Clinical trial NCT03041038
Conditions: Ichthyosis Autosomal Recessive Congenital Ichthyosis Lamellar Ichthyosis Congenital Ichthyosiform Erythroderma Epidermolytic Ichthyosis Netherton Syndrome
Sponsor: Northwestern University
Start date: 2016-12-01; Completion date: 2020-08-31
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation. There are no therapies based on growing understanding of what causes the disease. However, there have been recent discoveries of marked elevations in expression of interleukin-17A (IL-17A) and IL-17-related cytokines in the skin of individuals with ichthyosis, which may explain the inflammation. Investigators propose that IL-17-targeting therapeutics will safely suppress the inflammation and possibly the other features of ichthyosis, improving quality of life.

Detailed description:
The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation. The vast majority are orphan disorders and are associated with extremely poor quality of life related to social ostracism from altered appearance, associated itchiness and discomfort, and functional limitations from the skin disease. Among the most common of these orphan disorders are autosomal recessive congenital ichthyosis (ARCI) with its phenotypic subsets of lamellar ichthyosis (ARCI-LI) and congenital ichthyosiform erythroderma (ARCI-CIE), epidermolytic ichthyosis (EI) and Netherton syndrome (NS). Therapy is time-consuming for patients or parents and is supportive, focusing on clearance of the scaling. There are no therapies based on growing understanding of what causes the disease. There have been recent discoveries of marked elevations in expression of interleukin-17A (IL-17A) and IL-17-related cytokines in the skin of individuals with ichthyosis, which may explain the inflammation. Psoriasis, another inflammatory skin disorder with redness and scaling, has now been shown to result from IL-17 pathway activation and IL-17A inhibition is the most effective therapy known to treat psoriasis. Investigators propose that IL-17-targeting therapeutics will safely suppress the inflammation and possibly the other features of ichthyosis, improving quality of life. In this long-term, open-label extension, Investigators propose to treat adults with ichthyosis and at least moderate erythema with subcutaneously administered anti-IL-17 antibody (secukinumab) and to serially assess clinical response to this therapy and its safety.

Arms: arm 1: Secukinumab 300mg (liquid formation) administered subcutaneously weekly for 5 weeks then monthly until end of trial arm 2: Placebo (sterile saline) 2ml administered subcutaneously weekly for 5 weeks then monthly until end of trial
Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Anti IL-17A antibody intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
1
   
STUDY TITLE: A Pilot Study to Evaluate the Efficacy and Safety of 
Secukinumab in the Treatment of Patients with Ichthyoses
 
Sub-Study: A Multicenter Study with a Randomized, Double-Blind, Placebo-
Controlled Period, Followed by an Open-Label Maintenance Dosing Period to 
Evaluate the Efficacy and Safety of Secukinumab in Patients with Ichthyoses
 
Principal Investigator:   
Amy S. Paller, M.D.
Department of Dermatology
Northwestern University
676 N. St. Clair Street, Suite 1600
Chicago, IL 60611
Telephone: (312) 695-3721 
Fax: (312) 503-5900
Email: apaller@northwestern.edu
 
Date: 14 July 2018
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
2
Table of Contents
Investigator’s Agreement…………………………………………………………………………............5
Study Glossary ………………………………………………………………………………....................6
Synopsis….………………………………………………………………………………………………...7
1. Background and Rationale....................................................................................................................11
1.1 Disease………………………………………………………………………………………..11
1.2 IL-17 and Ichthyosis……………………..……………………………………………….…11
1.3 Clinical Hypotheses………………………………………………………………………….12
1.4 Rationale for Secukinumab use………………………………………………………….…12
1.5 Rationale for choice of comparator………………………………………………………...12
1.6 Risk and benefits of Secukinumab…………………………………………………………12
2. Endpoints…………………………………………………………………………………………........14
2.1 Primary and Secondary Endpoints Double Blind/Open Label……….…………………14
2.2 Secondary Safety Endpoints….…………………………………………………………….15
2.3 Exploratory Endpoints……………………………………………………………………...15
2.4 Mechanistic Endpoints……………………………………………………………………...15
3. Investigational Plan……………………………………………………………………………………15
3.1 Study Design………………………………………………………………………………....15
3.2 Study Centers………………………………………………………………………………..16
3.3 Study Organization……………………………………………………………………….....16
3.4 Study Duration………………………………………………………………………...…….16
3.4.1 Screening Period………………………………………………………………….16
3.4.2 Double Blind Phase-(Baseline Visit-Week 16)………………………………….17
3.4.3 Crossover Phase (Week 16-Week 19)…………………………………...……18
3.4.4 Open Label Phase (Week 20-Week 52)…………………………………...……..18
3.5 Biomarker Analysis……….............………………………………………………………...18
4. Subject Eligibility…………………………………………………………………………………..…19
4.1 Inclusion Criteria…………………………………………………………………………...19
4.2 Exclusion Criteria…………………………………………………………………………..20
5. Treatment Procedures………………………………………………………………………………..20
5.1 Investigational Treatment…………………………………………………………………..20
5.2 Double Blind Phase Treatment Arms………………………………………………….…..21
5.2.1Double Blind Phase: Secukinumab Arm………………………………………..21
5.2.2 Double Blind Phase: Placebo Arm………………………………………….…..21
5.3 Crossover Phase…………………………………………………………………………....21
5.3.1 Open Label Phase………………………………………………………………………..22
5.4 Treatment Assignment, Randomization…………………………………………………...............22
5.5 Treatment Blinding…………………………………………………………………………22
5.6 Dispense and Use of Investigational Treatment…………………………………………...23
5.6.1 Dispensing the Investigational Treatment…………...……………………….…23
5.6.2 Instructions for Prescribing and Taking Study Treatment………….………...24
5.6.3 Prohibited Treatment………………………………………………………….....24
5.7 Subject Withdrawal/Discontinuation……………….……………………………………..24
5.8 Study Completion and Post-study Treatment……………………………………………..25
6. Visit Schedule and Assessments……………………………………………………………………....25
6.1 Screening Visit……………………………………………………………………………….25
6.1.1 Consent…………......……………………………………………………………..25
6.1.2 Medical and Medication History…………………………………………….......26
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
3
6.1.3 Vital Signs and Height……………………………………………......………….26
6.1.4 Complete Physical Exam……………………………………………..…....….....26
6.1.5 Genotyping……………………………………………………………..………....26
6.1.6 Infectious Disease Testing…………………………………....………..…………27
6.1.7 Pregnancy Testing……………………………………………..…….......………..27
6.1.8 Complete Blood Count and Clinical Chemistry Testing…………….......…..…27
6.1.9 Severity Evaluation……………..…………………………………….......………27
6.1.10 TEWL and Tape Strips…………………………………………………………28
6.1.11 Photography………………………………………....…………………………..28
6.1.12 Skin Swabs and Scrapings for Microbiome…………………………………...28
6.2 Data Collection at Subsequent Study Visits…………………………...…………………..29
6.2.1 Complete Skin Exam……………………………………………….......………...29
6.2.2 Serum Sample………………………………………………………....…………..29
6.2.3 DLQI and IQOL-32……………………………………………….……..…...…..29
6.2.4 Skin Biopsy……………………………………………………………...………...29
6.2.5 Adverse Events Assessment…………………………………………...…………29
6.3 Unscheduled Visits………………………………….......…………………………………...30
6.4 Sample Collection, Preparation, Labeling and Shipment ………………………………..30
6.4.1 Sample collection …………………………………………………………………30
6.4.2 Labeling and de-identifying specimens ………………………………….……...30
6.4.3 Transporting specimens to Mount Sinai Medical Center……………………...30
6.4.4 Specimen management…………………………………………………………...30
7 Safety Data Collection, Recording and Reporting…………………………………………………...30
7.1 Adverse Events………………………………………..........………………………………..31
7.2  Unblinding and Followup of Subjects with Serious Adverse Events…...……..….......…31
7.3 Serious Adverse Events……………………………………………………………...……...31
7.3.1 Definition of SAE………………………………………………………….......….31
7.3.2 SAE Reporting……………………………………………………………......…..32
7.4 Pregnancy Reporting………………………………...………………………….......………33
8 Data Review and Database Management……………...………………………………….………….34
8.1 Site Monitoring………………………………………………………………….......……….34
8.2 Data Collection………………………………………………………………….......……….34
8.3 Data Disclosure and Subject Confidentiality.......................................................................34
9. Data Analysis……………………………………………………………………………….………….35
9.1 Analysis Sets………………………………………………………………………....………35
9.2 Subject Demographics and Other Baseline Characteristics……………………....……..35
9.3 Efficacy Analysis ...................………………………………………………….......……….35
9.4 Safety Variables………………………………...........................……………….......……....36
9.5 Sample Size Consideration……………………………………………………......……..….37
9.6 Analysis of Reliability ………………………………………………………………………37
10. Ethical Considerations…………………………………………….......…………………...………...37
10.1 Informed Consent.................................................................................................................37
10.2 Consent Forms.........................………………….................................…………………....37
10.3 Responsibility of the Investigator and IRB/IEC………………….............................…...37
10.4 Publication of Study Protocol and Results...........................................................…....….38
11. Protocol Adherence……………...………….………………………………………………………..38
11.1 Protocol Amendments…………………………......………………………………………38
12 References……………………………………………………………………………………………..38
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
4
13 Supporting Docs
Figure 1.....................................................................................................................................................40
Figure 2.....................................................................................................................................................40
Appendix 1 - Schedule ofAssessments...................................................................................................41 
Appendix 2 – Ichthyosis Area Severity Index.......................................................................................42 
Appendix 3 – Congenital Ichthyosis Severity Index (CISI)  ..............................................................44 
Appendix 4 – Modified Congenital Ichthyosis Severity Index (m-CISI) ……………………………45
Appendix 5 – Bodemer Ichthyosis Scale................................................................................................46 
Appendix 6 – Yale Ichthyosis Severity Scale …………………………………………………………47
Appendix 7-- Dermatology Life Quality Index (DLQI).......................................................................49
Appendix 8-- Ichthyosis Quality of Life (IQoL-32).............................................................................51
Appendix 9-- 5-D Pruritus Scale............................................................................................................54
Appendix 10-- Numerical Rating Scale for Itch (Itch NRS).................................................................55
Appendix 11 – Photography Protocol…………………………………………………………………56
Appendix 12 – Microbiome Survey and Swab Protocol……………………………………………..60
 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
5
INVESTIGATOR’S AGREEMENT 
With the co-PI, I have created and read the final version of the following protocol: A Pilot Study to 
Evaluate the Efficacy and Safety of Secukinumab in the Treatment of Patients with Ichthyoses; and Sub-
Study: A Multicenter Study with a Randomized, Double-Blind, Placebo-Controlled Period, Followed by 
an Open-Label Maintenance Dosing Period to Evaluate the Efficacy and Safety of Secukinumab in 
Patients with Ichthyoses, dated 14 July 2018 and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Conference on Harmonisation Guideline for Good 
Clinical Practice relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on this study. 
I have received and reviewed the Full Prescribing Information for secukinumab (issued June 2018). 
I agree that the study is ethical. 
I agree to conduct the study as outlined and in accordance with all applicable regulations guidelines. 
I agree to maintain the confidentiality of all information received or developed in connection with this 
protocol. 
This document contains confidential information, which must not be disclosed to anyone other than the 
recipient study staff and members of the Institutional Review Board. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of all Principal Investigators. 
____________________________________________                             _________________ 
Signature of Investigator 
Date 
____________________________________________ 
Printed Name of Investigator 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
6
STUDY GLOSSARY
Abbreviation/Term
Definition/Explanation
AE  
  
  
Adverse Event(s)
AIC
Akaike Information Criterion
ARCI    
Autosomal Recessive Congenital Ichthyosis
CMP
Comprehensive Metabolic Panel
CBC
Complete Blood Count
CIE
Congenital ichthyosiform erythroderma
CIL  
  
Coded Identifier List
DLQI
Dermatology Life Quality Index
DCC
Data Coordinating Center 
DSMB
Data Safety Monitoring Board
EI
Epidermolytic ichthyosis
ECG
Electrocardiogram
FDA
Food and Drug Administration
FIRST
Foundation for Ichthyosis and Related Skin Types 
HIV
Human Immunodeficiency Virus
IASI
Ichthyosis Area Severity Index
IASI-E
Erythema subscore of Ichthyosis Area Severity Index
IASI-S
Scaling subscore of Ichthyosis Area Severity Index
IP
Investigational Product
IRB  
  
Institutional Review Board
ITT
Intention-to-treat
IQoL-32
Ichthyosis Quality of Life- 32 items
LI
Lamellar ichthyosis
LOCF
Last-Observation Carried Forward
m-CISI
Modified congenital ichthyosis severity index
mITT
modified Intention-To-Treat
MMRM
Mixed-effect Model Repeated Measures
NRS
Numerical Rating Scale
NS
Netherton syndrome
PASI
Psoriasis Area Severity Index
SAE
Serious Adverse Event
s.c.
Subcutaneous
TEWL
Transepidermal water loss
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
7
PROTOCOL SYNOPSIS 
Title: A Pilot Study to Evaluate the Efficacy and Safety of Secukinumab in the Treatment of Patients 
with Ichthyoses
 
Sub-Study: A Multicenter Study with a Randomized, Double-Blind, Placebo-Controlled Period, Followed 
by an Open-Label Maintenance Dosing Period to Evaluate the Efficacy and Safety of Secukinumab in 
Patients with Ichthyoses
Investigation Type: Drug
Study Type: Randomized Control Trial
Purpose and Rationale: The ichthyoses are a group of lifelong genetic disorders which share 
characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation. The vast 
majority are orphan disorders and are associated with extremely poor quality of life related to social 
ostracism from altered appearance, associated itchiness and discomfort, and functional limitations from 
the skin disease. Among the most common of these orphan disorders are autosomal recessive congenital 
ichthyosis (ARCI), Netherton syndrome (NS) and epidermolytic ichthyosis (EI). Therapy is time-
consuming for patients or parents and is supportive, focusing on clearance of the scaling. There are no 
therapies based on our growing understanding of what causes the disease. We have recently found marked 
elevations in interleukin-17A (IL-17A) and IL-17-related cytokines in the skin of individuals with 
ichthyosis, likely explaining their inflammation. Psoriasis, another inflammatory skin disorder with 
redness and scaling, has now been shown to result from IL-17 pathway activation and IL-17A inhibition 
is the most effective therapy known to treat psoriasis. We propose that IL-17-targeting therapeutics will 
safely suppress the inflammation and possibly the other features of ichthyosis, improving quality of life. 
We propose to treat adults with ARCI and at least moderate erythema with subcutaneously administered 
anti-IL-17 antibody (secukinumab) and to serially assess clinical response to this therapy and its safety. 
Primary objective: To evaluate the efficacy and safety of secukinumab in the treatment of ichthyosis (as 
determined by reduction in Ichthyosis Area Severity Index (IASI) at week 16, and by monitoring for the 
occurrence of bacterial/fungal mucocutaneous infection at week 16)
Secondary objectives: 
1.
To evaluate reduction in other skin severity assessments
2.
To evaluate improvement in quality of life assessments
3.
To evaluate the reduction in skin and blood IL-17A expression as a function of clinical response.
4.
To determine response biomarkers to secukinumab in treated patients.
5.
To define the cellular and molecular immune profiles of patients with ichthyoses. 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
8
These clinical indices will be assessed as per the Schedule of Assessments flowchart (Appendix 1) and 
require minimal input or time commitment from the study participants, but are critical to analyze trends 
with time.
Safety Objectives: Assess the short term (16 weeks) and long term (32 and 52 weeks) safety profile of 
secukinumab 300 mg s.c. in subjects with ARCI, NS and EI by monitoring for adverse events and 
deleterious alterations in clinical examination or clinical laboratory results.
Study Design: After the screening period (21-28 days), the study begins with a double blind trial of 
placebo compared to secukinumab. Subjects will be stratified by disease subtype (ARCI-CIE, ARCI-LI, 
EI and NS) in blocks of 4 and randomized in a 1:1 ratio of one subject treated with secukinumab to one 
subject treated with placebo for 15 weeks as follows: Each subject will receive secukinumab or placebo at 
Baseline (Day 0), weeks 1, 2, 3, 4, and every 4 weeks thereafter (week 8, week 12) until 15 weeks have 
elapsed. At week 16 all subjects will receive 300mg secukinumab. At week 17, 18, and 19 subjects will 
receive either secukinumab (if previously on Placebo) or Placebo (if on secukinumab originally), 
followed by open-label secukinumab 300mg every 4 weeks starting on week 20 up to week 48.  The final 
assessment will be the end of study visit (week 52). 
Visit 
Number
1
2
3
4
5
6
7
8
9
10
   11
12
COW1*
OLW1**
OLW4**
OLW12**
OLW20**
OLW28**
OLW32**
Screen 
(28 d-21 
d of Day 
0)
Baseline/ 
Day 0
Wk 4
Wk 8
Wk 
12
Wk 16
Wk 20
Wk 24
Wk 32
Wk 40
Wk 48
Wk 52
Drug 
supplied
0
4 doses
Due on 
week 0, 
1,2,and 3
1 
1
1
4***
1
2
2
2
1
6
*Crossover Week (COW): Crossover Week 1 dosing occurs in study visit. COW2-4 dosing occurs at 
subject home weekly.
**Open Label Week (OLW): Open label Weeks 1, 4, 12, 20, and 28 occurs in study visits. OLW8, 16, 
and 24 dosing occurs at subject home every 4 weeks. 
*** Because dose on week 16 is 300mg secukinumab and no placebo will be given for any patient on that 
week, two prescriptions must be written to differentiate the crossover dose on week 17, 18, and 19.
Multi-Center:
Yes
Number of Centers:
2
Blinding:
Observer-Blind
Yes
Subject-Blind
Yes
Double-Blind
Yes
Study Duration: The clinical portion of the study will include 1.5 years for patient recruitment and up to 
52 weeks of treatment, bringing the total maximum clinical study duration to 2.5 years. 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
9
Test Medication:
Secukinumab 300 mg s.c. (Cosentyx®) 
Control Medication: 
Placebo s.c. (supplied by Novartis)
Study Population: 
40 evaluable subjects
 
Subjects must be at least 18 years of age with a diagnosis of ARCI, EI or 
NS and must show at least moderate erythema. These subjects will 
primarily come from the east coast (around New York City) and 
Midwest (around Chicago), but will be open to any subjects who are able 
to comply with study requirements and meet criteria. 
Inclusion Criteria
●
Subject has provided informed consent
●
Subjects are at least 18 years of age or older at the time of screening.
●
Female subjects must not be pregnant or breast-feeding. Female subjects of child-bearing 
potential with a negative urine pregnancy test and using at least one form of contraception 
(abstinence allowed).
●
Subjects must have a confirmed diagnosis of ARCI-LI, ARCI-CIE, EI or NS (either genotype or 
willingness to be genotyped)
●
Subjects must be clinically judged to be immunocompetent.
●
Subjects will have no allergy to secukinumab, latex, or components of the product..
●Subjects will have baseline laboratory testing (normal or non-significant CMP, CBC, HIV 
negative, hepatitis B, C negative, QuantiFERON®-TB gold negative).
●
Subjects must have an erythema score of at least 18 on IASI and an IASI-E score of 12 (at least 
moderate severity of erythema) at baseline
Exclusion criteria
●
Subjects who are unable to give informed consent or assent.
●
Subjects without a confirmed diagnosis of ARCI, EI, or NS.
●
Subjects who have a known allergy to secukinumab or to latex.
●
Female subjects who are pregnant or who are considering becoming pregnant. 
●
Subjects who have prior biologic use targeting IL-17A/IL-17 receptor A or IL-12/IL-23 or who 
have prior use of TNF-alpha blockers.
●
Subjects who have used a systemic retinoid or systemic anti-ichthyosis agent within 4 weeks prior 
to initiation.
●
Subjects who have used topical retinoids or keratolytics within one week prior to initiation.
●
Subjects who have used emollient on the area to be biopsied in the previous 24 hours
●
Subjects who have a history or diagnosis of inflammatory bowel disease
●
Subjects who are on any systemic immunosuppressive agent (i.e. cyclosporine)
Duration of Treatment: 40 ichthyosis-affected adults will be studied up to 52 weeks. The study will 
include an initial 16 weeks 1:1 placebo: secukinumab double-blind, randomized control phase, followed 
by a 4 week crossover period and 32 weeks open-label phase to assure long-term safety.
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
10
Each subject will receive secukinumab or placebo at Baseline (Day 0), Weeks 1, 2, 3, 4, and every 4 
weeks on week 8 and week 12. Then at Week 16 all subjects will receive 300mg secukinumab.  For 
Weeks 17, 18, and 19, subjects if on secukinumab originally will receive 3 weekly injections of placebo. 
For Weeks 17, 18, and 19 subjects if  previously on placebo will receive 3 weekly injections of 
secukinumab. During the Open label, they will continue to receive injections every 4 weeks for 32 
additional weeks (up to week 48) with 4 weeks followup.
Treatment randomization scheme:
Week 0 -15            
Week 16
Week 17, 18, 19
Week 20 – 48 (OLW1-28)
Randomized according to 
table; blinded
Open label 
Crossover; blinded
Open label
         A
       A
    B
  A
         B
       A
    A
  A
*A=secukinumab  B=placebo
Efficacy Assessments 
●
IASI: Ichthyosis Area Severity Index and subscores (IASI-E, IASI-S)
●
CISI: Congenital Ichthyosis Severity Index
●
A modified CISI (m-CISI), a new global assessment tool (for validation but not secondary 
endpoint assessment)
●
Bodemer Ichthyosis Score (clinical burden of disease)
●
Yale Ichthyosis Severity Index
●
DLQI: Dermatology Life Quality Index
●
iQoL-32: Ichthyosis-specific Quality of Life, including emotional impact
●
5-D Pruritus Scale
●
Itch NRS: Numerical Rating System for pruritus
●
TEWL (transepidermal water loss): Functional assessment of barrier
Note the severity assessments will be performed in tandem but blindly and without conferring by two 
physicians (IASI, CISI, m-CISI, Bodemer, Yale) and the CISI and m-CISI as well by the subject, 
allowing inter-rater reliability assessment. By doing this assessment at screening and 3-4 weeks later at 
baseline for those subjects who have no significant change in intervention, we will be able as well to 
evaluate intra-rater (test-retest) reliability.
Safety Assessments
●
Adverse events and serious adverse events monitoring:  adverse events of special interest 
include infections, particularly occurrence of bacterial or fungal mucocutaneous infection
●
Laboratory assessments (e.g., hematology, clinical chemistry, urine pregnancy)
●
Vital signs, physical examination
Other Assessments
●
Photography
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
11
●
Skin biopsy (4.5 mm) for immunohistochemistry and mRNA expression (qRT-PCR) of 4 genes 
(IL-17A and three IL-17A induced genes for interpretation)
●
Serum samples for cytokine analysis
●
Skin swabs and scrapings to evaluate skin microbiome
●
Tape strips to evaluate skin proteomics and lipidomics
Data Analysis
Statistical analysis of all clinical and translational studies will be performed by  a statistician at the Icahn 
School of Medicine at Mount Sinai and .
The data from both centers that participate in this study will be combined for analyses. The primary 
analysis population will be based on a modified intention-to-treat (mITT) population, which is defined as 
all randomized patients who received at least one dose of the randomized treatment. Because the loading 
dose is given at baseline, this should effectively include all the randomized patients.
Efficacy and other data will be summarized. Descriptive statistics of demographics and other baseline 
characteristics will be presented for all subjects. For more details, refer to Section 9.2.  The primary 
efficacy variable is the IASI (composite) at Week 16. The primary safety variable is the occurrence of 
bacterial and fungal mucocutaneous infections by Week 16.  Differences in change over time between 
treatment and placebo will be assessed using a mixed-effect model repeated measures. Outcomes for 
weeks 0 to 16 for all the subjects from phase 1 and the outcomes for weeks 16 to 52 for subjects 
randomized with secukinumab in both phases will be considered. For more details, refer to Section 9.  
Safety will be evaluated by tabulations of adverse events and will be presented with descriptive statistics 
at each visit for each treatment group. The statistical evaluations will be organized by Treatment Phase 
(Weeks 0-16 and 16-48), and Post-Treatment Phase (weeks 48-52), as appropriate. AEs will be coded 
using the CTCAE, Common Terminology Criteria for Adverse Events, V 4.03. The number and 
percentage of subjects experiencing an AE/SAE will be stratified by system organ class, or a preferred 
term, and severity of the adverse event, and recorded and tabulated overall by each sub-strata. For more 
details, refer to Section 9.
Key Words: Ichthyosis, secukinumab, IL-17, biologic, monoclonal antibody
1. BACKGROUND AND RATIONALE 
1.1 Disease
The ichthyoses are a group of lifelong genetic disorders which share characteristics of skin thickening, 
scaling and underlying cutaneous inflammation. Other than ichthyosis vulgaris (commonly associated 
with atopic dermatitis) and recessive X-linked ichthyosis (1:1500 boys), the >20 subtypes of ichthyosis 
are rare (<1:100,000 individuals). Among these rare subtypes are 3 predominant forms: i) epidermolytic 
ichthyosis, resulting from a mutation in one of the genes encoding suprabasal keratins; ii) Netherton 
syndrome, resulting from mutations in SPINK5, leading to excessive epidermal protease activity; and iii) 
autosomal recessive congenital ichthyosis (ARCI). This last group usually first manifests at birth as a 
collodion baby (Figure. 1A), in which a shiny “collodion-like” membrane encases the neonate. Within the 
first month of life, this membrane skin peels, revealing during the subsequent months a generalized skin 
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appearance ranging from variable redness (erythema) underlying darker, plate-like scaling (lamellar 
ichthyosis or LI, Fig. 1B) to intense erythema with fine scaling (congenital ichthyosiform erythroderma or 
CIE, Figure. 1C). Biallelic mutations, largely in genes encoding epidermal lipoxygenases, ichthyin, 
transporter ABCA12, and transglutaminase 1, lead to the ARCI phenotype. All ichthyosis types share a 
defective protein and lipid barrier, which manifests functionally as increased transepidermal water loss 
and percutaneous absorption.
These forms of ichthyosis lead to life-long disfigurement due to the highly visible erythema and scaling. 
The quality of life of affected children and adults is poor, not only because of their appearance and social 
ostracism, but also because of the frequent associated itchiness (pruritus) and functional limitations 
related to the inflamed, often fissured skin and limited joint mobility related to skin tightness and pain. 
Affected individuals also have a markedly reduced ability to sweat, restricting sports and outdoor 
activities in warmer weather. 
Therapy for the ichthyoses is supportive and time-consuming for patients. Most use long baths, emollients 
and agents that peel the thick scale, specifically keratolytics and topical retinoids. Oral retinoids are most 
effective at removing scale and skin thickening, but tend to increase skin and mucosal inflammation and 
have potential side effects (most commonly hypertriglyceridemia, teratogenicity, and with chronic use 
hyperostosis). The high risk of systemic absorption of topical steroids (and side effects of systemic 
steroids) restricts their use for the cutaneous inflammation associated with these lifelong diseases. There 
remains a huge unmet need for more effective and safer treatments, ideally therapy that improves both the 
scaling and the cutaneous inflammation with its associated pruritus and discomfort. 
 
1.2 IL-17 in Ichthyosis 
While the underlying gene mutations in most forms of ichthyosis are now well delineated, explaining at 
least in part the barrier defect, the molecular mechanism underlying the inflammation and the skin 
thickening and scaling, which is presumed to be compensatory, is poorly understood. To explore the 
immune basis for the erythroderma, we have recently surveyed the skin of individuals with ichthyosis of 
known underlying genotype, characterized clinically as ARCI, Netherton syndrome or epidermolytic 
ichthyosis. Interestingly, all studied forms of ichthyosis showed a biomarker pattern in skin of Th17 
immune skewing (Fig. 2). In these patients, the mRNA expression levels of IL-17A and other IL-17 
induced genes (such as S100A’s, CXCL1, CCL20, and PI3/elafin) was dramatically increased in contrast 
to normal skin, and almost as high and sometimes higher than that seen in lesional skin from individuals 
with psoriasis, a common skin disorder in which the erythema and increased scaling are now recognized 
to be driven by Th17.  In psoriasis, neutralization of IL-17 by specific IL-17A antagonism leads to 75% 
disease reversal (“PASI75”) in 93% of treated subjects by 16 weeks (Thaci et al 2015) and is the most 
effective intervention to date for psoriasis (Nast et al 2015). Antagonism of this "polar" cytokine pathway 
seems to produce fewer adverse effects compared to broader immune antagonism (Thaci et al 2015); 
(Nast et al 2015); (Langley et al 2014). 
1.3 Clinical Hypotheses
We hypothesize that Th17 activation plays an important role in the erythema and possibly the thickening 
and scaling of ichthyosis. Furthermore, we posit that IL-17-targeting therapeutics will safely suppress the 
inflammation and possibly the other features, improving quality of life. We propose to treat adults with 
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ARCI and at least moderate erythema with subcutaneously administered anti-IL-17 antibody 
(secukinumab) and serially assess clinical response to therapy and its safety. Throughout the course of the 
intervention, we will sample blood and skin biopsies, which will support our interpretation of result and 
allow us to perform more comprehensive mechanistic studies. We hypothesize that: a) intervention with 
anti-IL-17 antibody therapy (secukinumab) will improve ARCI severity as a function of IL-17 
suppression; and b) the administration of secukinumab will be well-tolerated.
1.4 Rationale for Secukinumab Use
This proposal takes a commercially available medication that is indicated for a common IL-17-
driven inflammatory skin disease (plaque psoriasis) and applies it to treat an orphan disease based on our 
innovative discovery that IL-17 levels correlate with severity in ichthyosis. Indeed, we have biopsied 
upper arm skin of >20 patients with the typical generalized features of ARCI, EI or Netherton syndrome 
and found dramatic increases in IL-17A and IL-17A-induced cutaneous markers in ichthyotic skin (Fig. 
2A). Using a severity scoring system that rates overall score (Ichthyosis Area Severity Index or “IASI”), 
and subscores of erythema (“IASI-E”) and scaling (“IASI-S”) based on intensity (0-4+) and extent (see 
Approach), the composite IASI (total score) and IASI-E  (Fig. 2B) are highly positively correlated with 
levels of IL-17A and related genes. IASI-E showed the highest correlations with IL-17A (r=0.74, 
p<0.001) and related genes, such as CXCL1 (r=0.74, p<0.001), PI3 (r=0.71, p<0.001), S100A8 (r=0.71, 
p<0.001), S100A9 (r=0.69, p=0.001), S100A12 (r=0.68, p=0.001), DEFB4B (r=.56, p=.01),  and LCN2 
(r=0.5, p=0.02). IASI-E is also correlated with transepidermal water loss (TEWL), a functional measure 
of barrier deficiency (r=0.47, p=0.04). IASI was also highly correlated with IL-17A (r=0.51, p=0.01), 
CXCL1, (r=0.54, p=0.01), PI3 (r=0.69 p=0.001), S100A8 (r=0.67, p=0.001), S100A9 (r=0.62, p=0.002), 
S100A12 (r=0.58, p=0.006), and LCN2, (r=0.55, p=0.01), as well as with IASI-E (r=0.73, p<0.001). In 
addition to IASI-E, TEWL showed significant correlations with IL-17 related markers (e.g., DEFB4 
(r=0.65, p=0.004) and S100A12 (r=0.62, p=0.009)). Finally, K16, a marker of epidermal 
proliferation/hyperplasia also was highly positively correlated with IASI (r=0.63, p=0.002) and IASI-
E (r=0.56, p=0.008). The biomarker alterations of ichthyosis cluster distinctly without subclustering by 
ichthyosis subtype; the clustering of ichthyosis closely resemble that of psoriasis and is distant from 
atopic dermatitis (Fig 2C).
 
Secukinumab is commercially available, administered subcutaneously (no oral formulation), and routinely 
administered at a dosage of 300 mg; in the first 4 weeks, a weekly dosage is standardly given, followed 
by monthly administration. This dosage for psoriasis was based on dose-finding studies and has been 
shown to be of superior efficacy to other biologics for psoriasis (Thaci JAAD 2015).  Because the drug is 
already available commercially (for adults with psoriasis), significant clinical improvement in this first 
double-blind, randomized, controlled trial of a biologic for ichthyosis can translate into rapid availability 
for patients. However, the proposed work has several additional innovative dimensions. First, it will 
better define the relationship between increases in IL-17 and the cutaneous manifestations of ARCI. 
These insights will be critical to understanding whether IL-17 drives the erythema, pruritus and barrier 
defect (increased transepidermal water loss) of the ARCI group of ichthyoses. Our limited assessment in 
this proposal of the effect in skin of systemically-administered IL-17 antagonism will allow us to 
correlate clinical improvement with reduction in IL-17-induced products, which is key for interpreting our 
results. Complementary biomarker assessments (performed in Dr. Guttman’s laboratory) will allow us to 
more comprehensively correlate biomarker changes with clinical response. The proposal also gives us the 
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Date: 14 July 2018
       
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opportunity to validate 3 severity scales for ichthyosis, which will hugely facilitate future research and its 
interpretation.
1.5 Rationale for Choice of Comparator 
A placebo arm is necessary to obtain reliable efficacy and safety measurements. 
1.6 Risks and Benefits of Secukinumab
Previous studies using secukinumab have found the following risks associated with treatment:

Infections: In clinical trials, a higher rate of infections was observed in subjects treated with 
secukinumab (31%) compared to placebo (18%). In trials for moderate-severe plaque psoriasis, 
psoriatic arthritis, and ankylosing spondylitis, higher rates of common infections such as 
nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and 
mucocutaneous infections with candida (1.2% versus 0.3%) were observed with secukinumab 
compared with placebo. Given that individuals with ichthyosis have an increased risk of 
staphylococcal and fungal/candidal infections of the skin, there is a possibility that there may 
be more skin infections (beyond the known increase in mucosal candida infections), which will 
require vigilance.

Inflammatory Bowel Disease: Both exacerbations and new onset cases of this condition 
occurred in patients treated with secukinumab in trials for plaque psoriasis, psoriatic arthritis 
and ankylosing spondylitis 

Hypersensitivity Reactions: Anaphylaxis and cases of rash or urticaria occurred in 
secukinumab treated patients in clinical trials. The removable cap of the COSENTYX 
Sensoready pen and the COSENTYX prefilled syringe contains natural rubber latex which may 
cause an allergic reaction in latex-sensitive individuals (Novartis Full Prescribing Information 
2016) 

Pharyngitis, fatigue and peripheral edema were noted more in subjects receiving 3 doses of 
secukinumab when compared to subjects receiving 1 or 2 doses (Papp et al 2013)

Mild to moderate (Grade 1 or 2) neutropenia was noted in 12.1% of patients receiving regular 
s.c. injections of secukinumab. However, there were no AEs resulting from this neutropenia 
and no subjects were discontinued from treatment because of this (Rich et al 2013)

IL-17A blockade does not appear to interfere with protective antibody levels after vaccinations 
such as the meningococcal vaccine or the influenza vaccine (Chioato et al 2012) when 
comparing antibody levels in individuals who had received secukinumab s.c. to those who did 
not.  

Currently, there is no evidence that secukinumab imparts an increased risk of malignancy 
2. STUDY ENDPOINTS
2.1 Primary and Secondary Endpoints: Double Blind and Open-Label Phases
Primary Efficacy Endpoint: Reduction at week 16 in the Ichthyosis Area Severity Index (IASI)
Primary Safety Endpoint: Occurrence of bacterial or fungal mucocutaneous infection through week 16 
Secondary Efficacy Endpoints (evaluated at weeks 8, 12, 16, 32 and 52):
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
Reduction in the IASI-E at weeks 8,12 and 16 (double blind portion)

Reduction in IASI-S at weeks 8,12 and 16 (double blind portion)

Reduction in CISI (Congenital Ichthyosis Severity Index) for skin redness/ erythema at weeks 
8,12 and 16 (double blind portion) by subject and by physician assessors

Reduction in CISI (Congenital Ichthyosis Severity Index) for skin hyperkeratosis/ scaling at 
weeks 8,12 and 16 (double blind portion) by subject and by physician assessors

Reduction in composite and erythema scores of Yale Ichthyosis Severity Index at weeks 8,12 and 
16 (double blind portion) 

Reduction in the IASI-E at weeks 32 and 52 as compared to baseline (open label portion)

Reduction in IASI-S at weeks 32 and 52 as compared to baseline (open label portion)

Reduction in CISI (Congenital Ichthyosis Severity Index) for skin redness/ erythema by subject 
and by physician assessors at weeks 32 and 52 as compared to baseline (open label portion)

Reduction in CISI (Congenital Ichthyosis Severity Index) for skin hyperkeratosis/ scaling by 
subject and by physician assessors at weeks 32 and 52 as compared to baseline (open label 
portion)

Reduction in composite and erythema scores of Yale Ichthyosis Severity Index at weeks 32 and 
52 as compared to baseline (open label portion)

A 2-point reduction in CISI for redness/erythema at weeks 16, 32, and 52 

A 2-point reduction in CISI for scale/hyperkeratosis at weeks 16, 32, and 52

A 50% reduction in IASI at weeks 16, 32 and 52

A 50% reduction in IASI-E or IASI-S at weeks 16, 32 and 52

A 75% reduction in composite and individual IASIs at weeks 16, 32 and 52

50% Reduction in the Bodemer score, which heavily weighs associated morbidity (contractures, 
ectropion, mouth tightness, fissures) in addition to erythema, scaling and thickening (Bodemer et 
al. 2011) at weeks 16, 32 and 52

A 3-point reduction in patient-reported itch and pain (each on a 10 point scale) at weeks 16, 32 
and 52

Improvement in the 5-D itch score

Reduction in transepidermal water loss (TEWL), a functional measure of barrier, at weeks 16, 32 
and 52

Reduction in the Dermatology Life Quality Index (DLQI) at weeks 16, 32 and 52

Reduction in the iQoL-32 index at weeks 16, 32 and 52
Reduction in the above assessments stratified by subtype, severity, and gender
These clinical indices will be assessed as per the Schedule of Assessments flowchart (Appendix 1) and 
require minimal input or time commitment from the study participants, but are critical to analyze trends 
with time.
2.2 Secondary Safety Endpoints
●
Assess the short term (16 weeks) and long term (32 and 52 weeks) safety profile of secukinumab 
300 mg s.c. in subjects with ARCI, NS and EI by monitoring for adverse events, SAE’s, 
infections, or deleterious alterations in vital signs, other components of the physical examination, 
and clinical laboratory results
2.3 Exploratory Endpoints
●
To explore secukinumab exposure/response relationship
●
To explore the effect of treatment with secukinumab on laboratory parameters of interest (i.e. IL-
17)
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Date: 14 July 2018
       
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●
To explore change in mRNA expression levels of IL-17 and IL-17 induced genes as measured by 
gPCR
●
To explore the alterations in bacterial and fungal microbiome before and after secukinumab 
therapy
●
To explore self-administration of secukinumab
●
To explore the relationship between disease severity and evidence for metabolic disease
●
To explore the inter-rater reliability for severity assessments in the use for ichthyosis
2.4 Mechanistic Endpoints: 

Change in mRNA expression levels of IL17 and IL-17-induced genes as measured by qRT-PCR.
3. INVESTIGATIONAL PLAN 
3.1 Study Design
To determine the efficacy and safety of IL-17 blockade with secukinumab on the clinical severity and 
morbidity of ARCI, NS and EI we propose to perform a 52 week study in 40 affected adults. The study will 
include an initial 16-week double-blind, randomized control phase in which 1:1 placebo: secukinumab is 
administered through week 12 with final evaluation of effects and safety at week 16.  This double blind 
placebo controlled phase is followed by a 4 week crossover phase in which subjects who initiated placebo 
will be transitioned to active intervention, then a 32 week open-label phase. In this study, the “placebo,” 
which does not restrict bathing or emollient use, is “standard of care”, since many patients do not tolerate 
or use retinoids.
 
3.2 Study Centers
This study will be performed at two sites: the Department of Dermatology at Northwestern University 
Feinberg School of Medicine in Chicago and the Department of Dermatology at the Mt. Sinai School of 
Medicine in New York. Much of the clinical component will be performed and database housed at 
Northwestern University. Clinical research, statistical assessments, and biomarker tissue and molecular 
analyses of blood and skin will be performed at Mt. Sinai.
 
3.3 Study Organization
In this multiple Principal Investigator (PI) project, both PIs will be responsible for protocol development, 
consenting of subjects, performing skin biopsies, treatment and evaluation of subjects, review of adverse 
events, and reporting adverse events to the DSMB. Each site will have a project manager whose duties will 
include protocol development, grant administration for the individual study site, purchasing, case report 
form and source document design and development, and oversight of the project at the study site.  The 
project manager at Northwestern will also be responsible for grant applications and yearly reports, and a 
liaison to the NIAMS grant administration (including the scientific officer, clinical coordinator, and 
program director) and the grant administrator at Mt. Sinai. An independent study safety monitor at each site 
will be contracted to perform review of consents, serious adverse events, and source verification on a 
quarterly basis throughout the study. This independent safety monitor in each institution will also assure 
that the data are correctly gathered, recorded, and put together concisely and accurately for prompt 
submission to the DSMB.  The study safety monitors will work with the statistician to complete any 
unblinded statistical analysis for the DSMB reports.  Thus, the audit function at each site is independent of 
the study research team. Data will be entered by study coordinators in a central REDCap database based at 
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Northwestern (DCC). The Dermatology Clinical Trials Unit currently manages both international and 
national multisite REDCap databases. A designated data manager will manage and document all clinical 
data in REDCap, assuring the correct insertion and transfer of data, and aligning the institutions. The 
statistician will meet with the DCC every two months to discuss the progress of the study. In addition, an 
Executive Committee consisting of the Principal Investigators, the project managers and the study 
statistician will meet every other week by phone or Skype to address issues and ensure that all activities are 
moving forward in a coordinated manner.
 
3.4 Study Duration 
The clinical portion of the study will include 1.5 years for subject accrual to allow up to 52 weeks of 
treatment duration, including followup. Complete data analysis, including limited gene expression analysis 
in skin, and manuscript preparation will require another 6 months, bringing the total anticipated study 
duration to 3 years.
3.4.1 Screening Period
The duration of the screening period will be from three to four weeks (21-28 days).  Screening will be 
used to assess subject eligibility. Screening for infection or immunodeficiency (QuantiFERON, hepatitis 
B and C, HIV testing), Complete Metabolic Panel and CBC will be assessed at screening. 
3.4.2 Double blind- Phase 1 (Baseline visit -- Week 15)
The double blind phase is defined as baseline visit [day 0] through week 15. At the start of the double 
blind phase, 6 eligible subjects with ARCI-CIE, 6 with ARCI-LI, 6 with EI and 6 with  NS will be 
stratified by disease subtype in random blocks of 4 then randomized in a 1:1 ratio to one of two treatment 
arms (secukinumab 300 mg s.c. or placebo) via a randomization list. Neither subjects nor assessors will 
know to which group the subject is assigned. Subjects will be deemed eligible as per inclusion/exclusion 
criteria outlined in section 4. Secukinumab (300 mg) or placebo (2 syringes each) will be administered 
subcutaneously at Weeks 0, 1, 2, 3, 4, 8, and 12.  Weeks 0, 4, 8, and 12 will be administered by the 
subject (or a doctor) in clinic during study visits. Weeks 1, 2, and 3 will be administered by the subject (or 
a caregiver) at home. Subjects will be examined at in clinic study visits at Weeks 0,  4, 8, and 12. 
3.4.3 Cross-Over Phase-Phase 2 (Week 16 -- Week 19)
At Week 16, all subjects will be eligible to crossover into the second phase of the study, in which all 
subjects will receive secukinumab (300 mg). In order to maintain the initial blind and complete 4 months 
of treatment, subjects who had been randomized to secukinumab in the double blind phase will continue 
to receive secukinumab at a dose of 300 mg s.c. at Week 16. However, they will also receive  three 
placebo injections at Weeks 17, 18, and 19, so that neither the subject nor the assessor knows if the 
subject had received secukinumab or placebo in the double blind phase. Subjects, who had been 
randomized to placebo in the double blind phase, will receive four doses of secukinumab at a dose of 300 
mg s.c. at Week 16 to be administered on week 16, 17, 18, and 19 for loading. Weeks 16 will be 
administered by the subject (or a doctor) in clinic during study visits. Weeks 17, 18, and 19 will be 
administered by the subject (or a caregiver) at home. At Week 16, the primary endpoint will be assessed. 
Complete Metabolic Panel, and CBC at will be assessed at Week 16.  
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3.4.4 Open Label Phase- Phase 3  (Week 20-Week 52 or End of Study) 
At Week 20, subjects who have crossed over into the open label phase will receive 300 mg s.c. 
secukinumab at Week 20, 24, 28, 32, 36, 40, 44, and 48. Subjects will be examined at in clinic study 
visits at Weeks 20, 24, 32, 40, and 48. Weeks 20, 24, 32, 40, and 48 will be administered by the subject 
(or a doctor) in clinic during study visits. Weeks 28, 36, and 44 will be administered by the subject (or a 
caregiver) at home. The final in clinic study visit will be at Week 52 four weeks after the last dose for 
follow-up. Complete Metabolic Panel and, CBC at will be assessed at Week 32. Complete Metabolic 
Panel and CBC at will be assessed at Week 52 or End of Study.  
3.5 Biomarker, Microbiome and Metabolic Analyses
In order to identify the molecular and cellular immune profile of the ichthyoses at baseline and identify 
treatment response biomarkers, we include blood analyses at screening (if on a systemic retinoid), 
baseline, Week 8, Week 16, Week 32, and Week 52.  We will in parallel obtain punch biopsies (4.5 mm 
in diameter) from the upper arm (with the exception of week 8 to minimize biopsies for patients). If a 
patient terminates early, blood and biopsy will be obtained at that time. Of note, these patients have total 
body involvement (e.g., there is no “uninvolved skin”). The upper arm was chosen to be able to wrap with 
self-adherent wrap (such as Coban), since tape does not stick to ichthyotic skin.
Blood analyses of IL-17, IL-22 and IL-13 cytokines (by Singulex),chemokines (by MSD-a Th1, Th2 
panel, and O-linked proteomics will be performed at screening (if on a systemic retinoid), baseline, Week 
8, Week 16 or Early Termination visit, Week 32, and Week 52. Gene expression studies (RT-PCR and 
gene arrays) and immunohistochemistry of biopsy samples will be conducted. The expression levels of 
markers in different immune pathways, including: Th1 (IFN-gamma, CXCL10, STAT1), Th17 (IL-17, 
IL23p19, IL23p40, CCL20, CXCL1), Th2 (IL-13, IL-31, IL-10, CCL17, CCL18, CCL22), T22/IL-22 
cytokine and IL-17/IL-22 regulated S100s genes (S100A7, A8, A9), will be evaluated using RT-PCR. We 
will also assess for modulation of IL-17 regulated antimicrobial peptides (i.e LL-37, elafin, lipocalin 2, 
hBD2. DEFB4B, inflammatory markers (i.e MMP12, S100A12), and innate immune genes (IL1b, IL-8) 
by RT-PCR.  Skin expression studies will be correlated by cytokine/chemokine expression in the blood, 
as assessed by O-linked proteomic assessment of blood. Serum and RNA (Pax RNA) will be banked and 
frozen for later assessments based on unanticipated findings. 
Skin infiltration by T-cells, DCs, and neutrophils will be assessed by immunohistochemistry. The 
following markers will be used: CD3 and CD8 for T cells, langerin for Langerhans cells, CD11c for 
myeloid DCs, neutrophil elastase to identify neutrophils, and lipocalin 2 (LCN2). Epidermal thickness 
will also be assessed by immunohistochemistry. Finally, gene arrays, particularly the Affymetrix U133A 
Plus 2 gene array platform, will also be performed. This same platform is being used in our other studies 
involving AD, psoriasis and alopecia areata (AA) patients. 
Tape strips (noninvasive) will be taken at baseline, Week 8, Week 16 or Early Termination visit, Week 
32, and Week 52 for lipidomic and proteomic assessments of the outer epidermis from the dominant arm 
(opposite to the nondominant arm used for TEWL, microbiome and biopsy measurements) at a site the 
clinically appears similar. A buccal swab will be collected and banked for future pharmacogenomics 
studies. Given our goal of determining whether the increases in skin Th17 cytokines reflect only a 
response to the barrier defect (for their antimicrobial effect) vs. pathogenic in driving inflammation – as 
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well as to gauge alterations in microbial organisms as Th17 activation is suppressed by treatment, we will 
capture swabs for future microbiome assessment. Swabs for bacteria and fungi (including candida) will be 
obtained from the forehead, buttock and outer arm (near the biopsy site) at each visit, beginning at 
baseline. In flow studies of activated lymphocytes from patients with ichthyosis, we have recently found 
increases in blood levels of IL-22 cytokine, providing evidence of systemic activation of the IL-23/Th17 
pathway.  As a result, at baseline, Week 8, Week 16 or Early Termination visit, Week 32, and Week 52 
we will also evaluate fasting lipids, glucose and CRP (as well as measure waist circumference) to assess 
for metabolic abnormalities.
4. SUBJECT ELIGIBILITY
Subjects should be at least 18 years of age with a clinical diagnosis of ARCI-LI, ARCI-CIE, EI or NS.
The enrollment goal during the double-blind 16-week period will be at least 6 subjects each with ARCI-
LI, ARCI-CIE, EI and NS (total 24), and an additional 16 patients, evenly divided into placebo and 
secukinumab groups and ideally (but less importantly) fairly evenly divided among ichthyosis subtypes 
(all comers will be included). 
All screened subjects initially considered for this study will be documented. Pre-screening logs will be 
kept at each study site, and potential subjects will be contacted by the study site in closest proximity or 
with which the patient has previously been affiliated. If the subject is excluded from the study, reasons for 
exclusion will be documented in the pre-screening log. 
4.1 Inclusion Criteria
Subjects are qualified for enrollment if they meet the following criteria:
●
Subject has provided informed consent
●
Subjects are at least 18 years of age or older at the time of screening.
●
Female subjects must not be pregnant or breast-feeding.
●
Female subjects of child-bearing potential with a negative urine pregnancy test and using at least 
one form of contraception (abstinence allowed).
●
Subjects must have a confirmed diagnosis of ARCI-CIE, ARCI-LI, EI or NS (by genotype or 
willingness to be genotyped).
●
Subjects must be clinically judged to be immunocompetent.
●
Subjects will have no allergy to secukinumab, latex, or components of the product.
●
Subjects will have baseline laboratory testing (normal or non-significant CMP and CBC, and 
negative for HIV, hepatitis B and C, QuantiFERON®-TB gold)
●
Subjects must have an erythema score of at least 18 on IASI and an IASI-E score of 12 (at least 
moderate severity of erythema) at baseline.
4.2 Exclusion Criteria
Participants are ineligible for enrollment if they meet any of the following criteria:
●
Subjects who are unable to give informed consent or assent.
●
Subjects without a confirmed diagnosis of ARCI, EI, or NS.
●
Subjects who have a known allergy to secukinumab or latex.
●
Female subjects who are pregnant or who are considering becoming pregnant. 
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●
Subjects who have prior biologic use targeting IL-17A/IL-17 receptor A or IL-12/IL-23 or who 
have prior use of TNF-alpha blockers.
●
Subjects who have used a systemic retinoid or systemic anti-ichthyosis agent within 4 weeks prior 
to initiation.
●
Subjects who have used topical retinoids or keratolytics within one week prior to initiation.
●
Subjects who have used emollient on the area to be biopsied in the previous 24 hours
●
 Subjects who have a history or diagnosis of inflammatory bowel disease
●
Subjects who are on any systemic immunosuppressive agent (i.e. cyclosporine)
5. TREATMENT PROCEDURES 
5.1 Investigational Treatment 
The following study treatments will be used:
●
Investigational drug
○
Secukinumab is a fully human IgG1κ monoclonal antibody that potently binds to IL-17A 
and not to other sequences or structurally related cytokines. In vitro, it blocks the ability 
of IL-17A to bind to its receptor and signal.
○
Secukinumab 300 mg, liquid formation in single-use prefilled syringes (two 150 mg pre-
filled syringes for total of 300 mg dose)
●
Reference therapy
○
Placebo to 300 mg secukinumab s.c. for injection will be provided in matching pre-filled 
syringes that contain a mixture of inactive excipients, matching the composition of the 
secukinumab 300 mg dose. 
○
Placebo to secukinumab 300 mg, liquid formation in single-use pre-filled syringes (two 
syringes for placebo dose)
5.2 Double-Blind Phase with four stratified diagnoses/subtype of EI, CIE, LI, and NS
At the baseline visit [day 0] subjects will be randomized into one of two treatment arms in a ratio of 1:1. 
Each arm will have at least 3 ARCI-CIE subjects, 3 ARCI-LI subjects, 3 EI subjects, and 3 Netherton 
syndrome subjects; there will be an additional 8 subjects in each arm with randomization designed to 
ensure that there is even matching by ichthyosis subtype. 
5.2.1 Double-Blind Phase: Secukinumab arm
Subjects who meet eligibility criteria and have a normal baseline physical examination and laboratory 
testing will be enrolled in the double-blind phase. Each subject will receive 300 mg s.c. of secukinumab 
(administered in two pre-filled syringes) at Baseline (Day 0), Weeks 1, 2, 3, 4, 8, and 12. 
Injections will be performed at the site for the initial visit to train subjects in proper aseptic and 
subcutaneous injection technique (per Novartis Package Insert 2016).  Subjects will use the second 
syringe to demonstrate the ability to inject themselves.  After this baseline instruction and observation of 
injection technique, subjects will be able to self-administer weekly or monthly injections.  
We will contact subjects weekly by phone/Skype/FaceTime (subject will designate which is best) on 
weeks 1-3 to answer questions, assess compliance with administration, including proper disinfection of 
subject’s hands and administration site, as well as to ensure safety and return at week 4.  Subjects will 
keep a diary of administration dates and times (as well as use of emollients and baths), which will be 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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reviewed at each appointment. All subjects who receive at least one dosage will be counted in the ITT 
population.
Week 16 will be the final endpoint for efficacy assessment of the double-blind phase.
5.2.2 Double-Blind Phase: Placebo arm
Subjects who meet eligibility criteria and have a normal baseline physical examination and laboratory 
testing will be enrolled in the double-blind phase. Each subject will receive 300 mg s.c. of placebo using 
two pre-filled syringes at Baseline (Day 0), Weeks 1, 2, 3, 4, 8 and 12. 
Injections will be performed at the site for the initial visit to train subjects in proper subcutaneous 
injection technique.  Subjects will use the second syringe to demonstrate the ability to inject themselves.  
After this baseline instruction and observation of injection technique, subjects will be able to self-
administer weekly or monthly injections.  
We will contact subjects weekly by phone/Skype/FaceTime (subject will designate which is best) on 
weeks 1-3 to answer questions, assess compliance with administration, including proper disinfection of 
patient’s hands and administration site, and ensure safety and return at week 4.  Subjects will keep a diary 
of administration dates and times (as well as use of emollients and baths), which will be reviewed at each 
appointment. All subjects who receive at least one dosage will be counted in the ITT population. 
Week 16 will be the final endpoint for efficacy assessment of the double-blind phase and, at week 16, we 
will switch placebo-treated patients to secukinumab as all patients enter the open-label phase. 
5.3 Crossover Phase
Because patients and investigators cannot know if they received secukinumab or placebo initially and the 
subjects who crossover need to receive weekly injections in the first month, all subjects will receive 
secukinumab 300mg at Week 16, followed by 3 weekly (week 17, 18, 19) administrations (2 syringes) of 
either placebo  (if on secukinumab originally) or secukinumab (if previously on placebo).  
5.3.1 Open Label Phase
All subjects will then continue with injections of secukinumab 300mg at week 20 and every 4 weeks 
thereafter through 48 weeks, with the final assessment at 52 weeks (Appendix 1).  In person study visits 
will occur at Weeks 20, 24, 32, 40, 48, and 52. 
5.4 Treatment Assignment, Randomization
At the baseline visit [day 0] eligible subjects will be randomized.  A randomization number will be 
assigned to the subject which will be used to link the subject to a treatment arm. 
Subject Identification 
Subjects are numbered sequentially. Each subject will be assigned a unique number and will keep this 
number for the duration of the study. Subject numbers will not be reassigned or reused for any reason. 
Subjects should be identified only by their assigned identified code number. The investigator must 
maintain a subject master log linking the subject number to the subject’s name. The investigator must 
follow all applicable privacy laws in order to protect a subject’s privacy and confidentiality. 
Randomization 
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A centralized randomization system will be implemented at NU. After fulfilling the enrollment criteria, 
study participants will be randomized on day 0/baseline to secukinumab or placebo in a 1:1 ratio. 
Randomization will be stratified by disease subtype (ARCI-CIE, ARCI-LI, EI and NS) in random blocks 
of 4. We will not stratify by center due to the small sample size.
Codes will be sent from the data coordinating center (NU) and distributed to a licensed pharmacist at 
each study site.  Records of the code/seed used to generate the randomization will be kept.  The 
pharmacy and data management personnel will keep clinical Investigators blind through the study until 
all clinical data has being collected and recorded. A revision and quality control assessment of the 
collected data will be carried out. Once all data quality issues are sorted out, the data analysis stage will 
start and investigators will be unblinded. Laboratory personnel conduction assays for the mechanistic 
studies will be blinded.
5.5 Treatment Blinding
Subjects, investigator/site staff, individuals performing the assessment will not know the treatment 
assignment for individual subjects. This will be assured via the following methods:
-
The randomization schema will be kept confidential until implementation. 
-
During the trial, all study personnel will be kept blinded except for the pharmacist. 
-
In order for study participants to remain blinded, a research pharmacist at each site will be 
assigned the responsibility of an unblinded dispenser and give the test article to the investigator or 
designee for administration. 
-
The research pharmacist may not administer the test article to study subjects. 
-
Contact between the unblinded dispenser and study subjects would be kept to a minimum. 
-
The investigator, study coordinator, and any study participants other than the unblinded dispenser 
must not be allowed to know the test article assigned to any study subject and must not be 
allowed to see the randomization chart, test article containers, or treatment records.
-
The packaging, labeling, schedule of administration and appearance of secukinumab and placebo 
will be identical.
-
Unblinding 
In case of an emergency, when knowledge of the test article assignment is required for the medical 
management of an individual subject, the subject will be unblinded. The code should be broken only in 
the event of a medical emergency, when knowing the treatment assignment is absolutely necessary. The 
investigators will notify the DSMB within 24 hours after determining that it is necessary to unblind the 
treatment assignment. The DSMB can also decide to unblind. The investigator must also indicate in 
source documents and in the case report form that the blind was broken and provide the date, time, and 
reason for breaking the blind. Any AE or SAE associated with breaking the blind must be recorded and 
reported as specified in this protocol. 
A clinical data manager will assemble all the subject data by groups (treatment versus placebo) and the 
data safety monitoring board or the biostatistician may request the unblinding of subject treatment 
assignment for analyzing safety data, upon the appearance of unequal adverse events.
5.6 Dispense and Use of Investigational Treatment 
5.6.1 Dispensing the Investigational Treatment
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Both study sites will be supplied by Novartis with secukinumab and placebo.
Secukinumab (AIN457) and placebo syringes from Novartis will be shipped to a designated, licensed 
pharmacist at the investigational pharmacy of each study site. The blinded study drug will be supplied as 
AIN457 150mg/1ml or placebo with 2 syringes per box.  A removable tear-off label will be found on each 
box that identifies whether the box contains active drug or placebo.  The Pharmacy will remove that label 
before the syringes are dispensed. Only the pharmacy staff and unblinded DCC staff will be aware 
whether the subject is receiving active drug or placebo for the blinded portion of the study. The subject 
and research physician will be blinded until completion of the study.  The randomized code will be 
broken in the case of a Serious Adverse Event and unblinding for an individual subject may occur.
Open label drug will be provided for the open label portion of the study as Cosentyx ® 150mg/1ml with 
one syringe per box.  
When delivery of a test medication is received at the investigational site, the Pharmacist, or a member of 
their staff specifically authorized and delegated by the Investigator, will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the required documentation and returning it as 
instructed. The date, time and condition of the package should also be documented at the time of receipt. 
A copy of this documentation will be retained for the Investigator file.  Packaging, syringes, and 
medication appearance will be identical with the exception of the unique medication number on the label 
of the treatment packaging.  This individual must store the treatment according to instructions specified 
on the packaging. An accurate record of the shipment and dispensing of these study agents will be kept by 
the respective pharmacist at each site. All unused study material will be returned by study subjects to the 
dispensary site. 
5.6.2 Instructions for prescribing and taking study treatment 
Throughout the study, treatment (either secukinumab or placebo) will be administered subcutaneously 
either by the subject or by an approved individual. Prefilled syringes will be provided by the site staff to 
the subject. Initial injections will be performed at the site to train subjects in proper subcutaneous 
injection technique.  Study personnel will perform first injection with subject observing, then subjects 
will use the second syringe to demonstrate the ability to inject themselves.  After this instruction and 
observation, subjects will be able to self-administer weekly or monthly injections.  
We will contact subjects weekly by phone/Skype/FaceTime (subjects will designate which is best) on 
weeks 1-3 to answer questions, assure adherence to administration, and ensure safety and return at week 
4. Subjects will keep a diary of administration dates and times, which will be reviewed at each 
appointment. All subjects who receive at least one dosage will be counted in the ITT population.  
Injections are to be administered at a different anatomic location (such as dominant upper arm, thigh, or 
any quadrant of the abdomen except for 2 inches around the navel area) than the previous injection. 
Subjects may not self-inject upper outer arm but this area may be used by caregiver or healthcare provider 
for injection. Injections should not be given in areas where the skin is tender, bruised, erythematous, or 
indurated if possible. 
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Product: Secukinumab
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5.6.3 Prohibited treatment
Subjects should not receive live vaccines during this study. They may not use any topical agent for the 
treatment of ichthyosis other than over the counter emollients. They may not be on any systemic agents 
for the treatment of ichthyosis. Subjects who experience skin infection requiring antibiotics during the 
study will not be discontinued from study drug or withdrawn from the study. The therapies they require 
will be noted by investigator on the case report form. 
5.7 Subject Withdrawal/Discontinuation
Subjects will be evaluable if they complete all required assessments and visits through and including 
Week 16.  If subjects fail to return for study visits, or become lost to follow up, subjects will be 
considered withdrawn. The PI and/or designated study staff will attempt to follow up with these 
individuals to discern the reason for their non-compliance. Similarly, if subjects choose to discontinue 
their participation in the study, study staff will attempt to contact the subject to determine their reason for 
discontinuation. The subject may also be discontinued by the PI for lack of efficacy.
Study treatment must be discontinued and the subject withdrawn if the investigator believes that 
continuation would compromise the subject’s well-being. Treatment must be discontinued under the 
following circumstances:
●
Occurrence of any AEs determined by the PI to prevent subject continuation with treatment
●
Neutrophil count is less than 1000 or less than 1500 accompanied with fever
●
Pregnancy
●
Use of prohibited treatment
●
Emergency unblinding 
Subjects who discontinue study treatment will return at next scheduled visit to undergo an end of study 
visit and then be discontinued from the trial. 
5.8 Study Completion and Post-study Treatment 
Study participation is completed for the subject at the conclusion of their week 52 study visit. Adverse 
events that occur within 30 days of this visit must be documented and reported by the PI. 
The study as a whole will be completed when all 40 randomized subjects have completed their 52 week 
treatment course as per the protocol and the complete data analysis, including limited gene expression 
analysis in skin has been performed. 
Upon completion of their study participation, subjects will return to individual treatment, as determined 
by their regular treating physician. 
6. VISIT SCHEDULE AND ASSESSMENTS 
Appendix 1 lists the assessments and indicates with an “X” when the visits are performed. Subjects 
should be seen for all visits on the designated day or as close as possible to the original planned visit 
schedule (recommended visit windows are provided in Appendix 1). Special respect and effort for the 
baseline, week 8, week 16, week 32, and week 52 visits should be made. 
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Date: 14 July 2018
       
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In the event that subjects do not present for their study visit, study staff will document their attempts to 
contact these individuals. 
6.1 Screening Visit
The screening visit is to be performed within 21-28 days of baseline visit [day 0]. After providing 
informed consent, subjects will be assessed for study eligibility at the screening visit (day -28 to day -21), 
which includes blood tests, infection screening, assessment of vital signs, assessment of skin severity 
scores, genotyping, photography, skin swabs and scrapings, and pregnancy test (if applicable).
6.1.1 Consent 
Consent will be obtained by the study investigator or by approved study staff at the screening visit (visit 
1) as indicated in Appendix 1. All participants will be given time to read the pre-approved consent forms, 
and ask any questions they may have. The consenter will emphasize that the study is voluntary. Consent 
forms will be kept in a designated study office in a locked drawer. 
6.1.2 Medical and Medication History
A PI or designated study staff member will collect information regarding relevant medical history/current 
medical conditions excluding ARCI-LI, ARCI-CIE, NS or EI at every study visit as indicated in 
Appendix 1. All collected information will be documented. When possible, diagnoses (rather than 
symptoms) will be recorded. The history regarding ARCI-CIE, ARCI-LI, NS or EI will also be obtained 
including date of diagnosis and prior treatments. Medications including current medications and those 
taken within six months preceding enrollment will be recorded. Particular attention must be paid to any 
history of joint pain and IBD (history of diarrhea/constipation, bloody/painful stool, increased 
gas/bloating). Attention should also be paid to current treatments for ichthyosis (including bleach baths, 
any recent topical or systemic antibiotic use, skin care regimen and use of any topical or systemic 
medication). 
6.1.3 Vital Signs and Height
Vital signs, including blood pressure, pulse, respiratory rate, temperature, weight will be collected at 
every study visit for all subjects as indicated in Appendix 1. Height will be recorded at the first visit as 
indicated in Appendix 1. 
6.1.4 Complete Physical Examination
A complete physical examination will be performed by a physician or a qualified, licensed healthcare 
professional. A full examination will occur at the screening and baseline visits, as well as Weeks 16, 32, 
and 52; a full skin exam including measurement of TEWL will occur at visits 2-12 as indicated in 
Appendix 1. TEWL will be measured at upper outer arm near biopsy site and upper buttock. Waist 
circumference will be measured at baseline, weeks 16, 32, and 52.  Additional exam components and 
maneuvers may be necessary depending on presenting symptomatology and are at the discretion of the PI 
or study staff. Results will be documented in the Medical History if present before signing the informed 
consent. If examination shows abnormal findings that meet criteria for an AE after the informed consent 
form has been signed and the subject has been enrolled with study drug initiation, these findings will be 
documented as such in the subject’s file. 
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Date: 14 July 2018
       
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6.1.5 Genotyping & Genetic testing
At Northwestern University, all patients must either have known genotype available to the investigator or 
agree to be separately consented to undergo saliva-based DNA testing as offered at no cost by Dr. Keith 
Choate at Yale on a research basis; the investigator will know the mutated gene, but not the exact 
mutation and will be able to report this information to the subject. Consent will be per Lurie Children’s 
Hospital Institutional Review Board-approved project STU00202786 under Dr. Paller.  Sampling for Dr. 
Choate will be performed by saliva collection.  
At Mt. Sinai, subjects’ genotype information will be collected only if already available (i.e. subject can 
provide documentation).  
In addition, buccal swabs will be collected at screening visit for banking (e.g., potential 
pharmacogenomics) at both sites.  
6.1.6 Infectious Disease Testing
Testing for HIV, hepatitis B and C, and quantiferon gold testing for tuberculosis (TB) will be performed 
at the site of screening (Northwestern or Mt. Sinai) for all subjects at visit 1 as indicated in Appendix 1. A 
blood draw by a trained phlebotomist will be necessary for HIV, hepatitis B and C testing. Subjects must 
have negative testing for all infectious diseases tested to be randomized. If the subject has an 
indeterminate QuantiFERON®-TB gold, the test may be repeated once. If the result is positive or remains 
indeterminate, the subject may not participate in the study.  Patients will be referred for any positive or 
indeterminate rest result to an appropriate physician for management. If the subject has been treated in the 
past for active or latent TB, they will be excluded from the study.
Should there be suspicion of an infectious complication (such a bacterial or fungal/candida infection), the 
area will be photographed for documentation, and infection confirmed by culture as appropriate. 
6.1.7 Pregnancy Testing
All female study subjects will be tested for pregnancy at the baseline and end study visits as indicated in 
Appendix 1. Urine HCG testing will be obtained. Any woman with a confirmed positive pregnancy test 
during screening is not eligible for randomization and participation in this study. 
6.1.8 Complete Blood Count and Clinical Chemistry Testing 
A blood draw by a trained phlebotomist at visits 1, 2, 4, 6, 9, and 12 as indicated in Appendix 1. As per 
the schedule, hemoglobin, hematocrit, platelet count and white blood cell count with differential will be 
measured. Additionally, hepatic transaminases, blood urea nitrogen, creatinine, sodium, potassium, 
chloride, bicarbonate and glucose will be measured. At visits 2, 4, 6, 9, and 12 fasting lipids, glucose and 
C-reactive protein (CRP) will be measured.  
6.1.9 Severity Evaluations (Appendices 2-6, 9, 10)
Severity evaluations will be performed at every study visit. Severity assessments will be performed by: 
Ichthyosis Area and Severity Index (IASI), Congenital Ichthyosis Severity Instrument (CISI), a modified 
CISI (m-CISI), the Bodemer scoring system (Bodemer et al 2011), and the Yale Ichthyosis Severity 
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Index.  CISI is a validated score that assesses individual scores for erythema, scaling and alopecia, but is 
limited in that it is not a single score, includes a feature found in the minority of patients (alopecia) and 
includes non-uniform Likert scales (0-4+ or 0-5+). M-CISI eliminates the alopecia score, adopts a 5-point 
Likert for erythema and scaling, and averages the erythema and scaling scores for a single global 
assessment; it is a new scale that is being validated herein but will not be used for endpoints. IASI is a 
composite score based on the global CISI score that captures differences in severity in different body 
regions as a function of their body surface area and also standardizes the number of choices within the 
Likert scales for erythema and scaling. As in the EASI score for AD and the PASI score for psoriasis, 
IASI evaluates erythema and scaling as 0-4+ in severity at each of 4 locations: head and neck (including 
scalp); arms (including palms); legs (including soles); and trunk, prorated based on body surface area in 
these sites and the percentage of involvement in each of these sites (total possible score for each is 24 and 
total composite score is 48).  To include a patient-reported severity score, we will use the Congenital 
Ichthyosis Severity Index, which has been validated for patient use (Kamalpour et al 2010), and the m-
CISI. We will also pilot in the US a complex, non-validated burden of disease scoring system proposed 
by Bodemer et al in France, which heavily weighs associated morbidity (contractures, ectropion, mouth 
tightness, fissures) in addition to other measures of severity. All investigators/ sub-investigators will be 
trained based on photographs before study initiation to uniformly assign CISI, m-CISI, Bodemer, and 
IASI scores. A huge issue is the paucity of validated scores for ichthyosis severity. Our evaluations will 
be performed concurrently (but without conferring) by two investigators to allow inter-rater reliability, as 
well as at screening and again at baseline (at 3-4 weeks to minimize recall bias) for assessing test-retest 
reliability.  As such, we hope to use this opportunity to assess reliability in these un-validated instruments. 
Patient-reported itch will be quantified on a 0-10 numerical rating scale (NRS) and by 5-D itch score 
(Elman et al 2009); a 1-10 score pain assessment is part of the Bodemer scale. The Yale Severity Index 
was recently developed and tested at a recent meeting of the Foundation for Ichthyosis and Related Skin 
Types. It includes a 0-4+ scale for erythema and for scaling, and provides pictorial representations for 
comparison, dividing scaling into lamellar and keratoderma scale scores. This study is the first time it will 
be applied to patients in an investigation.
6.1.10 TEWL and Tape Strips
TEWL will be performed at the biopsy and skin swab sites (nondominant arm and upper buttocks) to 
assess the skin barrier at visits 2-12. Tape strips will be also be obtained from ichthyosis subjects at 
baseline and weeks 8, 16, 32 and 52. Tape strips are purchased from CuDerm. Tape stripping will be 
performed on the dominant upper outer arm (same sites serially) using circular 2x2 or 3x3 cm transparent 
tape strips at lesional skin sites for each patient or unaffected skin site for controls. The tape strips will be 
used for detection of alterations of epidermal lipids and proteins in the outer stratum corneum of 
epidermis. We will be sending tape strips for proteomics and lipidomics analysis to the laboratories at Mt. 
Sinai/Rockefeller University medical center under the supervision of Dr. Emma Guttman and other 
designated laboratories. Alternating tape strips will be obtained for these analyses. Equal pressure will be 
applied to affected areas for 10 seconds. Up to 32 tape strips will be serially extracted on skin sites. Tape 
stripping is painless and, in our experience and that of the literature, has no adverse sequelae.
6.1.11 Photography (Appendix 11)
Photography will be done at study visits 1-12 as indicated in Appendix 1. Photos will be labeled using 
subject’s study ID as well as subject visit number and date of the photo.  Photos will be uploaded to a 
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secure, password-locked file per institutional Data security Plan and deleted from the camera memory 
card as soon as possible. 
6.1.12 Skin Swabs and Scrapings for Microbiome (Appendix 12)
Skin swabs and scrapings will be collected at visits 1-12. Subjects will be instructed to not bathe, shower, 
or apply any topical product to the area that will be tested 24 hrs before the visit.  Vigorous activity will 
also be minimized for several hours prior to swab. A questionnaire will be administered along with 
swabs. Swabs and scrapings will be collected from the nondominant side at upper outer arm (at biopsy 
and TEWL site), upper buttock, and scalp.  Swabs will be labeled with the subject’s study ID, study visit 
number, and visit date.
6.2 Data Collection at Subsequent Study Visits
Study visits including baseline visit [day 0] and visits 1-12 will occur at one of the study sites (Appendix 
1)
6.2.1 Complete Skin Examination
A targeted exam (necessary components determined by PI or qualified study staff) will occur at visits 2-
12 as indicated in Appendix 1.  Additional exam components and maneuvers may be necessary depending 
on presenting symptomatology and are at the discretion of the PI or study staff. If exam findings occur 
after the informed consent form has been signed and meet the criteria for an AE, they will be documented 
as such in the subject’s file. 
6.2.2 Blood Samples for Biomarkers
A blood sample will be collected at screening (if on a systemic retinoid) and visits 2, 4, 6, 9, and 12 as 
indicated in Appendix 1 for biomarkers and RNA analysis.  A blood draw by a licensed phlebotomist will 
be collected by study staff. Serum samples will be labeled with the subject’s study ID, study visit number, 
and visit date and stored at -80oC until analysis for cytokines is performed. 
6.2.3 DLQI and iQoL-32 (Appendices 7,8)
DLQI and iQoL-32 will be obtained at the baseline visit, Visit 4 (week 8), visit 6 (week 16), visit 9 (week 
32), and visit 12 (week 52) as indicated in Appendix 1. DLQI is the most commonly used and first 
dermatology-specific quality of life assessment tool (Basra et al 2008). It can be used to assess various 
dermatologic conditions and has been a reliable measure of quality of life (Finlay 1994). IqoL-32 is a 
validated, 32-item quality of life questionnaire that is specific to ichthyosis and has been shown to be 
highly correlated to clinical severity (Dreyfus et al 2013). 
6.2.4 Skin Biopsy 
Skin biopsies will be obtained from the non-dominant upper outer arm and will occur during the baseline 
visit, visit 6 (week 16), visit 9 (week 32), and visit 12 (week 52) as indicated in Appendix 1. Subjects will 
be instructed to not bathe, shower, or apply any topical product to the area that will be biopsied 24hrs 
before the visit.  The area will be marked and then cleaned with an antiseptic wash. A 4.5 mm punch 
biopsy will be obtained and bisected for immunohistologic and qRT-PCR studies. The defect will be 
closed with a suture and dressed with a self-adherent compression dressing. The subject will be provided 
with instructions for wound care and suture removal. 
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6.2.5 Adverse Event Assessment 
Adverse event assessments will occur at visits 1-12. Additionally, subjects will be queried by study 
coordinator about tolerability and any adverse events during the weekly phone or Skype sessions during 
weeks 1-3 of the study.  Adverse event definitions are detailed in section 7.  
6.3 Unscheduled Visits
In the event of a suspected AE that needs evaluation by the PI or needs laboratory testing or intervention, 
a subject may schedule a visit at any time. During their baseline visit, instructions will be provided 
detailing how to schedule a visit. These instructions will include a phone number and office address that 
subjects may use to contact the study group. During unscheduled visits, study treatment will not be 
administered and assessments will not be performed.
6.4 Sample Collection, Preparation, Labeling and Shipment 
6.4.1 Sample collection 
All samples will collected as specified in the schedule of events flowchart and as per SOP of 
the respective institution. 
6.4.2 Labeling and de-identifying specimens 
Specimens will not have patient identifiers attached to them (i.e., name, initials, DOB, or social 
security number). They will be labeled with a unique patient ID number or code and date of visit. The key 
to the code will be kept at each institution in a password —protected computer, to be accessed only by the 
clinical staff at each institution delegated to this task. Should a specimen be transported to Mount Sinai 
Medical Center with any patient identifiers, the specimen will be returned to Northwestern for proper 
labeling. 
6.4.3 Transporting specimens to Mount Sinai Medical Center 
All specimens will be transported to Mt. Sinai either by hand by a member of the investigative staff (if 
acquired at Mt. Sinai) or by competent courier (eg. Fedex) for the frozen skin and blood samples. 
Biobanked serum and PAX RNA samples, swabs for microbiome and a buccal swab for future 
pharmacogenomics will be retained in the Paller lab. The shipment will be traceable and that the chain of 
custody will be documented. The specimens will be delivered to a competent member of the study team, 
who will assure that the specimens have been properly de-identified and stored/transported in the proper 
environment (see above). 
6.4.4 Specimen management
Specimens will be logged into a password protected electronic database by a qualified member of the 
research team. Samples will stored at the storage facility for a period of at least 5 years following the date 
the analysis is complete and used solely for objectives outlined in this study. After this date, residual sera 
will be destroyed. Patient confidentiality will be maintained. Results of all experiments will be reviewed 
by one of the PIs and the source of the data will be verified. Regular meetings of the specimen/data 
analysis team will occur. Regular study monitoring will also occur by qualified members of the research 
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team. The samples will be retained for 5 years from the end of the clinical completion of the study. In 
addition, samples can be destroyed at any time at the request of the subject.
7.
SAFETY DATA COLLECTION, RECORDING AND REPORTING 
7.1
Adverse Events
An adverse event (AE) is any untoward medical occurrence experienced by a subject after completing 
written informed consent to participate in a clinical study. AEs may not be causally or temporally 
associated with the investigational product or procedure. Lack of drug effect is not considered an AE 
because the purpose of the study is to establish drug effect. 
All AEs and SAEs will be recorded and reported from the time the subject signs the informed consent 
form to 4 weeks after administration of the last dose of test article. Subjects will be instructed to report 
AEs and SAEs during this time period. The investigators will follow up on all AEs and SAEs until the 
events have subsided, returned to baseline, or in case of permanent impairment, until the condition 
stabilizes. 
Aggregated AEs will be evaluated monthly by the PI/research teams. Safety data will be reviewed by the 
investigators, study teams, biostatisticians and a monitor unrelated to the study approximately every 3 
months, depending on the number of subjects enrolled.  A DSMB will be organized to assess safety and 
overall risk to benefit ratio throughout the study. The DSMB will meet via phone conference quarterly or 
as deemed necessary by the PIs.  The first DSMB meeting via a phone conference will be assembled after 
the first 3 months (or 8 patients, whichever is first)  are enrolled to assure that the study is proceeding 
according to expectations and no changes in the protocol and consent are needed. An independent safety 
monitor in each institution will assure that the data is correctly gathered, recorded, and assembled 
concisely and accurately for DSMB review.  
Most notable side effects per secukinumab Full Prescribing Information include increased risk of 
infection (including but not limited to nasopharyngitis, upper respiratory tract infection, and 
mucocutaneous infections with candida), exacerbations and new cases of inflammatory bowel disease, 
and hypersensitivity reactions. Adverse reactions reported by greater than 1% of subjects also include 
diarrhea, rhinitis, oral herpes, pharyngitis, urticaria, and rhinorrhea. Adverse reactions reported by less 
than 1% of subjects include sinusitis, tinea pedis, conjunctivitis, tonsillitis, oral candidiasis, impetigo, 
otitis media, otitis externa, increased liver transaminases, and neutropenia. There is an increased 
prevalence of staphylococcal and fungal cutaneous infections in ichthyosis, and patients respond normally 
to traditional anti-bacterial and anti-fungal agents when detected. Investigators will be vigiliant to the 
possibility that patients with ichthyosis will experience an increased incidence of these infections; if 
discovered, mucocutaneous infection will be treated with standard measures. 
7.2     Unblinding and Followup of Subjects with Adverse Events
 If a subject develops an adverse event that requires early termination, then we will document whether 
they were receiving secukinumab or placebo. 
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If subjects are experiencing unresolved adverse events at the time of study completion or early 
termination, then the investigator will schedule a follow-up visit to determine the outcome of the adverse 
event. 
7.3
Serious adverse events 
7.3.1.
Definition of SAE
A serious adverse event (SAE) is any adverse event which:
●
is fatal or life-threatening
●
results in persistent or significant disability/incapacity
●
constitutes a congenital anomaly/birth defect
●
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
○
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
○
elective or pre-planned treatment for a pre-existing condition that is unrelated to 
indication under study and has not worsened since signing the informed consent
○
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
○
social reasons and respite care in the absence of any deterioration in the subject’s general 
condition
●
is medically significant, i.e., defined as an event that jeopardizes the subject or may require 
medical or surgical intervention
All malignant neoplasms will be assessed as serious under “medically significant” if other seriousness 
criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk ofdeath at the 
time of the reaction; it does not refer to a reaction that hypothetically might havecaused death if more 
severe or ongoing. 
Medical and scientific judgment should be exercised in deciding whether other situations
should be considered serious reactions, such as important medical events that might not be
immediately life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above.
Examples of such events are intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or
development of dependency or abuse.
Any suspected transmission via a medicinal product of an infectious agent is also considered a
serious adverse reaction.
All AEs (serious and non-serious) are captured on the case report form; SAEs also require individual
reporting to DSMB and to Novartis Medical Affairs as per Section 7.2.2.
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7.3.2.
SAE Reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has provided 
informed consent and until 30 days after the last study visit, must be reported to the DSMB within 24 
hours of learning of its occurrence.  SAE must also be reported to Novartis by the DSMB within 15 days 
per federal prompt reporting requirements.  Any SAEs experienced after the 30-day period should be 
reported to DSMB if the investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the 
original episode, regardless of when the event occurs. This report must be submitted to the DSMB within 
24 hours of the investigator receiving the follow-up information. An SAE that is considered completely 
unrelated to a previously reported one should be reported separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded on the paper 
Serious Adverse Event Report Form. The investigator must assess the relationship of each SAE to study 
treatment, complete the SAE Report Form in English, and send the completed, signed form by fax within 
24 hours after awareness of the SAE to the DSMB. The original copy of the SAE Report Form and the 
fax confirmation sheet must be kept with the subject’s source documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a follow-up to a 
previously reported SAE.
Follow-up information provided should describe whether the event has resolved or continues, if and how 
it was treated, whether the treatment code was broken or not and whether the subject continued or 
withdrew from study participation. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs.
If the SAE is not previously documented in the Full Prescribing Information, (new occurrence) and is 
thought to be related to the study treatment, the DSMB may urgently require further information from the 
investigator. An Investigator Notification (IN) may need to be issued to inform investigators involved in 
any study with the same study treatment that this SAE has been reported
Deaths or any serious adverse events will be reported to the DSMB and Novartis within 24 hours of 
becoming aware of the event. This information will be communicated by the PI via email.  The DSMB 
will confirm receipt by email. All serious adverse events will be reported to the IRB of each institution 
according to their policies, and these events will also be reported by the DSMB and Novartis. Non-serious 
adverse events will be reported to each Institution’s IRB per their IRB’s policies. SAEs will be reported to 
PI immediately, and if the number of subjects experiencing AEs exceeds the pre-determined threshold, a 
meeting will be called to evaluate and determine if an early termination is needed. 
7.4.
Pregnancy Reporting
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must be 
reported the DSMB within 24 hours of learning of its occurrence, and to Novartis Medical Affairs within 
15 days. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
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Date: 14 July 2018
       
33
abnormalities, or maternal and/or newborn complications. This includes both cases of pregnancy with 
paternal or maternal exposure to investigational products.
Pregnancy should be recorded on the Clinical Trial Pregnancy Form and be reported by the 
investigator/qualified site staff to DSMB. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy must be reported on the SAE Report Form.
8.
DATA REVIEW AND DATABASE MANAGEMENT
In this multicenter project, both PIs (or their designee) will be responsible for protocol development, 
consenting of subjects, performing skin biopsies, treatment and evaluation of subjects, review of adverse 
events, and reporting adverse events to the DSMB.  Each site will have a project manager whose duties will 
include protocol development, grant administration for the individual study site, purchasing, case report 
form and source document design and development, and oversight of the project at the study site.  An 
independent study safety monitor at each site will be contracted to perform review of consents, serious 
adverse events, and source verification on a quarterly basis throughout the study. This independent safety 
monitor in each institution will also assure that the data are correctly gathered, recorded, and put together 
concisely and accurately for prompt submission to the DCC. Thus, the audit function at each site is 
independent of the study research team. Data will be entered by study coordinators in a central REDCap 
database based at Northwestern. The Dermatology Clinical Trials Unit currently manages both international 
and national multisite REDCap databases. A designated data manager will manage and document all 
clinical data in REDCap, assuring the correct insertion and transfer of data, and aligning the institutions. 
The statistician will meet with the DCC every two months to discuss the progress of the study. In addition, 
an Executive Committee consisting of the Principal Investigators, the project managers and the study 
statistician will meet every other week by phone or Skype to address issues and ensure that all activities are 
moving forward in a coordinated manner.  The DSMB will assess safety and overall risk to benefit ratio 
throughout the study.  The DSMB will meet every 3 months to review aggregate adverse events, with 
additional meetings and conference calls if deemed necessary by the PIs.  The first meeting via a phone 
conference will be assembled after the first 3 subjects are enrolled, in order to assure that the study is 
proceeding according to expectations and no changes in the protocol or consent are needed. 
8.1.
Site Monitoring
The Project Manager at Mt. Sinai will remotely monitor the Northwestern site, and the Project Manager at 
Northwestern will monitor the Mt. Sinai site. Sites will also be monitored internally by the Data 
Coordinating Center and remotely by the Data Safety Monitoring Board.
8.2.
Data Collection
Demographics, medical information, and data points will be recorded. Once collected by the study staff, 
data for each subject will be transferred to a secure REDCap database. 
8.3 
Data Disclosure and Subject Confidentiality
Each subject will be given a unique identifier code. The subject’s name and code will be maintained on a 
password protected Coded Identifier List (CIL), on a password protected computer, in a secured building. 
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Product: Secukinumab
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Date: 14 July 2018
       
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An additional spreadsheet with the unique identifier codes will be maintained and used for data collection. 
Only authorized study staff will have access to the spreadsheets.
 
Subject medical information obtained as a result of this study is considered confidential and disclosure to 
third parties other than the principal investigators and the study team is prohibited. Data generated as a 
result of this study will be available for inspection on request by the Institutional Review Board (IRB). 
Subjects’ personal information collected from medical records will be maintained on the CIL. An 
additional spreadsheet will be maintained with only the subjects’ unique codes. These spreadsheets will 
be maintained on password-protected computers, in password protected network folders per institutional 
Data Security Plan.
9.
DATA ANALYSIS
Statistical analysis of all clinical and translational studies will be performed by statistician at the Icahn 
School of Medicine at Mount Sinai and Northwestern University. Descriptive statistics of demographics 
and other baseline characteristics will be presented for all subjects.
9.1.
Analysis Sets
Definition of Trial Analysis Sets: All subjects who provide informed consent and are registered in the trial 
will be accounted for in the clinical trial report. The inclusion/exclusion of subjects and/or subject data 
from the trial analysis sets will be documented in the statistical analysis plan before breaking the 
randomization code. 
‘Modified Intention-to-Treat’ Analysis Set: The primary analysis population will be based on a modified 
intention-to-treat (mITT) population, which is defined as all randomized patients who received at least 
one dose of the randomized treatment. Because the loading dose is given at baseline, this should 
effectively include all the randomized patients. 
9.2.
Subject Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for all subjects. 
Demographics include age, sex, race, ethnicity, and skin type. Other baseline characteristics include 
height, weight, and vital signs, concurrent diagnoses (from medical history and indications for 
concomitant medication), concomitant medications, and previous treatments.
9.3.
Efficacy Analyses: 
All data will be analyzed after the 16-week double blinded portion of the study is completed. However, 
all patients and blinded study personnel will remain shielded from any information regarding the data 
after these analyses until the conclusion of the study. 
Analysis of primary efficacy endpoint
The primary efficacy endpoint is the change from baseline to week 16 in the composite IASI score. 
Differences in change over time in the composite IASI score between treatment and placebo will be 
assessed using a mixed-effect model. The model will include treatment and treatment-by visit interaction 
as fixed effects and study subjects as random effects. Orthogonal contrasts will be used to test differences 
in the treatment effect at the different time points. This model produces unbiased treatment effect, even if 
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Product: Secukinumab
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35
some subjects have missing values (provided that the missing data is missing at random). Besides the 
change in the composite IASI score, final results will be presented as percent changes from baseline, 
calculated from the least square means of the model above (Vickers et al, 2001). 
Analysis of primary safety endpoint
Safety analyses will be presented rates of bacterial or fungal mucocutaneous infection in each treatment 
group from baseline through week 16. The rate of infections will be compared using poisson regression. 
The proportion of subjects experiencing bacterial or fungal mucocutaneous infection during the study 
period in each treatment group will also be reported and compared using a Fisher exact test.
Analysis of secondary efficacy endpoint
We anticipate that, given the small sample size, a formal subgroup analysis (for ARCI-LI vs ARCI-CIE vs. 
EI vs. NS) will not be possible. However, we will report means and 95% confidence interval to descriptively 
compare the performance of the treatment across the four subgroups.
 
To compare secukinumab to placebo according to the proportion of patients who achieve IASI50/IASI75 
at week 16, a Fisher´s exact test for contingency tables analysis will be used. The same approach will be 
used for all other binary outcomes, including a 2-point reduction in CISI, 50% (or 75%) reduction in IASI-E, 
EASI-S, a 3-point reduction in patient-reported itch or pain (each on a 10 point scale); and a 50% reduction 
in TEWL. 
Mechanistic Endpoints: mRNA expression values will be normalized to housekeeping gene hARP and 
log2-transformed for analysis. Measurements under the limit of detections will be imputed as 20% of the 
minimum value observed for that gene. Similar to the IASI score, qRT-PCR expression data was modeled 
using a mixed effect models. 
9.4
Safety Variables
Safety will be evaluated by tabulations of adverse events and will be presented with descriptive statistics 
at each visit for each treatment group. The statistical evaluations will be organized by Treatment Phase 
(Weeks 0-16) and Crossover/Open-label phase (16-52). The number and percentage of subjects 
experiencing an AE/SAE will be stratified by system organ class, or a preferred term, and severity of the 
adverse event, and recorded and tabulated overall by each sub-strata.  Each subject will be counted only 
once within a system organ class or a preferred term using the adverse events with the highest severity 
within each category. All information pertaining to adverse events noted during the study will be listed by 
subject, detailing verbatim given by the investigator, preferred term, system organ class, date of onset, 
date of resolution, severity, and relationship to treatment. A tabulation of Serious Adverse Events (SAEs), 
will be provided by subject within treatment groups. The proportion of subjects in each treatment group 
reporting adverse events that occur in ~ 5% in either treatment group will be compared using the Fisher’s 
exact test.
 The specific system organ classes and preferred terms analyzed will be those that are reported by at least 
five percent of the subjects in either treatment group.
9.5.
Sample size Justification:
Sample size estimation for this trial is based on the comparison of the change in the composite IASI score 
from baseline to 16 weeks post treatment between the secukinumab and placebo arms.  Data from our cohort 
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Protocol Number: CAIN457AUS05T
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of 21 adolescents and adults was used to estimate the sample size.  The mean composite IASI score in this 
cohort was 28.9 with a standard deviation of 9.0. Assuming a correlation between the pre and post treatment 
IASI scores of 0.55, we estimated the standard deviation of the baseline to week 16 change at approximately 
8.5. Fixing the type I error at 0.05 for a two tailed t-test, a sample size of 16 subjects per group provides 
80% power to detect a treatment effect of 30% for change in the IASI composite score (40% reduction in 
the secukinumab vs. an 10% reduction in the placebo arm). To account for an anticipated 20% dropout rate, 
20 subjects in each treatment group (total 40) will be randomized.
9.6. 
Analysis of Reliability
To determine inter-rater reliability, the two trained blinded investigators at each medical center will 
perform all assessments. To study intra-rater (test-retest) reliability, measures will be carried out by the 
subject (for the patient-reported severity outcome) and by the same two physicians (for the disease scores) 
at both screening and baseline visits, which will be separated by 3-4 weeks to minimize recall bias. Intra-
rater and inter-rater reliability will be assessed by the intraclass correlation (ICC) for agreement (Shrout 
and Fleiss, 1979) and will be calculated within the linear mixed-effects model framework (Eldridge et al, 
2009). The ICC for the inter-rater agreement will be calculated in the random coefficient model with 
covariates center and random intercepts for the patient and the physician. Bland-Altman plots will also be 
used to study patterns of agreements. As per Cicchetti (Cicchetti et al, 1994), interpretation for kappa or 
ICC for inter-rater agreement measures will be as follows: poor <0.40; fair 0.40-0.59; good 0.60-0.74; 
excellent 0.75-1.00.
10.
ETHICAL CONSIDERATIONS.
10.1.
Informed Consent
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2.
Consent Forms
Prior to study entry, a written informed consent must be obtained from the subject (≥ 18 years old).  A 
copy of the subject’s signed consent form must be retained in the study file. Documentation of consent 
process will be placed in source document for each study subject. 
10.3.
Responsibilities of the Investigator and IRB
A periodic review will be submitted to the IRB at least once per year. The IRB will be notified of 
completion of the study. After study completion or termination, a final report will be provided to the IRB 
to close the study. The investigator will maintain an accurate and complete record of all submissions 
made to the IRB, including a list of all reports and documents submitted. Serious Adverse Events that are 
reported to Novartis will be submitted promptly to the IRB per IRB guidelines.
 
At least once per year, the IRB will review and give written approval in order to continue the study. This 
trial will be conducted in accordance with Good Clinical Practices and the Declaration of Helsinki.
10.4.
Publication of Study Protocol and Results
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Product: Secukinumab
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The Principal Investigator and co-investigators may publish the results of this study in conjunction with 
appropriate scientific and medical personnel of either institution.  Information obtained from this study 
may be used for teaching, research, publications, or presentations at scientific meetings. If individual 
results are discussed, subject identities will be protected by using a subject number rather than name or 
other identifying information.
11.
PROTOCOL ADHERENCE
This protocol defines the study objectives, the study procedures and the data to be collected on study 
participants. Additional assessments required to ensure safety of subjects should be administered as 
deemed necessary on a case by case basis. Under no circumstances should an investigator collect 
additional data or conduct any additional procedures for any research related purpose involving any 
investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the IRB/IEC and 
health authorities, where required, it cannot be implemented. All significant protocol deviations will be 
recorded and reported. 
11.1.
Protocol Amendments
All changes must be submitted to the IRB. Protocol modifications that impact subject safety or the 
validity of the study must be approved by the IRB and Novartis Medical Affairs before initiation.
12.
REFERENCES
References are available upon request. 
Basra MK, Fenech R, Gatt RM, et al. (2008) The Dermatology Life Quality Index 1994-2007: a 
comprehensive review of validation data and clinical results. Br J Dermatol. 159(5):997-1035. 
Bodemer C, Bourrat E, Mazereeuw-Hautier J et al. (2011) Short- and medium-term efficacy of specific 
hydrotherapy in inherited ichthyosis. Br J Dermatol. 165 (5): 1087–1094. 
Chioato A, Noseda E, Stevens M, et al. (2012) Treatment with the interleukin-17A-blocking
antibody secukinumab does not interfere with the efficacy of influenza and meningococcal
vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single center
study. Clin Vaccine Immunol. 10(10):1597-602.
Dreyfus I, Taïeb C, Barbarot S, et al. (2013) iQoL-32: a new ichthyosis-specific measure of quality of 
life. J Am Acad Dermatol. 69(1):82-7. 
Elman S, Hynan LS, Gabriel V, et al. (2009) The 5-D itch scale: a new measure of pruritus.  Br J 
Dermatol. 162(3): 587-93. 
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Finlay AY, Khan GK. (1994) Dermatology Life Quality Index (DLQI)—a simple practical measure for 
routine clinical use. Clin Exp Dermatol. 19(3):210-6.
Kamalpour L, Rice ZP, Pavlis M, et al. (2010) Reliable methods to evaluate the clinical severity of 
ichthyosis. Pediatr Dermatol 27(2):148-153.
Langley RG, Elewski BE, Lebwohl M, et al (2014); ERASURE Study Group; FIXTURE Study Group. 
Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 371(4):326-38. 
Nast A, Jacobs A, Rosumeck S, et al. (2015) Efficacy and safety of systemic long-term treatments for 
moderate-to-severe psoriasis: A systematic review and meta-analysis. J Invest Dermatol. 135(11):2641-8.
 
Novartis Full Prescribing Information (Novartis Pharmaceuticals Corporation). January 2016
Papp, K.A., Langley, R.G., Sigurgeirsson, B., et al. (2013), Efficacy and safety of secukinumab in the 
treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II 
dose-ranging study. British Journal of Dermatology 168:412–421. 
Puel A, Cypowyj S, Bustamante J, et al. (2011) Chronic mucocutaneous candidiasis in humans with inborn 
errors of interleukin-17 immunity. Science  332:65-68
Rich P, Sigurgeirsson B, Thaci, D, et al. (2013) Secukinumab induction and maintenance therapy in 
moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-
finding study. British Journal of Dermatology 168: 402–411. 
Styperek AR, Rice ZP, Kamalpour L, et al (2010) Annual direct and indirect health costs of the congenital 
ichthyoses. Pediatr Dermatol. 27(4):325-36. 
Thaçi D, Blauvelt A, Reich K, et al. (2015) Secukinumab is superior to ustekinumab in clearing skin of 
subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad 
Dermatol. 73(3):400-9. 
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Fig. 1 (left). A. Most patients with ARCI are collodion babies at birth. B-C. 
The extent of redness (erythema) and scaling varies within ARCI, ranging 
from lamellated scaling, generally with less visible erythroderma (B, 
lamellar ichthyosis (ARCI-LI)) to intense redness with finer scale (C, 
congenital ichthyosiform erythroderma (ARCI-CIE))
Fig. 2 (below). Biomarker expression in ichthyosis skin shows IL-17 
skewing. A. mRNA expression of IL-17A and IL-17A-induced genes is 
increased in ichthyosis, including ARCI (CIE/LI) vs.controls. *p<.05; 
*p<.01; ***p<.001. B. Highly positive correlation of IL-17A mRNA levels 
with IASI-Erythema (B) and IASI (not shown). C. Ichthyosis patients 
cluster in their expression patterns, and are closest to psoriasis patients. 
13.
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Appendix 1: Schedule of Assessments Flowchart 
Phase 1 (double-blind): Visits 1-5; 
Crossover: Visit 6
Open label: Visits 7-12
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
COW1
OLW1
OLW4
OLW12
OLW20
OLW28
OLW32
Screen (28 d-21 d of Day 0)
Baseline/ Day 0
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Wk 32
Wk 40
Wk 48
Wk 52
Visit Window
 
 
+3 days
+3 days
+1 wk
+3 days
+3 days
+1 wk
+1 wk
+1 wk
+1 wk
+1 wk
Consent 
X
Demographics
X
Inclusion/Exclusion
X
X
Medical History
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
Full Skin Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (incl. weight)
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Waist circumference
X
X
X
X
Randomization
X
Saliva Genotyping (if unknown) 2
X
Buccal swab
X
Blood Biomarkers
X1
X
X
X
X
X
PAX RNA
X1
X
X
X
X
X
QuantiFERON®-TB gold
X
X
Hep B/C, HIV testing
X
Urine HCG(if applicable)
X
X
Chem-20, CBC
X
X
X
X
Lipid panel, glucose, CRP (fasting)
X
X
X
X
Severity evaluations 
X
X
X
X
X
X
X
X
X
X
X
X
TEWL
X
X
X
X
X
X
X
X
X
X
X
Tape Strips
X
X
X
X
X
Itch scores
X
X
X
X
X
X
X
X
X
X
X
DLQI and iQoL-32
X
X
X
X
Skin Biopsy (4.5 mm)
X
X
X
X
Photography
X
X
X
X
X
X
X
X
X
X
X
X
Skin Swabs
X
X
X
X
X
X
X
X
X
X
X
X
Injection & Teaching
X
Dispense study treatment
X
X
X
X
X
X
X
X
X
X
Review Subject Diary
X
X
X
X
X
X
X
X
X
X
1.
To be drawn at screening if the patient is on systemic retinoid
2.
At Northwestern only.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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All investigators will be trained by Dr. Paller before initiation.
Appendix 2: Ichthyosis Area and Severity Index (IASI)
The IASI (Ichthyosis Area and Severity Index) is a modification of the global CISI score (see 
Appendix 2) that incorporates extent through the techniques used for assessment in the EASI 
and PASI scores for eczema (AD) and psoriasis, respectively. IASI takes only a few minutes to 
assess and the totals are calculated automatically in spreadsheets. All investigators will be 
trained by Dr. Paller before initiation and with the first few patients using representative 
examples of different scores in different skin tones and body sites. While this is not a validated 
score to date, the proposed study is an opportunity to validate this scoring instrument.
The steps for the IASI are as follows:
a) Determine mean INTENSITY of erythema or scaling in a body region (A1 = head and 
neck; A2 = upper limbs; A3 = trunk; A4 = lower limbs) through either selecting a 
representative area of ichthyosis or averaging the intensity within a body region. The 
intensity of redness/ erythema and scaling of the ichthyosis is assessed as none (0), 
mild (1), moderate (2), severe (3) or very severe (4). 
0
None
1
Mild
2
Moderate
3
Severe
4
Very Severe
b) Determine what percentage of AREA within a body region is affected by ichthyosis. In 
each region, the area is expressed as nil (0), 1-9% (1), 13-29% (2), 30-49% (3), 50-69% 
(4), 70-89% (5) or 90-100% (6). Many with ichthyosis have generalized involvement with 
100% of area affected (e.g., score of 6), but it is possible that areas may be spared (e.g., 
palms or soles). The mean intensity score (A1-A4 for each site) is multiplied by the 
number correlating with the percentage within a region with ichthyosis (B1-4).
% involvement
0
1-9%
10 - 
29%
30 - 
49%
50 - 
69%
70 - 
89%
90 - 
100%
Region score
0
1
2
3
4
5
6
c)
Determine TOTAL EXTENT by using a multiplier that takes into account the percentage 
of the total body surface area represented by each body region (C1 = 0.1 for head and 
neck; C2 = 0.2 for upper limbs; C3 = 0.3 for trunk; C4 = 0.4 for lower limbs).
The FINAL SCORE for each intensity measure (IASI-E or IASI-S) is thus the composite of 
(A1+B1)xC1) + (A2+B2)xC2) + (A3+B3)xC3) + (A4+B4)xC4).
The composite score IASI (max potential 48) = IASI-E (max potential = 24) + IASI-S (max 
potential = 24). 
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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Body region
Erythema
(0-4)
Scaling
(0-4)
Region score
(0-6)
Multiplier
Score per 
body region
Head/neck
(
      +
                   )
X
X 0.1
Trunk
(
      +
                   )
X
X 0.3
Upper extremities
(
      +
                   )
X
X 0.2
Lower extremities
(
      +
                   )
X
X 0.4
TOTAL(Sum Score per Region):
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
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Date: 14 July 2018
       
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Appendix 3: Congenital Ichthyosis Severity Score (CISI): *To be performed by 
Investigators and by Subject
2.  Please indicate your level of redness, as it appears today:
1.
Please indicate your level of skin scale, as it appears today:
3.  Please indicate your level of hair loss, as it appears today:
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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Appendix 4: Modified CISI (m-CISI): *To be performed by Investigators and by Subject
1. Please indicate your level of skin scale, as it appears today:
0: No scale
1: Minimal 
Scale
2: Moderate Scale
3: Severe Scale
4: Very Severe 
Scale
CIE
2. Please indicate your level of skin redness, as it appears today:
0: No red    
coloration
1: Light red 
coloration
2: Moderate red 
coloration
3: Bright red 
coloration
4: Dusky Red 
Coloration
TOTAL(scale +erythema scores):
Appendix 5: Bodemer Scale
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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Appendix 6: YALE ICHTHYOSIS SEVERITY INDEX
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
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Date: 14 July 2018
       
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There are two sets of scaliness standards, one (called lamellar scale and labeled L) for the 
typical flat scales that occur in most forms of ichthyosis and one (called keratoderma scale and 
labeled K) for the more columnar scales that are typical of epidermolytic ichthyosis and 
erythrokeratodermas.  Severities range from 0-4 where 0 indicates no perceptible scale or 
surface hyperkeratosis and 4 represents very severe scale or surface hyperkeratosis.  Each 
photographic standard has a written description of features characteristic of the severity score 
represented.  We have also provided those written descriptions below. 
To utilize the severity index, use either the lamellar or keratoderma standards for scale, and the 
single standard for erythema.  First decide whether the K standard or the L standard is the best 
match for a particular patient, and then score scale for that patient with a number (0-4) and a 
letter (L if you used the lamellar standard or K if you used the keratoderma standard) for each 
site.  Then use the single set of erythema standards to score erythema at all sites (0-4). 
SCORING DESCRIPTORS
Definitions: 
scale = visibly separated/fractured stratum corneum
smoothening = diminished fine skin markings; shininess; waxiness 
surface accentuation = organized or geometric exaggeration of coarse skin 
                           markings, such as corrugation or follicular prominence 
columnar hyperkeratosis = piles of scale with vertical fracturing  
Guidelines for scoring:
Scoring for scaliness should be done for the entire region.  That is, it should be more of an 
average than an indication of the worst score for that region.  The score you give to a particular 
region should be representative of a rectangle that for the:
Upper back extends laterally from one posterior axillary fold to the other and from T1-T10.  It 
excludes posterior arms and neck.
Upper arm extends from the acromial process to the lower humerus and includes the anterior 
axillary fold.  It excludes antecubital fossa, elbow and any portion of the trunk that may be 
visible.
Lower leg extends from, and includes, the kneecap to the lower tibia.  It excludes the ankle.
Dorsal foot extends from the tip of the toes to the ankle.  It excludes glabrous skin. 
By contrast, because erythema can be obscured by scale, the erythema score for a particular 
region should be the worst score for that region.
Scaliness descriptors (for LI and CIE phenotypes)
0 = normal skin; no perceptible scale or smoothening 
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Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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1 = areas of normal skin intermixed with areas showing smoothening (diminished fine skin 
markings;
       shininess; waxiness) or small scales (visibly separated/fractured stratum corneum)
2 = confluent smoothening (diminished fine skin markings; shininess; waxiness) 
       or small scales (visibly separated/fractured stratum corneum) 
3 = confluent scales (visibly separated/fractured stratum corneum) including some large (>1cm), 
       thick scales
4 = confluent, primarily large, thick scales 
Scaliness descriptors (for keratoderma phenotypes)
0 = normal skin; no perceptible scale or surface accentuation 
1 = areas of normal skin intermixed with areas showing hyperkeratotic surface accentuation 
(organized   or geometric exaggeration of coarse skin markings, such as corrugation or 
follicular prominence)
2 = confluent surface accentuation (organized or geometric exaggeration of coarse skin 
markings, such as corrugation or follicular prominence) and/or flat scale 
3 = confluent surface accentuation (organized or geometric exaggeration of coarse skin 
markings, such as corrugation or follicular prominence), scales and some columnar 
hyperkeratosis (piles of scale with vertical fracturing)
4 = confluent, primarily columnar hyperkeratosis (piles of scale with vertical fracturing)
Erythema descriptors
0 = no perceptible redness
1 = barely perceptible pink
2 = pink
3 = red
4 = deep red-purple 
Scoring:
Upper Back
Upper Arm
Lower Leg
Dorsal Foot
Scale
Erythema
Sum by Region
Total Score (Add Sum by Region, & phenotype scored):
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
Protocol Number: CAIN457AUS05T
Date: 14 July 2018
       
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Appendix 7
DERMATOLOGY LIFE QUALITY INDEX
 DLQI
Site  No:
Date
:
Score:
Visit Number:
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST WEEK.  Please 
tick  one box for each question.
1.
Over the last week, how itchy, sore, 
Very much

painful or stinging has your skin 
 
A lot

been? 
A little

Not at all

2.
Over the last week, how embarrassed
Very much

or self conscious have you been because 
A lot

of your skin?
 
A little

Not at all

3.
Over the last week, how much has your 
Very much

skin interfered with you going
 
A lot

shopping or looking after your home or 
A little

garden?       
Not at all

Not relevant 
4.
Over the last week, how much has your 
Very much

skin influenced the clothes 
A lot

you wear?
A little

Not at all

Not relevant 
5.
Over the last week, how much has your 
Very much

skin affected any social or 
A lot

leisure activities?
A little

Not at all

Not relevant 


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6.
Over the last week, how much has your 
Very much

skin made it difficult for 
A lot

you to do any sport?
A little

Not at all

Not relevant 
7.
Over the last week, has your skin prevented
Yes

you from working or studying?
No

Not relevant 
If "No", over the last week how much has 
A lot

your skin been a problem at 
A little

work or studying?
Not at all

8.
Over the last week, how much has your 
Very much

skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant 
9.
Over the last week, how much has your 
Very much

skin caused any sexual 
A lot

difficulties?
A little

Not at all

Not relevant 
10.
Over the last week, how much of a 
Very much

problem has the treatment for your
A lot

skin been, for example by making
A little

your home messy, or by taking up time? 
Not at all

Not relevant 
Please check you have answered EVERY question. Thank you. 
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors.


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Appendix 8
IQoL-32
The following questions concern different periods of time. There are no right or wrong answers. Answer each one as 
spontaneously as possible by ticking the proposed answer that seems closest to your opinion. If a question does not 
concern you, tick the corresponding box.
In the past 4 weeks…
1. … Has your skin been red?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
2. … Has your skin been sensitive or painful (tense, uncomfortable)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
3. … Have you had dry or thick skin, with a lot of scales (dead skin)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
4. … Has your skin been itchy?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
5. … Does your skin hurt because of cracking?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
6. … Because of your ichthyosis, has your eyes bothered you (dryness, pain, watering, impaired vision, redness)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
7. … Because of your ichthyosis, have your ears bothered you (earwax plug, impaired hearing, pain, itching)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
8. … Did your skin have trouble adapting to temperature and/or weather changes?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
9. … Have you been bothered by the smell of your skin?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable


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10.… Have you felt like your skin was unsightly because of your disease?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
11.… Does the disease make you feel dirty?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
12.… Have you felt uncomfortable performing certain everyday actions (such as writing, moving) because of the pains 
or stiffness caused by ichthyosis?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
13.… Have you felt “fatigue” in connection with your ichthyosis?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
14.… Does your scalp bothered you (combing, hair care, pain, or itching)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
… have you performed all desired activities (sports and leisure) without fear that others might see your skin?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
15.… Have you changed your vacation plans or the places you go because the planning required by your ichthyosis 
was too complicated?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
16.… Have you felt that your ichthyosis was a handicap (aesthetic or physical), even if you do not consider yourself a 
handicapped person?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
17.… Have you experienced mood swings because of ichthyosis?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
18.… Have you felt sad, discouraged or powerless in the face of your disease?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
19.… have you felt lonely or withdrawn because of the disease?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable


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20.… Have you experienced a feeling of anger, being “fed up,” a sense of injustice because of your disease?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
21.… Have you felt afraid of the future (treatments losing their effectiveness, worsening, difficulty applying the creams 
with age)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
22.… Have you felt afraid that the disease could restrain a romantic/sexual relationship?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
23.… Have you had the unpleasant feeling of being stared at or avoided by others?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
24.… Have you been afraid of being rejected or humiliated by others?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
25.… Have you felt afraid that others find your skin oily, sticky or rough?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
26.… Do you have bothersome side effects because of the medications?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
27.… Does the disease hampered you in performing your work or going about your studies?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
28.… Does ichthyosis influenced the way you dress?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
29.… Have you had a surplus of household chores because of your ichthyosis (skin flakes, oily clothes)?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
30.… Have you found caring for your skin difficult and unpleasant?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable
31.… Has care taken too much of your time each day?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable


Product: Secukinumab
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32.… Has ichthyosis caused you significant expenses or inconvenient administrative procedures?
☐tremendously                     ☐a lot
             ☐a little                    ☐not at all                   ☐not applicable


Product: Secukinumab
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Appendix 9
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


Product: Secukinumab
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Appendix 10
Numerical Rating Scale (NRS) for Pruritus (over past 3 days and nights)
Numerical Rating Scale (NRS) for Pain (over past 3 days and nights)
No pain
Worst imaginable pain
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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Appendix 11: Photography Protocol
Prior to photography: Have patient remove all wristbands and jewelry. Bras and underwear do not need to 
be removed. Photography should be performed on blue background.
PHOTOGRAPHS
1.
First, take a photograph of a card with subject ID, visit number, date of visit.
2.
Take photo of face and shoulders with eyes open.
3.
Take photo with body perpendicular to backdrop, left ear, eyes open.
4.
Take photo with body perpendicular to backdrop, right ear, eyes open.
5.
Take photo of shoulders and back of head.
6.
Take photo of scalp directly perpendicular to camera, capturing crown and tip of nose.
7.
Take photo of abdomen to neck, capturing drape.
8.
With patient's arms raised and hands behind head, take photo from elbows to drape.
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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9.
Take photo of back to neck, capturing drape.
10. Have patient put arm parallel to floor, and bring arm back to expose flank.  Rest closed fist on 
abdomen.  Left side.
11. Have patient put arm parallel to floor, and bring arm back to expose flank.  Rest closed fist on 
abdomen.  Right side.
12. Raise drape as high as possible, take photo toes to drape.
13. Zoom in to capture upper legs from knee to drape in more detail.
14. Zoom in to capture lower legs from knee to foot in more detail.
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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15. Raise drape as high as possible, take photo heels to drape.
16. Zoom in to capture upper legs from posterior knee to drape in more detail.
17. Zoom in to capture lower legs from posterior knee to foot in more detail. 
18. Have patient kneel on block or chair draped with blue cloth, take photo of soles.
19. Have patient stand on blue cloth, take photo of dorsal feet.
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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20. Take photo of palms with fingers flat, forearms together and fingers evenly spaced.
21.  Flip hands over, take photo of dorsal hands with thumbs touching and fingers evenly spaced.
22. Bring finders together take photo capturing nails and fingertips.  Pose is relaxed, not tightly 
clenched.
Appendix 12: Microbiome Survey and Swabs—(Scalp, Upper outer arm, Upper buttock)
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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1.
Have patient fill out lifestyle questionnaire (next page)
2.
Make sure to take skin swabs before any disinfection to area (for blood or biopsy)!
3.
Explain the procedure to the participant
4.
Put on a surgical mask and gloves
5.
Start with swabbing scalp, proceed with upper arm and upper buttock
6.
Unpack the first swab. To avoid contamination each swab should be unpacked only 
immediately before sampling.
7.
The swab is performed on an area of 2-4 cm2 by rubbing gently back and forth (20 times 
in 15 seconds).
8.
Insert the swab into the tube (with 500 μl Stabilizer solution/Zirkonia) without touching its 
edge. Break off the swab shaft to leave the swab within the solution and close it tightly. 
Shake down the swab tip to the bottom of the tube by tapping the tube to the working 
surface in order to cover the entire tip with buffer.
9.
Label tube with collection date, subject ID, visit number, location and procedure. Dispose 
of swab. 
10. Collect tissue scraping from an adjacent site immediately after swabbing 
11. Take sterile weighing spatulas and use to vertically scrape scale into a sterile small Petri 
dish
12. Transfer to a 1.5 ml sterile Eppendorf to freeze.
13. Label tube with collection date, subject ID, visit number, location and procedure. 
14. Repeat process for next areas to be swabbed (upper outer arm near biopsy site, upper 
buttock)
15.  Place tubes for subject into a ziplock bag (label with date, subject ID, visit number).
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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Microbiome Survey (to be filled out by patient)
City, State of Residence:
Ethnicity: Non-Hispanic Caucasian Hispanic/Latino African American Asian 
Other:_______________________ 
Skin Type Check all that apply: ☐ Dry ☐ Oily ☐ Mixed ☐ Sensitive 
Which skin conditions do you have in addition to ichthyosis? Check all that apply: ☐ Acne ☐ 
Atopic Dermatitis ☐ Psoriasis ☐ Ezcema ☐ Rosacea ☐ Dandruff ☐ Other:_______________ 
How happy are you with your skin on a scale of 1 to 10? : 1 2 3 4 5 6 7 8 9 10 
Please indicate:  Bath    or      Shower
Frequency of Bath/ Shower
Duration of Bath/Shower
Please list the products (brand) you are currently using on your skin, and how often:
Cleanser: 
Face moisturizer:
Body Wash/Soap: 
Body Moisturizer: 
Topical medications:
Oral Medications:
Makeup/Sunscreen products:
Shampoo/Conditioner:
Bleach Baths (or use of vinegar, baking soda, other additives):
Topical antibiotics:
Exfoliation:
Other:
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.


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Did you use products to swabbed areas within 24 hours of sample collection?
In the past year, have you used any antibacterial products (soap, topical cream/ointment, or oral 
antibiotics?):
If Yes, What and When?
How many hours of sleep on average per night?:____________hours 
Hours of sun exposure on average in the past week?:______________hours   
Which Best Describes Your Diet ? (circle): Balanced    Paleo    Flexitarian (occasional meat) 
Pescetarian (Fish but not other meat)     Vegetarian     Vegan     *Elimination Diet 
Other__________________________________________________ 
*WHAT DO YOU ELIMINATE: _____________________________________________ 
Do you avoid white bread, sugar and pasta?: Y   N 
Do you eat a diet high in dairy products?: Y   N 
Do you drink skim milk?: Y   N 
Do you select organic, hormone free meats and dairy products? Y   N 
____________________________________________________________________________
WOMEN ONLY: Circle your current menstrual cycle stage: menstruating      in menopause post 
menopause          irregular menstruation 
Pill?__________________________________________ Are you on hormone therapy? 
____________________________________________ 
Allergies: 
___________________________________________________________________________ 
List Medications, Vitamins, Supplements [include brand name]: 
____________________________________________________________________________
____________________________________________________________________________
Do you take probiotics?: Y N [Brand name]: _____________________________________ 
Smoker: Y  
Pets: Y Type__________________________  No 
How many times do you exercise per week?: _________________________________ 
Exercise Intensity: Light Moderate Vigorous Exercise Type: Aerobic Strength Training Mixed 
Any Exercise in past 3-4 hours?  Y   N
IRB #: STU00202022-MOD0014 Approved by NU IRB for use on or after 10/1/2018 through 6/17/2019.