visit; W = study week.
a
The parent or legal guardian will sign the informed consent form (ICF), and the subject will sign the assent form prior to any study assessments, examinations, 
or procedures being performed.  An ICF should be signed by the subject when the legal age is reached as determined by the country regulations.
i
For training purposes, the proper procedures for preparation of needed dose of etanercept and administration of the initial injection will be performed by 
clinical staff at Week 0 (Visit 2).  Each subject must return to the clinical site for all injections and be trained to self-inject etanercept under the supervision of 
the investigator until the investigator judges the subject sufficiently competent to perform the self-injections independently.  After this time, the subject will 
be allowed to self-inject at home. If the subject is unable to perform the injection, a caregiver may inject etanercept to the subject.  In this case, the caregiver 
will also be trained to inject etanercept to the subject at the study site until the investigator judges the caregiver sufficiently competent to inject.  All 
subsequent injections will be administered by the subject or caregiver. The subject or the caregiver will record information in the Study Drug Administration 
Log, including the date, time, and anatomical location of administration of IP (for treatment compliance); carton number; who administered the IP; and the 
reason if IP was not fully administered.
k
Group 1:  Subjects receiving ixekizumab 20 mg or 40 mg will receive 1 SC injection of ixekizumab at Week 0 (Visit 2) and 1 SC injection of ixekizumab 
Q4W at Weeks 4 and 8.  Subjects receiving ixekizumab 80 mg will receive 2 SC injections of ixekizumab at Week 0 (Visit 2) and 1 SC injection of 
ixekizumab Q4W at Weeks 4 and 8.
Subjects receiving placebo for ixekizumab 20 mg or 40 mg will receive 1 SC injection of placebo at Week 0 (Visit 2) and 1 SC injection of placebo Q4W at 
Weeks 4 and 8.  Subjects receiving placebo for ixekizumab 80 mg will receive 2 SC injections of placebo at Week 0 (Visit 2) and 1 SC injection of placebo 
Q4W at Weeks 4 and 8.
Group 2:  Subjects randomized to etanercept will receive etanercept every week (Q1W) at Week 0 through Week 11. After training by the clinical staff, 
injections of etanercept will be self-administered by the subject or caregiver, as described in Section 7.1.
u
All subjects receiving IP must enter into the Post-Treatment Follow-Up Period (Period 5) and complete through Visit 802.  Subjects may be followed beyond 
Visit 802 for continued monitoring of their neutrophil counts. If a subject discontinues IP early, the subject will complete the ETV and then enter the 
Post-Treatment Follow-Up Period (Period 5).
v
This visit will only occur if a subject’s neutrophil counts have not returned to the defined criteria.
w Group 1:  All subjects from non-EU countries and nonresponders from EU countries will receive 1 SC injection of ixekizumab Q4W.
Group 2:  Responders from EU countries will be rerandomized to either ixekizumab or placebo.  Subjects will receive 1 SC injection Q4W.  Subjects on 
placebo will receive ixekizumab upon disease relapse to psoriasis (sPGA ≥2).

I1F-MC-RHCD(2.1) Clinical Protocol Addendum
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Attachment 2.Protocol Addendum RHCD(2.1)
Study Design
The figure below illustrates the study design for Protocol Addendum I1F-MC-RHCD(2.1).

I1F-MC-RHCD(2.1) Clinical Protocol Addendum
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Abbreviations:  EU = European Union; LV = date of last visit; OEU = outside the European Union; Ps = plaque psoriasis ; Q1W = 
every week; Q4W = every 4 weeks; RW = randomized withdrawal; SC = subcutaneous; V = visit; W = weeks.
a
Randomization will be stratified by region (United States/Canada, EU countries, and rest of the world) and by etanercept 
approval status:  (1) Subjects with severe pediatric psoriasis (PASI ≥20 or sPGA ≥4) who are from countries where etanercept is 
approved for the treatment of severe pediatric psoriasis will be randomized to ixekizumab, etanercept, or placebo in a 2:2:1 ratio.  (2) 
Per the main protocol, all other subjects (including those with moderate-to-severe Ps [PASI ≥12 and sPGA ≥3] from countries where 
etanercept is not approved for the treatment of severe pediatric psoriasis and subjects with moderate pediatric psoriasis [(PASI ≥12 
to PASI <20) and sPGA = 3] in countries where etanercept is approved for the treatment of severe pediatric psoriasis) will be 
randomized to either ixekizumab or placebo in a 2:1 ratio.

I1F-MC-RHCD(2.1) Clinical Protocol Addendum
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b
At Visit 2, randomization will occur according to the following weight groups:  (1) <25 kg:  randomization to ixekizumab 
20 mg, receiving a starting dose of 40 mg; (2) 25 kg to 50 kg:  randomization to ixekizumab 40 mg, receiving a starting dose of 
80 mg; (3) >50 kg:  randomization to 80 mg, receiving a starting dose of 160 mg.  A staggered approach to enrollment by weight 
group will be implemented, with subjects aged 12 years or older and weighing >50 kg enrolling initially to the study.  After an initial 
safety analysis of the first 12 weeks of treatment of 15 subjects weighing >50 kg and if no safety concern is identified, subjects will 
start to enroll in the 25- to 50-kg group.  Once data for Week 12 for approximately 15 subjects in the 25- to 50-kg group is gathered, 
an interim analysis of PK, safety, and efficacy data for all subjects in the study at that point will be performed to confirm doses for 
future subjects in the study.  Once confirmed, all weight groups will be open for enrollment.
Protocol Addendum RHCD(2) Study Design
c
Subjects receiving ixekizumab 20 mg or 40 mg will receive 1 SC injection of ixekizumab at Week 0 (Visit 2) and 1 SC 
injection of ixekizumab Q4W at Weeks 4 and 8.  Subjects receiving ixekizumab 80 mg will receive 2 SC injections of ixekizumab at 
Week 0 (Visit 2) and 1 SC injection of ixekizumab Q4W at Weeks 4 and 8.
d
Subjects receiving placebo for ixekizumab 20 mg or 40 mg will receive 1 SC injection of placebo at Week 0 (Visit 2) and 
1 SC injection of placebo Q4W at Weeks 4 and 8.  Subjects receiving placebo for ixekizumab 80 mg will receive 2 SC injections of 
placebo at Week 0 (Visit 2) and 1 SC injection of placebo Q4W at Weeks 4 and 8.
e
Subjects will be randomized to receive etanercept 0.8 mg/kg and up to a maximum of 50 mg per dose.  All subjects will 
receive etanercept SC Q1W at Week 0 through Week 11.
f
Unblinded site personnel will prepare the doses of ixekizumab and placebo.
g
Subjects will initiate Maintenance Period as follows:  (1) Subjects randomized to the ixekizumab arm during Period 2 will 
receive 1 SC injection of ixekizumab and 1 SC injection of placebo at Week 12. (2) Subjects randomized to the placebo arm during 
Period 2 will be assigned to receive ixekizumab at doses of 20, 40, or 80 mg according to weight and will receive 2 ixekizumab 
injections as follows—subjects assigned to 20 mg will receive a starting dose of 40 mg; subjects assigned to 40 mg will receive a 
starting dose of 80 mg; subjects assigned to 80 mg will receive a starting dose of 160 mg.  All subjects will receive 2 SC injections
at Week 12.  (3) Subjects randomized to etanercept during Period 2 will receive no injections at Weeks 12 and 16.  At Week 20, 
subjects will be assigned to receive ixekizumab at doses of 20, 40, or 80 mg according to their weight.  Subjects assigned to 20 mg 
will receive a starting dose of 40 mg.  Subjects assigned to 40 mg will receive a starting dose of 80 mg.  Subjects assigned to 80 mg 
will receive a starting dose of 160 mg.  Treatment with ixekizumab is weight based.  If a subject changes weight category during the 
study and after the Double-Blind Treatment Period, the dose will be adjusted accordingly.
h
All subjects will receive 1 SC injection of ixekizumab Q4W.
i
Subjects from EU countries who meet the response criterion at Week 60 (defined as sPGA [0,1]) will be rerandomized to 
ixekizumab or placebo (1:1 ratio).  Subjects from EU countries who do not meet response criteria and subjects from non-EU 
countries will continue with open-label treatment with ixekizumab.
j
Subjects will receive ixekizumab upon disease relapse to psoriasis (sPGA ≥2).
k
All subjects receiving investigational product must enter into the Post-Treatment Follow-Up Period (Period 5) and complete 
through Visit 802.  Subjects may be followed beyond Visit 802 for continued monitoring of their neutrophil counts if needed or if 
determined by the sponsor/investigator that additional monitoring is needed.

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Revised Protocol Addendum
Note:
Deletions have been identified by strikethroughs.
Addition to I1F-MC-RHCD(2) Clinical Protocol have been identified by the use 
of underscore.
Additions to I1F-MC-RHCD(2.1) Clinical Protocol Addendum have been 
identified by the use of double underscore.
Attachment 2: Protocol Addendum RHCD(2.1) Study Design
a Randomization will be stratified by region (United States/Canada, EU countries, and rest of the world) and by 
etanercept approval status:  (1) Subjects with severe pediatric psoriasis (PASI ≥20 or sPGA ≥4) who are from 
countries where etanercept is approved for the treatment of severe pediatric psoriasis will be randomized to 
ixekizumab, etanercept, or placebo in a 2:2:1 ratio.  (2) Per the main protocol, all other subjects (including those 
with moderate-to-severe Ps [PASI ≥12 and sPGA ≥3] from countries where etanercept is not approved for the 
treatment of severe pediatric psoriasis and subjects with moderate pediatric psoriasis [(PASI ≥12 to PASI <20) 
and sPGA = 3] in countries where etanercept is approved for the treatment of severe pediatric psoriasis) will be 
randomized to either ixekizumab or placebo in a 2:1 ratio.
b At Visit 2, randomization will occur according to the following weight groups:  (1) <25 kg:  randomization to 
ixekizumab 20 mg, receiving a starting dose of 40 mg; (2) 25 kg to 50 kg:  randomization to ixekizumab 40 mg, 
receiving a starting dose of 80 mg; (3) >50 kg:  randomization to 80 mg, receiving a starting dose of 160 mg.  A 
staggered approach to enrollment by weight group will be implemented, with subjects aged 12 years or older and 
weighing >50 kg enrolling initially to the study.  After an initial safety analysis of the first 12 weeks of treatment 
of 15 subjects weighing >50 kg and if no safety concern is identified, subjects will start to enroll in the 25- to 
50-kg group.  Once data for Week 12 for approximately 15 subjects in the 25- to 50-kg group is gathered, an 
interim analysis of PK, safety, and efficacy data for all subjects in the study at that point will be performed to 
confirm doses for future subjects in the study.  Once confirmed, all weight groups will be open for enrollment.

Leo Document ID = b88f7f39-71e3-431d-a8f5-bfd9b5dfd793
Approver: 
Approval Date & Time: 19-Jul-2017 16:05:37 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 20-Jul-2017 13:03:12 GMT
Signature meaning: Approved
PPD
PPD