An Open-Label, Proof-of-Concept Study of Ixekizumab in the Treatment of Pyoderma Gangrenosum
Phase: PHASE2
Conditions: Pyoderma Gangrenosum
Sponsor: Ohio State University

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
Page 1 of 43 
STUDY SYNOPSIS  
Title: 
An Open-Label, Proof-Of-Concept, Study of 
Ixekizumab in the Treatment of Pyoderma 
Gangrenosum  
 
Protocol number: 
 
Phase: 
II 
Indication: 
Pyoderma Gangrenosum 
Study drug and 
comparator: 
Ixekizumab SQ 
No comparator is used in this study. 
Main Objectives: 
Primary Objective: the proportion of subjects achieving 
a two point reduction in the five-point investigator global 
assessment (IGA) for the target ulcer from baseline to 
week 12 
Secondary Objectives:  
-Analysis of frequency of total closure of target/total 
ulcers from baseline to week 12  
-Analysis of change in total surface area of target/total 
ulcers from baseline to week 12 
-Analysis of change Patient Global Assessment (PGA) 
from baseline until week 12 
-Analysis of change in patient pain perception using 10-
point visual analog scale from baseline to week 12 
-Analysis of change in patient quality of life using the 
dermatology life quality index (DLQI) from baseline to 
week 12 
 
Study design: 
This is a Phase II study that will be open label and include 
a total of five patients who will receive the investigational 
product. These patients will have histological testing to 
rule out competing etiologies and require 3rd party 
adjudication/confirmation on agreement of the diagnosis. 
These patients will undergo 12 weeks of ixekizumab dosed 
every 2 weeks with follow-up until week 16.  
Major 
inclusion/exclusion 
criteria: 
For the complete list of inclusion/exclusion, criteria refer 
to Section 4. 
Major inclusion criteria: 
- Have a clinical diagnosis of classic PG for at least 3 
months as determined by the investigator and an external 
reviewer on the basis of results from clinical, histological 
and laboratory assessments  
- At screening, have a PG ulcer characterized by ‘item a’ 
AND 3/5 features in ‘item b’ OR 2/5 features in ‘item b’ 
with support from one of the conditions listed in c.   
a. Stable or increasing size within 2 months 
preceding screening by patient report or 
documentation  

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November, 4, 2016 
 
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b. Features such as violaceous border, 
undermining, cribriform scarring, pustules, 
peristomal location 
c. Identifiable secondary systemic condition, such 
as IBD, arthritis, MGUS, noncancerous 
hematologic disease, streptococcal carriage, 
levamisole-tainted cocaine, Bruton’s 
agammaglobulinemia 
 
- Have a PG target ulcer that has an area ≥ 2 cm2 and ≤ 
200 cm2 at screening  
- Initial IGA of 3 or higher on a 5 point scale (0-4) 
 
Major exclusion criteria: 
1. Any condition (e.g., psychiatric illness, severe 
alcoholism, or drug abuse) or situation that may 
compromise the ability of the subject to give written 
informed consent, may put the subject at significant 
risk, may jeopardize the subject’s safety after exposure 
to the study drug, may confound the study results, or 
may interfere significantly with the subject’s 
participation in the study 
2. History of malignancy within 2 years of screening other 
than carcinoma in situ of the cervix or adequately 
treated, non-metastatic, squamous or basal cell 
carcinoma of the skin 
3. History of seropositivity for HIV antibody; active or 
carrier status of hepatitis B [surface antigen (HBsAg) 
positive, or core antibody (anti-HBc) positive with 
negative surface antibody]; active hepatitis C (i.e. not 
treated or not cleared spontaneously, as confirmed by 
HCV PCR)  
4. History of severe allergic or anaphylactic reaction to  
    monoclonal antibodies  
5. Systemic infection (excluding wound colonization) 
requiring oral antibiotics within 2 weeks of Day 0 
6. History of the following treatments: 
a. Anti-TNF or other biologic therapies within 5 
    half-lives of screening 
b. Changes (addition, discontinuation, or changes 
in dose) in immunosuppressive medication 
(including cyclosporine, azathioprine, 
methotrexate, mycophenolate mofetil, 
apremilast, dapsone, or corticosteroids) within 2 
months of Day 0  
c. Systemic corticosteroids > 20 mg per day 
(prednisone or prednisone equivalent) within 8 
weeks of Day 0, or change in dose within 8 

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November, 4, 2016 
 
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weeks of Day 0. Steroids may be tapered 
(although not increased above the Day 0 dose) 
during the trial as determined by the 
investigator.  
d. Intralesional corticosteroids within 8 weeks of 
day 0; topical immunomodulators are permitted.  
e. Wound debridement within 2 weeks of Day 0; 
dressing changes allowed per investigator 
discretion.  
g. Systemic antibiotics within 2 weeks of Day 0 
h. Live, attenuated vaccines within 3 months of 
Day 0; or live, seasonal-flu- or H1N1 vaccines 
within 2 weeks of Day 0. Note: recombinant- 
and/or killed vaccines are permitted. 
i. Hyperbaric treatment within 4 weeks of Day 0 
j. Investigational drug or investigational device 
within 30 days or 5 half-lives of Day 0, 
whichever is longer 
k. Prior exposure to ixekizumab 
l. Other treatments not described above should be 
maintained at a stable dose and frequency 
throughout the study as best as possible  
13. Major, general surgery within 3 months of screening, 
or anticipated general surgery during the study period 
14. Pregnancy, plans to become pregnant during the 
course of the study, delivery within 3 months of 
screening, or breast-feeding 
15. If previous use of cyclosporine or systemic 
corticosteroids, failure to have any 
stabilization/response is exclusionary. This potentially 
indicates the disease is not PG. 
 
Endpoints: 
• Change in IGA between baseline and week 12 
Safety plan: 
Enrollment and toxicities on this trial will be monitored by 
the principal investigator and the OSU Data and Safety 
Monitoring Committee (DSMC)  
Study treatment: 
Ixekizumab subcutaneous injection 160 mg at d0, 80 mg q 
2 weeks with the last dose at week 12.  
Concomitant therapy 
and clinical practice: 
As PG is a disease responsive to immunosuppression, use 
of concomitant medications will be carefully monitored, 
and patents will be required to have stable or worsening 
disease on a consistent dose of immunosuppression at 
screening.  
1. Mycophenolate mofetil, azathioprine, cyclosporine, 
leflunomide, dapsone, apremilast and methotrexate will be 
allowed, but the patient is required to have 
stable/worsening disease for 4 weeks prior to screening, 

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
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while on a stable dose of immunosuppression for > 8 
weeks prior to baseline. 
2. Anti-TNF or other biologic therapies will not be 
allowed within 5 half-lives before screening, or during the 
study.  
3. Oral corticosteroids above 20 mg daily of prednisone 
(or equivalent) are excluded. Lower doses are allowed 
provided they are prescribed at stable doses for two 
months prior to baseline and are 20 mg or less per day of 
prednisone or other equivalently-dosed corticosteroids.  
4. Intralesional corticosteroids within 4 weeks of 
screening and during the study  are not permitted 
5. Other therapies that are non-immunosuppressive and 
non-investigational can be started or continued at 
physician discretion provided the medicine has no history 
of association with progressive multifocal 
leukoencephalopathy. Antibiotics may be used as needed 
for evidence of superinfection, positive culture results, 
malodor, green discharge, etc.  
 
Statistical methods: 
The primary objective of a two-point IGA decrease in the 
target ulcer will be analyzed as the difference from 
baseline, with the null hypothesis that no patients will 
obtain the specified improvement if the investigational 
product does not have efficacy. The endpoint will be 
analyzed using the Fisher Exact test. The secondary and 
exploratory objectives will be analyzed in comparison to 
baseline measurements and at each time point to evaluate 
for efficacy using either the Fisher Exact test/Chi-square 
test or the Wilcoxon Rank Sums test. We anticipate that 
the basic statistics will be completed within 1-2 months of 
the last patient completing his/her week 12 visit. 
Analyzing the interferon multiplex assay and microbiome 
will take longer, but will primarily be descriptive at the 
different time points and be analyzed by T-testing for 
continuous variables.  

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
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1.0 
BACKGROUND INFORMATION 
 
Pyoderma Gangrenosum (PG) (Figure 1) is a neutrophilic inflammatory condition that 
results in ulcerations, classically over the lower extremity, which can be disfiguring and 
disabling. Most often, this disease is associated with inflammatory bowel disease or 
hematologic diseases such as MGUS, myelodysplastic syndrome, multiple myeloma, or 
acute myelogeneous leukemia1.  Less frequently, it has been associated with underlying 
conditions such as streptococcal infections/carriage, seronegative arthritis, hidradenitis 
suppurativa, and Bruton’s agammaglobulinemia. 
 
Unlike most 
dermatologic 
diseases, PG poses a 
significant mortality 
risk, with an 8-year 
mortality rate as high 
as 16%1. IL-1, IL-6, 
TNF, and other acute 
phase inflammatory 
cytokines have been 
shown to be 
elevated2 and, 
consequently, 
biologics targeting 
the acute phase 
reactants such as IL-1 and TNF have demonstrated efficacy in treating pyoderma 
gangrenosum3,4. These cytokines are elevated in a wide variety of inflammatory skin 
diseases though. More specific cytokines, such as Interleukin-23, a critical cytokine for 
T-helper 17 cell (Th17) expression, has been found to be elevated in patients with 
pyoderma gangrenosum5. Furthermore, in a study of 15 patients with PG, not only was 
Th17 expression found to be elevated, but also regulatory T-cells were decreased6. Thus, 
there is basic science to suggest a benefit of IL-17 inhibition in patients with pyoderma 
gangrenosum.  
 
Currently, PG is a disease without a preferred steroid-sparing option. Numerous options 
are available but no clearly effective low-risk agent is favored7. Corticosteroids are 
generally the first line treatment, patients with PG typically tend to have incurable 
comorbidities that are driving their disease (i.e. if immunosuppression is withdrawn, the 
underlying disease will worsen and PG will intensify concurrently). Further, when 
corticosteroids were compared with cyclosporine, neither was shown to be superior, 
although corticosteroids were shown to be associated with more infectious side-effects8. 
Both therapies ultimately take effect in PG similarly to how they modulate psoriasis; they 
are effective treatments but they are overly broad in their immunosuppression, less 
specific to the disease and, therefore, may present a greater than needed patient risk when 
compared to new biologic therapies. Based on the chronic nature of the disease, the 
Figure 1 Classic Pyoderma Gangrenosum associated with undiagnosed and asymptomatic 
inflammatory bowel disease on the tibia 

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
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recrudescence upon stopping immunomodulating treatments and the associated mortality 
risk, new treatment options are urgently needed.   
 
The proposed study is not starting at ground zero. Multiple clinical trials worldwide have 
successfully been completed, with others still in progress. There is an IL-1 modulator still 
in progress (MABp1), as well as a secukinumab investigator-initiated trial (IIT) in 
progress in Europe (ClinicalTrials.Gov). While the data are not published for these trials, 
or for a recently terminated IL-1 modulator trial (gevokizumab), several randomized 
controlled trials have been previously conducted. In the IBD patient, infliximab has been 
compared to placebo and was shown to successfully treat PG3. Similarly to this current 
proposed study, the infliximab trial did not use complete closure, but rather an 
investigator global scale as the primary endpoint3. A recently published British study 
compared cyclosporine to prednisolone but did not determine a difference in 
improvement between the groups, although more infections in the were noted in the 
prednisolone group8. Despite these trials, PG is in the same position that that psoriasis 
was 20 years ago before the advent of biologic agents, with clinicians choosing between 
two nonspecific immunosuppression agents. Thus, further treatment options are still 
needed. 
  
The principle investigator is an assistant professor of dermatology at Ohio State 
University with a specific interest in neutrophilic disease and pyoderma gangrenosum. He 
has experience in clinical trials, with four currently active, industry-sponsored clinical 
trials and two investigator-initiated trials. His site has three research coordinators and a 
clinical trial fellow. Despite PG being a rare disease, the principle investigator was the 
leading enroller nationwide for patients with pyoderma gangrenosum in two separate 
industry-sponsored clinical investigating the biologics MABp1 and gevokizumab in 
2015-2016. These trials have ended/are ending, so no competing trials are anticipated.  
 
1.1 
STATEMENT ON COMPLIANCE 
 
This study will be conducted in compliance with this protocol, GCP, Declaration of 
Helsinki, and all applicable national and local regulations governing clinical studies. 
 
2.0 
STUDY OBJECTIVES AND PURPOSE 
 
2.1 
STUDY PURPOSE 
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with a multitude of 
presentations extending from pustules to vegetative lesions. It most consistently presents 
as an ulceration of the lower extremities with deep, undermining, and violaceous borders. 
The disease is an orphan disease without any FDA approved treatments. Classically, it is 
associated with inflammatory bowel disease (IBD), chronic streptococcal infections, 
acute myelogeneous leukemia (AML), myelodysplastic syndrome, or monoclonal 
gammopathy of unknown significance (MGUS). Corticosteroids and cyclosporine have 
been the primary treatments for patients; however, biologics also appear to be effective. 
The most closely studied is infliximab, an inhibitor of tumor necrosis factor (TNF)3. A 
subcutaneous injection of an interleukin-1 (IL-1) modulator recently went through a 
pivotal trial to obtain FDA approval for the treatment of PG; however, the trial was 
stopped short and the data has not been published, leaving an open horizon for finding the 

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
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ideal steroid-sparing treatment for this disease. New options are needed. IL-17 inhibition 
has demonstrated an effect on neutrophil numbers and function, suggesting the likely 
benefit of ixekizumab. Similarly, secukinumab, an alternate IL-17 inhibitory monoclonal 
antibody is currently being studied for the treatment of PG in an ongoing trial in 
Germany (ClinicalTrials.Gov).  
 
Methodologically, this study will be conducted as an open-label, non-randomized, proof-
of-concept study in patients with confirmed pyoderma gangrenosum. Patients will be 
initiated with psoriasis dosing of ixekizumab and will continue q2 week dosing to week 
12. The primary endpoint for this study will be the proportion of subjects achieving a 
two-point improvement in the five-point investigator global scale (IGA). This is a simpler 
endpoint than the use of complete resolution of target ulcers and will allow for 
demonstration of benefit in a much shorter interval than complete resolution of ulcers. In 
addition, this endpoint may be more familiar to clinicians because dermatologists 
implicitly perform this grading every office visit as opposed to measuring and 
mathematically calculating an improvement with each visit.  
 
2.2 
OBJECTIVES 
 
PRIMARY OBJECTIVE 
The primary objective of this study is the proportion of subjects achieving a two point 
reduction in the five-point investigator global assessment (IGA) for the target ulcer from 
baseline to week 12. We hypothesize that ixekizumab, started at psoriasis dosing until 
ulcer closure will allow for healing of target and additional ulcers. However, 12 weeks is 
a short period to allow for complete ulcer resolution. Because of this, the use of an IGA 
endpoint was chosen as opposed to complete target ulcer healing. Thus, target and total 
ulcer complete healing between week 0 and 12 will be secondary objectives. There is no 
comparative group as this is a proof-of-concept study without a placebo.  
 
SECONDARY OBJECTIVES 
In addition to the primary objective, further secondary objectives include:  
-Analysis of frequency of total closure of target and total ulcers from baseline to week 12  
-Analysis of change in total surface area of target/total ulcers from baseline to week 12 
-Analysis of change Patient Global Assessment (PGA) from baseline until week 12 
-Analysis of change in patient pain perception using 10-point visual analog scale from 
baseline to week 12 
-Analysis of change in patient quality of life using the dermatology life quality index 
(DLQI) from baseline to week 12 
 
EXPLORATORY OUTCOMES 
-Evaluation of an [IGA x Ulcer Area] scoring metric for target ulcer at each time-point  
-Change in microbiome of ulcer between baseline and week 12 
-Change in inflammatory markers between baseline and week 12: C-reactive protein 
(CRP), erythrocyte sedimentation rate (ESR), absolute neutrophils and total leukocytes in 
serum; IL-1, IL-6, IL-8, and TNF in target lesion tissue.  
-Change in serum biomarker (if can be ascertained), depending on underlying cause (i.e. 
perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and anti-saccharomyces 
cerevisiae antibodies (ASCA) in patients with IBD, anti-streptolysin-O (ASO) in patients 

Taltz for Pyoderma Gangrenosum, Kaffenberger, OSU-IIT 
November, 4, 2016 
 
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with streptococcus- driven disease, or levels of monoclonal/polyclonal protein in patients 
with MGUS/elevated IgA levels.  
 
3.0 
STUDY DESIGN 
 
1. Intent:  
The intent of this study is to demonstrate evidence for the use of ixekizumab in the 
treatment of PG. Ixekizumab is an IL-17 inhibitor that is currently FDA approved for the 
treatment of psoriasis. There is evidence to suggest targeting the IL-17 cytokine pathway 
will be valuable in treating PG: IL-23, a critical cytokine for activation of Th17 and 
subsequent IL-17 production, has been found to be elevated in patients with pyoderma 
gangrenosum5, as has the expression of Th17 cells themselves6.  
 
2. Location  
The study will be conducted in Columbus, OH, at The Ohio State University (OSU) 
dermatology clinical trials center. Both the principal investigator and the OSU 
dermatology center have extensive experience with industry-sponsored clinical trials in 
PG, having completing two trials in 2015-16. At this time, we anticipate no competing 
trials in PG, and we estimate that 8-9 cases of classic PG are diagnosed by or referred to 
the investigator every year. Further, the investigator currently has 5 patients with chronic, 
active PG in need of new, potential treatment options. He will have additional support 
from an agreement with Dr. Jeff Callen at the University of Louisville, who will serve as 
an unbiased expert and who will have the opportunity to agree or disagree that alternate 
diagnoses have been properly excluded (i.e. trigger a screen failure). This is an important 
step because PG is a diagnosis of exclusion that even experts can misdiagnose and, 
subsequently, potentially publish data erroneously9. Having the unbiased expert agree to 
the diagnosis will not only add credibility to both the trial and the eventual publication, 
but it will also ensure validity and the homogeneity of pathogenesis among the patients 
enrolled. Dr. Callen will not be sent PHI. Laboratory results will be obtained through the 
OSU Wexner Medical Center at predefined research discounts in the budget. 
Complications, unforeseen events or additionally-needed hospitalizations, medicines, or 
office visits will be outside of the scope of the trial and will be funded by the patient’s 
health insurance. Institutional Review Board approval will be obtained from the OSU 
Biomedical IRB.  
 
3. Population 
Patients with a diagnosis of pyoderma gangrenosum for at least 3 months, on a stable 
dose of medications listed in the inclusion and exclusion criteria, and with agreement of 
an external expert medical dermatologist may be enrolled in the study. Prisoners, children 
< 18 years of age, women who are breast-feeding, pregnant women or those desiring to 
become pregnant will not be included in the study population.  
 
4. Subject Recruitment: 
Patients will be recruited to this trial based on the diagnosis of pyoderma gangrenosum 
from the principle investigator’s clinic, as well as through the use of the OSU Wexner 
Medical Center patient database for patients who have been seen in the past four years 
with an encounter diagnosis code of 686.01. Specific advertisement will be targeted 
towards local community dermatologists, and will consist of letters and emails for 

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November, 4, 2016 
 
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notification of the study and referral options. Once patients are identified through the 
information query or through investigator records, the investigator will review the 
patient’s chart from multiple encounters to ensure that the patient has the diagnosis of PG 
(per chart review), as the diagnosis can be difficult even for expert clinicians9. After the 
screening visit, an unassociated expert (Dr. Callen) will confirm the diagnosis before 
patients undergo a baseline visit or start the investigational medicine.  
 
5. Treatment Groups:  
We have received funding for only a small pilot study to prove a benefit from IL-17 
inhibition in PG. Therefore, there is only one treatment arm. The primary outcome will 
be a comparison of week 12 to baseline regarding a two-point improvement in the IGA. 
  
6. Assignment strategy: 
There will be only one treatment group, so there is no assignment strategy.  
 
7. Subjects per Treatment Group: 
We anticipate consenting and screening a maximum of 8 patients will yield 5 eligible 
subjects who will continue on to receive the investigational product.  
 
 
3.1 
PRIMARY ENDPOINTS 
 
The proportion of subjects achieving a two point reduction in the five-point investigator 
global assessment (IGA) for the target ulcer from baseline to week 12. 
 
3.2 
SECONDARY ENDPOINTS 
-Frequency of total closure of target and total ulcers from baseline to week 12  
-Change in total surface area of target and total ulcers from baseline to week 12 
-Change Patient Global Assessment (PGA) from baseline until week 12 
-Change in patient pain perception using 10-point visual analog scale from 
baseline to week 12 
-Change in patient quality of life using the dermatology life quality index (DLQI) 
from baseline to week 12 
 
3.3 
EXPLORATORY ENDPOINT 
 
-Evaluation of an [IGA x Ulcer Area] scoring metric for target ulcer at each time-
point  
-Change in microbiome of target ulcer between baseline and week 12 
-Change in inflammatory markers between baseline and week 12: C-reactive    
  protein (CRP), erythrocyte sedimentation rate (ESR), absolute neutrophils and  
  total leukocytes in serum; IL-1, IL-6, IL-8, and TNF in target lesion tissue.  
-Change in serum biomarker (if can be ascertained), depending on underlying 
cause (i.e. perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and 
anti-saccharomyces cerevisiae antibodies (ASCA) in patients with IBD, anti-
streptolysin-O (ASO) in patients with streptococcus- driven disease, or levels of 
monoclonal/polyclonal protein in patients with MGUS/elevated IgA levels).  
 

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November, 4, 2016 
 
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4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
4.1 
INCLUSION CRITERIA 
 
Inclusion:  
1. Have given written informed consent before participating in any study-specific activity  
2. Have a clinical diagnosis of classic PG as determined by the investigator and an 
external reviewer on the basis of results from clinical, histological and laboratory 
assessments  
3. Have a PG ulcer characterized by ‘item a’ AND 3/5 features in ‘item b’ OR 2/5 
features in ‘item b’ with support from one of the conditions listed in c.   
a. Stable or increasing size within 2 months preceding screening by patient report 
or documentation  
b. Features such as violaceous border, undermining, cribriform scarring, pustules, 
peristomal location 
c. Identifiable secondary systemic condition, such as IBD, arthritis, MGUS, 
noncancerous hematologic disease, streptococcal carriage, levamisole-tainted 
cocaine, Bruton’s agammaglobulinemia 
 
4. Have a PG target ulcer that has an area ≥ 2 cm2 and ≤ 200 cm2 at screening  
5. Initial IGA of 3 or higher on a 5 point scale (0-4) at screening 6. Age at least 18 years 
at screening  
7. Negative quantiferon tuberculosis (TB) test, or normal chest x-ray with previous 
treatment for latent TB in the previous 12 months prior to screening 
8. A negative pregnancy test (for females of childbearing potential) at both screening and   
at Day 0  
9. For subjects with reproductive potential, a willingness to use methods* of 
contraception that will prevent the subject or the subject’s partner from becoming 
pregnant during the study. 
 
*Acceptable methods of contraception include proper use of condoms, cervical caps, 
diaphragms, hormonal contraceptive pills, contraceptive implants, intrauterine devices, 
or total abstinence 
 
4.2 
EXCLUSION CRITERIA 
 
1. Any condition (e.g., psychiatric illness, severe alcoholism, or drug abuse) or situation 
that may compromise the ability of the subject to give written informed consent, may 
put the subject at significant risk, may jeopardize the subject’s safety after exposure to 
the study drug, may confound the study results, or may interfere significantly with the 
subject’s participation in the study 
2. History of malignancy within 2 years of screening other than carcinoma in situ of the 
cervix or adequately treated, non-metastatic, squamous or basal cell carcinoma of the 
skin 
3. History of seropositivity for HIV antibody; active or carrier status of hepatitis B 
[surface antigen (HBsAg) positive, or core antibody (anti-HBc) positive with negative 
surface antibody]; active hepatitis C (i.e. not treated or not cleared spontaneously, as 
confirmed by HCV PCR)  

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November, 4, 2016 
 
Page 11 of 43 
4. History of severe allergic or anaphylactic reaction to monoclonal antibodies  
5. Systemic infection (excluding wound colonization) requiring oral antibiotics within 2 
weeks of Day 0 
6. History of the following treatments: 
a. Anti-TNF or other biologic therapies within 5 half-lives of screening 
b. Changes (addition, discontinuation, or changes in dose) in immunosuppressive 
medication (including cyclosporine, azathioprine, methotrexate, 
mycophenolate mofetil, apremilast, dapsone, or corticosteroids within 2 
months of Day 0  
c. Systemic corticosteroids > 20 mg per day (prednisone or prednisone equivalent) 
within 8 weeks of Day 0, or change in dose within 8 weeks of Day 0. Steroids 
may be tapered (although not increased above the Day 0 dose) during the trial 
as determined by the investigator.  
d. Intralesional corticosteroids within 8 weeks of day 0; topical 
immunomodulators are permitted.  
e. Wound debridement within 2 weeks of Day 0; dressing changes allowed per 
investigator discretion.  
g. Systemic antibiotics within 2 weeks of Day 0 
h. Live, attenuated vaccines within 3 months of Day 0; or live, seasonal-flu- or 
H1N1 vaccines within 2 weeks of Day 0. Note: recombinant- and/or killed 
vaccines are permitted. 
i. Hyperbaric treatment within 4 weeks of Day 0 
j. Investigational drug or investigational device within 30 days or 5 half-lives of 
Day 0, whichever is longer 
k. Prior exposure to ixekizumab 
l. Other treatments not described above should be maintained at a stable dose and 
frequency throughout the study as best as possible  
13. Major, general surgery within 3 months of screening, or anticipated general surgery 
during the study period 
14. Pregnancy, plans to become pregnant during the course of the study, delivery within 3 
months of screening, or breast-feeding 
15. If previous use of cyclosporine or systemic corticosteroids, failure to have any 
stabilization/response is exclusionary. This potentially indicates the disease is not PG. 
 
4.3 
SUBJECT WITHDRAWAL FROM TREATMENT OR FOLLOW UP 
 
Patients will be withdrawn at his/her request at any point during the study. Patients 
becoming pregnant on therapy or no longer agreeing to contraception will be withdrawn 
from the study. Patients with SAEs will be withdrawn with the exception of patients 
admitted for pain control/pain management or wound infections at the discretion of the 
investigator, as these are both known complications of severe PG and do not necessarily 
represent worsening of disease.  
 
 
 
 
 

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November, 4, 2016 
 
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5.0 
TREATMENT OF SUBJECTS 
 
5.1 
RANDOMIZATION AND BLINDING 
 
Subjects enrolled will receive open-label ixekizumab as such no blinding procedures 
occur during this study.  All subjects will receive the same study regimen and as such 
there will be no randomization during this study. 
 
5.2 
CONCOMITANT THERAPY 
 
5.2.1 
Permitted Concomitant Therapy 
As PG is a disease responsive to immunosuppression, use of concomitant medications 
will be carefully monitored, and patients will be required to have stable or worsening 
disease on a consistent dose of immunosuppression at screening.  
 
1. Mycophenolate mofetil, azathioprine, cyclosporine, leflunomide, dapsone, apremilast 
and methotrexate are allowed if the dosage has been stable for >8 weeks prior to 
screening and the patient has had stable/worsening disease for 4 weeks prior to screening. 
2. Oral corticosteroids up to 20 mg daily of prednisone (or equivalent) are allowed if the 
dosage has been stable for >8 weeks prior to screening and the patient has had 
stable/worsening disease for 4 weeks prior to screening.  
3.  Other therapies that are non-immunosuppressive and non-investigational may be 
started or continued at physician discretion. Antibiotics may be used as needed for 
evidence of superinfection, positive culture results, malodor, green discharge, etc.  
 
5.2.2 
Prohibited Concomitant Therapy 
1. Intralesional corticosteroids are not permitted within 4 weeks prior to screening and/or 
during the study. 
2.  Anti-TNF or other biologic therapies are not permitted within 5 half-lives prior to 
screening or during the study. 
3. Oral corticosteroids above 20mg daily of prednisone (or equivalent) are not permitted 
during the study.   
 
Aside from that which is administered during the study, any chemotherapy, 
immunotherapy, medications associated with PML, experimental therapy, or radiotherapy 
are prohibited.   
 
6.0 
STUDY PROCEDURES 
 
The schedules of events are shown in Table 6.1.  Descriptions of the scheduled evaluations 
are outlined below and complete information on study drug and dosing is provided in 
Section 5.0. 
 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments.  Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.

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November, 4, 2016 
 
                                                    Page 13 of 43 
Table 6-1.  Schedule of Assessments 
Treatment Period 
Follow Up  
  
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 16 
Windows (Days) 
-28 to -1 
0 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
Informed consent 
X 
  
  
  
  
  
  
 
  
Medical History 
X 
  
  
  
  
  
  
 
  
Disease History 
X 
  
  
  
  
  
  
 
  
Inclusion  and Exclusion Criteria 
X 
  
  
  
  
  
  
 
  
Demographics 
X 
  
  
  
  
  
  
 
  
Study Drug Dispensation*  
  
X 
X 
X 
X 
X 
X 
X 
 
Confirm PG Diagnosis 
X 
  
  
  
  
  
  
 
  
Investigator Global Scale of PG 
severity 
  
X 
  
  
  
  
  
X 
X 
VAS 
  
X 
  
  
  
  
  
X 
X 
DLQI 
  
X 
  
  
  
  
  
X 
X 
PGA  
 
X 
 
 
 
 
 
X 
X 
Lesion Assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
  
X 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
  
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 X 
 X 
X  
 X 
X 
X  
X 
X 
Photography 
X 
X 
  
  
 X 
 
  
X 
X 

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                                                    Page 14 of 43 
Treatment Period 
Follow Up  
  
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 16 
Windows (Days) 
-28 to -1 
0 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
General Labs if not < x mo  
  
  
  
  
  
 
  
 
  
Biopsy for exclusion if <12 mo 
X 
  
  
  
  
  
  
 
  
CBC and Edif =1 mo 
X 
X 
  
X 
  
X 
  
X 
 
Complete Metabolic Panel = 1 
mo 
X 
  
  
  
  
  
  
 
  
HIV = 12 mo 
X 
  
  
  
  
  
  
 
  
Hepatitis Panel = 12 mo 
X 
  
  
  
  
  
  
 
  
Quantiferon TB-Gold = 12 mo 
X 
  
  
  
  
  
  
 
  
General Bacterial Culture 
X 
X 
  
  
 X 
 
  
 
 
Urine hCG (if of childbearing 
potential) = 1mo 
X 
X 
  
X 
  
X 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 End Point Related Labs  
  
  
  
  
  
  
  
 
  
C-Reactive Protein** 
X 
X 
  
 
X 
 
  
X 
 
Erythrocyte Sedimentation 
Rate** 
X 
X 
  
 
X 
 
  
X 
 
Saccharomyces Cervisae 
Antibodies** 
X 
X 
  
  
X 
 
  
 
 
Antistreptolysin-O** 
X 
X 
  
  
X 
 
  
 
 
Rheumatoid Factor** 
X 
X 
  
  
X 
 
  
 
 
Serum protein 
electrophoresis** 
X 
 X 
  
  
 
 
  
X 
 
Serum protein 
immunofixation**  
X 
 X 
  
  
 
 
  
X 
 
Biopsy for Analysis of Th17 and 
Inflammatory Cytokines *** 
  
X 
  
  
  
  
  
X 
 
Microbiome of target ulcer 
 
X 
 
 
X 
 
 
X 
 
 
*Drug dispensation: 160mg at Week 0, then 80mg at subsequent dosing visits. 
**End-point related labs: only repeat after baseline if baseline labs are elevated. 
 
***Includes immunohistochemistry of tissue expression; Inflammatory cytokines include IL-1, IL-6, IL-8 and TNF

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                                                    Page 15 of 43 
 
6.1 
DESCRIPTION OF PROCEDURES 
Informed Consent and HIPAA Authorization 
Screening 
Before initiating any screening or treatment activity that is not standard of care, the subject must read, 
understand, and sign the Institutional Review Board (IRB)-approved combined informed consent form 
(ICF) and HIPAA authorization to confirm his or her willingness to participate in this study and grant 
permission to use protected health information, respectively.  
 
Medical History 
Screening 
The subject’s complete history through review of medical records and by interview must be collected and 
recorded.  Concurrent medical signs and symptoms must be documented to establish baseline severities.  
All medications and therapies administered within the past 14 days and a lifetime history of previous 
treatments must be recorded as part of the medical history.  A disease history, including the date of initial 
diagnosis and list of prior treatments, and responses and duration of response to these treatments (if 
available), will also be recorded.   
 
Adverse Events 
At all visits 
The accepted regulatory definition for an AE is provided in Section 7.  All medical occurrences from the 
time of signing the informed consent that meet this definition must be recorded. SAEs occurring prior to 
therapy will not be considered dose-limiting toxicities (DLTs). Important additional requirements for 
reporting SAEs are explained in Section 7 as well.  
 
Physical Examination & Vital Signs & Weight 
At all visits 
The physical examination will include, at a minimum, the general appearance of the subject, height 
(screening only) and weight, as well as examination of the skin, nose, throat, lungs, heart, abdomen, 
extremities, and lymphatic system. 
Symptom-directed physical exams will be done during the treatment period and at the termination and 
safety follow-up visit. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be measured at every 
visit.  
 
Urine Pregnancy Test 
Monthly (Females of Pregnancy Potential) 
Pregnancy tests are required only for women with childbearing potential at screening, and Weeks 0, 4, 8, 
12. 
 
Lesion Assessment 
Ulcerative lesions will be examined and measured during each study visit. The length and width of up to 
5 ulcers will be measured at each study visit and the total surface area will be calculated. Additional 
assessment will include: 
• Photography- Ulcers will be imaged by photography at Screening, and Weeks 0, 6, 12 and 16.  
• Biopsy- Biopsy will be performed of an inflammatory edge of the target ulcer. A 4mm punch 
biopsy will be used under local anesthesia, and the site will be closed with gel foam. This procedure 
is considered minimal risk by the IRB. Immunohistochemistry for Th17 and related inflammatory 

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November, 4, 2016 
 
                                                    Page 16 of 43 
cytokines will be performed on biopsied tissue collected during Weeks 0 and 12. Biopsy may also 
be performed during screening to rule out other possible etiologies of the ulcer.  
• Swab- General culture swabs will be performed at Screening, and Weeks 0 and 6. The microbiome 
analysis will be performed from swabs of the target ulcer and utilize bacterial DNA as a proxy to 
estimate organismal identity and abundance. Microbiome analysis will be performed at Weeks 0, 
6 and 12.   
 
Blood Draws  
Routine blood draws will be performed by a phlebotomy laboratory at Screening and during Weeks 0, 4, 
6, 8, and 12. 
 
7.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of protocol-
specified hematology, clinical chemistry, urinalysis, and other laboratory variables; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drug(s). 
7.1.1 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade of an 
AE (see below).  “Serious” is a regulatory definition and is based on subject or event outcome or action 
criteria usually associated with events that pose a threat to a subject’s life or functioning.  Seriousness (not 
severity) serves as the guide for defining regulatory reporting obligations from the Sponsor to applicable 
regulatory authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
 
• It results in death (i.e. the AE actually causes or leads to death). 
• It is life-threatening (i.e. the AE, in the view of the investigator, places the subject at immediate risk 
of death.  It does not include an AE that, had it occurred in a more severe form, might have caused 
death). 
• It requires or prolongs inpatient hospitalization.  Exception will be admission due to inability to 
complete therapy as a consequence of limited clinic hours. 
• It results in persistent or significant disability/incapacity (i.e. the AE results in substantial disruption 
of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product. 
• It is considered a significant medical event by the investigator based on medical judgment (i.e. may 
jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
7.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS ADVERSE 
EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study, as outlined in the prior sections, are recorded on the electronic CRF (eCRF).  All SAEs also 
must be reported within 24 hours.  
 
7.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study, including SAEs, begins when the subject signs informed consent 
and ends with the safety follow-up visit.   

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                                                    Page 17 of 43 
 
7.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points during the 
study.  All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, clinically significant laboratory test, or other 
means will be recorded in the subject’s medical record and on the AE eCRF and, when applicable, on an 
SAE/Product Compliant form. 
Each recorded AE or SAE will be described by its duration (i.e. start and end dates), severity, regulatory 
seriousness criteria, if applicable, suspected relationship to the investigational product (see following 
guidance), and any actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
 
Fatal: 
Adverse event resulted in death. 
 
Unrelated: 
Another cause of the adverse event is more plausible; a temporal 
sequence cannot be established with the onset of the adverse event and 
administration of the investigational product; or, a causal relationship is 
considered biologically implausible. 
 
Possibly Related: 
There is a clinically plausible time sequence between onset of the adverse 
event and administration of the investigational product, but the adverse 
event could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures. Possibly related should be used when 
the investigational product is one of several biologically plausible adverse 
event causes. 
 
Definitely Related: 
The adverse event is clearly related to use of the investigational product. 
 
7.2.3 
Pregnancy 
A subject must immediately inform the investigator if the subject or subject’s partner becomes pregnant 
from the time of consent to 30 days after the last dose of study drug.  Abortion, whether therapeutic, 
elective or spontaneous, will be reported as an SAE. 
Any female subjects receiving ixekizumab who become pregnant must immediately discontinue study 
drug.  The investigator should counsel the subject, discussing any risks of continuing the pregnancy and 
any possible effects on the fetus.   
 
7.2.4 
Type and Duration of Follow-up of Subjects After Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should be 
followed to resolution, or until the investigator assesses the subject as stable, a new pyoderma 
gangrenosum therapy is initiated, or the subject is lost to follow-up or withdraws consent. 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
OVERVIEW  
 
The primary objective of a two-point IGA decrease in the target ulcer will be analyzed as the difference 
from baseline, with the null hypothesis that no patients will obtain the specified improvement if the 

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November, 4, 2016 
 
                                                    Page 18 of 43 
investigational product does not have efficacy. The endpoint will be analyzed using the Fisher Exact 
test. The secondary and exploratory objectives will be analyzed in comparison to baseline measurements 
and at each time point to evaluate for efficacy using either the Fisher Exact test/Chi-square test or the 
Wilcoxon Rank Sums test. We anticipate that the basic statistics will be completed within 1-2 months of 
the last patient completing his/her week 12 visit. Analyzing the interferon multiplex assay and 
microbiome will take longer, but will primarily be descriptive at the different time points and be 
analyzed by T-testing for continuous variables.  
 
8.2 
ANALYSIS AND PUBLICATION PLAN:  
 
The goal of the study will be a publication in a high-impact international dermatology journal such as 
the Journal of the American Academy of Dermatology, JAMA Dermatology or British Journal of 
Dermatology. We aim for a national level presentation at the American Academy of Dermatology 
annual meeting.  
Sample Size: 8 with 3 anticipated screen failures 
 
Proposed Enrollment and Study Completion Plan: 
 
Total number of patients to be enrolled 
8 with 3 anticipated screen failures 
Number of investigative sites 
1 
Total study length 
up to 20 weeks, including up to 4 weeks for 
screening 
Enrollment period   
Up to 6 weeks 
Treatment period 
12 weeks 
Anticipated date of first patient visit 
3/1/17 
Anticipated date of the last patient visit 
3/1/18 
Anticipated date of final study report 
submission to Lilly 
5/31/18 
Anticipated publication date  
12/31/2018 
 
9.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
 
This study will be performed with support from Eli Lilly and Company.  Eli Lilly and Company retains 
the right to terminate the study from the study site at any time. Specific circumstances that may precipitate 
such termination are: 
• Unsatisfactory subject enrollment with regard to quality or quantity 
• Significant or numerous deviations from study protocol requirements, such as failures to perform 
required evaluations on subjects and maintain adequate study records 
• The incidence and/or severity of AEs in this or other studies indicating a potential health hazard caused 
by the study treatment. 
 

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                                                    Page 19 of 43 
9.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE 
 
The protocol, informed consent, prescribing information, and any other relevant supporting information 
(i.e. recruitment and advertising materials) will be submitted to the IRB for review and approval before 
study initiation.  A letter confirming IRB approval of the protocol and informed consent, and a statement 
that the IRB is organized and operates according to GCP and the applicable laws and regulations must be 
forwarded to Eli Lilly and Company before screening subjects for the study.  Amendments to the protocol 
must also be approved by the IRB and local regulatory agency, as appropriate, before the implementation 
of changes in this study. 
 
9.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH INFORMATION 
AUTHORIZATION 
 
A copy of the IRB-approved informed consent must be forwarded to Eli Lilly and Company for regulatory 
purposes.  The investigator, or designee must explain to each subject the purpose and nature of the study, 
the study procedures, the possible adverse effects, and all other elements of consent as defined in § 21CFR 
Part 50, and other applicable national and local regulations governing informed consent.  Each subject 
must provide a signed and dated informed consent before enrollment into this study.  Subjects who are 
incapable of providing informed consent will be ineligible for the study.   
In accordance to individual local and national subject privacy regulations, the investigator or designee 
must explain to each subject that for the evaluation of study results, the subject’s protected health 
information obtained during the study may be shared with Eli Lilly and Company and its designees, 
regulatory agencies, and IRBs.  Eli Lilly and Company will not use the subject’s protected health 
information or disclose it to a third party without applicable subject authorization.  It is the investigator’s 
or designee’s responsibility to obtain written permission to use protected health information from each 
subject. If a subject withdraws permission to use protected health information, it is the investigator’s 
responsibility to obtain the withdrawal request in writing from the subject and to ensure that no further 
data will be collected from the subject.  Any data collected on the subject before withdrawal will be used 
in the analysis of study results. 
 
9.3 
RECORD RETENTION 
 
The investigator and other appropriate study staff are responsible for maintaining all documentation 
relevant to the study.  Mandatory documentation includes copies of study protocols and amendments, each 
FDA Form 1572, IRB approval letters, signed ICFs, drug accountability records, SAE forms transmitted 
to Eli Lilly and Company, subject files (source documentation) that substantiate entries in eCRFs, all 
relevant correspondence and other documents pertaining to the conduct of the study. 
 
An investigator shall retain records for a period of at least 2 years after the date the last marketing 
application is approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  The investigator must notify 
Eli Lilly and Company and obtain written approval from Eli Lilly and Company before destroying any 
clinical study records at any time.  Eli Lilly and Company will inform the investigator of the date that 
study records may be destroyed or return to Eli Lilly and Company. 
 
Eli Lilly and Company must be notified in advance of, and Eli Lilly and Company must provide express 
written approval of, any change in the maintenance of the foregoing documents if the investigator wishes 

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                                                    Page 20 of 43 
to move study records to another location or assign responsibility for record retention to another party.  If 
the investigator cannot guarantee the archiving requirements set forth herein at his or her study site for all 
such documents, special arrangements must be made between the investigator and Eli Lilly and Company 
to store such documents in sealed containers away from the study site so that they can be returned sealed 
to the investigator for audit purposes. 
 
9.4 
PROTOCOL AMENDMENTS 
 
The investigators will initiate any change to the protocol in a protocol amendment document.  Prior to 
IRB submission, this will be reviewed by Eli Lilly and Company. The amendment will be submitted to 
the IRB together with, if applicable, a revised model ICF.  Additionally under this circumstance, 
information on the increased risk and/or change in scope must be provided to subjects already actively 
participating in the study, and they must read, understand, and sign any revised ICF confirming willingness 
to remain in the trial. 
 
9.5 
PUBLICATION OF STUDY RESULTS 
 
Eli Lilly and Company may use the results of this clinical study in registration documents for regulatory 
authorities in the United States or abroad.  The results may also be used for papers, abstracts, posters or 
other material presented at scientific meetings or published in professional journals or as part of an 
academic thesis by the OSU investigators.  In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Eli Lilly and Company reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Eli Lilly and Company sufficient time to make 
appropriate comments before submission for publication.  
 
GENERAL INVESTIGATOR RESPONSIBILITIES 
 
The principal investigator must ensure that: 
1. 
He or she will personally conduct or supervise the study. 
2. 
His or her staff and all persons who assist in the conduct of the study clearly understand their 
responsibilities and have their names included in the Delegation of Authority Log. 
3. 
The study is conducted according to the protocol and all applicable regulations. 
4. 
The protection of each subject’s rights and welfare is maintained. 
5. 
Signed and dated informed consent and permission to use protected health information are 
obtained from each subject before conducting nonstandard of care study procedures.  If a subject 
or subject’s legal guardian withdraws permission to use protected health information, the 
investigator will obtain a written request from the subject or subject’s legal guardian and will 
ensure that no further data be collected from the subject. 
6. 
The consent process is conducted in compliance with all applicable regulations and privacy acts. 
7. 
The IRB complies with applicable regulations and conducts initial and ongoing reviews and 
approvals of the study. 
8. 
Any amendment to the protocol is submitted promptly to the IRB. 
9. 
Any significant protocol deviations are reported to Eli Lilly and Company and the IRB according 
to the guidelines at each study site. 
10. 
All IND Safety Reports are submitted promptly to the IRB. 
11. 
All SAEs are reported to Eli Lilly and Company Drug Safety/Designee within 24 hours of 
knowledge and to the IRB per their requirements. 
 

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                                                    Page 21 of 43 
10.0 
REFERENCES 
1.  
Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: A retrospective review 
of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol. 
2011;165(6):1244-1250.  
2.  
Marzano A V, Ceccherini I, Gattorno M, et al. Association of pyoderma gangrenosum, acne, and 
suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other 
autoinflammatory diseases. Medicine (Baltimore). 2014;93(27):e187.  
3.  
Brooklyn TN, Dunnill MGS, Shetty A, et al. Infliximab for the treatment of pyoderma 
gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-509. 
4.  
Kolios AGA, Maul JT, Meier B, et al. Canakinumab in adults with steroid-refractory pyoderma 
gangrenosum. Br J Dermatol. 2015;173(5):1216-1223. 
5.  
Guenova E. Interleukin 23 Expression in Pyoderma Gangrenosum and Targeted Therapy With 
Ustekinumab. Arch Dermatol. 2011;147(10):1203.  
6.  
Caproni M, Antiga E, Volpi W, et al. The Treg/Th17 cell ratio is reduced in the skin lesions of 
patients with pyoderma gangrenosum. Br J Dermatol. 2015;173(1):275-278.  
7.  
Al Ghazal P, Dissemond J. Therapy of pyoderma gangrenosum in Germany: results of a survey 
among wound experts. J Dtsch Dermatol Ges. 2015;13(4):317-324.  
8.  
Ormerod AD, Thomas KS, Craig FE, et al. Comparison of the two most commonly used 
treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial. 
BMJ. 2015;350:h2958.  
9.  
Weenig RH, Davis MDP, Dahl PR, Su WPD. Skin ulcers misdiagnosed as pyoderma 
gangrenosum. N Engl J Med. 2002;347(18):1412-1418.  
 

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                                                    Page 22 of 43 
 
Appendix 1 VAS 
 
 
Visual Analogue Scale 
  
What has been the typical level of pain over the past 24 hours, where 0 equals no pain and 10 equals the most pain 
you have ever experienced?     
 
  
                              
 
 
Make a mark on the line which best correlates with your pain level. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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                                                    Page 23 of 43 
 
Appendix 2  DQLI 
 
DERMATOLOGY LIFE QUALITY INDEX  
 
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick ➾ one box for each question.  
  
1. 
Over the last week, how itchy, sore,   
  
  
    Very much ❒  
 
painful or stinging has your skin     
  
  
   A lot ❒  
 
been?    
  
  
  
  
  
           A little ❒  
 
  
  
  
  
  
  
  
       Not at all ❒  
  
2. 
Over the last week, how embarrassed  
  
  
    Very much ❒    or 
self conscious have you been because     
              A lot ❒     of your 
skin?      
  
  
                                 A little ❒  
  
  
  
  
  
  
  
  
  
         Not at all ❒  
  
3. 
Over the last week, how much has your      
               Very much ❒  
skin interfered with you going  
  
   
  
              A lot ❒    
shopping or looking after your home or     
                      A little ❒  
  
garden?          
  
  
  
  
  
        Not at all ❒  
 
                                                                                             Not relevant ❒  
  
4. 
Over the last week, how much has your      
               Very much ❒ 
skin influenced the clothes you wear? 
  
  
  
   A lot ❒  
 
  
  
  
  
  
  
                      A little ❒  
 
  
  
  
  
  
  
  
        Not at all ❒ 
 
                                                                              Not relevant ❒  
  
5. 
Over the last week, how much has your      
               Very much ❒      
skin affected any social or leisure    
  
  
  
 A lot   ❒ 
activities?  
  
  
  
  
  
                     A little  ❒  
  
  
  
  
  
  
                  Not at all ❒  
                                
  
 
 
 
 
 
 
 
 
    Not relevant ❒ 
 
6. 
Over the last week, how much has your      
                Very much ❒       
skin made it difficult for   
  
  
  
  
            A lot   ❒  
you to do any sport?  
  
  
  
  
           A little  ❒  
  
  
  
  
 
 
 
           Not at all ❒  
                                

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November, 4, 2016 
 
                                                    Page 24 of 43 
 
 
 
 
 
 
 
            
    Not relevant ❒ 
  
7. 
Over the last week, has your skin prevented  
  
 
    Yes ❒  
  
you from working or studying?  
  
  
                           No ❒  
 
 
 
 
 
 
Not relevant ❒  
  
  
  If "No", over the last week how much has     
 
 
A lot   ❒  
                 your skin been a problem at     
  
          A little ❒  
  
work or studying?     
  
  
  
      Not at all ❒  
  
8. 
Over the last week, how much has your      
              Very much ❒  
skin created problems with your      
  
                        A lot ❒       
partner or any of your close friends  
  
                     A little ❒  
  
or relatives?    
  
  
  
  
  
       Not at all ❒  
    
 
  
 
 
 
 
 
   Not relevant ❒  
  
9. 
Over the last week, how much has your      
               Very much ❒  
skin caused any sexual  difficulties? 
  
  
              A lot ❒ 
 
  
  
  
  
                                           A little ❒  
 
  
  
  
  
  
  
  
       Not at all ❒ 
 
                                                                               Not relevant ❒  
  
10. 
Over the last week, how much of a   
  
  
     Very much ❒  
problem has the treatment for your  
  
  
            A lot   ❒  
skin been, for example by making    
  
                     A little ❒  
           your home messy, or by taking up time?    
  
        Not at all ❒  
 
                                                                              Not relevant ❒  
Please check you have answered EVERY question. Thank you.   
 

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                                                    Page 25 of 43 
Appendix 3 Investigator Global Assessment 
 
 
 
INVESTIGATOR’S GLOBAL ASSESSMENT (IGA) 
How you would assess the Subject’s current level of pyoderma gangrenosum disease activity? 
 
              
  None (0) 
 
  Mild (1) 
 
  Moderate (2) 
 
  Severe (3) 
 
  Extreme (4) 
 
Grade 
Improvement from Baseline 
0 
Total resolution of ulcers with no sign of active PG 
1 
Almost completely healed ulcers with only minimal signs 
of active PG 
2 
Evidence of ulcer healing which involves >50% of 
ulcer/margin 
3 
Evidence of ulcer healing which involve 25-50% of 
ulcer/margin 
4 
Evidence of ulcer healing which involves <25% of 
ulcer/margin 
5 
No evidence of ulcer healing 

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                                                    Page 26 of 43 
 
Appendix 4 Lesion Assessment 
 
PG 
Lesion # 
Location and Description 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
 
Lesion # 
1 
2 
3 
4 
5 
Length (cm) 
 
 
 
 
 
 
Width (cm) 
 
 
 
 
 
 
Surface Area (cm2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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                                                    Page 27 of 43 
 
 
 
 
Appendix 5 Patient Global Assessment 
 
 
 
Patient Global Assessment 
How do you feel your pyoderma gangrenosum is doing overall, where 0 equals remission of disease and 10 equals 
very severe disease?     
 
 
     
             
 
 
Make a mark on the line which best correlates with your disease severity. 
 
 
 
 
 
 
 
 
 
 
 

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                                                    Page 28 of 43 
 
 
 
 
 
 
 
 
 
Protocol: Taltz for Pyoderma Gangrenosum,  
PI: Dr. Benjamin Kaffenberger 
Protocol number: 2017H0045 
Trial Type: OSU-IIT  
 
Date document written: May 14, 2018  
End of Study Report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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                                                    Page 29 of 43 
 
Summary of Patients Screened/Enrolled  
  
  
Pt  Age  Sex  Comorbidity  
Disease 
length  
Previous 
Treatments  
Concomitant 
Treatments  
Enrolled?  
01  62  
M  
MGUS  
2yrs  
Cyclosporine, 
gevokizumab,  
prednisone,  
RA-18C3  
ASA, atorvastatin, 
carvedilol, cilostazol, 
clopidogrel, mupirocin, 
omeprazole, oxycodone,  
prednisone, spironolactone, 
triamcinolone, Bactrim DS.  
Yes  
02  23  
M  
Bruton’s 
agammaglobulinemia 
2yrs  
Prednisone, 
gevokizumab  
Ibuprofen, vancomycin, 
Zosyn, morphine, 
Levaquin, Motrin,  
Benadryl, ampicillin, 
APAP, prednisone, 
Hizentra, Claritin D,  
Asmanex, tramadol, Paxil, 
omeprazole  
Yes  
03  55  
F  
+ASO, minor  
MGUS  
20yrs  
Debridement, 
prednisone, 
vein ablation  
Tramadol, Zosyn, dilaudid, 
vancomycin, cefepime, 
KCl, Hylenex, gadoterate 
meglumine, minocycline, 
senokot, naproxen,  
morphine, metronidazole, 
heparin,  
Ca-VitD, docusate, 
pentoxifylline, maxipime, 
APAP, doxycycline,  
prednisone  
Yes  
04  49  
F  
IgA  
vasculitis  
3yrs  
Debridement, 
dapsone, MMF,  
fluocinonide, 
silversulfadiazene  
  
No  

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                                                    Page 30 of 43 
05  58  
M  
Presumptive  
Crohns (based on 
Prometheus  
testing)  
50yrs  
Skin grafting, 
hyperbaric tx, 
debridement,  
collagen/silver 
dressings, 
mafenide 
cream   
Lipitor, dexamethasone, 
Benadryl,  
Allegra, Lopid, Norco, 
Combivent,  
Syntroid, multiVit, 
probiotic,  
Januvia, Cozaar, 
mafenide,  
Metformin, Actos, Dakins 
soln,  
APAP, Immodium, 
Flonase, lidocaine 1% 
inj, fluconazole,  
meropenem, docusate-
senna, GoLytley, 
daptomycin, vancomycin, 
Alteplase,  
metronidazole, MgSO4, 
heparin,  
Lispro, gadoterate 
meglumine, dilaudid,   
Yes  
  
1.1  
PRIMARY ENDPOINTS  
  
The proportion of subjects achieving a two point reduction in the five-point investigator global assessment (IGA) for the target 
ulcer from baseline to week 12.  
  
Pt  
Baseline IGA  
Completion IGA  
Notes (or completion 
wk)  
01  
3  
3  
  
02  
3  
N/A (not captured at Wk 2)  
Lost to FU after Wk 2  
03  
3  
4  
EOT visit at Week 6   
05  
4  
4  
EOT visit at Week 6   
Mean  
3.25  
3.67  
  
  
1.2  
SECONDARY ENDPOINTS  
-Frequency of total closure of target and total ulcers from baseline to week 12   
Pt  
Closure of Target?  
Closure of Any?  
Notes (or completion 
wk)  

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November, 4, 2016 
 
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01  
No  
No  
  
02  
No  
No  
Lost to FU after Wk 2  
03  
No  
No  
ET visit at Week 6   
05  
No  
No  
ET visit at Week 6   
Mean  
No  
No  
  
  
-Change in total surface area of target/total ulcers from baseline to week 12  
Pt  
Baseline Area  
Completion Area  
Notes (or completion 
wk)  
01  
14.56 cm2  
19.38 cm2  
  
02  
2.28 cm2  
3.96 cm2  
Lost to FU after Wk 2  
03  
23.4 cm2  
41.4 cm2  
ET visit at Week 6   
05  
20.48 cm2  
32 cm2  
ET visit at Week 6   
Mean  
15.18 cm2  
24.19 cm2  
  
  
-Change Patient Global Assessment (PGA) from baseline until week 12  
Pt  
Baseline  PGA  
Completion PGA  
Notes (or completion 
wk)  
01  
3  
3  
  
02  
3  
N/A (not captured at Wk 2)  
Lost to FU after Wk 2  
03  
8  
7  
ET visit at Week 6   
05  
10  
6  
ET visit at Week 6   
Mean  
  
5.33  
  
  
-Change in patient pain perception using 10-point visual analog scale from baseline to week 12  
Pt  
Baseline Pain VAS  
Completion Pain VAS  
Notes (or completion 
wk)  
01  
6  
6  
  
02  
5  
N/A (not captured at Wk 2)  
Lost to FU after Wk 2  

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                                                    Page 32 of 43 
03  
10  
8  
ET visit at Week 6   
05  
4.5  
4  
ET visit at Week 6   
Mean  
6.37  
6  
  
  
-Change in patient quality of life using the dermatology life quality index (DLQI) from baseline to week 12  
  
  
Pt  
Baseline DLQI  
Completion DLQI  
Notes (or completion 
wk)  
01  
6  
7  
  
02  
3  
3  
Lost to FU after Wk 2  
03  
15  
17  
ET visit at Week 6   
05  
18  
6  
ET visit at Week 6   
Mean  
10.5  
5.75  
  
  
1.3  
EXPLORATORY ENDPOINT  
  
-Evaluation of an [IGA x Ulcer Area] scoring metric for target ulcer at each time-point   
-Change in microbiome of ulcer between baseline and week 12  
-Change in inflammatory markers between baseline and week 12 – C-reactive protein (CRP), erythrocyte sedimentation rate 
(ESR), absolute neutrophils, total leukocytes, IL-1, IL-6, IL-8, and TNF in serum.   
-Change in serum biomarker (if can be ascertained), depending on underlying cause (i.e. perinuclear anti-neutrophil cytoplasmic 
antibodies (pANCA) and anti-saccharomyces cerevisiae antibodies (ASCA) in patients with IBD, anti-streptolysin-O (ASO) in 
patients with streptococcus- driven disease, or levels of monoclonal/polyclonal protein in patients with MGUS/elevated IgA 
levels.   
  
Due to few patients and only one patient completing a full 12 weeks of the study, the exploratory endpoints were not 
further assessed and rather nanostring technology was performed to evaluate whether there were gene expression 
markers of the biopsy prepost treatment in the skin demonstrating diminished inflammatory pathways. Data attached. 
Unfortunately, there were very few genes showing consistent changes in regulation and of those, the change in expression 
was small.  
  

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                                                    Page 33 of 43 
  
Clinical Image and Timeline:   
(Note: As Subject 02 only completed visit 2, there are no photographs to compare to baseline)  
  
 
     BASLINE   
  
     Subject 01   
  
EOT (W16)  
  
  
  
  
  
  
  
  
 
     BASLINE   
  
     Subject 03   
  
EOT (W6)  

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     BASLINE   
  
     Subject 05   
  
EOT (W6) 
  
  
  
  
  
  
ANALYSIS AND PUBLICATION PLAN:   
  

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                                                    Page 35 of 43 
The goal of the study will be a publication in a high-impact international dermatology journal such as the Journal of the American 
Academy of Dermatology, JAMA Dermatology or British Journal of Dermatology. We aim for a national level presentation at the 
American Academy of Dermatology annual meeting.   
Sample Size: 5  
  
Proposed Enrollment and Study Completion Plan:  
  
Total number of patients to be enrolled  
Number of investigative sites  
Total study length  
Enrollment period    
Treatment period  
STUDY SYNOPSIS   
Title:  
An Open-Label, Proof-Of-Concept, Study of Ixekizumab 
in the Treatment of Pyoderma Gangrenosum   
  
Protocol number:  
  
Phase:  
II  
Indication:  
Pyoderma Gangrenosum  
Study drug and 
comparator:  
Ixekizumab SQ  
No comparator is used in this study.  
Anticipated date of first patient visit  
Anticipated date of the last patient visit  
3/1/17  
Anticipated date of final study report 
submission to Lilly  
Anticipated publication date   
 
 
Study Synopsis:   
5/31/18  
5 
1 
16 weeks  
Up to 6 weeks 
12 weeks 
3 /1/ 18 
12/31/2018 

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                                                    Page 36 of 43 
Main Objectives:  
Primary Objective: the proportion of subjects achieving a 
two point reduction in the five-point investigator global 
assessment (IGA) for the target ulcer from baseline to week 
12  
Secondary Objectives:   
-Analysis of frequency of total closure of target and total 
ulcers from baseline to week 12   
-Analysis of change in total surface area of target/total  
ulcers from baseline to week 12  
-Analysis of change Patient Global Assessment (PGA) from 
baseline until week 12  
-Analysis of change in patient pain perception using 10point 
visual analog scale from baseline to week 12 -Analysis of 
change in patient quality of life using the dermatology life 
quality index (DLQI) from baseline to week 12  
  
Study design:  
This is a Phase II study that will be open label and enroll a 
total of five patients. These patients will have histological 
testing to rule out competing etiologies and require 3rd  
 
 
party adjudication/confirmation on agreement of the 
diagnosis. These patients will undergo 12 weeks of 
ixekizumab dosed every 2 weeks with follow-up until week 
16.   

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Major  
inclusion/exclusion 
criteria:  
For the complete list of inclusion/exclusion, criteria refer to 
Section 4.  
Major inclusion criteria:  
Have a clinical diagnosis of classic PG for at least 3 months 
as determined by the investigator and an external reviewer 
on the basis of results from clinical, histological and 
laboratory assessments   
At screening, have a PG ulcer characterized by ‘item a’ 
AND 3/5 features in ‘item b’ OR 2/5 features in ‘item b’ 
with support from one of the conditions listed in c.    
a. 
Stable or increasing size within 2 months preceding 
screening by patient report or documentation   
b. 
Features such as violaceous border, undermining, 
cribriform scarring, pustules, peristomal location  
c. 
Identifiable secondary systemic condition, such as 
IBD, arthritis, MGUS, noncancerous hematologic 
disease, streptococcal carriage, levamisole-tainted 
cocaine, Bruton’s agammaglobulinemia  
  
Have a PG target ulcer that has an area ≥ 2 cm2 and ≤ 200 
cm2 at screening   
Initial IGA of 3 or higher on a 5 point scale (0-4)  
  
Major exclusion criteria:  
1. Any condition (e.g., psychiatric illness, severe alcoholism, 
or drug abuse) or situation that may compromise the 
ability of the subject to give written informed consent, 
may put the subject at significant risk, may jeopardize the 
subject’s safety after exposure to the study drug, may 
confound the study results, or may interfere significantly 
with the subject’s participation in the study  
2. History of malignancy within 2 years of screening other 
than carcinoma in situ of the cervix or adequately treated, 
non-metastatic, squamous or basal cell carcinoma of the 
skin  

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3. History of seropositivity for HIV antibody; active or 
carrier status of hepatitis B [surface antigen (HBsAg) 
positive, or core antibody (anti-HBc) positive with 
negative surface antibody]; active hepatitis C (i.e. not 
treated or not cleared spontaneously, as confirmed by 
HCV PCR)   
4. History of severe allergic or anaphylactic reaction to   

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                                                    Page 40 of 43 
 
    monoclonal antibodies   
5. Systemic infection (excluding wound colonization) 
requiring oral antibiotics within 2 weeks of Day 0  
6. History of the following treatments:  
a. Anti-TNF or other biologic therapies within 5     
half-lives of screening  
b. Changes (addition, discontinuation, or changes in 
dose) in immunosuppressive medication (including 
cyclosporine, azathioprine, methotrexate, 
mycophenolate mofetil, apremilast, dapsone, or 
corticosteroids within 2 months of  
Day 0   
c. Systemic corticosteroids > 20 mg per day 
(prednisone or prednisone equivalent) within 8 
weeks of Day 0, or change in dose within 8 weeks 
of Day 0. Steroids may be tapered (although not 
increased above the Day 0 dose) during the trial as 
determined by the investigator.   
d. Intralesional corticosteroids within 8 weeks of day 
0; topical immunomodulators are permitted.   
e. Wound debridement within 2 weeks of Day 0; 
dressing changes allowed per investigator 
discretion.   
g. Systemic antibiotics within 2 weeks of Day 0  
h. Live, attenuated vaccines within 3 months of Day  
0; or live, seasonal-flu- or H1N1 vaccines within 
2 weeks of Day 0. Note: recombinant- and/or 
killed vaccines are permitted.  
i. Hyperbaric treatment within 4 weeks of Day 0  
j. Investigational drug or investigational device 
within 30 days or 5 half-lives of Day 0, whichever 
is longer  
k. Prior exposure to ixekizumab  

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                                                    Page 41 of 43 
l. Other treatments not described above should be 
maintained at a stable dose and frequency 
throughout the study as best as possible   
13. Major, general surgery within 3 months of screening, or 
anticipated general surgery during the study period  
14. Pregnancy, plans to become pregnant during the course 
of the study, delivery within 3 months of screening, or 
breast-feeding  
15. If previous use of cyclosporine or systemic 
corticosteroids, failure to have any stabilization/response 
is exclusionary. This potentially indicates the disease is 
not PG.  
  

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                                                    Page 42 of 43 
Endpoints:  
• Change in IGA between baseline and week 12  
Safety plan:  
Enrollment and toxicities on this trial will be monitored by  
 
the principal investigator and the OSU Data and Safety 
Monitoring Committee (DSMC)   
Study treatment:  
Ixekizumab subcutaneous injection 160 mg at d0, 80 mg q 2 
weeks with the last dose at week 12.   
Concomitant therapy 
and clinical practice:  
As PG is a disease responsive to immunosuppression, use of 
concomitant medications will be carefully monitored, and 
patents will be required to have stable or worsening disease 
on a consistent dose of immunosuppression at screening.   
1. Mycophenolate mofetil, azathioprine, cyclosporine, 
leflunomide, dapsone, apremilast and methotrexate will be 
allowed, but the patient is required to have stable/worsening 
disease for 4 weeks prior to screening, while on a stable dose 
of immunosuppression for > 8 weeks prior to baseline. 2. 
Anti-TNF or other biologic therapies will not be allowed 
within 5 half-lives before screening, or during the study.   
Oral corticosteroids above 20 mg daily of prednisone (or 
equivalent) are excluded. Lower doses are allowed provided 
they are prescribed at stable doses for two months prior to 
baseline and are 20 mg or less per day of prednisone or other 
equivalently-dosed corticosteroids.   
Intralesional corticosteroids within 4 weeks of screening and 
during the study  are not permitted  
Other therapies that are non-immunosuppressive and 
noninvestigational can be started or continued at physician 
discretion provided the medicine has no history of 
association with progressive multifocal leukencephalopathy. 
Antibiotics may be used as needed for evidence of 
superinfection, positive culture results, malodor, green 
discharge, etc.   
  

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                                                    Page 43 of 43 
Statistical methods:  
The primary objective of a two-point IGA decrease in the 
target ulcer will be analyzed as the difference from baseline, 
with the null hypothesis that no patients will obtain the 
specified improvement if the investigational product does 
not have efficacy. The endpoint will be analyzed using the 
Fisher Exact test. The secondary and exploratory objectives 
will be analyzed in comparison to baseline measurements 
and at each time point to evaluate for efficacy using either 
the Fisher Exact test/Chi-square test or the Wilcoxon Rank 
Sums test. We anticipate that the basic statistics will be 
completed within 1-2 months of the last patient completing 
his/her week 12 visit. Analyzing the interferon multiplex 
assay and microbiome will take longer, but will primarily be 
descriptive at the different time points and be analyzed by T-
testing for continuous variables