Conditions: Atopic Dermatitis
Keywords: Atopic dermatitis extrinsic atopic dermatitis intrinsic atopic dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
Atopic Dermatitis, also known as atopic eczema, or eczema, is a common skin disease that can affect males and females of all ages, but often starts in childhood. Recent studies show at least 4-7% of adults and 15-25% of children to be affected, with one third of patients having severe disease. It results in very itchy, red, swollen, and cracked skin. Scratching worsens the symptoms and causes the skin to become thickened over time. Patients with atopic dermatitis have an increased risk of skin infections, and many also develop hay fever or asthma. Atopic dermatitis can cause significant distress to both patients and their families.

In this study, the aim is to assess the effects of a new treatment called secukinumab in patients with atopic dermatitis. A total of 30 patients will be included in the study, which will run for a total of 52 weeks.

Detailed description:
This is a randomized, double-blind, pilot study of a total of 44 subjects with AD (22 with intrinsic and 22 with extrinsic AD) consisting of 2 phases. Subjects will be randomized (2:1) to either receive secukinumab 300 mg or placebo via subcutaneous injection using 2 prefilled syringes.

Arms:
arm 1: Secukinumab (300 mg) via subcutaneous injection using 2 prefilled syringes arm 2: Placebo via subcutaneous injection using 2 prefilled syringes

Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: At Weeks 0, 1, 2, 3, 4 and every 2 weeks thereafter through and including Week 12 in phase 1 of the study. intervention 2: At Weeks 0, 1, 2, 3, 4 and every 2 weeks thereafter through and including Week 12 in phase 1 of the study.

Protocol document:
Prot_SAP_000.pdf: 
 
1
A Pilot Study to Evaluate the Efficacy and Safety of Secukinumab in the Treatment of 
Moderate to Severe Atopic Dermatitis.  
Principal Investigator: 
Emma Guttman, MD, PhD 
NCT02594098 
Document Date: 11-2-2015 
 


 
2
 
 
A Pilot Study to Evaluate the Efficacy and Safety of Secukinumab in 
the Treatment of Moderate to Severe Atopic Dermatitis.  
 
Protocol Version Date: August 17, 2015 
 
Amendment #2: November 2nd, 2015 
 
 
 
 
 
 
 
 
Investigators: 
 
Principal Investigator: 
Emma Guttman, MD, PhD 
Sub-Investigators:       
Yasaman Mansouri, MD  
 
 
 
 
  
 
 
 
 
Institution: 
 
Icahn School of Medicine at Mount Sinai 
Department of Dermatology  
, Box 1048 
New York, NY 10029 
Tel:  212-241-3288 
Fax: 212-876-8961 
 
 
 
 
 
 
 
  
 
 
 


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4
extrinsic and intrinsic AD, respectively). As shown in Fig. 1, there is significantly 
higher mRNA expression of IL-17 and IL-22 cytokines in intrinsic compared with 
extrinsic skin lesions (~8 fold), with corresponding increases in CCL20, Elafin/PI3 
and S100A proteins (these products are induced in keratinocytes by IL-17). Higher 
expression of IL-23p40 mRNA was also detected in intrinsic AD lesions.  
The Th17 immune skewing in intrinsic AD has important therapeutic implications, 
suggesting that targeting this axis might preferentially benefit intrinsic AD patients. 
Despite high levels of IgE in extrinsic AD, similar expression levels of Th2-related 
products were observed in both extrinsic and intrinsic AD, suggesting that these 
phenotypes might have similar responses to Th2 antagonism, as recently shown in 
the NEJM paper with dupilumab, a fully human monoclonal antibody that blocks IL-4 
and IL-13.(3)  
Therefore, we hypothesize that blocking IL-17 would be able to clinically and 
mechanistically reverse atopic dermatitis effectively in AD patients. 
 
HYPOTHESIS: 
 
Primary Hypothesis: 
 
1. It is hypothesized that IL-17 is involved in the pathogenesis of atopic 
dermatitis (AD). 
 
Secondary Hypothesis: 
 
1. Secukinumab is superior to placebo in the treatment of patients with moderate 
to severe AD. 
 
 
OBJECTIVES:  
Primary objective: To evaluate the efficacy of secukinumab in the treatment of 
intrinsic and extrinsic atopic dermatitis by measuring reduction in epidermal thickness 
at Week 16. 
Secondary objectives:  
1. To evaluate reduction in K16 expression at Week 16 compared to Baseline. 
2. To evaluate the efficacy of secukinumab in the treatment of intrinsic and 
extrinsic atopic dermatitis by measuring different scoring systems (SCORAD, 
EASI, and IGA, see appendix) for AD. 
3. To determine response biomarkers to secukinumab in treated patients with AD, 
which can be followed in future trials. 
4. To define the cellular and molecular immune profiles of patients with AD as 
compared with non-lesional skin (from AD patients), and normal skin.  
 


 
5
ENDPOINTS:  
 
Primary endpoint: Change in epidermal thickness of lesional skin after 16 weeks of 
treatment. 
Secondary endpoints:  
1. Change in K16 expression of lesional skin after 16 weeks of treatment. 
 
2. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline objective SCORAD at Week 16 of secukinumab treatment. 
3. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline EASI score at Week 16 of secukinumab treatment. 
4. The proportion of patients who achieve a score of “clear-0” or “almost clear-1” 
in the static IGA score at Week 16 as compared to Baseline. 
5. Percentage decrease in SCORAD/EASI scores at Week 16. 
6. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline objective SCORAD at Week 32 of secukinumab treatment. 
7. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline EASI score at Week 32 of secukinumab treatment. 
8. The proportion of patients who achieve a score of “clear-0” or “almost clear-1” 
in the static IGA score at Week 32 as compared to Baseline. 
9. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline objective SCORAD at Week 52 of secukinumab treatment. 
10. The proportion of patients who achieve an improvement of 50% or greater 
from their Baseline objective EASI score at Week 52 of secukinumab 
treatment. 
11. The proportion of patients who achieve a score of “clear-0” or “almost clear-1” 
in the static IGA score at Week 52 as compared to Baseline. 
12. To determine the safety of secukinumab in the treatment of intrinsic and 
extrinsic AD. 
 
Secondary (Translational) Endpoints 
1. Change of IL-17 regulated keratinocyte products (elafin/Pi3, CCL20, CXCL1, 
S100A7, A8, A9, A12) at Week 16 of treatment (as compared with Baseline). 
This will be assessed by a reduction of the mRNA gene expression levels of 
elafin/Pi3, CCL20, CXCL1, S100A7, A8, A9, A12 after 16 weeks of treatment 
by RT-PCR. 
Exploratory Aims 
1. To determine the effect of secukinumab therapy on suppression of immune 
driven inflammation, and related inflammatory cells (T-cells, dendritic cells 
(DCs), eosinophils), cytokines, and chemokines in lesional and non-lesional 
skin biopsies. Skin infiltration by T-cells (CD3, CD8), DCs (myeloid/CD11c, 


 
6
IDECs/fcEpsilonRI, CD206, Langerhans cells/CD1a) will be assessed in pre- 
and post lesional and non-lesional skin biopsies after 16-weeks post first 
treatment with secukinumab by immunohistochemistry.  
2. To determine what immune pathways are suppressed during treatment with 
secukinumab. Suppression of Th2, and Th22 immune pathways will be 
assessed by changes in Th2 inflammatory cytokines (including IL-13, IL-31, IL-
10), and Th22/IL-22 cytokine and downstream response genes of IL-22 
(including S100A7, and A8 that are co regulated by IL-17 and IL-22). We will 
also assess for gene modulation during treatment of Th1 and Th17 
inflammatory cell markers (such as IFN-gamma, CXCL9, CXCL10/Th1, and IL-
17A, IL-17F, IL-23p19 IL-23p40, CCL20, CXCL1, Elafin/PI3/Th17). RT-PCR 
will be used to determine these markers. 
3. To determine the effect of treatment on the epidermal pathology that consists 
of epidermal hyperplasia and barrier/terminal differentiation abnormalities.  
The epidermal hyperplasia will be measured by epidermal thickness, K16, and 
Ki67 {by IHC, RT PCR (K16) and arrays}. Major differentiation genes such as 
loricrin, filaggrin, and periplakin will be measured before and after 16-week 
treatment with secukinumab on lesional and non-lesional AD skin by IHC 
(filaggrin), RT-PCR (filaggrin, loricrin and periplakin), and gene array. 
4. In the group of patients that will respond to treatment by a reduction of at least 
50% in SCORAD (“responders”), as well as in the non-responders, we will 
evaluate the correlation between clinical response to therapy with 
secukinumab (as measured by the SCORAD) with suppression of the 
pathologic epidermal and immune phenotypes. The epidermal hyperplasia will 
be measured by epidermal thickness and protein as well as gene expression 
of K16. The immune phenotype will be measured by gene expression changes 
in Th17/IL-17A, IL-23p40, IL-23p19, elafin/PI3, CXCL1, CXCL2), Th2/IL4 
and/IL-13, and “T22”/IL-22, S100A7, and S100A8. We will also correlate the 
reduction in epidermal hyperplasia with the overall suppression of immune 
responses by a multivariate analysis.  
 
 
 
RESEARCH DESIGN 
This is a randomized, double-blind, pilot study of a total of 44 subjects with AD (22 
with intrinsic and 22 with extrinsic AD) consisting of 2 phases. Subjects will be 
randomized (2:1) to either receive secukinumab 300 mg or placebo via subcutaneous 
injection using 2 prefilled syringes. 
 
METHODS 
 
Informed consent will be obtained at the study site at the time of the first consultation 
for participation in this study.  
 


 
7
Phase 1: 
After providing informed consent, subjects will be assessed for study eligibility at the 
Screening visit (day -28 to day -1). At the Screening visit the following procedures will 
be performed by the blinded investigator:  
1. medical history and concomitant as well as prior medications/treatments will 
be reviewed 
2. physical examination will be performed (including vital signs) 
3. skin examination will be performed (including assessment of SCORAD, EASI, 
and IGA)  
4. electrocardiogram (ECG) will be performed 
5. approximately 9 cc (approximately 2 teaspoons) of blood will be drawn for a 
chemistry panel (including renal function tests, electrolytes, liver function tests) 
and complete blood count (including MCV). 
6. approximately 6 cc (approximately 1 ¼ teaspoons) of blood will be drawn for a 
QuantiFERON TB-Gold test (QFT) assay; or subjects will undergo tuberculin 
purified protein derivative (PPD) testing. 
7. HIV, hepatitis B surface antigen (HBsAg) and hepatitis C (HCV) 
antibody testing will be done in subjects deemed at risk. These include 
subjects with a history of injection drug use, homosexual subjects, and 
subjects with known sexual contact with an HIV positive partner. 
8. females of child bearing potential will have a serum pregnancy test performed. 
This test must be negative in order to qualify for the study.   
 
Subjects will be deemed eligible as per inclusion/exclusion criteria. Qualified subjects 
meeting all the inclusion and exclusion criteria will be randomized at Day 0 by an 
unblinded research staff member (designated drug dispenser) to either the 
secukinumab group or placebo group (within 28 days of signing the consent form). 
Female subjects of child-bearing potential will have 2 teaspoons of urine collected for 
a pregnancy test prior to randomization (only if the Screening visit was more than 7 
days prior to randomization).  
Assessments at this Baseline visit include skin examination, assessment of 
SCORAD, EASI and IGA scores, clinical photographs, bloods tests for chemistry and 
hematology (6 cc  - approximately 1 ¼ teaspoons), as well as for mechanistic 
studies, and two punch biopsies (4.5 mm in size) will be obtained from involved and 
uninvolved skin. 
Subjects with intrinsic AD (22 subjects) will be randomized (2:1) to either receive 
secukinumab (300 mg) or placebo via subcutaneous injection using 2 prefilled 
syringes at Weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter through and including 
Week 12. Subjects with extrinsic AD (22 subjects) will be randomized separately (2:1) 
to either receive secukinumab (300 mg) or placebo via subcutaneous injection using 
2 prefilled syringes at Weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter through and 
including Week 12. Study drug will be administered subcutaneously by a blinded 
study investigator or designated research staff member in the Dermatology 
department. 


 
8
At Week 1, subjects will return for study product administration, assessment of 
concomitant medications and adverse events. 
 
At Week 2, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events. 
 
At Week 3, subjects will return for study product administration, assessment of 
concomitant medications and adverse events. 
 
At Week 4, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, a urine pregnancy test (if applicable), laboratory tests for 
mechanistic studies, and one biopsy from involved skin only, close to the area that 
was biopsied at Baseline. 
 
At Week 8, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, a urine pregnancy test (if applicable), and clinical photography. 
 
At Week 12, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, and a urine pregnancy test (if applicable). 
 
Concomitant treatments prohibited prior to randomization and during the study are 
listed below. Subjects will be allowed to drop out of the study if they complete all 
required assessments and visits through and including Week 4. At Week 16, the 
primary endpoint will be assessed.  
 
 
Phase 2: 
At Week 16, all subjects will be eligible to enter into the second phase of the study, in 
which all subjects will receive secukinumab (300 mg). In order to maintain the initial 
blind, subjects who had been randomized to secukinumab in Phase 1 will continue to 
receive secukinumab at a dose of 300 mg SQ every 4 weeks starting Week 16 until 
Week 52 (Weeks 16, 20, 24, 28, 32, 36, 40, 44, and 48), however, they will also 
receive two saline 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 phase 1. 
Subjects, who had been randomized to placebo in Phase 1, will receive secukinumab 
at a dose of 300 mg SQ at weeks 16, 17, 18, 19, and 20, followed by every 4 weeks 
until Week 48 (Weeks 24, 28, 32, 36, 40, 44, and 48). The final study visit will be at 
Week 52. 
 
At Week 16, subjects will undergo vital signs, skin assessment (including SCORAD, 
EASI, and IGA), study product administration, assessment of concomitant 
medications, adverse events, pregnancy test (if applicable), clinical photography, 


 
9
blood tests for mechanistic studies. Two skin biopsies will be performed, in the 
vicinity of the involved and uninvolved areas biopsied at Baseline. 
 
At Week 17, subjects will return for study product administration, assessment of 
concomitant medications and adverse events. 
At Week 18, subjects will return for skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events. 
At Week 19, subjects will return for study product administration, assessment of 
concomitant medications and adverse events. 
 
At Week 20, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, and pregnancy test (if applicable). 
 
At Week 24, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, pregnancy test (if applicable), clinical photography, and bloods tests 
for chemistry and hematology. 
 
At Week 28, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, pregnancy test (if applicable). 
 
At Week 32, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, pregnancy test (if applicable), and clinical photography. 
 
At Weeks 36, 40, and 44, subjects will undergo skin assessment (including 
SCORAD, EASI, and IGA), study product administration, assessment of concomitant 
medications and adverse events, and pregnancy test (if applicable). 
 
At Week 48, subjects will undergo skin assessment (including SCORAD, EASI, and 
IGA), study product administration, assessment of concomitant medications and 
adverse events, pregnancy test (if applicable), and laboratory tests for chemistry and 
hematology. 
 
At Week 52, subjects will return for skin assessment (including SCORAD, EASI, and 
IGA), assessment of concomitant medications and adverse events, clinical 
photography, blood tests for mechanistic studies, and one optional biopsy will be 
performed (in the vicinity of the involved areas biopsied at Baseline). 
 
Adverse events and changes in concomitant medications will be assessed at each 
visit (through and including Week 52). 
 
We will recruit patients at the Dermatology department at MSSM.  Patients will be 
informed of the study when attending the Dermatology department, if they qualify for 


 
10
the study. Potential subjects will further be recruited from our database of patients 
who have requested to be contacted for future studies, and they will be referred by 
in-house residents and affiliated attendings 
In order to identify the molecular and cellular immune profile of AD at Baseline and 
identify treatment response biomarkers, we include blood analyses at Baseline, 
Week 4, 16 and Week 52, in addition to punch biopsies (4.5 – 5.0 mm in size) at 
Baseline (one from involved skin and one from uninvolved skin), at Week 4 (one 
biopsy from involved skin only, close to the area that was biopsied at Baseline), at 
Week 16 (two biopsies, in the vicinity of the involved and uninvolved areas biopsied 
at baseline), and at Week 52, one optional biopsy will be performed (in the vicinity of 
the involved areas biopsied at Baseline).  
Blood analyses of IL-17, IL-22 and IL-13 cytokines (by Singulex) and chemokines (by 
MSD-a Th1, Th2 panel) will be performed at baseline, Week 4, Week 16, and Week 
52 or Early Termination visit. 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, CXCL9, 
CXCL10, MX-1, STAT1), Th17 (IL-17, IL23p19, IL23p40, CCL20, CXCL1), Th2 (IL-
13, IL-5, IL-10, CCL17, CCL18, CCL22, CCL5), T22/IL-22 cytokine and IL-17/IL-22 
regulated S100s genes (S100A7, A8), Th9/IL-9, and Treg/FOXP3 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), inflammatory markers (i.e MMP12, 
S100A12), and innate immune genes (IL1b) by RT-PCR. Additionally, skin infiltration 
by T-cells, DCs, eosinophils, mast cells, and neutrophils will be assessed by 
immunohistochemistry. The following markers will be used: CD3 and CD8 for T cells, 
Langerin for Langherans cells, CD11c for myeloid DCs, TRAIL for inflammatory DCs, 
CD83/DC-LAMP as markers of mature activated DCs, MBP to identify eosinophils, 
and neutrophil elastase to identify neutrophils. 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 lesional/affected and non-lesional/normal 
skin of AD patients.  
 
 
PATIENT POPULATION:  
 
Prior to enrollment, all subjects must meet the following inclusion and exclusion 
criteria: 
 
Inclusion criteria:  
 
1. Male or female subject at least 18 years of age 
2. If female, the subject is not pregnant or nursing 
3. Subject is able to provide written informed consent and comply with the 
requirements of this study protocol.  
4. Chronic (>6 months) atopic dermatitis (intrinsic disease with IgE levels that are 
below 500, and extrinsic disease with IgE levels above 500). 


 
11
5. Moderate to severe AD (SCORAD index ≥25, and IGA index≥3). 
6. Subjects who are women of childbearing potential must have a negative urine 
pregnancy test at screening and must be practicing an adequate, medically 
acceptable method of birth control for at least 30 days before Day 0 and at 
least 6 months after the last study drug administration. Acceptable methods of 
birth control include intrauterine device (IUD); oral, transdermal, implanted or 
injected hormonal contraceptives (must have been initiated at least 1 month 
before entering the study); tubal ligation; abstinence and barrier methods with 
spermicide. Otherwise, if not of childbearing potential, subjects must: have a 
sterile or vasectomized partner; have had a hysterectomy, a bilateral 
oophorectomy or be clinically diagnosed infertile; or be in a menopausal state 
for at least a year. 
7. Tuberculin purified protein derivative (PPD) or QuantiFERON TB-Gold test 
(QFT) negative at the time of screening, or if patient has a history of positive 
PPD or QuantiFERON, he/she has completed the appropriate prophylaxis.   
8. Subject is judged to be in good general health as determined by the principal 
investigator based upon the results of medical history, laboratory profile, and 
physical examination. 
9. Patients with stable chronic asthma, treated with inhaled corticosteroids, will 
be allowed to participate. 
 
 
Exclusion criteria:  
 
1. Any subject who is pregnant or refuses to practice an acceptable method of 
birth control (as stated in inclusion criterion # 6) 
2. History of an ongoing, chronic or recurrent infectious disease, or evidence of 
tuberculosis infection as defined by a positive tuberculin purified protein 
derivative (PPD) or QuantiFERON TB-Gold test (QFT) at Screening. Subjects 
with a positive or indeterminate PPD or QFT test may participate in the study if 
a full tuberculosis work up (according to local practice/guidelines) is completed 
within 12 weeks prior to randomization and establishes conclusively that the 
subject has no evidence of active tuberculosis. If presence of latent 
tuberculosis is established, then treatment must have been initiated at least for 
4 weeks prior to randomization and the course of prophylaxis is planned to be 
completed. 
3. Skin colonization by S. aureus is expected in a high percentage of AD patients 
with active disease and will not be considered an exclusion criterion. 
4. Active Crohn’s disease 
5. Known hypersensitivity to latex  
6. Subjects with a history of HIV, or history of positive HCV or HBV 
7. Previous exposure to Secukinumab or other drug targeting IL-17A or its 
receptor 
8. Use of phototherapy (i.e. UVB, UVA) or systemic immunosuppressive drugs 
(including cyclosporine, corticosteroids, mycophenolate mofetil, azathioprine, 
methotrexate) within four weeks prior to Baseline/Randomization (Visit 2).  


 
12
9. Use of interferon-γ within 12 weeks prior to Baseline/Randomization (Visit 2).  
10. Use of abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, 
infliximab, or tocilizumab within 12 weeks prior to Baseline/Randomization 
(Visit 2).  
11. Use of omalizumab, rituximab, ustekinumab, alefacept, briakinumab, or other 
therapeutic 
antibody 
products 
within 
24 
weeks 
prior 
to 
Baseline/Randomization (Visit 2).  
12. Use of any investigational drug within four weeks or five PK or PD half lives 
(whichever is longer) prior to Baseline/Randomization (Visit 2).  
13. Use of topical corticosteroid preparations, topical calcineurin inhibitors, or 
other topical preparations with immunomodulatory properties within 2 weeks 
prior to Baseline/Randomization (Visit 2).  
14. Serious concomitant illness that could require the use of systemic 
corticosteroids or otherwise interfere with the patient’s participation in the trial. 
 
15.  Clinically important deviation as judged by the investigator (such as >3 times 
the norm for LFTs, or, WBC< 3) from normal limits in physical examination, 
vital sign measurements, 12-lead electrocardiograms (ECGs), or clinical 
laboratory tests results, not associated with a chronic, well-controlled medical 
condition. 
 
 
 
STATISTICAL METHODS 
 
Determination of Sample Size 
This is a pilot study, and therefore the sample size has been kept relatively low. No 
formal analysis of statistical power for the primary endpoint of the trial lies behind this 
decision; however the consequence on precision of the parameter of interest is 
described in the following paragraph assuming the use of a 1-sided alpha of 0.05 in 
the Fisher’s exact test: 
The sample size estimation is driven by the primary endpoint, namely the epidermal 
thickness change observed at Week 16. Prior studies with Cyclosporine [4, 5] show a 
reduction of 90 on epidermal thickness with 62.79 as standard deviation after 12 
weeks of treatment. To be conservative about the effect of Secukinumab we will 
assume a reduction of 85 on treatment group and no change on placebo group after 
16 weeks of treatment.  The same standard deviation will be considered for both 
groups. Under these assumptions, a sample size of 30:14 (Treatment/Placebo) will 
allow testing the hypothesis that the change in the Treatment group is different than 
the change in the Placebo group. This sample size will be able to detect an effect 
size equal to 1.35 with 96% power. For the subgroup analysis, based on IgE status, a 


 
13
sample size of 15:7 in each subgroup (Intrinsic/Extrinsic) will allow to detect the same 
effect size with 80% power. 
 
Definition of Trial Analysis Sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been 
obtained and who have been registered in a clinical 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. 
 
Analysis Populations 
‘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. 
 
Statistical Analysis 
 
Random Allocation of Subjects 
A randomized block design will be performed to guarantee a 15:7 Treatment/Placebo 
proportion within the Intrinsic/Extrinsic AD subgroups. The IgE status will be 
considered as a blocking factor. This means that subjects will be randomly allocated 
to each treatment (Secukinumab/Placebo) with a proportion 15:7 inside each level of 
the factor. 
Disposition of Subjects 
The reasons for leaving the trial will be presented for all randomized subjects by last 
visit attended and by treatment group. For patients who prematurely discontinued the 
trial the last observation carried forward (LOCF) will be considered by last visit 
attended. 
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, duration of 
atopic dermatitis, concurrent diagnoses (from medical history and indications for 
concomitant medication), concomitant medication, previous atopic dermatitis 
treatments and IgE. 
Analysis of Primary Endpoint 
The primary objective is to study the efficacy of secukinumab in the treatment of 
intrinsic atopic dermatitis by measuring change of epidermal thickness at Week 16 


 
14
from baseline. To compare this endpoint between secukinumab versus placebo, a 
mixed-effect model will be used to estimate the means for outcomes at Phase 1 
(Weeks 0-16). Observed measure at Week 4 will be considered in the model. Under 
the assumption of LOCF, a sensitivity analysis will be performed. A secondary 
analysis will be done, also including the outcomes at Phase 2 (Weeks 16-32) for 
subjects randomized as Placebo at Phase 1. For this cohort, observed measure at 
Week 20 will be considered in the model. 
 
Analysis of Secondary Endpoints 
For K16, the same analysis as for epidermal thickness will be performed. 
To compare secukinumab versus placebo according to the proportion of patients who 
achieve an improvement of 50% or greater from their baseline for SCORAD, EASI 
and IGA (“clear-0” or “almost clear-1”) at Week 16 a Fisher´s exact test for 
contingency tables analysis will be used. Additionally to Phase 1 data, the group who 
started with treatment at Week 16 in Phase 2 will be already included.  
For long term efficacy analysis of secukinumab, Phase 1 and Phase 2 data will be 
used to calculate Confidence Intervals at 95% significance level for to the proportion 
of patients who achieve an improvement of 50% or greater from their baseline for 
SCORAD, EASI and IGA (“clear-0” or “almost clear-1”). 
Differences in change over time on SCORAD/EASI between treatment and placebo 
will be assessed using a Mixed-effect model repeated measures (MMRM) to detect 
any overall differences in the treatment effect as compared to placebo. Outcomes for 
Weeks 0 to 16 for all subjects from Phase 1 and the outcomes for Weeks 16 to 32 for 
subjects randomized with secukinumab in both phases will be considered. The model 
will include the fixed, categorical effects of treatment, and treatment-by visit 
interaction. Likelihood ratio tests and the AIC will be use to determine which 
covariance structure, CS or unstructured, provides the best fit to the data. Contrasts 
will be defined in the mixed-model to test for treatment differences at the different 
time points. Final results will be communicated as percentages change from 
baseline, calculated from the least square means of the model above. For patients 
who prematurely discontinued the trial missing values will be considered. Sensitive 
analysis will be performed treating them as: (a) LOCF, (b) data as observed. 
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 16-32), and Post-Treatment 
Phase (long-term follow-up), as appropriate. AEs will be coded using the CTCAE, 
Common Terminology Criteria for Adverse Events, V 4.0. 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 


 
15
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. 
 
Analysis of Secondary (Translational) Endpoints 
Outcomes for Weeks 0 to 16 for all subjects from Phase 1, and the outcomes for 
Weeks 16 to 32 for subjects randomized with placebo in Phase 1, and to 
secukinumab in Phase 2 will be considered.  
Change of the pathological epidermal disease phenotype of lesional and non-lesional 
skin between baseline values and those after treatment at Week 16 will be estimated 
as a reduction of epidermal thickness and K16 expression using a two-tailed t-
Student test for paired samples at 95% significance.  
 
Analysis of Exploratory Endpoints 
Mixed-effect model will be used to assess the change on cell counts and RT-PCR-
derived expression levels after 16 weeks of treatment. The goal is to estimate the 
drug effect on both lesional and non-lesional biopsies. RT-PCR will be normalized to 
hARP and Log2 transformed prior the analysis.  
To assess correlations between clinical resolution of disease and the treatment 
response of skin biomarkers Spearman correlation coefficient will be used. Additional 
multivariate methods such as multivariate regression, clustering algorithms and PCA 
will be used to explore patterns in the data such as biomarkers with the same 
resolution pattern and outliers. A variety of data mining tools may be used to further 
explore hypothesis generated on the analysis stage. 
 
ADVERSE EVENTS 
A total of 3430 psoriasis subjects were treated with secukinumab in controlled and 
uncontrolled clinical trials. Of these, 1641 subjects were exposed for at least 1 year. 
Side effects seen in studies with secukinumab that occurred in greater than 1% of 
subjects (greater than 1 in 100 patients) include nasopharyngitis, diarrhea, upper 
respiratory tract infection, rhinitis, oral herpes, pharyngitis, urticaria, and rhinorrhea. 
Side effects seen in studies with secukinumab that occurred in less than 1% of 
subjects (less than 1 in 100 patients) include hypersensitivity reactions, anaphylaxis, 
sinusitis, tinea pedis, conjunctivitis, tonsillitis, skin or oral candidiasis, impetigo, otitis 
media, otitis externa, inflammatory bowel disease, increased liver transaminases and 
neutropenia, various infections, worsening of Crohn’s disease. Live vaccines should 
be avoided during treatment with secukinumab. 
 
 


 
16
 
 
SAFETY MONITORING 
 
The study will be conducted in accordance with our department’s Standard Operating 
Procedures, which are based on US FDA Title 21 Code of Federal Regulations and 
ICH Good Clinical Practice guidelines.   
 
An investigator will review all laboratory results and assess for adverse events.  The 
principal investigator will be informed of all adverse events.  In the event that a 
subject’s safety is compromised, the investigator will discontinue the subject 
immediately.   
 
The Principal Investigator will provide safety data to an independent Data and Safety 
Monitoring Board every 12 months.  This DSMB will be comprised of board certified 
dermatologists who are not directly related to this study. The DSMB will review the 
data and provide a report of their findings to the Principal Investigator.  
 
  
Pharmacovigilance requirements: 
 
Definition of an AE: Any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the 
investigational medicinal product. 
=Investigational Medicinal Product (IMP) includes the drug under evaluation and the 
comparator drug(s) if specified as part of the research objective, given at any time 
during the study. Medical conditions/diseases present before starting the drug of 
interest are only considered adverse events if they worsen after starting the drug of 
interest. 
The occurrence of adverse events will be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. All adverse events will be 
recorded in the study database including the following information: 
1. the severity grade (mild, moderate, severe)  
2. its relationship to the drug(s) of interest (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
A SAE is any untoward medical occurrence that at any dose: 
- 
results in death, 
- 
is life-threatening, 
- 
requires inpatient hospitalization or prolongation of existing hospitalization, 
- 
results in persistent or significant disability/incapacity, 
- 
is a congenital anomaly/birth defect,  
- 
is otherwise a significant medical event. 


 
17
This includes any SAEs likely to arise from the trial indication or progression of 
underlying/concomitant illness (es) (e.g. progression of cancer in oncology trials), 
unless specified in the protocol as study specific exemptions. 
Any SAE, irrespective of causality, occurring after the subject has provided informed 
consent and until four weeks after the subject has stopped study participation must 
be reported unless otherwise stated in the protocol. SAEs occurring after four weeks 
from ending study participation should only be reported if considered by the 
Investigator attributable to the exposure to the investigational drug(s) during the trial 
period. This includes the period in which the study protocol interferes with the 
standard medical treatment given to a subject, even if study treatment has not yet 
started (e.g. withdrawal of previous treatment during washout period, change in 
treatment to a fixed dose of concomitant medication). 
 
Timelines: All serious adverse events (SAEs) from interventional clinical trials must 
be reported by the sites to the sponsor within 24 hours of occurrence of the SAE. The 
timelines for investigator-initiated trials reporting to Novartis will be done as per Third 
Party Study/Investigator Initiated Trial Agreement.   
 
 
Follow-up reports:  
SAEs will be followed until resolution or until it is judged to be permanent, and an 
assessment will be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the drug of interest, the 
interventions required to treat it, and the outcome.  
The Sponsor shall support Novartis in the following-up of all SAEs so that complete 
information is available to maintain patient safety and also as part of any 
commitments by Novartis to any Health authority OR specific Health authority follow-
up requests for the product under investigation. 
 
Pregnancies: Any occurrences of a pregnancy in a patient (or a patients partner) 
during study participation will be collected. All pregnancies will 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 abnormalities, or 
maternal and/or newborn complications. 
 
All other AEs will be reported by the PI directly to the Icahn School of Medicine at 
Mount Sinai IRB in the annual report.  
Should a temporary or permanent suspension occur, we would report the occurrence 
to all appropriate authorities. 
 
 
EARLY TERMINATION 
 
Any individual whose health or well being may be threatened by continuation in this 
study will be discontinued by the investigator.  
 


 
18
If a female subject becomes pregnant at anytime during the study, she will be 
discontinued immediately.  She will be asked to provide the investigator with medical 
updates throughout her pregnancy and on the final outcome of the pregnancy.   
 
Any subject who chooses to discontinue the study, or is discontinued from the study 
by the investigator will be asked to return for a final visit to have some or all of the 
following procedures: a blood test; pregnancy test; skin photography; skin evaluation 
including SCORAD, EASI, and IGA; and biopsy.  
 
 
INVESTIGATIONAL DRUG SUPPLY 
 
In this double-blind study, the investigator will supply secukinumab 300 mg (two 
injections of 150 mg each) for up to 44 subjects and placebo (comprised of silica and/or 
cellulose) for up to 15 subjects. The secukinumab and placebo will be provided by 
Novartis as 150 mg secukinumab (and matching placebo) pre-filled syringes. Both the 
150 mg secukinumab and the matching placebo pre-filled syringes will be of the same 
quality and identical in size and shape.  
All study medication will be stored in a secure cool area between 2-80C (under 
refrigeration).  Study drug will be administered to subjects at each visit, and any unused 
study drug will be kept at the study site. The number of missed doses will be 
documented for each subject.  The investigative site will account for all study drug 
dispensed and stored during the study.   
 
 
 
 
 
LABORATORY SPECIMEN 
 
All blood and urine samples will be processed through the Mount Sinai Center for 
Clinical Laboratories, One Gustave Levy Place, New York, NY 10029. 
INSTITUTIONAL REVIEW BOARD 
 
Prior to beginning this study, approval for all study related documents (protocol, 
consent form, advertising) will be obtained from the Icahn School of Medicine at 
Mount Sinai Program for the Protection of Human Subjects (Institutional Review 
Board), One Gustave Levy Place, Box 1081, New York, NY 10029. 
 
 


 
19
APPENDIX 1 
 
Schedule of events:  
 
Visit # 
1 
Screening 
2 
Baseline 
3-5 
6 
7 
8 
9 
10-12 
13-15 
16 
17-20 
21 
Early 
Term 
Visit 
Week 
 
0 
1,2,3 
4 
8 
12 
16 
17,18,19 20,24,
28 
32 
36,40, 
44, 48 
52 
 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inc/Exc Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Past Med Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Phys Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
CBC, CMP 
X 
 
 
 
 
 
 
 
X1 
 
X2 
 
X8 
Quantiferon Test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, HCV 
antibody, HIV 
screening (if 
deemed at risk) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
(incl. SCORAD, 
EASI, IGA) 
X 
X 
X3 
X 
X 
X 
X 
X4 
X 
X 
X 
X 
X 
Pregnancy Test5 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X9 
Disp Study Med 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Photographs 
 
X 
 
 
X 
 
X 
 
X6 
X 
 
X 
X 
Blood Sample for 
Mechanistic Studies 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Biopsy   
 
X 
 
X 
 
 
X 
 
 
 
 
 X7 
X10 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 CBC and CMP at Weeks 24 only. 
2 CBC and CMP at Weeks 48 only. 
3 Clinical Assessment at Week 2 only. 
4 Clinical Assessment at Week 18 only.  
5 Serum pregnancy test at Screening and urine at other time points. Pregnancy test at Baseline only if Screening 
occurred more than 7 days prior. 
 
6 Photographs at Week 24 only. 
7 Optional biopsy at Week 52 from lesional skin only. 
8 Only if Early Term Visit occurs before Week 48. 
9 Only if Early Term Visit occurs before Week 48. 
10 Only if Early Term Visit occurs before Week 32. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
20
APPENDIX 2: 
  
SCORAD Index(6): The most widely accepted clinical assessment tool for AD 
disease severity index is known as SCORAD (SCORing for Atopic Dermatitis). This 
tool combines clinical features of AD such as erythema, dryness, lichenification, 
percent body surface area, as well as quality of life issues such as pruritus and loss 
of sleep due to disease.  
To measure the extent of AD, the rule of nines is applied on a front⁄back drawing of 
the patient’s inflammatory lesions. The extent can be graded 0–100. The intensity 
part of the SCORAD index consists of six items: erythema, edema⁄papulation, 
excoriations, lichenification, oozing⁄crusts and dryness. Each item can be graded on 
a scale 0–3. The subjective items include daily pruritus and sleeplessness. Both 
subjective items can be graded on a 10-cm visual analogue scale. The maximum 
subjective score is 20. All items should be filled out in the SCORAD evaluation form. 
The SCORAD index formula is: A ⁄5 + 7B ⁄2 + C. In this formula A is defined as the 
extent (0–100), B is defined as the intensity (0–18) and C is defined as the subjective 
symptoms (0–20). The maximum SCORAD score is 103.  
EASI score(7): The Eczema Area and Severity Index (EASI) is a validated tool to 
objectively assess dermatitis severity incorporating surface area involvement. It was 
designed by modifying the general scheme used in the PASI (psoriasis area and 
severity index) scoring system, which has been utilized effectively in the assessment 
of psoriasis. The EASI index assigns proportionate values to 4 body regions (head 
and neck, 10%; trunk, 30%; upper limbs, 20%; lower limbs, 40%. Each region is 
assessed 
separately 
for 
erythema, 
infiltration/papulation, 
excoriation, 
and 
lichenification. The average clinical severity of each sign in each of the 4 body 
regions is assigned a score of 0 to 3, indicating none, mild, moderate, and severe 
expression. This percentage of area involved for each of the four body regions is 
assigned a proportional score from 0 to 6 during the analysis: 0=no eruption; 1=10%; 
2=10%–29%; 3=30%–49%; 4=50%–69%; 5=70%–89%; and 6=90%–100%. The 
buttocks and feet are counted as part of the lower extremities; the internal axillae and 
groin are counted as part of the trunk; and 3) the external axillae and hands are 
counted as part of the upper extremities. The total body score for each body region is 
obtained by multiplying the sum of the severity scores of the four key signs by the 
area score, then multiplying the result by the constant weighted value assigned to 
that body region. The sum of these scores gives the EASI total, which ranges from 0 
to a maximum 72.  
IGA index(8): a static IGA (Investigator’s Global Assessment) score is widely used as 
a primary efficacy point of treatment success in many studies of dermatological 
diseases including AD. The static IGA score represents an overall static evaluation of 
dermatitis, performed by the investigator at each visit. It utilizes a scale of 6-points, 
ranging from 0 (clear) to 5 (very severe disease), with 0-clear, 1-almost clear, 2- mild 
disease, 3-moderate disease, 4-severe disease, and 5-very severe disease. IGA 
scores measure disease severity based on morphology, without referring back to the 
baseline state. 
 


 
21
 
 
 
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C, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune 
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