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Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Griffiths CEM, Reich K, Lebwohl M, et al, for the UNCOVER-2 and
UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in
moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3
randomised trials. Lancet 2015; published online June 10. http://dx.doi.org/10.1016/
S0140-6736(15)60125-8.
Appendix

Supplemental Methods

Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:

[1] Are male or female patients 18 years or older.


[1a] Male patients agree to use a reliable method of birth control during the study.
[1b] Female patients:
Are women of childbearing potential who test negative for pregnancy and agree to use a reliable method of birth
control or remain abstinent during the study and for at least 12 weeks following the last dose of investigational
product, whichever is longer. Methods of contraception considered acceptable include oral contraceptives,
contraceptive patch, intrauterine device, vaginal ring, diaphragm, or condom with contraceptive gel.
-or-
Are women of non-childbearing potential, defined as:
Women who have had surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation);
-or-
Women who are 60 years of age;
-or-
Women 40 and <60 years of age who have had a cessation of menses for 12 months and a follicle-stimulating
hormone (FSH) test confirming non-childbearing potential (40 mIU/mL).
[2] Present with chronic plaque Ps based on a confirmed diagnosis of chronic plaque Ps for at least 6 months prior to
baseline (Week 0; Visit 2).
[3] Have 10% BSA involvement at screening (Visit 1) and baseline (Week 0; Visit 2).
[4] Have both an sPGA score of 3 and PASI score 12 at screening (Visit 1) and baseline (Week 0; Visit 2).
[5] Are a candidate for phototherapy and/or systemic therapy.
[6] Have given written informed consent approved by Lilly, or its designee, and the Investigational Review Board
(IRB)/ERB governing the site.

Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:

[7] Have pustular, erythrodermic, and/or guttate forms of Ps.


[8] Have a history of drug-induced Ps.
[9] Had a clinically significant flare of Ps during the 12 weeks prior to baseline (Week 0; Visit 2).
[10] Prior use of etanercept.
[11] Have received systemic non-biologic Ps therapy (including, but not limited to oral psoralens and ultraviolet A
[PUVA] light therapy, cyclosporine, corticosteroids, MTX, oral retinoids, mycophenolate mofetil, thioguanine,
hydroxyurea, sirolimus, azathioprine, fumaric acid derivatives, or 1, 25 dihydroxy vitamin D3 and analogues) or
phototherapy (including either oral and topical PUVA, ultraviolet B [UVB], or self-treatment with tanning beds or
therapeutic sunbathing) within 4 weeks prior to baseline (Week 0; Visit 2); or had topical Ps treatment (including,
but not limited to, corticosteroids, anthralin, calcipotriene, topical vitamin D derivatives, retinoids, tazarotene,
emollients and other non-prescription topical products containing urea, >3% salicylic acid, or alpha- or beta-
hydroxyl acids, and medicated shampoos [for example those that contain >3% salicylic acid, corticosteroids, coal
tar, or vitamin D3 analogues]) within the previous 2 weeks prior to baseline (Week 0; Visit 2)

Exceptions: class 6 [mild, such as desonide] or class 7 [least potent, such as hydrocortisone] topical steroids will be
permitted for use limited to the face, axilla, and/or genitalia.
[12] Cannot avoid excessive sun exposure or use of tanning booths for at least 4 weeks prior to baseline (Week 0;
Visit 2) and during the study.
[13] Concurrent or recent use of any biologic agent within the following washout periods: infliximab, adalimumab,
or alefacept <60 days; golimumab <90 days; ustekinumab <8 months; rituximab or efalizumab <12 months; or any
other biologic agent <5 half-lives prior to baseline (Week 0; Visit 2).
[14] Have ever received natalizumab or other agents that target alpha-4-integrin.
[15] Have previously completed or withdrawn from this study, participated in any other study with ixekizumab, or
have participated in any study investigating other IL-17 antagonists.
[16] Have a known allergy or hypersensitivity to any biologic therapy that would pose an unacceptable risk to the
patient if participating in this study.
[17] Had a live vaccination within 12 weeks prior to baseline (Week 0; Visit 2), or intend to have a live vaccination
during the course of the study, or within 12 months of completing treatment in this study, or have participated in a
vaccine clinical study within 12 weeks prior to baseline. Investigators should review the vaccination status of their
patients and follow the local guidelines for adult vaccination with non-live vaccines intended to prevent infectious
disease prior to therapy. (Note: Killed/Inactive or subunit vaccines are expected to be safe; however, their efficacy
with concomitant ixekizumab treatment is unknown.)
[18] Had a vaccination with Bacillus Calmette-Gurin (BCG) within 12 months prior to baseline (Week 0; Visit 2),
or intend to have this vaccination with BCG during the course of the study, or within 12 months of completing
treatment in this study.
[19] Had any major surgery within 8 weeks prior to baseline (Week 0; Visit 2), or will require such during the study
that, in the opinion of the investigator in consultation with Lilly or its designee, would pose an unacceptable risk to
the patient.
[20] Have current or a history of lymphoproliferative disease; or signs or symptoms of lymphoproliferative disease;
or have active or history of malignant disease. (Note: Patients with successfully treated basal-cell carcinoma [no
more than 3], squamous-cell carcinoma of the skin, or cervical carcinoma in situ, with no evidence of recurrence
within the 5 years prior to baseline [Week 0; Visit 2] may participate in the study).
[21] Presence of significant uncontrolled cerebro-cardiovascular (for example, myocardial infarction [MI], unstable
angina, unstable arterial hypertension, moderate-to-severe heart failure [New York Heart Association (NYHA) class
III/IV], or cerebrovascular accident [CVA]), respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic,
neurologic or neuropsychiatric disorders, or abnormal laboratory values at screening that, in the opinion of the
investigator, pose an unacceptable risk to the patient if participating in the study or of interfering with the
interpretation of data.
[22] Have a history of uncompensated heart failure, fluid overload, or MI, or evidence of new-onset ischemic heart
disease or in the opinion of the investigator other serious cardiac disease, within 12 weeks prior to baseline (Week 0;
Visit 2).
[23] Presence of significant uncontrolled neuropsychiatric disorder, have history of a suicide attempt, have a score
of 3 on Item 12 (Thoughts of Death or Suicide) of the QIDS-SR16 at screening (Visit 1) or baseline (Week 0; Visit
2), or are clinically judged by the investigator to be at risk for suicide.
[24] Presence or history of demyelinating disorder.
[25] Had a serious infection (for example, pneumonia, cellulitis, sepsis), have been hospitalized, or have received
intravenous (IV) antibiotics for an infection, within 12 weeks prior to baseline (Week 0; Visit 2), or had a serious
bone or joint infection within 24 weeks prior to baseline, or have ever had an infection of an artificial joint, or are
immunocompromised to an extent such that participation in the study would pose an unacceptable risk to the patient.
[26] Have or had an infection typical of an immunocompromised host, and/or that occurs with increased incidence
in an immunocompromised host (including, but not limited to, Pneumocystis jirovecii pneumonia, histoplasmosis, or
coccidioidomycosis); or have a known immunodeficiency.

[27] Have or had a herpes zoster or any other clinically apparent varicella-zoster virus infection within 12 weeks of
baseline (Week 0; Visit 2).
[28] Have any other active or recent infection within 4 weeks of baseline (Week 0; Visit 2) that, in the opinion of the
investigator, would pose an unacceptable risk to the patient if participating in the study; these patients may be
rescreened (1 time) 4 or more weeks after documented resolution of symptoms.
[29] Have an oral body temperature 38C (100.5F) at baseline (Week 0; Visit 2); these patients may be
rescreened (1 time) 4 weeks after documented resolution of elevated temperature.
[30] Have evidence or suspicion of active or latent TB (refer to Section 10.3.2.2 for details on determining full TB
exclusion criteria).
[31] Have uncontrolled arterial hypertension characterised by a systolic blood pressure (BP) >160 mm Hg or
diastolic BP >100 mm Hg. (Note: Determined by 2 consecutive elevated readings. If an initial BP reading exceeds
this limit, the BP may be repeated once after the patient has rested sitting for 10 minutes. If the repeat value is less
than the criterion limits, the second value may be accepted.)
[32] Are positive for human immunodeficiency virus serology (HIV; positive for human immunodeficiency virus
antibody [HIVAb]).
[33] Have evidence of or test positive for hepatitis B by any of the following criteria: 1) positive for hepatitis B
surface antigen (HBsAg+); 2) positive for anti-hepatitis B core antibody (HBcAb+) and negative for anti-hepatitis B
surface antibody (HBsAb); 3) HBcAb+ and positive for anti-hepatitis B surface antibody (HBsAb+) with a
concentration of HBsAb <200 mIU/mL; or 4) HBcAb+, HBsAb+ (regardless of HBsAb level), and positive for
serum hepatitis B virus (HBV) DNA. (Note: Patients who are negative for hepatitis B surface antigen (HBsAg),
HBcAb+, HBsAb+ with a concentration of HBsAb >200 mIU/mL, and negative for serum HBV DNA may
participate in the study. Patients who meet these criteria at screening will be identified by the central laboratory and
will be monitored during the study. [34] Have evidence of or test positive for hepatitis C virus (HCV). A positive
test for HCV is defined as: 1) positive for hepatitis C antibody (anti-HCV Ab), and 2) positive via a confirmatory
test for HCV (for example, HCV polymerase chain reaction).
[35] Have clinical laboratory test results at screening that are outside the normal reference range for the population
and are considered clinically significant, and/or have any of the following specific abnormalities:
[35a] Neutrophil count <1500 cells/L
[35b]Lymphocyte count <500 cells/L
[35c] Platelet count <100,000 cells/L
[35d]Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal
(ULN)
[35e] Total white blood cell (WBC) count <3000 cells/L
[35f] Hemoglobin <8.5 g/dL (85.0 g/L) for male patients and <8.0 g/dL (80 g/L) for female patients
[35g]Serum creatinine >2.0 mg/dL.
(Note: The AST and ALT may be repeated once within a week if the initial response exceeds this limit, and the
repeat value may be accepted if it is below the limit stated above. Other laboratory tests should not be repeated
unless there is a technical error or clinical reasons to believe a result may be erroneous.)
[36] Have electrocardiogram (ECG) abnormalities that are considered clinically significant and would pose an
unacceptable risk to the patient if participating in the study.
[37] Have known allergy to rubber or latex.
[38] Have any other condition that precludes the patient from following and completing the protocol, in the opinion
of the investigator.
[39] Have donated blood of more than 500 mL within the last 4 weeks, or intend to donate blood during the course
of the study.
[40] Are women who are lactating or breastfeeding.
[41] Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate
family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

[42] Are Lilly employees or are employees of third-party organizations (TPOs) involved in the study.
[43] Are currently enrolled in, or discontinued from a clinical trial involving an investigational product or
nonapproved use of a drug or device within the last 4 weeks or a period of at least of 5 half-lives of the last
administration of the drug, whichever is longer, or concurrently enrolled in any other type of medical research
judged not to be scientifically or medically compatible with this study.
[44] Have any condition or contraindication as addressed in the local labeling for etanercept that would preclude the
patient from participating in this protocol.

Additional Details about Randomisation

At Week 0 (Visit 2), patients who met all criteria for enrollment at Visits 1/1A and 2 were randomized at a 2:2:2:1
ratio to double-blind treatment groups (that is, 80 mg ixekizumab Q2W, 80 mg ixekizumab Q4W, etanercept, or
placebo) as determined by a computer-generated random sequence using an interactive voice response system
(IVRS). The IVRS was used to assign double-blind investigational product to each patient. Site personnel
confirmed that they had located the correct assigned investigational product package by entering a confirmation
number found on the package into the IVRS. Patients treatment assignments were stratified by center.

Additional Details of Blinding

UNCOVER-2 was a double-blind study; patients and study site personnel were blinded to study treatment
until all patients reach Week 60 (Visit 19) or discontinued from the study (moved into Post-Treatment Follow-Up
Period). To preserve the blinding of the study, a minimum number of sponsor personnel not in direct contact with
study sites had access to the randomization table and treatment assignments before the study was unblinded.

UNCOVER-3 was a double-blind study, where patients, investigators, and all other personnel involved in the
conduct of the study were blinded to individual treatment assignments until all patients had either completed
Week 12 or had discontinued from the study treatment (moved into the Post-Treatment Follow-Up Period). To
preserve the blinding of the study, a minimum number of sponsor personnel not in direct contact with study sites had
access to the randomization table and treatment assignments before the study was unblinded.

Details of Clinical Outcomes


The sPGA is the physicians assessment of the severity of a patients psoriasis lesions overall at a given time point.
Overall lesions are evaluated for induration, erythema, and scaling. For the analysis of responses, the patients
psoriasis is determined to be clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5). The PASI
is a combination of the extent of body-surface involvement in four anatomical regions (head, trunk, arms, and legs)
and the severity of scaling, erythema, and plaque induration (thickness) in each region, resulting an overall score of
0 for no Ps to 72 for the most severe disease. Dermatology Life Quality Index (DLQI) is a 10-question patient-
administered questionnaire that covers six quality-of-life domains including symptoms and feelings, daily activities,
leisure, work and school, personal relationships, and treatment, with total scores ranging from 0-30 (less to more
impairment). The Itch Numeric Rating Scale (NRS) is a single-item, 11-point horizontal scale in which patients
reported their average itch from a 0 to 10 scale where 0 = no itch and 10 = worst itch imaginable.

Major Secondary Endpoints


Major secondary endpoints evaluated included PASI 90 (90% improvement in PASI from baseline) response, or
complete resolution of psoriatic plaques as defined by PASI 100 (100% improvement in PASI from baseline) or
sPGA (0) at Week 12 for both UNCOVER-2 and UNCOVER-3. Patient-reported outcomes included DLQI and Itch
NRS. Week 12 proportions of patients who had baseline 4 Itch NRS score with 4 point improvement in Itch NRS,
and mean change in DLQI were additional major secondary endpoints in UNCOVER-3 and were also the secondary
endpoints in UNCOVER-2. Other secondary endpoints included mean change from baseline PASI and proportion of
patients achieving a DLQI of 0 or 1, which equates to no effect of disease on patients quality of life, through Week
12. Primary and most secondary endpoints were collected at patient visits during Weeks 0, 1, 2, 4, 8, and 12. DLQI
was collected at Weeks 0, 2, 4, and 12.

Additional Details of Statistical Analyses

Continuous efficacy and quality of life measures were analysed using mixed model for repeated measures
analysis. The model included treatment, pooled center, baseline value, visit, and the interaction of treatment-by-visit
as fixed factors. The covariance structure to model the within-patient errors was unstructured. If the unstructured
covariance matrix resulted in a lack of convergence, the heterogeneous Toeplitz covariance structure, followed by
the heterogeneous autoregressive covariance structure were used. The Kenward-Roger method was used to estimate
the denominator degrees of freedom. Type III tests for the LS means was used for the statistical comparison.

We performed the logistic regression analysis testing treatment*centre interaction for both UNCOVER 2 and
UNCOVER 3, the treatment*centre interaction were not significant for each study. Within each centre, the
treatment group differences were evaluated by using Fishers exact test. There was no further modelling or
aggregation conducted due to no significant treatment*centre interaction.

Additional Details of Non-inferiority and Inferiority Analyses

Criteria for non-inferiority of ixekizumab compared with etanercept was analysed using the fixed-margin approach,
in which ixekizumab would be deemed to be non-inferior to etanercept if the lower bound of the 2-sided 97.5% CI
for the difference in proportions of responders on ixekizumab minus the proportion of responders on etanercept was
greater than the prespecified non-inferiority margin of -12%. Superiority would be conferred to ixekizumab if the
lower bound of the 97.5% CI for the difference in proportions of responders on ixekizumab minus etanercept
exceeded 0.

Details of Gatekeeping Testing Strategy


For each study, a gatekeeping testing strategy for the primary and major secondary analyses was implemented to
control the overall type I error rate at a 2-sided alpha level of 0.05. This allowed simultaneous inference of all of the
primary and major secondary endpoints. The underlying procedure was derived using the methodology developed
in Dmitrienko and Tamhane (Dmitrienko A, Tamhane AC. Mixtures of multiple testing procedures for gatekeeping
applications in clinical trials. Stat Med. 2011;30:1473-1488.). The gatekeeping procedure is based on the
Bonferroni test and utilizes an intuitive, stepwise testing algorithm. The alpha levels for the p-values associated
with the primary and secondary analyses have been computed at each step depending on the outcomes of the
preceding significance tests.

In order to reflect the test order and how the multiple doses were analyzed, the doses have been renamed:
80 mg ixekizumab Q2W = Dose 1
80 mg ixekizumab Q4W = Dose 2
The following is a list of the primary and major secondary comparisons was tested for each ixekizumab dosage
regimen:
Primary 1 (Test 1) Proportion of patients with a sPGA (0,1) at Week 12 (Visit 7) compared with placebo
Primary 2 (Test 2) Proportion of patients with a PASI 75 at Week 12 (Visit 7) compared with placebo
Primary 3 (Test 3) Proportion of patients with a sPGA (0,1) at Week 12 (Visit 7), non-inferiority to etanercept
Primary 4 (Test 4) Proportion of patients with a PASI 75 at Week 12 (Visit 7), non-inferiority to etanercept
Primary 5 (Test 5) Proportion of patients with a sPGA (0,1) at Week 12 (Visit 7), superiority to etanercept
Primary 6 (Test 6) Proportion of patients with a PASI 75 at Week 12 (Visit 7), superiority to etanercept
Secondary 1 (Test 7) Proportion of patients achieving a sPGA (0) at Week 12 (Visit 7) compared with placebo
Secondary 2 (Test 8) Proportion of patients with a PASI 90 at Week 12 (Visit 7) compared with placebo
Secondary 3 (Test 9) Proportion of patients with a PASI 100 at Week 12 (Visit 7) compared with placebo
Secondary 4 (Test 10) Proportion of patients achieving a sPGA (0) at Week 12 (Visit 7), superiority to etanercept
Secondary 5 (Test 11) Proportion of patients with a PASI 90 at Week 12 (Visit 7), superiority to etanercept
Secondary 6 (Test 12) Proportion of patients with a PASI 100 at Week 12 (Visit 7), superiority to etanercept
Secondary 7 (Test 13) Proportion of patients achieving an Itch NRS 4 point reduction from baseline at Week 12
(Visit 7) compared with placebo (for patients who had baseline Itch NRS 4) [UNCOVER-3 only]
Secondary 8 (Test 14) Change from baseline in DLQI at Week 12 (Visit 7) compared with placebo [UNCOVER-3
only]
Secondary 9 (Test 15) Change from baseline in NAPSI (for fingernails) at Week 12 (Visit 7) compared with
placebo [UNCOVER-3 only]

The 15 statistical tests have been grouped into 2 parallel branches. The first branch includes tests of Dose 1 versus
placebo and etanercept in Period 2 (Induction Dosing Period). The second branch includes tests of Dose 2 versus
placebo and etanercept in Period 2 (Induction Dosing Period). Test 2 has been performed for a dose only if Test 1 of
that dose was significant. Similarly, each test for a particular dose has been performed only if all prior tests of that
dose are significant. For each dose, if a test was not significant, all subsequent tests were not significant.

Step 1: Test 1 for Doses 1 and 2 compared with placebo were carried out using the Bonferroni procedure; that is,
each test was carried out at a 2-sided = 0.025.
Step 2: Test 2 for Doses 1 and 2 compared with placebo were carried out using the Bonferroni procedure. If Test 1
for Dose 1 was significant, Test 2 for Dose 1 was carried out at a 2-sided = 0.025; and, if Test 1 for Dose 2 was
significant, Test 2 for Dose 2 was carried out at a 2-sided = 0.025.
Step 3: Test 3 for Doses 1 and 2 compared with etanercept were carried out using the Bonferroni procedure. If Test
2 for Dose 1 was significant and etanercept was superior to placebo at the 2-sided = 0.05, Test 3 for Dose 1 was
carried out at a 2-sided = 0.025; and, if Test 3 for Dose 2 was significant and etanercept was significantly better
than placebo at the 2-sided = 0.05, Test 3 for Dose 2 was carried out at a 2-sided = 0.025. (Etanercept compared
with placebo was tested at the 2-sided = 0.05 even if only 1 dose was significant in Step 2.)
Step 4: Test 4 for Doses 1 and 2 compared with etanercept were carried out using the Bonferroni procedure. If Test
3 for Dose 1 was significant and etanercept was superior to placebo at the 2-sided = 0.05, Test 4 for Dose 1was
carried out at a 2-sided = 0.025; and, if Test 3 for Dose 2 was significant and etanercept was significantly better
than placebo at the 2-sided = 0.05, Test 4 for Dose 2 was carried out at a 2-sided = 0.025. (Etanercept compared
with placebo was tested at the 2-sided = 0.05 even if only 1 dose was significant in Step 3.)
Steps 5 through 15 were carried out similar to Step 2 with the current step depending on the result of the previous
step.

There was no adjustment for multiple comparisons for any other analyses.

Supplemental Table 1: UNCOVER-2 Participating Study Sites and Principal Investigators

The UNCOVER-2 induction period was conducted from May 2012- March 2014 at 126 sites throughout the world.
vHorizons Clinical Research Center, LLC, Denver, CO, Klinikum Darmstadt Hautklinik - Darmstadt, Germany
USA Maurizio Podda, M.D.
David J. Kerr, M.D.
Praxis Dr. Rieken, Berlin, Germany
Clinical Pharmacology Study Group, Worcester, MA, Tilmann Rieken, M.D.
USA
Charles Birbara, M.D. Clinical Research Hamburg GmbH, Hamburg, Germany
Christine Grigat, M.D.
Arizona Skin and Laser Therapy Inst., LTD.,
Scottsdale, AZ, USA Universittsklinikum Jena, Jena, Germany
William T. Ko, M.D. Johannes Norgauer, M.D.

Medical Center for Clinical Research, Universittsklinikum Carl Gustav Carus,


San Diego, CA, USA Dresden, Germany
William D. Koltun, M.D. Gottfried Wozel, M.D.

TKL Research, Inc., Paramus, NJ, USA and Universittsklinikum Essen, Essen, Germany
Fair Lawn, NJ, USA Andreas Koerber, M.D.
Jonathan S. Dosik, M.D.
Ihre Hautrzte Bredlich, Rosenbach and Thiele,
Arkansas Primary Care Clinic Family Practice, Osnabrck, Germany
Little Rock, AR, USA Thomas Rosenbach, M.D.
Derek Lewis, M.D.
Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie,
Medical Faculty Associates, Washington, DC, USA Klinika Dermatologii, Wenerologii i Dermatologii
Alison Ehrlich, M.D., MHS Dziecicej, Lublin, Poland
Grazyna Chodorowska, M.D.
Department of Dermatology, University of Connecticut
Health Center, Farmington, CT, USA Samodzielny Publiczny Szpital Kliniczny nr 2 Pomorski
Bruce E. Strober, M.D., Ph. D., FAAD Uniwersytet Medyczny w Szczecinie Klinika Chorb
Skrnych i Wenerycznych
Wilmington Dermatology Center, Wilmington, NC, USA Romuald Maleszka, M.D.
Rosalyn E. George, M.D.
Centrum Medyczne "DERMED" Sp. z o.o., d; Poland
Central Sooner Research, Norman, OK, USA Andrzej Kaszuba, M.D.
Paul Gillum, M.D.
Centralny Szpital Kliniczny Ministerstwa Spraw
Atlanta Dermatology, Vein and Research Center, Wewntrznych w Warszawie Klinika Dermatologii,
Alpharetta, GA, USA Warszawa, Poland
Tiffani K. Hamilton, M.D. Lidia Rudnicka, M.D.
Elzbieta B. Szymanska, M.D.
National Clinical Research, Inc. (NCRI),
Richmond, VA, USA NOVUM Instytut Dermatologii Leczniczej i Estetycznej,
John A. Hoekstra, M.D., Ph.D., CPI Opole, Poland
Elzbieta Klujszo, M.D.
Dermatology Treatment and Research Center,
Dallas, TX, USA Uniwersyteckie Centrum Kliniczne Klinika Dermatologii,
William Abramovits, M.D. Wenerologii i Alergologii, Gdask, Poland
Roman Nowicki, M.D.
Mount Sinai School of Medicine, New York, NY, USA
Mark G. Lebwohl, M.D. Prywatny Gabinet Dermatologiczny Elbieta Kujszo,
Kielce, Poland
Center for Clinical Studies, Webster, TX, USA Grazyna Wasik, M.D.
Patricia C. Lee, M.D.

Medical Development Centers, LLC, Baton Rouge, LA, Spitalul Clinic Municipal de Urgenta Hospital,
USA Timisoara, Romania
Ira H. Thorla, Jr., M.D. Caius Solovan, M.D.

Arlington Research Center, Inc., Arlington, VA, USA SC IASIPREST SRL Cabinete Medicale Mihalache, Iasi,
Angela Moore, M.D. Romania
Dorin Mihalache, M.D.
The Skin Wellness Center PC, Knoxville, TN, USA
Kimberly Grande, M.D. Spitalul Clinic Colentina, Bucuresti, Romania
George-Sorin Tiplica, M.D.
ORA Clinical Research and Development, Andover,
MA, USA RODERMA, Iasi, Romania
Jeffrey M. Sobell, M.D. Anca Zbranca-Toporas, M.D.

DermAssociates, PC, Rockville, MD, USA Spitalul Clinic Judetean de Urgenta Hospital, Craiova,
Benjamin Lockshin, M.D. Romania
Ion Florea, M.D.
Radiant Research, Inc., Greer, SC, USA
John M. Humeniuk, M.D. Centrul Medical SANA, Bucuresti, Romania
Horia Beti, M.D.

Avail Clinical Research, LLC, DeLand, FL, USA Monklands Hospital, Airdrie, Lanarkshire, United
Bruce G. Rankin, M.D. Kingdom
Nicholas Wainwright, M.D.
North Florida Dermatology Associates, PA,
Jacksonville, FL, USA Salford Royal Hospital, Manchester, United Kingdom
Joseph G. Delamo, M.D. Christopher Griffiths, M.D.

Virginia Clinical Research, Inc., Norfolk, VA, USA Royal Free London NHS Foundation Trust, London,
David M. Pariser, M.D. United Kingdom
Sandy McBride, M.D.
Central Dermatology, PC, St. Louis, MO, USA
Craig L. Leonardi, M.D. Western Infirmary, Glasgow, United Kingdom
David Burden, M.D.
Dermatology Clinical Research Center of San Antonio,
San Antonio, TX, USA Ninewells Hospital, Dundee, United Kingdom
Steven A. Davis, M.D. John Foerster, M.D.

University of Pittsburgh Medical Center, Department of Scunthorpe General Hospital, North Lincolnshire, United
Dermatology, Pittsburgh, PA, USA Kingdom
Laura K. Ferris, M.D., Ph.D. Aamir Butt, M.D.

Skin Care Research, Inc., Boca Raton, FL, USA National Institute for Health Research, Clinical Research
Marta I. Rendon, M.D. Facility, Sheffield, United Kingdom
Andrew Messenger, M.D.
Advanced Medical Research, Inc, Atlanta, GA, USA
and Peachtree Dermatology Associates Research Center Central Sydney Dermatology, Sydney, NSW, Australia
Jamie D. Weisman, M.D. Adrian Lim, M.D.

Dermatology of Boca, Boca Raton, FL, USA


Jeffrey S. Fromowitz, M.D. Eastern Health, Box Hill, Victoria, Australia
John Su, M.D.
Alliance Dermatology and MOHS Center, PC., Phoenix,
AZ, USA Emeritus Research, Malvern East, Victoria, Australia
S. Sasha Jazayeri, M.D. Stephen Hall, M.D.

The Dermatology Group, PC, Verona, NJ, USA


Robert Nossa, M.D. Royal North Shore Hospital, Sydney, NSW, Australia
Alan Cooper, M.D.

Parish Dermatology, Philadelphia, PA, USA North Eastern Health Specialists, Hectorville, South
Lawrence C. Parish, M.D. Australia, Australia
Shireen Sidhu, M.D.
Austin Dermatology Associates, Austin, TX, USA
Daniel A. Carrasco, M.D., FAAD. Woden Dermatology, Phillip, ACT, Australia
Diana Rubel, M.D.
Kansas City Dermatology, PA, Overland Park, KS, USA
Mark A. McCune, M.D. Skin and Cancer Foundation, Melbourne, Victoria,
Australia
Premier Clinical Research, Spokane, WA, USA Peter Foley, M.D.
William P. Werschler, M.D.
Specialist Connect, Brisbane, Queensland, Australia
West Dermatology, Riverside, CA, USA Lynda Spelman, M.D.
Kevin T. Belasco, D.O., MS
Cabinet mdical du Dr Bodokh, Cannes, France
Palm Beach Research Center, West Palm Beach, FL, Isaac Bodokh, M.D.
USA
Abe Marcadis, M.D. Hpital Charles Nicolle Dermatologie, Rouen, France
Anne-Benedicte Duval-Modeste, M.D.
Tri Cities Skin and Cancer, Johnson City, TN, USA
Timothy L. Gardner, M.D. C.H.U. DE POITIERS LA MILETRIE, Poitiers, France
Gerard Guillet, M.D.
The Indiana Clinical Trials Center, PC, Plainfield, IN,
USA Hpital Larrey Dermatologie, Toulouse, France
Scott T. Guenthner, M.D. Carle Paul, M.D.

University of South Florida College of Medicine, L'Archet Hospital, Nice, France


Department of Dermatology and Cutaneous Surgery, Jean-Philippe Lacour, M.D.
Tampa, FL, USA St Jacques Hospital, Besanon, France
Christopher G. Nelson, M.D. Francois Aubin, M.D.

Toronto Research Centre, Toronto, Ontario, Canada CHU Amiens - HPITAL SUD, Amiens, France
Ben Barankin, M.D. Guillaume Chaby, M.D.

Guildford Dermatology Specialists, Surrey, British Hopital Timone Aix Marseille UnivDermatologie
Columbia, Canada Vnrologi, Marseille, France
Lorne Albrecht, M.D. Jean-Jacques GROB, M.D.

SKiN Centre for Dermatology, Peterborough, Ontario, UMC (Universitair Medisch Centrum), Nijmegen, The
Canada Netherlands
Melinda Gooderham, M.D. Peter Van de Kerkhof, M.D.

Centre de Dermatology, Ste-Foy, Quebec, Canada Amphia Ziekenhuis, Breda, The Netherlands
Yves Poulin, M.D. Wim de Kort, M.D.

North Bay Dermatology Centre, North Bay, Ontario, Erasmus MC, Rotterdam, The Netherlands
Canada Martiin Bastiaan Van Doorn, M.D.
Leslie Rosoph, M.D.
AKH Wien, Wien, Austria
Q & T Research Sherbrooke Inc., Sherbrooke, Quebec, Elisabeth Riedl, M.D.
Canada
Jean Sebastien Gauthier, M.D. Landeskrankenhaus Feldkirch, Feldkirch, Austria
Robert Strohal, M.D.
Dermatrials Research Dermatology Centre Inc.,
Hamilton, Ontario, Canada LKH Innsbruck, Innsbruck, Austria
Ronald Vender, M.D. Matthias Schmuth, M.D.

Medizinische Unviverstit Graz, Graz, Austria


Stratica Medical, Edmonton, Alberta, Canada Wolfgang Salmhofer, M.D.
Norman Wasel, M.D.
10

Fakultni nemocnice Kralovske Vinohrady, Praha, Czech


Manna Research Inc., Toronto, Ontario, Canada Republic
Benjamin Lasko, M.D. and Petr Arenberger, M.D.
Azhar Toma, M.D.
Fakultni nemocnice u sv. Anny v Brne, Brno, Czech
Northwest Dermatology & Laser Centre, Calgary, Republic
Alberta, Canada Vladimir Vasku, M.D.
Derek Woolner, M.D.
Fakultni nemocnice v Motole, Praho,
Kirk Barber Research, Calgary, Alberta, Canada Czech Republic
Kirk Barber, M.D. Alena Machovcova, M.D.

The Guenther Dermatology Research Centre, London, Hospital Universitari Germans Trias i Pujol, Badalona,
Ontario, Canada Spain
Lyn Guenther, M.D. Carlos Ferrandiz, M.D.

Lynderm Research Inc., Markham, Ontario, Canada Hospital Universitario Clnico San Carlos,
Charles Lynde, M.D. Madrid, Spain
Lopez Bran Eduardo, M.D.
Research Toronto, Toronto, Ontario, Canada
Sam Hanna, M.D. Hospital de la Santa Creu I Sant Pau.,
Barcelona, Spain
Mediprobe Research Inc/Dermsearch Inc., Lluis Puig Sanz, M.D.
London, Ontario, Canada
Aditya Gupta, M.D. Hospital Clnico Universitario Virgen de la Victoria,
Mlaga, Spain
Ultranova Skincare, Barrie, Ontario, Canada Enrique Herrera Ceballos, M.D.
Rodion Kunynetz, M.D.
Hospital Universitario Fundacin Alcorcn, Madrid,
Spain
Praxis Dr. Hoffmann, Witten, Germany Jose Lopez Estebaranz, M.D.
Matthias Hoffmann, M.D.
Hospital General Universitario de Alicante, Alicante,
Medizinische Hochschule, Hannover, Spain
Hannover, Germany Isabel Belinchon Romero, M.D.
Thomas Werfel, M.D.
Hospital del Mar, Barcelona, Spain
SCIderm, Hamburg, Germany Ramon Pujol, M.D.
Kristian Reich, M.D.
Hospital Universitario, Madrid, Spain
Gemeinschaftspraxis Dres. Beate Bru und Antje Gro, Francisco Vanaclocha Sebastian, M.D.
Giessen, Germany
Beate Brau, M.D. Hospital Universitario de Gran Canaria Doctor Negrn,
Las Palmas de Gran Canaria, Spain
Eberhard-Karls Universitt Tbingen, Gregorio Carretero Hernandez, M.D.
Tbingen, Germany
Kamran Ghoreschi, M.D. Hospital Universitario Virgen Macarena,
Sevilla, Spain
Universittsmedizin Gttingen, Gttingen, Germany Lara Ferrandiz Pulido, M.D.
Rotraut Moessn, M.D.

11

Supplemental Table 2: UNCOVER-3 Participating Study Sites and Principal Investigators


The UNCOVER-3 induction period was conducted from July 2012 to May 2014 year at 126 sites throughout the world.

Oregon Medical Research Center, Portland, Oregon, Synexus Clinical Research GmbH, Klinisches
USA Prfzentrum, Berlin, Germany
Andrew Blauvelt, M.D. Janna Stoessel, M.D.
Hans Konig, M.D.
Altman Dermatology, Arlington Heights, Illinois, USA
Michael Bukhalo, M.D. DERMAKIEL Allergie und Haut Centrum, Kiel,
Germany
David Stoll, MD, Beverly Hills, California, USA Harald Bruning, M.D.
David Stoll, M.D.
Synexus Clinical Research GmbH, Klinisches
Bakersfield Dermatology and Skin Cancer Medical Prfzentrum, Dresden, Germany
Group, Bakersfield, California, USA Richard Piechatzek, M.D.
Jeffrey Crowley, M.D. Irina Lohrbacher-Kozak, M.D.

University of Michigan, Ann Arbor, Michigan, USA Synexus Clinical Research GmbH, Klinisches
Yolanda Helfrich, M.D. Prfzentrum, Frankfurt/Main, Germany
Christel Contzen, M.D.
Stephen Miller, MD, PA, San Antonio, Texas, USA
Stephen Miller, M.D. Klinische Forschung Berlin-Buch GmbH, Berlin,
Germany
DermResearchCenter of New York, Inc., Stony Brook, Andrei Khariouzov, M.D.
New York, USA
Elyse Rafal, M.D. Klinische Forschung Dresden GmbH, Dresden, Germany
Peter Heymer, M.D.
Leavitt Medical Associates of Florida, Ormond Beach, Kristen Kreutzmann, M.D.
Florida, USA
James Solomon, M.D. Klinikum Hanau GmbH, Hanau, Germany
Hans-Michael Ockenfels, M.D.
DermDox, Hazleton, Pennsylvania, USA Dr. med Thomas Wildfeuer und Partner Praxis fr
Stephen Schleicher, M.D. Haut- und Geschlechtskrankheiten im rztehaus
"Rudolf Virchow", Berlin, Germany
Advanced Skin Research Center, Omaha, Nebraska, USA Thomas Wildfeuer, M.D.
Joel Schlessinger, M.D.
Medizinisches Zentrum Bonn Friedensplatz, Bonn,
Dermatology Research Associates, Los Angeles, Germany
California, USA Uwe Reinhold, M.D.
Howard Sofen, M.D.
Hautarztpraxis Dr. Kurzen, Freising, Germany
Dermatologist and Cosmetic Sur, High Point, North Hjalmar Kurzen, M.D.
Carolina, USA
Zoe Diana Draelos, M.D. Hautarztpraxis, Stuttgart, Germany
Christian Termeer, M.D.
J. Woodson Dermatology & Associates, Henderson,
Nevada, USA Rothhaar Studien GmbH, Berlin, Germany
Johnnie Woodson, M.D. Alex Rothhaar, M.D.

Gemeinschaftspraxis fr Hautkrankheiten,
Friedrichshafen, Germany
Peter Radny, M.D.

12

Integrated Clinical Trial Serv,


West Des Moines, Iowa, USA Hautarztpraxis Gellrich, Berlin, Germany
James Coggi, M.D. Sylke Gellrich, M.D.
Jeffrey Lenz, M.D.
Hautarztpraxis Dr. med. Dorittke u. Dr. med. Kardorff,
Anaheim Clinical Trials, LLC, Anaheim, CA, USA Mnchengladbach, Germany
Kevin Kuettel, M.D. Bernd Kardorff, M.D.

SRCR, Inc., Bell Gardens, California, USA PraxisKlinik Dr. Anita Rtter,
Salem Galal, M.D. Mnster, Germany
Anita Rtter, M.D.
Academic Dermatology Associates, Albuquerque, New
Mexico, USA
Eduardo Tschen, M.D. Dermatologie Dr. Ludolph-Hauser, Ergolding, Germany
Dagmar Ludolph-Hauser, M.D.
Dermatology Specialists, Inc., Oceanside, California,
USA Gemeinschaftspraxis Mahlow, Mahlow, Germany
Ruth Gilboa, M.D. Michael Sebastian, M.D.

Dawes Fretzin Clinical Research Group, LLC, Universittsklinikum Mnster - Klinik fr


Indianapolis, Indiana, USA Hautkrankheiten, Mnster, Germany
Scott Fretzin, M.D. Athanasios Tsianakas, M.D.

Wake Forest University Health Sciences, Winston-Salem, CardioSec Clinical Research GmbH, Erfurt, Germany
North Carolina, USA Doerte Wolf, M.D.
Alan Fleischer, M.D.
Klinikum Mannheim GmbH, Mannheim, Germany
Jordan Valley Dermatology Center, West Jordan, Utah, Wiebke Ludwig-Peitsch, M.D.
USA
Douglass Forsha, M.D. Charit Campus Mitte, Charit, Universittsmedizin
Berlin, Klinik fr Dermatologie, Venerologie und
Radiant Research, INC, Anderson, South Carolina, USA Allergologie, Psoriasis-Studienzentrum, Berlin, Germany
Theresa Knoepp, M.D. Sandra Philipp, M.D.

University Clinical Trials, Inc., San Diego, California, Universittsklinikum Hamburg-Eppendorf


USA Competenzzentrum Dermatologische Forschung- CeDeF,
Walter Nahm, M.D. IVDP, Hamburg, Germany
Mathias Augustin, M.D.
NorthShore University Health System,
Skokie, IL, USA DCC Sveti Georgi, Plovdiv, Bulgaria
Stephanie Mehlis, M.D. Rumyana Yankova, Associate Professor

Menter Dermatology Research Institute, Dallas, Texas, UMHAT Alexandrovska, Sofia, Bulgaria
USA Jana Kazandjieva, Associate Professor
Martin Menter, M.D.
MMA MHAT Varna, Varna, 9010, Bulgaria
Clinical Science Institute, Santa Monica, California, USA Iliya Tsingov, M.D.
Paul Yamauchi, M.D.
Medical Centre "Doverie" AG, Sofia, Bulgaria
The Savin Center, New Haven, Connecticut, USA Tzetza Vlaeva, M.D.
Ronald Savin, M.D.

13

Sadick Research Group, New York, New York, USA Military Medical Academy, Sofia, Bulgaria
Neil Sadick, M.D. Miroslava Kadurina, Professor

Dermatology Specialists Research, Louisville, Kentucky, Niepubliczny Zaklad Opieki Zdrowotnej Specjalistyczna
USA Przychodnia Dermatologiczna "SPECDERM",
Joseph Fowler, M.D. Biaystok, Poland
Maria Poznanska, M.D.
Owensboro Dermatology Associates, Owensboro, KY,
USA Maopolskie Centrum Medyczne s.c., Krakw, Poland
Artis Truett, M.D. Lidia Rajzer, M.D.

Kaiser Permanente Medical Group, Los Angeles, Clinical Research Group Sp. z o.o., Warszawa, Poland
California, USA Kamila Padlewska, M.D.
Jashin Wu, M.D.
Centro de Dermatologa de Monterrey, Monterrey,
Encore Research Group-Jacksonville, Jacksonville, Nuevo Len, Mexico
Florida, USA Remigio F Gonzalez Soto, M.D.
Michael Bernhardt, M.D.
CRI Centro Regiomontano de Investigacin S.C.,
Progressive Clinical Research, San Antonio, Texas, USA Monterrey, Nuevo Len, Mexico
Mark Lee, M.D. Javier A Gonzalez, M.D.

Psoriasis Treatment Center of Central New Jersey, East Szegedi Tudomnyegyetem Szent Gyrgyi Albert
Windsor, New Jersey, USA Klinikai Kzpont Brgygyszati Klinika, Szeged,
Jerry Bagel, M.D. Hungary
Lajos Kemeny , M.D.
Renstar Medical Research, Ocala, Florida, USA
Frederick Behringer, M.D. Debreceni Egyetem Orvos- s Egszsgtudomnyi
Centrum Brgygyszati Klinika, Debrecen, Hungary
DermResearch, PLLC, Louisville, Kentucky, USA Eva Remenyik, M.D.
Leon Kircik, M.D.
Miskolci Semmelweis Krhz s Egyetemi Oktatkrhz
International Dermatology Research, Inc., Miami, Brgygyszati Osztly, Miskolc, Hungary
Florida, USA Zsuzsanna Karolyi, M.D.
Javier Alonso-Llamazares, M.D.
Brgygyszati s Allergolgiai Magnrendels, Szolnok,
Riverside Clinical Research, Edgewater, Florida, USA Hungary
Susan Hole, M.D. Noemi Bakos, M.D.

Oregon Dermatology and Research Center, Portland, Oroshzi Krhz, Oroshza, Hungary
Oregon, USA Edina Nemes, M.D.
Phoebe Rich, M.D.
Csolnoky Ferenc Krhz, Veszprm, Hungary
Northwestern Medical Faculty Foundation, Chicago, IL, Levente Kovago, M.D.
USA
Kenneth Gordon, M.D. Markusovszky Egyetemi Oktatkrhz Brgygyszati
Osztly, Szombathely, Hungary
ActivMed Practices & Research, Newington, New Eniko Telegdy, M.D.
Hampshire, USA
James Campbell, M.D.

14

University of Utah, Salt Lake City, UT, USA


Kristina Callis-Duffin, M.D. Pcsi Tudomnyegyetem ltalnos Orvostudomnyi
Kar Br-, Nemikrtani s Onkodermatolgiai Klinika,
Tufts Medical Center, Boston, Massachusetts, USA Pcs, Hungary
Alice Gottlieb, M.D. Rolland Gyulai, M.D.
Dalma Varszegi, M.D.
University of California, Irvine, Irvine, CA, USA
Jennifer Soung, M.D. Bcs-Kiskun Megyei Krhz Szegedi Tudomnyegyetem
ltalnos Orvostudomnyi Kar Oktat Krhza
University of Colorado, Anschutz Medical Campus, Brgygyszati Szakrendels, Kecskemt, Hungary
Aurora, Colorado Ivan Orojan, M.D.
April Armstrong, M.D.
David Norris, M.D. Csongrd Megyei Egszsggyi Ellt Kzpont
Hdmezvsrhely-Mak Brgygyszati osztly, Mak,
Derm Research @ 888, Inc., Vancouver, BC, Canada Hungary
Richard Thomas, M.D. Dosa Piroska, M.D.

Institute for Skin Advancement, Calgary, Alberta, Synexus Magyarorszg Kft., Budapest, Hungary
Canada Ildiko Vincze, M.D.
Stewart Adams, M.D.
UNO Medical Trials Kft., Budapest, Hungary
K. Papp Clinical Research, Waterloo, Ontario, Canada Eva Melegh, M.D.
Kim Papp, M.D.
Moscow Research and Practice Center of
Eastern Canada Cutaneous Research Assoc. Ltd, Halifax, Dermatovenereology and Cosmetology of Health Board
Nova Scotia, Canada of Moscow city, Moscow, Krylatskie Cholmy, Russia
Richard Langley, M.D. Yuriy N Perlamutrov, Professor

Dr Isabelle Delorme Inc., Drummondville, Quebec, State Budgetary Healthcare Institution "Clinical
Canada dermatovenereological dispensary" Healthcare
Isabelle Delorme, M.D. Department of Krasnodarskiy Kray, Krasnador,
Krasnodarskiy Kray, Russia
Office of Dr. Michael Robern, Ottawa, Ontario, Canada Nikolay Murashkin, M.D.
Michael Robern, M.D.
St. Petersburg State Budgetary Healthcare Institution
University of British Columbia, Vancouver, BC, Canada "Skin-venerologic dispensary 10", St. Petersburg,
Youwen Zhou, M.D. Russia
Alexey Sukharev, Professor
Windsor Clinical Research, Windsor, Ontario, Canada LLC Alliance Biomedical- Russian group, St. Petersburg,
Jerry Tan, M.D. Russia
Anton Edin, M.D.
The Centre for Dermatology, Richmond Hill, Ontario,
Canada
Mani Raman, M.D. American Medical Clinic LLC, St. Petersburg, Russia
Yana Smirnova, M.D.
Dr. Sharma Dermatologist and Laser Clinic, Brampton, Kirill Rudinskiy, M.D.
ON, Canada
Shakti Sharma, M.D.

Innovaderm Research Inc, Montreal, Quebec, Canada


Catherine Maari, M.D.

15

licca Fachklinik fr sthetisch-operative Dermatologie State Budgetary Educational Institution of High


und Chirurgie, Augsburg, Germany Professional Education "North-Western State Medical
Georg Popp, M.D. University n.a. I.I. Mechnikov " of the Ministry of Health
of Russian Federation, Scientific and Research Institute
Gemeinschaftspraxis Prof.Dr. Vanscheidt und Dr. Ukat, of Medical Mycology, St. Petersburg, Russia
Freiburg, Germany Konstantin Raznatovskiy, M.D.
Wolfgang Vanscheidt, M.D.
Center of Clinical Trials of Diagnostic and
Klinikum und Fachbereich Medizin, Johann Wolfgang Pharmaceutical Products, Smolensk, Russia
Goethe-Universitt, Frankfurt, Germany Olga Stetsiouk, M.D.
Roland Kaufmann, M.D.
Diamant Thaci, M.D. St. Petersburg State Healthcare Institution
"Dermatovenerologic Dispensary #8", St. Petersburg,
Universittsklinikum Wrzburg Klinik und Poliklinik Russia
fr Dermatologie, Venerologie und Allergologie, Stanislav Givirovskiy, M.D.
Wrzburg, Germany
Sandrine Benoit, M.D. State Budgetary Clinical Healthcare Institution of
Yaroslavl Region "City Clinical Hospital n.a. N.A.
Klinische Forschung Hamburg GmbH, Hamburg, Semashko", Yaroslavl, Russia
Germany Petr Chizhov, Professor
Andrea Thron, M.D.
Petra Kast, M.D. Centro Internacional de Estudios Clnicos (CIEC),
Santiago, Chile
SRH Wald-Klinikum Gera gGmbH, Zentrum fr Fernando Valenzuela, M.D.
Klinische Studien, Gera, Germany
Martin Kaatz, M.D. Clinica Dermacross, S.A., Claudia De La Cruz, Santiago,
Chile
Universittsmedizin der Johannes Gutenberg-Universitt Fernandez, M.D.
Mainz Hautklinik / Clinical Research Center, Mainz,
Germany Buenos Aires Skin, S.A., Buenos Aires, Argentina
Rudolf Schopf, M.D. Pablo Gonzalez, M.D.

Hospital Italiano de Buenos Aires (Sociedad Italiana de


Beneficencia en Buenos Aires), Ciudad Autnoma de
Klinische Forschung Schwerin GmbH, Schwerin, Buenos Aires, Argentina
Germany Ricardo Luis Galimberti, M.D.
Elisabeth Theis, M.D.
Christine Paschen, M.D.
Centro de Investigaciones Dermatolgicas S.A Pte. J. E.,
Klinische Forschung Berlin-Mitte GmbHk, Berlin, Buenos Aires, Argentina
Germany Gabriel Alejandro Magarinos, M.D.
Liebhild Stratmann, M.D.

Dermatologische Privatpraxis Dr. med. A. Grfe,


Northeim, Germany
Andrea Graefe, M.D.

Synexus Clinical Research GmbH, Leipzig, Germany


Kristin Kreutzmann, M.D.
Elizaveta Degtyareva, M.D.

16

Supplemental Table 3: Prior Biologics Used by Patients enrolled in UNCOVER-2 and 3 and Reasons for Discontinuation

UNCOVER-2 UNCOVER-3

PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
(N=168) (N=358) (N=347) (N=351) (N=193) (N=382) (N=386) (N=385)
n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Biologic Agent 43 (25.6) 76 (21.2) 84 (24.2) 84 (23.9) 33 (17.1) 60 (15.7) 58 (15.0) 58 (15.1)
efalizumab 3 (1.8) 3 (0.8) 4 (1.2) 4 (1.1) 0 4 (1.0) 5 (1.3) 4 (1.0)
ustekinumab 9 (5.4) 25 (7.0) 36 (10.4) 32 (9.1) 10 (5.2) 18 (4.7) 26 (6.7) 20 (5.2)
infliximab 5 (3.0) 16 (4.5) 18 (5.2) 16 (4.6) 1 (0.5) 9 (2.4) 9 (2.3) 9 (2.3)
etanercept 0 0 0 0 0 1 (0.3) 0 0
alefacept 4 (2.4) 3 (0.8) 1 (0.3) 8 (2.3) 1 (0.5) 3 (0.8) 1 (0.3) 0
adalimumab 9 (5.4) 27 (7.5) 30 (8.6) 35 (10.0) 14 (7.3) 23 (6.0) 19 (4.9) 21 (5.5)
golimumab 1 (0.6) 1 (0.3) 1 (0.3) 2 (0.6) 1 (0.5) 0 0 0
Other 21 (12.5) 28 (7.8) 22 (6.3) 24 (6.8) 12 (6.2) 17 (4.5) 17 (4.4) 22 (5.7)
Reason for
discontinuing biologic
agent
Inadequate response 15 (8.9) 24 (6.7) 32 (9.2) 37 (10.5) 8 (4.1) 17 (4.5) 15 (3.9) 24 (6.2)
Completed scheduled
15 (8.9) 29 (8.1) 29 (8.4) 34 (9.7) 15 (7.8) 19 (5.0) 18 (4.7) 14 (3.6)
treatment
Treatment availability 10 (6.0) 12 (3.4) 10 (2.9) 11 (3.1) 6 (3.1) 6 (1.6) 12 (3.1) 13 (3.4)
Inability to afford
4 (2.4) 7 (2.0) 17 (4.9) 6 (1.7) 6 (3.1) 13 (3.4) 11 (2.8) 7 (1.8)
medication
Subject decision 4 (2.4) 7 (2.0) 9 (2.6) 8 (2.3) 1 (0.5) 7 (1.8) 6 (1.6) 4 (1.0)
Adverse event 3 (1.8) 7 (2.0) 4 (1.2) 7 (2.0) 1 (0.5) 3 (0.8) 2 (0.5) 3 (0.8)
Contraindication 1 (0.6) 2 (0.6) 0 0 0 3 (0.8) 3 (0.8) 0

17

Supplemental Table 4: Baseline Medical History of Cardiovascular Risk Factors Pooled Studies

UNCOVER-2 and UNCOVER-3


PBO ETN IXE Q4W IXE Q2W
(N=360) (N=739) (N=729) (N=734)
Hypertension, n (%) 114 (31.7) 215 (29.1) 189 (25.9) 194 (26.4)
Diabetes mellitus, Type I, n (%) 2 (0.6) 3 (0.4) 2 (0.3) 5 (0.7)
Diabetes mellitus, Type II, n (%) 33 (9.2) 61 (8.3) 78 (10.7) 55 (7.5)
Coronary Artery Disease, n (%) 12 (3.3) 29 (3.9) 15 (2.1) 20 (2.7)
Stroke, n (%) 2 (0.6) 3 (0.4) 4 (0.5) 8 (1.1)
Dyslipidemia, n (%) 41 (11.4) 85 (11.5) 94 (12.9) 91 (12.4)

18

Supplemental Table 5: Baseline Medical History of Cardiovascular Risk Factors for UNCOVER-2 and UNCOVER-3

UNCOVER-2 UNCOVER-3
PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
(N=168) (N=358) (N=347) (N=351) (N=193) (N=382) (N=386) (N=385)
Hypertension, n (%) 55 (32.7) 88 (24.6) 89 (25.6) 76 (21.7) 59 (30.6) 127 (33.2) 100 (26.1) 118 (30.6)
Diabetes mellitus, Type I, n (%) 2 (1.2) 2 (0.6) 2 (0.6) 2 (0.6) 0 1 (0.3) 0 3 (0.8)
Diabetes mellitus, Type II, n (%) 14 (8.3) 22 (6.1) 37 (10.7) 27 (7.7) 19 (9.8) 39 (10.2) 41 (10.7) 28 (7.3)
Coronary Artery Disease, n (%) 4 (2.4) 13 (3.6) 11 (3.2) 10 (2.8) 8 (4.1) 16 (4.2) 4 (1.0) 10 (2.6)
Stroke, n (%) 0 1 (0.3) 3 (0.9) 5 (1.4) 2 (1.0) 2 (0.5) 1 (0.3) 3 (0.8)
Dyslipidemia, n (%) 22 (13.1) 39 (10.9 49 (14.1) 42 (12.0) 19 (9.8) 46 (12.0) 45 (11.7) 49 (12.7)

19

Supplemental Table 6: Adverse Events, n (%) for UNCOVER-2 and UNCOVER-3

UNCOVER-2 UNCOVER-3

PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
(N=167) (N=357) (N=347) (N=350) (N=193) (N=382) (N=382) (N=384)
Any TEAE 89 (533) 211 (591) 204 (588) 216 (617) 70 (363) 187 (490) 215 (563) 205 (534)
Death 0 0 0 0 0 0 0 0
Nonfatal serious AE 2 (12) 8 (22) 8 (23) 5 (14) 5 (26) 5 (13) 6 (16) 9 (23)
Any Infection 46 (275) 98 (275) 100 (288) 104 (297) 27 (140) 59 (154) 88 (230) 82 (214)
Common TEAE*
Nasopharyngitis 17 (102) 36 (101) 29 (84) 35 (100) 11 (57) 19 (50) 29 (76) 26 (68)
Upper respiratory
7 (42) 26 (73) 16 (46) 19 (54) 5 (26) 8 (21) 8 (21) 8 (21)
tract infection
Injection-site
1 (06) 39 (109) 19 (55) 39 (111)a 3 (16) 41 (107) 43 (113 37 (96)
reaction
Injection-site
2 (12) 18 (50) 9 (26) 12 (34) 0 11 (29) 5 (13) 12 (31)
erythema
Injection-site pain 2 (12) 4 (11) 6 (17) 13 (37) 3 (16) 5 (13) 3 (08) 8 (21)
Pruritus 4 (24) 4 (11) 7 (20) 7 (20) 1 (05) 4 (10) 9 (24) 7 (18)
Headache 3 (18) 20 (56) 18 (52) 17 (49) 5 (26) 11 (29) 16 (42) 16 (42)
Arthralgia 4 (24) 10 (28) 8 (23) 7 (2.0) 4 (2.1) 7 (1.8) 10 (2.6) 13 (3.4)
*Common is defined as any treatment-emergent adverse event with frequency of 2% or greater in both ixekizumab dose groups in combined trials; TEAE=Treatment-Emergent
Adverse Event

Note: The data cut-off dates for UNCOVER-3 interim lock was earlier than the integrated UNCOVER-2 and UNCOVER-3 data cut-off date, therefore,
integrated study tables contain a few more data points than individual study data combined.

20

Supplemental Table 7: Adverse Events of Special Interest Pooled Studies

UNCOVER-2 and UNCOVER-3


PBO ETN IXE Q4W IXE Q2W
(N=360) (N=739) (N=729) (N=734)
Any infection 74 (20.6) 159 (21.5) 191 (26.2) 190 (25.9)
Injection-site reactions* 13 (3.6) 121 (16.4) 97 (13.3) 127 (17.3)
Allergic reactions/
hypersensitivities 7 (1.9) 18 (2.4) 25 (3.4) 25 (3.4)
(anaphylaxis)
Anaphylaxis 0 0 0 0
Non-anaphylaxis 7 (1.9) 18 (2.4) 25 (3.4) 25 (3.4)
Malignancy 0 1 (0.1) 0 3 (0.4)
Basal cell carcinoma 0 0 0 2 (0.3)
Thyroid neoplasm 0 0 0 1 (0.1)
Malignant melanoma 0 1 (0.1) 0 0
Adjudicated Cerebro-
1 (0.3) 2 (0.3) 2 (0.3) 0
cardiovascular Events
Myocardial infarction 1 (0.3) 1 (0.1) 0 0
Atrial fibrillation 0 0 1 (0.1) 0
Peripheral arterial
0 1 (0.1) 0 0
occlusive disease
Cerebral artery
embolism 0 0 1 (0.1) 0

n (%), *Term includes all injection-site reactions, including reaction, erythema, pain, bruising, swelling, etc.

21

Supplemental Table 8: Adverse Events of Special Interest for UNCOVER-2 and UNCOVER-3

UNCOVER-2 UNCOVER-3
PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
(n=167) (n=357) (n=347) (n=350) (n=193) (n=382) (n=382) (n=384)
Any infection 46 (275) 98 (275) 100 (288) 104 (297) 27 (140) 59 (154) 88 (230) 82 (214)
Injection-site
7 (42) 62 (174) 42 (121) 69 (197) 6 (31) 59 (154) 55 (144) 58 (151)
reactions*
Allergic reactions/
hypersensitivities 3 (18) 11 (3.1) 14 (4.0) 13 (3.7) 4 (21) 7 (18) 11 (29) 12 (31)
(anaphylaxis)
Anaphylaxis 0 0 0 0 0 0 0 0
Non-anaphylaxis 3 (18) 11 (3.1) 14 (4.0) 13 (3.7) 4 (21) 7 (18) 11 (29) 12 (31)
Malignancy 0 1 (0.3) 0 3 (09) 0 0 0 0
Basal cell carcinoma 0 0 0 2 (06) 0 0 0 0
Thyroid neoplasm 0 0 0 1 (03) 0 0 0 0
Malignant 0 1 (0.3) 0 0 0 0 0 0
melanoma
Adjudicated Cerebro-
cardiovascular 0 2 (06) 1 (03) 0 1 (05) 0 1 (03) 0
Events
Myocardial
0 1 (03) 0 0 1 (05) 0 0 0
infarction
Atrial fibrillation 0 0 1 (03) 0 0 0 0 0
Peripheral arterial
0 1 (0.3) 0 0 0 0 0 0
occlusive disease
Cerebral artery
embolism 0 0 0 0 0 0 1 (0.3) 0

n (%),*Term includes all injection-site reactions, including reaction, erythema, pain, bruising, swelling, etc.

Note: The data cut-off dates for UNCOVER-3 interim lock was earlier than the integrated UNCOVER-2 and UNCOVER-3 data cut-off date, therefore,
integrated study tables contain a few more data points than individual study data combined.

22

Supplemental Table 9: Candida or Suspected Candida Infections Pooled Studies

UNCOVER-2 and UNCOVER-3


PBO ETN IXE Q4W IXE Q2W
(N=360) (N=739) (N=729) (N=734)
Total, n (%) 2 (0.6) 5 (0.6) 4 (0.5) 12 (1.6)
Oral 0 1 (0.1) 1 (0.1) 6 (0.8)
Genital/vulvovaginal 1 (0.3) 4 (0.5) 3 (0.4) 2 (0.3)
Skin/intertrigo 1 (0.3) 0 0 2 (0.3)*
Otitis externa 0 0 0 1 (0.1)
Oesophageal 0 0 0 1 (0.1)
*All Candida infections resolved with standard oral or local/topical treatments, except for one moderate skin Candida infection of the axilla and groin reported hyperhidrosis,
which started 6 weeks after initial Candida diagnosis, both of which may have contributed to the difficulty of resolution. The skin infection was treated with topical clotrimazole
BID (twice daily) for about 1 month, and then with topical Travocort, which contains a combination of isoconazole (an antifungal agent) and topical corticosteroid for about 2
weeks; no further information on Candida treatment or resolution of infection was reported. This patient continued therapy.

23

Supplemental Table 10: Candida or Suspected Candida Infections for UNCOVER-2 and UNCOVER-3

UNCOVER-2 UNCOVER-3

PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
(N=167) (N=357) (N=347) (N=350) (N=193) (N=382) (N=382) (N=384)
Total, n (%) 1 (06) 2 (06) 1 (03) 5 (15) 1 (05) 3 (08) 3 (08) 7 (18)
Oral 0 (0) 0 (0) 1 (03) 2 (06) 0 (0) 1 (03) 0 (0) 4 (10)
Genital/vulvovaginal 0 (0) 2 (06) 0 (0) 1 (03) 1 (05) 2 (05) 3 (08) 1 (03)
Skin/intertrigo 1 (06) 0 (0) 0 (0) 1 (0.3) 0 (0) 0 (0) 0 (0) 1 (03)
Otitis externa 0 (0) 0 (0) 0 (0) 1 (03) 0 (0) 0 (0) 0 (0) 0 (0)
Oesophageal 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (03)

24

Supplemental Table 11: Neutropenia Pooled Studies

UNCOVER-2 and UNCOVER-3


PBO ETN IXE Q4W IXE Q2W
Neutropenia Grade
(N=360, (N=739, (N=729, (N=734,
(worsening from
Nx = 358) Nx = 734) Nx = 724) Nx = 730)
baseline)
n (%) n (%) n (%) n (%)
Grade 1 (less than
the lower limit of
normal to 15 x 8 (2.2) 66 (9.0) 44 (6.1) 43 (5.9)
9
10 /L)
Grade 2 (<15 to
9 1 (0.3) 24 (3.3) 17 (2.3) 19 (2.6)
10 x 10 /L)
Grade 3 (<10 to
9 1 (0.3) 4 (0.5) 0 2 (0.3)
05 x 10 /L)
Grade 4 (<05 x
9 0 0 1 (0.1)* 0
10 /L)
N=number of patients in the analysis population, Nx=number of patients with non-missing data in each category. *Only 1 patients had Grade 4 neutropenia and
levels were normal after a two day retest.

25

Supplemental Table 12: Neutropenia in UNCOVER-2 and UNCOVER-3

UNCOVER-2 UNCOVER-3
PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W
Neutropenia Grade
(N=167, (N=357, (N=347, (N=350, (N=193, (N=382, (N=382, (N=384,
(worsening from
Nx = 166) Nx = 354) Nx = 344) Nx = 348 ) Nx = 192) Nx = 380) Nx = 380) Nx = 382)
baseline)
n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Grade 1 (less than
the lower limit of
normal to 15 x 6 (36) 38 (107) 17 (49) 23 (66) 2 (10) 28 (74) 27 (71) 20 (52)
9
10 /L)
Grade 2 (<15 to
9 1 (06) 10 (28) 9 (26) 7 (20) 0 14 (37) 8 (21) 12 (31)
10 x 10 /L)
Grade 3 (<10 to
9 1 (06) 1 (03) 0 0 0 3 (08) 0 2 (05)
05 x 10 /L)
Grade 4 (<05 x
9 0 0 0 0 0 0 1 (03) 0
10 /L)
N=number of patients in the analysis population, Nx=number of patients with non-missing data in each category.

26

Supplemental Figure 1: Proportion of patients who had a DLQI 0/1 over the 12-week induction period in (A) UNCOVER-2 and (B) UNCOVER-3

100
UNCOVER-2 A 100
UNCOVER-3 B
% Patients with DLQI 0/1

90 90

% Patients with DLQI 0/1


80 64.1 80
64.7
70 59.9 70 63.7
60 60
44.4 42.7 43.7
50 37.9 50 40.5
33.8
40 40
23.6 22.0
30 20.5
15.9
30 21.3
21.5
20 6.0 20 10.7 7.8
7.8 8.9
10 10 4.7 5.7
0 6.5 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
PBO (N=168) Weeks ETN (N=358) PBO (N=193) Weeks ETN (N=382)
IXE Q4W (N=347) IXE Q2W (N=351) IXE Q4W (N=386) IXE Q2W (N=385)

Significant differences were observed between each ixekizumab dose group vs. placebo and etanercept as early at Week 2 (first
visit where DLQI evaluated post-baseline) and continued through Week 12 (p<00001 for each ixekizumab dose vs. placebo or
etanercept).

27

Supplemental Figure 2: Proportion of patients who had an Itch NRS score 4 at baseline achieved an improvement of 4 points or greater through the
12-week induction period in UNCOVER-2 and UNCOVER-3

A B
100 UNCOVER-2 100 UNCOVER-3
85.1
Impovement in Itch NRS
% Patients with 4 Point

82.2

Impovement in Itch NRS


% Patients with 4 Point
90 71.0 90 82.5
71.3 79.4
80 76.8 80 73.4
54.8
70 57.0 77.1 57.8 70 79.9
56.6 77.0
60 47.7 60 69.0
36.6 64.1
50 37.9 35.3 50 41.3 56.5 57.1
40 40 40.4
30 19.9 30 38.0 24.7
11.1 12.6 14.1
20 10.5 20 20.9
10 14.1 17.7
10 12.0
0
14.8 10.4 7.0 10.1
0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Weeks Weeks
PBO (N=135) ETN (N=306) PBO (N=158) ETN (N=312)
IXE Q4W (N=293) IXE Q2W (N=303) IXE Q4W (N=313) IXE Q2W (N=320)

Significant differences were observed between each ixekizumab dose group vs. placebo and etanercept as early at Week 1 and
continued through Week 12 (p<00001 for each ixekizumab dose vs. placebo or etanercept).

28

Supplemental Figure 3: PASI 75 response by prior biologic use in UNCOVER-2 and UNCOVER-3.

100 UNCOVER-288.892.9 100 UNCOVER-3 89.7


90 90 85.1 86.9
78.6 79.3
80 74.1 80
70 70
60 60 55.9
50 44.7 50 40.0
40 30.3 40
30 30
20 20
8.1
10 3.2 0 10 3.0
0 0
Ns = 125 43 282 76 262 85 267 84 Ns = 160 33 322 60 328 58 327 58
PBO ETN IXE Q4W IXE Q2W PBO ETN IXE Q4W IXE Q2W

Biologic Nave
Biologic Experienced

P<0.0001 for each ixekizumab group vs. placebo and etanercept and for etanercept vs. placebo in either biologic nave or biologic experienced subgroups.

29

Supplemental Figure 4: Percentage of patients in each study achieving DLQI 0/1 at Week 12 at each PASI response level in UNCOVER-2 and
UNCOVER-3

30