Characterizing Pyoderma Gangrenosum Lesion Regression and Remission by IL-36 Receptor Targeting With Spesolimab
Phase: PHASE2
Conditions: Pyoderma Gangrenosum
Sponsor: Icahn School of Medicine at Mount Sinai

Characterizing Pyoderma Gangrenosum Lesion Regression and Remission 
by IL-36 Receptor Targeting With Spesolimab 
PI: Saakshi Khattri
NCT06092216 
Document Date: 2/27/2024

1
Characterizing Pyoderma Gangrenosum Lesion Regression and Remission by
 IL-36 Receptor Targeting with Spesolimab 
Principal Investigator:
Saakshi Khattri, MD
Investigators:
Mark G. Lebwohl, MD 
Mark Taliercio, MD
Anusha Pasumarthi, MD
Study Site:
Icahn School of Medicine at Mount Sinai
Department of Dermatology 
5 East 98 Street, 5th Floor
New York, NY 10029
Protocol Version:
October 1st, 2023 
Amendment 1:
August 10, 2023
Amendment 2: 
December 21, 2023
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Table of Contents
Background....……………………………...
3
Treatment Rationale…………………......
4
Hypothesis……………………….…….….
8
Objectives……………………….….…..…
8
Endpoints………………………..………..
8
Study Design Overview……………….....
8
Patient Population 
Inclusion Criteria…………………. 
10
Exclusion Criteria…………………          11
Potential Risks of Spesolimab…………..           11
Table 1. Summary of Adverse Reactions          12
Prior Treatment………………………...…
13
Concomitant Treatment………………….
13
Prohibited Treatment…………………….
13
Procedures………………………………..
13
Safety Monitoring……………………..….
16
Adverse Event Reporting………………..            16
Study Withdrawal……………………..….
20
Table 2. Total Volume of Blood …………           20
Discontinuation of Treatment and 
Withdrawal of Subjects…………
21
Measures to Minimize/Avoid Bias………
22
Investigational Drug Supply…………….. 
22
Statistical Considerations………………..
23
Table 3. Schedule of Events Q4 Dosing Only
25
Table 4. Schedule of Events Q4 Dosing 
Followed by Q3 Dosing…………
27
References……………………………….       
30
Appendix 1. Clinician Assessment of 
Pyoderma Gangrenosum ……………….            32
Appendix 2. Patient Pyoderma Gangrenosum 
Questionnaire…………………………….             35
Appendix 3 – Amendments……………..
 38
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BACKGROUND:
Pyoderma gangrenosum (PG) is a rare, inflammatory neutrophilic disease that is 
characterized by rapidly developing, painful and necrotizing skin ulcers with peripheral, 
violaceous erythema and undermined or “rolled” borders1. The condition most frequently 
occurs in adults between the ages of 41-72 years of age with a predisposition to the 
female sex2. It is estimated that 3-10 people per million are diagnosed with PG each 
year3.
PG is often a chronic condition harboring a significant impact on patient mortality and 
quality of life4. Approximately 30% of individuals with PG have co-existing immune-
mediated conditions such as inflammatory bowel disease, rheumatoid arthritis, or 
myeloproliferative disorders4. Clinically, the lesions appear as non-healing wounds or 
pustule eruptions that slowly ulcerate into crater-like holes and fistular tracks5. While 
rarely diagnostic, histopathology of PG lesions may show prominent dermal neutrophilic 
infiltrate with abscess formation in conjunction with a lack of signs for infection or 
vasculopathies1. Thus, the diagnosis of PG is most often one of exclusion. 
The PARACELSUS scoring tool is a diagnostic tool that helps distinguish PG from ulcers 
caused by a different etiology6. The tool consists of three major diagnostic criteria (3 
points each) and seven minor criteria (2 points each)6. Major criteria include: progressing 
disease, assessment of relevant differential diagnosis, and reddish-violaceous wound 
borders6. Minor criteria include: amelioration by immunosuppressant drugs, 
characteristically irregular shape of ulceration, extreme pain >4/10 on a visual analogue 
scale, localization of lesion at site of trauma, suppurative inflammation on histopathology, 
undermined wound borders, and associated systemic diseases such as inflammatory 
bowel disease or rheumatoid arthritis6. If a patient had a score greater than or equal to 
10 points, the patient had a high likelihood of having PG6.  Biopsy has not been found to 
a reliable diagnostic criterion7.
While the mechanism of PG has not been fully elucidated, there has already been 
significant progress. PG is a destructive autoinflammatory process driven by the innate 
immune system. The process is attributed to pathergy in which initial insult releases 
cytokines and danger signals that result into aberrant inflammation and cutaneous 
neutrophilic infiltration1. Ulcerative PG occurs in response to pathergy, often in the 
postoperative setting. Upon trauma, keratinocytes release interleukin-36 (IL-36) which is 
thought to play a central role in PG pathogenesis and neutrophil recruitment8. 
To date, there is no gold standard for treatment of PG. Rapidly progressing cases 
require early systemic therapies such as prednisone and cyclosporine to contain lesions 
and halt spread1. On the contrary, slowly progressing, smaller areas may be 
conservatively managed with topical corticosteroids or calcineurin inhibitors as well as 
intralesional corticosteroid injections9,10. More recently, anti-TNF-  therapies such as 
𝛼
infliximab, adalimumab and etanercept have also been used in refractory cases with 
moderate success11,12,13,. Patients with pyoderma gangrenosum suffer from severe pain 
and poor quality of life due to frequent dressing changes and disfiguring lesions. More 
importantly, rapidly progressing ulcers present an important risk for infection, morbidity, 
and mortality for patients. 
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Spesolimab is humanized antagonistic monoclonal IgG1 antibody that blocks human 
IL36R signalling and subsequent downstream pro-inflammatory pathways14. The IL-36 
receptor blocker was recently approved for generalized pustular psoriasis (GPP)15. 
Similar to ulcerative PG, IL-36 cytokines are aberrantly expressed in GPP skin lesions8. 
In 2021, Bachelez et al. demonstrated in a phase 2 randomized trial that spesolimab 
treatment resulted in significant clearing of GPP lesions compared to placebo15. In the 
same vein, we hypothesized that targeting IL-36 in refractory, ulcerative postoperative 
PG may result in regression and resolution of a patient’s lesions.  
TREATMENT RATIONALE: 
To date, there is a lack of specific, efficacious, and safe treatment options for severe PG. 
Treatment of the condition largely consists of immunosuppressants such as prednisone 
and cyclosporine, both of which harbor side effect profiles that render them not suitable 
for long-term use16. For patients with refractory PG, long-term use of these 
immunosuppressants may lead to development of Cushing syndrome and osteoporosis in 
the case of prednisone and nephrotoxicity and malignancy in long-term use of 
cyclosporine16,17. More recently, TNF-α blockers (adalimumab, infliximab, etanercept) 
have seen moderate success in treatment of pyoderma gangrenosum10-13. However, while 
safer than cyclosporine and prednisone for long term use, TNF-α blockers also harbor risk 
for malignancy16. It is imperative to find safe, alternative treatment for chronic, severe 
pyoderma gangrenosum refractory to current treatment therapies. 
In addition, given the rarity and difficult diagnostic nature of this disease, there are very 
few clinical trials that exist for pyoderma gangrenosum. Literature concerning therapies for 
PG consists mostly of case reports and case series. Thus, it is essential that we conduct 
clinical trials in order to investigate safer, alternative therapies for those suffering from this 
debilitating disease. 
While the pathogenesis of pyoderma gangrenosum has not been fully elucidated, pathergy 
has been thought to play a large role. Upon trauma, keratinocytes release IL-36 which 
triggers both the innate and adaptive immune system into a positive feedback loop (Figure 
1)8.
IL-36 is a member of the interleukin-1 cytokine family, which has been implicated in 
neutrophilic inflammation and the pathogenesis of PG. Lacking a specific caspase-
cleavage motif, IL-36 requires proteolytic cleavage by surrounding neutrophil-derived 
proteases: Cathepsin G, elastase, and proteinase-38. Once cleaved and activated, IL-36 
upregulates expression of inflammatory cytokines and chemokine release resulting in 
increased neutrophil recruitment8. In response to IL-36, human keratinocytes have been 
shown to produce increased levels of TNF, IL-17A, IL-6, IL-8, and CXCL8, which 
propagate pro-inflammatory signals and recruitment of immune cells such as neutrophils, 
macrophages, and T cells 4, 18, 19. Recruited neutrophils degranulate and result in 
increased levels of activated IL-36, leading the cycle to repeat itself. At the same time, 
IL-36 has been reported to skew T cell differentiation towards Th1 and away from Treg, 
which further propagates aberrant, pro-inflammatory signaling20,21. Taken together, IL-36 
appears to play a central role in propagation of a pro-inflammatory cycle in PG, which 
leadings to neutrophil recruitment and skin ulceration (Figure 1). To further confirm this, 
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biopsies of PG skin ulcers demonstrate elevated levels of IL-36 22. Thus, targeting IL-36 
downstream signaling is likely to halt disease propagation and lead to skin healing.
Figure 1. Proposed Mechanism: IL-36 Plays Key Role in the Inflammatory Cycle of 
Pyoderma Gangrenosum8, 18-21
Upon skin injury, there is RNA release which activates the innate immune response and leads to 
neutrophil activation and degranulation. At the same time, keratinocyte injury leads to IL-36 
release. Simultaneous occurrence of these events leads to activation of IL-36 by neutrophil-
derived proteases. Activated IL-36 leads to increased expression of pro-inflammatory, neutrophil 
recruiting cytokines IL-8, TNF, CXCL-8, IL-17A, and IL-6. Further, IL-36 activation also leads to 
skewed Th1 differentiation with decreased Treg differentiation; thereby amplifying the 
inflammatory response and progression of disease. Spesolimab, an IL-36 receptor blocker, 
inhibits pro-inflammatory downstream effects of activated IL-36; thereby breaking the 
inflammatory cycle in pyoderma gangrenosum. (Figure made courtesy of Biorender.com)
Already, we have seen successful treatment of two of our patients with severe PG with 
spesolimab. The first patient had severe, refractory PG on his face and chest, which 
showed marked improvement within five weeks of his first spesolimab infusion (Figure 
2). A second spesolimab-treated patient with pyoderma gangrenosum also saw near 
resolution of PG lesions after two spesolimab infusions at week 0 and week 4.
The first patient treated with spesolimab for severe, refractory PG was started on 900mg 
IV spesolimab every 4 weeks. However, it was noted that he began seeing signs of 
purulence by week 3 post-treatment. Thus, approval was obtained from Boehringer 
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Ingelheim and the FDA for 900mg q3 week dosing and we anticipate this dosing to better 
control his disease process. 
The successful treatment of these two patients suggests that spesolimab effectively 
blocks the IL-36 receptor and thereby halts the PG inflammatory cycle. Their rapid 
response also suggests that IL-36 plays a crucial role in the pathogenesis of PG and 
may be a worthwhile target for future PG therapies. Further, the lack of severe adverse 
effects in our patient demonstrates that spesolimab may be a safe, alternative to long-
term, systemic immunosuppressive therapies that have well-established, dangerous side 
effects. This will be an important study that will help fill the gap in available clinical trial 
evidence for pyoderma gangrenosum treatment. 
A
B
A
B
A
B
A
B
C
D
E
F
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Figure 2. 75-year-old male Pyoderma Gangrenosum
A-C. Prior to Spesolimab treatment (A. Right Cheek, B. Left Face, C. Chest)
D-F. Five weeks after first 900mg infusion of spesolimab (D. Right Cheek, E. Left Face, F. Chest)
HYPOTHESIS:
Primary Hypothesis: 

Blocking the IL-36 receptor with spesolimab will be effective in improving and/or 
resolving PG lesions and their associated morbidities. 
OBJECTIVES:
Primary Objectives: 

To study the rate of improvement of patients with pyoderma gangrenosum lesions 
treated with 900 mg infusions of spesolimab at week 16 
Secondary Objectives 

To evaluate the rate of complete re-epithelization of PG lesions to spesolimab 
treatment 

To evaluate the rate of recurrence of PG lesions upon spesolimab treatment 
cessation and over 4-month follow-up period 

To evaluate safety spesolimab treatment in patients with pyoderma gangrenosum 

To evaluate change in patient pain severity 

To evaluate the change in patient-reported symptoms and impact of skin problems 
on quality of life 
ENDPOINTS:
Primary Endpoint 

One point decrease from baseline in target lesion Global PG (GPG) Severity Score 
at  Week 16  
Secondary Endpoints 

Complete re-epithelization of PG lesions (GPG Severity Score of 0) at visits 3, 4, 5, 
6, 7, 8, and 9.  

Absolute change from baseline in patient-reported pain severity (Pain-VAS) at visits 
3, 4, 5, 6, 7, 8, and 9 and at complete re-epithelization of ulcer.

Absolute change in quality of life (DLQI) from baseline at visits 3, 4, 5, 6, 7, 8, and 
9 and at complete re-epithelization of ulcer.  

Recurrence of PG lesions after complete re-epithelization (GPG score 0) of all 
lesions and spesolimab cessation
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
Time to worsening (1 or more GPG point increase) of target PG lesion from  
spesolimab cessation
STUDY DESIGN OVERVIEW:
This study is a prospective, proof-of-concept, open label clinical trial. The study will take 
place at Icahn School of Medicine at Mount Sinai. 
The study will screen up to 25 subjects in order to enroll a total of up to 20 patients with at 
least one clinically measurable ulcerative PG lesion. Subjects will receive 900 mg of 
spesolimab intravenously (IV) over 90 minutes at a frequency of every 4 weeks until Week 
28 with the following exceptions:

At the Week 8 visit, subjects who do not show any improvement, show only minimal 
improvement, or those that begin to lose their initial improvement response 
(decrease in pain or wound drainage), may be switched to a dosing frequency of  
every 3 weeks through Week 26, at the discretion of the investigator. These 
subjects will still return at Week 16 for an endpoint visit, but will not receive 
treatment at this visit. Refer to Tables 3 and 4 for schedule of events. 
All subjects will be monitored monthly for 4 months subsequent to treatment cessation. 
Subjects who reach GPG score 0 at anytime during the study will continue to receive 
treatments until week 28 (or Week 26 depending on dosing frequency) and will then be 
monitored for 4 months subsequent to treatment cessation. 
Subjects who are experiencing improvement in their PG but who have not reached 
complete wound healing will continue treatment until Week 28 (or Week 26 for those who 
were switched to every 3 week dosing), even if primary endpoint has been achieved.  
These subjects will then be monitored for 4 months subsequent to treatment cessation. 
  
Subjects who have not improved and not worsened significantly will also continue to 
receive treatments until week 28 (or Week 26 depending on dosing frequency) and will 
then be monitored for 4 months subsequent to treatment cessation. 
Any subject that experiences significant worsening will be discontinued from the study. 
After providing consent, subjects will be assessed for study eligibility during the screening 
period (within 28 days of baseline). The screening visit includes a review of the subject’s 
past and current medical conditions as well as a review of family history of associated 
relevant diagnoses such as inflammatory bowel disease, rheumatoid arthritis, and 
hematological malignancy. Subjects will also be asked to review past surgical history and 
history of any relevant skin trauma. Subjects will also be asked to report past and current 
treatment regimens of their PG and their perception of response to each treatment trialed. 
A limited physical exam will be performed, vitals collected, blood samples collected for 
safety tests (including screenings for HIV, hepatitis B and C and tuberculosis), and the 
physician will assess number, location, and severity of PG lesions. 
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Subjects who meet inclusion criteria for eligibility will undergo Baseline assessments at 
Week 0, including clinical assessments, review of concomitant medications, limited 
physical examination, vitals, standardized clinical photography, questionnaires (patient PG 
questionnaire, pain VAS and DLQI). Blood samples (CBC, CMP, CRP, serum cytokine 
profiles, pharmacokinetics, Nab, ADA) will be collected to monitor for adverse effects of 
medication and overall inflammatory response. 
During each treatment visit the subject will undergo clinical assessments (number, 
location, measurement of lesions, and GPG Score (Appendix 1)). Each visit will also 
consist of vitals, medication review, blood collection, patient PG questionnaire (wound 
dressings, pain VAS and DLQI (Appendix 2) and monitoring for adverse events. O-Link ® 
Inflammatory Serum Cytokine Panel, IL-1ß, and IL-36 subtype cytokine levels will be run 
from blood serum samples collected at Baseline/Week 0, Week 16, all follow-up visits, 
and/or at early termination visits. Blood samples for pharmacokinetics and antibody testing 
(Nab and ADA) will be collected at Baseline, Week 8, Week 16, Week 28 (or Week 26 
depending on dosing frequency) and/or early termination visit. An extra 10mL aliquot of 
serum sample will be reserved for any additional exploratory serum testing done in the 
future. 
PATIENT POPULATION:
Prior to enrollment, all subjects must meet the following inclusion and exclusion criteria: 
Inclusion Criteria: 
1) Male or female subjects > 18 years of age at the time of signing the informed 
consent document 
2) Subject is able to understand and voluntarily sign an informed consent document 
prior to participation in any study assessments or procedures 
3) Subject is able to adhere to the study visit schedule and other protocol 
requirements.
4) Subject has clinically diagnosed ulcerative PG with PARACELSUS score greater 
than or equal to 10 (6)
5) Subject has at least one clinically measurable ulcerative PG lesion on his/her/their 
body that has failed to respond to at least one prior therapy such as (but not limited 
to) topical corticosteroids, intralesional triamcinolone, prednisone, cyclosporine, IL-
23 inhibitor, IL-17 inhibitors, IL-1 inhibitors, or TNF-α blocker therapy
6) Subject has moderate to severe PG as determined by a GPG severity score of >3
7) Subject is judged to be in otherwise good overall health as judged by the 
investigator, based on medical history, limited physical examination, and laboratory 
testing. (NOTE: The definition of good health means a subject does not have 
uncontrolled significant co-morbid conditions).
8) Females of childbearing potential (FCBP) must have a negative pregnancy test at 
Screening and Baseline.  While on investigational product and for at least 28 days 
after taking the last dose of investigational product, FCBP who engage in activity in 
which conception is possible must use one of the approved contraceptive options 
described below:
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Option 1: Any one of the following highly effective contraceptive methods: 
hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); 
intrauterine device (IUD); tubal ligation; or partner’s vasectomy.
OR 
Option 2: Male or female condom (latex condom or nonlatex condom NOT made 
out of natural [animal] membrane [for example, polyurethane]); PLUS one 
additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with 
spermicide; or (c) contraceptive sponge with spermicide.
The female subject’s chosen form of contraception must be effective by the time 
the female subject presents for her Baseline visit (for example, hormonal 
contraception should be initiated at least 28 days before first spesolimab infusion 
at Baseline).
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1)
Subject has a persistent or recurring bacterial infection requiring systemic 
antibiotics, or clinically significant viral or fungal or helminth parasitic infections, 
within 2 weeks of the Screening Visit. Any treatment of such infections must have 
been completed at least 2 weeks prior to the Screening Visit and no new/recurrent 
infections should have occurred prior to the Baseline Visit. 
2)
Subject with current or history of positive human immunodeficiency virus (HIV), or 
congenital 
or 
acquired 
immunodeficiency 
(i.e. 
Common 
Variable 
Immunodeficiency [CVID]), hepatitis B or C, or active or untreated latent 
tuberculosis.
3)
Subject has clinically significant (as determined by the investigator) renal, hepatic, 
hematologic, intestinal, endocrine, pulmonary, cardiovascular, neurological, 
psychiatric, immunologic, or other major uncontrolled diseases that will affect the 
health of the subject during the study, or interfere with the interpretation of study 
results. Uncontrolled disease defined as hospitalization within 1 month of 
screening visit or determined by specialist (rheumatologist, gastroenterologist) 
consulted prior to study start. 
4)
Subject has presence of acute demyelinating neuropathy 
5)
Major surgery (according to the investigator’s assessment) performed within 12 
weeks prior to receiving first dose of spesolimab or planned during trial such as 
hip replacement, aneurysm removal, stomach ligation, or otherwise determined by 
investigator 
6)
Subject has a suspected or active lymphoproliferative disorder or malignancy 
7)
Subject was treated previously with spesolimab or another IL-36R inhibitor biologic
8)
Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treatment basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix. 
9)
Subject has received a live attenuated vaccine ≤ 30 days prior to study initiation.
10) History of adverse systemic or allergic reactions to any component of the study 
drug.
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11) Female subject who is pregnant or breast feeding
POTENTIAL RISKS OF SPESOLIMAB 
Preclinical and clinical data demonstrates that spesolimab is safe for chronic use in 
humans with a good safety profile and minimal anticipated adverse events (AE). Animal 
studies demonstrated that administration of 1 and 10mg/kg/dose of spesolimab to mice 
twice per week for 4 weeks was well tolerated without any signs of toxicity14. Further, 
there was no clinical signs of toxicity in mice after administration of spesolimab for 26 
weeks. Spesolimab is not expected to be carcinogenic or teratogenic in mouse models; 
however, further studies in humans are still required14.  
Specific adverse reactions for spesolimab include infection, risk of tuberculosis, and 
hypersensitivity and infusion-related reactions. Of note, the two reported cases of 
6DRESS were categorized as “no” DRESS and “possible” DRESS with the RegiSCAR 
DRESS validation scoring. Other previously reported potential adverse events include 
Guillan-Barre Syndrome and other peripheral neuropathy. 
In the phase 2 trial investigating spesolimab use in GPP, there were no serious adverse 
events in the spesolimab 900mg intravenous infusion group15. Serious adverse events 
reported included: drug reaction with eosinophilia and systemic symptoms, urinary tract 
infection, drug induced hepatic injury, arthritis, influenza, worsening of chronic plaque 
psoriasis and squamous cell carcinomas of skin15. The most common selected adverse 
reactions occurring in >1% of spesolimab treated individuals in the Effisayil-1 trial when 
compared to placebo was: asthenia and fatigue, nausea and vomiting, headache, 
pruritus and prurigo, infusion site hematoma and bruising, urinary tract infection, 
bacteremia, bacteriuria, cellulitis, herpes dermatitis and oral herpes, upper respiratory 
tract infection, dyspnea, eye edema, and urticaria14. The most common adverse 
reactions noted in the package insert for spesolimab are:  asthenia and fatigue, nausea 
and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising and 
urinary tract infection14.
The paragraphs above provide the safety information described in the US PI (spesolimab 
label in US) according to the FDA approval process. However, Boehringer-Ingelheim´s 
position concerning the adverse drug reactions of spesolimab in patients with flares of 
Generalized Pustular Psoriasis is described in the table 1 below:
Table 1 Summary of Adverse Reactions
MedDRA System Organ Class 
terminology
Spesolimab adverse reactions
Infections and infestations
Urinary tract infection
Upper respiratory tract infection
Skin and subcutaneous tissue 
disorders
Pruritus
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General disorders and administration 
site
conditions
Injection site reactions
Fatigue
Moreover, there are some important potential risks still under evaluation for spesolimab 
which are part of its core Risk Management Plan. These important potential risks are the 
following:

Serious or opportunistic infections

Systemic hypersensitivity reactions

Malignancy 

Peripheral Neuropathy
Contraindications to spesolimab treatment include patients with severe or life-threatening 
hypersensitivity to spesolimab or to any of the excipients in spesolimab14. In our 
experience, patients infused with spesolimab exhibited no adverse reactions during or 
after treatment with no pre-medication required. There is limited data available on the 
impact of antidrug antibodies on safety and efficacy upon retreatment. Furthermore, it is 
not known whether spesolimab increases or decreases the efficacy of other medications.
PRIOR TREATMENT:
All relevant treatment received by the subject within 30 days before screening will be 
recorded. 
CONCOMITANT TREATMENT:
Concomitant medications are permitted for the treatment of stable, chronic illness as well 
as for pyoderma gangrenosum. Concomitant treatments for pyoderma gangrenosum will 
tapered over spesolimab treatment course as tolerated. Use of such concomitant 
medication or other medications that may be required throughout the study will be 
recorded (including the reason for treatment and name, dose, unit, route, and the date of 
treatment as appropriate) until treatment termination and throughout follow-up period. 
Patients will be allowed to continue with biologic therapies used to treat comorbidities. 
PROHIBITED TREATMENT: 
All treatments prohibited by clinician during the screening period are also prohibited 
throughout the course of the study. No live attenuated vaccinations are permitted 
throughout the study. 
PROCEDURES:
Monitoring of AEs will begin at the time of signing the informed consent form and will be 
continued throughout the course of the study. All study procedures will be completed at 
designated times during the study period (see Tables 3 and 4). Subjects will receive 
900mg IV spesolimab at a frequency of every 4 weeks through Week 8, at which time, at 
the discretion of the investigator, dosing frequency may be increased to every 3 weeks. 
Subjects will continue to dose every 4 or 3 weeks through Week 28 or 26 (depending on 
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13
dosing frequency). Subjects will be monitored once a month, for 4 months after treatment 
cessation. Patients that, in the opinion of the investigator, are benefiting from treatment at 
week 28 but need more therapy to achieve wound closure may be eligible to continue on 
treatment (on case-by-case basis) to a maximum of 52 week after discussion with 
Boehringer Ingelheim trial team.
Trained assessors will perform clinical assessments. It is strongly recommended that the 
same assessor/s perform clinical assessments for a subject at all study visits. The 
following procedures will be performed at each visit:
Screening
Visit 1 – Screening (within 4 weeks of Baseline)* 

Obtain signed IRB-approved informed consent and HIPPA agreement

Review Inclusion and Exclusion Criteria

Review PARACELSUS Criteria and confirm the PARACELSUS score for patient 
and target lesion is greater than or equal to 10 

Record gender, race, ethnicity, and medical history

Review personal and family history of PG, inflammatory bowel disease, rheumatoid 
arthritis, hematological, and autoimmune diseases as well as personal lifetime 
surgical history

Perform limited physical exam and vitals, including blood pressure and heart rate

Record all concomitant medications as well as all those received within the three 
months prior to screening; assess adverse events.

PG history assessment (date of onset for each PG lesion) extracted from electronic 
medical records or obtained from referring provider 

Record all prior topical, systemic therapies/treatments or interventional treatment 
for pyoderma gangrenosum

Serum HCG for all female subjects of child-bearing potential to confirm subject is 
not pregnant.   

Complete blood count (CBC) with differential, Comprehensive metabolic panel 
(CMP), C-reactive protein (CRP), QuantiFERON-TB Gold test or PPD, HIV, 
Hepatitis B (Core, Surface Antigen, Surface Antibody), Hepatitis C Antibody. 

PG clinical assessments (including number/location/measurements of PG lesions, 
GPG score for target lesion)
*If more than 28 days has lapsed between screening and Baseline/Visit 2, then all 
procedures should be repeated except for re-obtaining informed consent. 
Baseline
Visit 2 – Baseline (Week 0)

Confirm all inclusion and exclusion criteria have been met

Record concomitant medications (including use of pain medication) and adverse 
events

Patient Pyoderma Gangrenosum Questionnaires and DLQI

Obtain vital signs
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
Perform limited physical exam 

Standardized clinical photography of target lesion and other PG lesions

PG clinical assessments (including number/location/measurements of PG lesions, 
GPG score of target lesion)

Assess status of associated co-morbidities such as IBD or RA. Categorize co-
morbid condition status as “improved, no change, worsening”.

Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant

Collect blood samples for CBC with differential, CMP, and C-reactive protein (CRP), 
,serum cytokine profiling (O-link® inflammatory cytokine panel, IL-1ß, and IL-36 
subtypes), Nab, ADA, and Pre- and post dose pharmacokinetics.

Administer study drug
Spesolimab Treatment Phase 
Visits 3 thru 9 (subjects that dose every 4 weeks) or Visits 3 thru 11 (subjects that are 
switched to every 3 week dosing at Week 8)

Record concomitant medications (including use of pain medication) and adverse 
events

Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant

Patient Pyoderma Gangrenosum Questionnaires and DLQI 

Obtain vital signs

Standardized clinical photography of target lesion and other PG lesions

PG clinical assessments (including number/location/measurements of PG lesions 
and GPG score for target lesion) 

Assess status of associated comorbid conditions (improved, no change, worse)

Collect blood samples for CBC with differential, CMP, and C-reactive protein (CRP)

Only at Week 8 and Week 28 (subjects dosed every 4 weeks) or Week 26 
(subjects switched to dosing every 3 weeks): Nab, ADA, and pre dose 
pharmacokinetics.

Only at Week 16: serum cytokine profiling (O-link® inflammatory cytokine panel, 
IL-1ß, and IL-36 subtypes), Nab, ADA, and pre dose pharmacokinetics.

Administer study drug
 
Post-Spesolimab Follow-up Phase 
Visits 10 thru 13 (subjects dosed every 4 weeks) or Visits 12-15 (subjects switched to 
dosing every 3 weeks) 
Follow-Up Visits at 1 Month, 2 Months, 3 Months and 4 Months Post-Spesolimab 
Treatment Cessation

Record concomitant medications (including use of pain medication) and adverse 
events

Patient Pyoderma Gangrenosum Questionnaires and DLQI

Assess status of associated comorbid conditions (improved, same, worse)

Standardized clinical photography of target lesion and other PG lesions
Effective Date: 2/27/2024
End Date:8/14/2024

15

PG clinical assessments (including number/location/measurements of PG lesions, 
and GPG score of target lesion) 

Collect blood for serum cytokine profiling (O-link® inflammatory cytokine panel, IL-
1ß, and IL-36 subtypes)

If subject worsens or sees progression of their PG during the 4- month follow-up 
period (defined as 1 or more increase in GPG score of target lesion), then patient 
will be discontinued from the study and started on available, standard PG therapies.
Early Termination Visit (if applicable) 

Record concomitant medications (including use of pain medication) and adverse 
events

Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant

Patient Pyoderma Gangrenosum Questionnaires and DLQI.

Assess status of associated comorbid conditions (improved, same, worse)

Obtain vital signs

Standardized clinical photography of target lesion and other PG lesions

PG clinical assessments (including number/location/measurements of PG lesions 
and GPG score of target lesion) 

Collect blood samples for CBC with differential, CMP, and C-reactive protein (CRP), 
and serum cytokine profiling (O-link® inflammatory cytokine panel, IL-1ß, and IL-
36 subtypes)
SAFETY MONITORING:
The study will be conducted in accordance with our department’s Standard Operating 
Procedures, which are based on US FDA Title 21 Code of Federal Regulations and ICH 
Good Clinical Practice guidelines. An investigator will review all laboratory results and 
assess for adverse events. The principal investigator will be informed of all adverse events. 
In the event that a subject’s safety is compromised, the investigator will discontinue the 
subject immediately.
ADVERSE EVENT REPORTING:
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who 
received a pharmaceutical product. The event does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following should also be recorded as an AE in the CRF and BI SAE form (if 
applicable): 

Worsening of the underlying disease or of other pre-existing conditions 
Effective Date: 2/27/2024
End Date:8/14/2024

16

Changes in vital signs, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator. 
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria: 
- results in death, 
-is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe, 
- requires inpatient hospitalization or prolongation of existing hospitalization 
- results in persistent or significant disability or incapacity, 
- is a congenital anomaly / birth defect, 
- is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of dependency or abuse. 
Adverse events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment 
within this trial, e.g. the potential for Aes based on knowledge from other compounds in 
the same class.  AESIs need to be reported to the Pharmacovigilance Department of 
Boehringer Ingelheim within the same timeframe that applies to SAEs.
Patients with AESIs need to be followed up appropriately, regardless of the origin of the 
laboratory data (e.g. central, local etc.). The Investigator should consider which, if any, 
concomitant therapies should not be taken during evaluation.  Discontinued treatments 
can be reintroduced per Investigator discretion.
The following are considered as AESIs:
(1) Potential Severe Drug-Induced Liver Injury (DILI)
A hepatic injury is defined by the following alterations of hepatic laboratory parameters 
after randomisation: 

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood draw sample, or in samples drawn within 
30 days of each other, or, 

aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.
Effective Date: 2/27/2024
End Date:8/14/2024

17
These laboratory findings constitute a hepatic injury alert and the patients showing these 
abnormalities need to be followed up according to medical judgement.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory 
results (ALT, AST, total bilirubin) available, the Investigator should make sure these 
parameters are analysed, if necessary, in an unscheduled blood test.
(2) Systemic hypersensitivity reactions including infusion reaction and anaphylactic 
reaction
Includes any suspicion of severe systemic hypersensitivity including infusion reactions 
and any anaphylactic reaction should be defined and assessed using the criteria 
discussed in the statement paper from Sampson et al. – Sampson HA, Muñoz-Furlong 
A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the 
definition and management of anaphylaxis: Summary report—Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
Journal of Allergy and Clinical Immunology. 2006 Feb 1;117(2):391–7.
(3) Severe infections (according to RCTC/CTCAE version 5.0 grading)
(4) Opportunistic and Mycobacterium tuberculosis infections
Includes pneumocystis jirovecii, BK virus disease including PVAN,  CMV, posttransplant 
lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and disseminated 
forms only), paracoccidioides, penicillium marneffei, sporothrix schenckii, 
cryptosporidium species (chronic only), microsporidiosis, leishmaniasis (visceral only), 
trypanosoma cruzi infection (Chagas’ disease) (disseminated only), campylobacteriosis 
(invasive only), shigellosis (invasive only), vibriosis (invasive due to vibrio vulnificus), 
HCV progression.
(5) Peripheral Neuropathy 
Any event suspected or diagnosed as peripheral neuropathy would be considered as an 
AESI. For the treatment interruption rules, please see Section DISCONTINUATION OF 
TREATMENT AND WITHDRAWAL OF SUBJECTS
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild: Awareness of sign(s) or symptom(s) that is/are easily tolerated. 
Moderate: Sufficient discomfort to cause interference with usual activity. 
Severe: Incapacitating or causing inability to work or to perform usual activities. 
Causal relationship of adverse event
Effective Date: 2/27/2024
End Date:8/14/2024

18
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
Yes (related): There is a reasonable causal relationship between the investigational 
product administered and the AE. 
Arguments that may suggest that there is a reasonable possibility of a causal 
relationship could be: 

The event is consistent with the known pharmacology of the drug. 

The event is known to be caused by or attributed to the drug class. 

A plausible time to onset of the event relative to the time of drug exposure. 

Evidence that the event is reproducible when the drug is re-introduced. 

No medically sound alternative etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications). 

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 

An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is reduced). 
No (not related): There is no reasonable causal relationship between the investigational 
product administered and the AE. 
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be: 

No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days / weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned). 

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger. 

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a 
more likely explanation for the observed event than the drug concerned). 

Disappearance of the event even though the trial drug treatment continues or 
remains unchanged.
Responsibilities for SAE reporting to Boehringer-Ingelheim (BI)
The Sponsor shall report (i.e., from signing the informed consent onwards through the 
protocol specified follow-up period after discontinuing spesolimab) all SAEs and non-
serious Aes which are relevant for a reported SAE and Adverse Events of Special 
Interest (AESI) by fax or other secure method using BI IIS SAE form to the BI Unique 
Entry Point in accordance with timeline specified in the Safety Data Exchange 
Agreement. 
BI Unique Entry point for SAE/AESI reporting:
Effective Date: 2/27/2024
End Date:8/14/2024

19
Fax: 1-203-837-4329
SAE/AESI reporting timelines
•
within five (5) calendar days upon receipt of initial and follow-up SAEs containing 
at least one fatal or immediately life-threatening event;
•
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs 
and AESIs.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, causality and action taken with the BI study 
drug.  The investigator will determine the expectedness of the investigational drug to the 
Aes as defined in the Listed Adverse Events section of the Boehringer Ingelheim’s (BI’s) 
Investigator Brochure for the Product or Product Information (PI) for the authorized Study 
Drug provided by BI.
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial (including any protocol specified 
follow-up period), it should be reported to BI if investigator considers it as relevant to the 
BI study drug. 
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant 
after having taken trial medication, the Investigator must report immediately (within 24 
hours) the drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point. 
The Pregnancy Monitoring Form for Studies (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up and reported to the Sponsor’s unique entry point on the Pregnancy 
Monitoring Form for Studies (Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying 
SAE and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an 
SAE form must be completed in addition.
STUDY WITHDRAWAL:
In the event a study subject wants to withdraw early from the study for any reason, the 
subject will be asked to return for an Early Termination visit (see above for procedures). 
Table 2: TOTAL VOLUME OF BLOOD COLLECTED DURING THE STUDY:
Treatment 
Follow-
Up
Visit
1
Screening
2
Baseline
3, 5, 7, 8, 
9
4
6
10-13
Effective Date: 2/27/2024
End Date:8/14/2024

20
Blood + 
Serum  
23
32
15
20
23
23
Total 
volume
23
23
15
20
23
23
The total estimated blood volume is between 15 and 23 mL per month during treatment, 
and 23 mL per month during Follow-Up period. Additional volumes may be required for 
repeat testing or as part of unscheduled visits.
DISCONTINUATION OF TREATMENT AND WITHDRAWAL OF SUBJECTS:
The reasons why a subject may discontinue or be withdrawn from the study by the 
investigator include, but are not limited to the following: subject request, protocol violation, 
loss to follow up, subject non-compliance, significant worsening of subject’s disease, study 
termination by investigators, and a confirmed grade 3 or higher adverse event (using 
Common Terminology Criteria for Adverse Events), which is suspected to be related to 
test article administration. Subjects that elect to withdraw from the trial due to lack of 
efficacy and/or exacerbation of disease will undergo an Early Termination visit (see 
Procedure Section and Schedule of Events)
Stopping Rules
Patients will be permanently discontinued from study treatment in the event of:

Anaphylactic reaction or other severe systemic reaction to study drug injection

Pregnancy at any time during the study period 

Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, 
or squamous or basal cell carcinoma of the skin

Treatment with any prohibited concomitant medication or procedure

Any infection that is opportunistic, whose nature or course may suggest an 
immunocompromised status
Study drug dosing may be temporarily suspended in the event of:

Intercurrent illnesses or major surgery

An infection that requires systemic treatment with antibiotic, antifungal, antiviral, 
anti-parasitic, or anti-protozoal agents or requires oral treatment with such 
agents for longer than 2 weeks. Treatment of certain infections such as latent 
tuberculosis may be treated concurrently with spesolimab treatment 
Duration of study drug suspension should be reviewed on a case-by-case basis and can 
be discussed with the PI. 
In case of systemic hypersensitivity including infusion reactions and anaphylactic 
reaction, emerging during or after infusion/injection of study medication, the investigator 
should consider in accordance with severity of the reaction and local standard of care to:

Immediately interrupt the infusion/injection
Effective Date: 2/27/2024
End Date:8/14/2024

21

Treat with systemic anti-histamines, intravenous steroids, and in case of a severe 
allergic reaction (e.g., anaphylactic reaction) epinephrine

Blood draw for plasma sample of IgE and ADA/neutralizing antibody (Nab), serum 
tryptase, and complement components 
In case of systemic hypersensitivity including infusion reactions, based on patient’s 
clinical course and medical judgment, the infusion may be re-initiated in case of mild or 
moderate infusion reactions at lower speed with gradual increase to complete the 
infusion as detailed in the label. Regardless, the total duration of infusion should not 
exceed 180 minutes (3 hours).
Safety Evaluation
This is an open label, proof-of-concept study with an FDA-approved drug. Safety and 
tolerability will be evaluated from the AEs, limited physical examinations, and vital sign 
measurements. More frequent safety evaluations may be performed if clinically indicated 
or at the discretion of the investigator.
Aggregated AEs will be evaluated monthly by the PI/research teams.
Safety data will be reviewed by the investigators who will monitor the study on a regular 
basis and meet regularly (approximately once a month, depending on the number of 
subjects enrolled). The local IRBs, FDA, and Boehringer Ingelheim will be notified of 
adverse events (as required by each institution).
Physical Examination/Vital Signs
Qualified personnel will perform limited physical examinations, blood pressure and heart 
rate at each visit.  
Limited physical examination consists of assessments of general appearance; skin; head, 
eyes, ears, nose, and throat (HEENT); heart; lungs; abdomen; extremities; neurological 
function; and lymph nodes.
MEASURES TO MINIMIZE/AVOID BIAS: 
Subject Identification 
Subjects are numbered sequentially. Each subject screened (total of 25 screened) will be 
assigned a unique screening number for the duration of the study. Subject screening 
numbers will also become a subjects treatment number if they are enrolled in the study 
after providing informed consent and meeting inclusion criteria. Subjects who discontinue 
or withdraw from the study before receiving a treatment assignment code, but re-enroll at 
a later time must be assigned a new screening number. The investigator must maintain a 
master log linking the subject number to the subject’s name. The investigator must follow 
all applicable privacy laws in order to protect a subject’s privacy and confidentiality. 
INVESTIGATIONAL DRUG SUPPLY :
Effective Date: 2/27/2024
End Date:8/14/2024

22
Eligible participants will receive 900 mg intravenous spesolimab starting at Visit 2/week 
0/Baseline. All participants will receive a total of 8 or 9 infusions (depending on dosing 
frequency) through Week 28 or Week 26 (depending on whether the subject’s dosing 
frequency is increased  to every 3 weeks at Week 8), unless there is significant worsening.  
All subjects should be observed for 30 minutes following the infusion at Baseline to assess 
safety. Select cases will be offered the opportunity to continue treatment through Week 52 
on case-by-case basis if the patient would benefit from continued treatment. All subjects 
who have not been discontinued will be monitored once a month, for 4 months after 
treatment cessation. 
All study medication will be provided by Boehringer Ingelheim, refrigerated and stored 
between 2-8°C in a secure area. Study drug will be administered to subjects at each study 
visit in office. The investigative site will account for all study drug dispensed and stored 
during the study.
STATISTICAL CONSIDERATIONS:
Sample Size
This is a proof-of-concept, open-label trial. Twenty patients will be enrolled in the trial to 
demonstrate efficacy of spesolimab in a population of patients with moderate-severe, 
refractory PG. Although there is no formal power calculation, a sample size of n=20 
subjects allows 81% power at 2.5% significance for a one-sided binomial test to detect at 
Week 16 a difference of 36.6% in the proportion of GPG success compared to a constant 
set to be equal to 10%. The choice of the constant was based on data from a randomized 
clinical trial for efficacy of infliximab where a group of 17 PG placebo-treated patients 
showed 6% response at Week 2 (Brooklyn et al.,2006). 
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics of patients will be 
summarized with mean, median, and standard deviation for quantitative outcomes, and 
frequency and percentage tables for categorical outcomes.. Other baseline characteristics 
include sex, age, height, weight, vital signs, duration of PG, history of pathergy or PG 
trigger (if known), concurrent diagnoses from medical history and indications for 
concomitant medication, concomitant medication, and previous PG treatments.
Target Lesion Measurement and Digital Image Assessments 
Size of target PG lesion will be approximated at each visit by measuring the length, width 
and depth of the lesion. Target lesion will also be analyzed using Image J software to 
obtain a more precise surface area of each lesion using digital photographs taken at each 
visit. 
Analysis of Primary Endpoint
We will compare the proportion of patients achieving one-point decrease in target lesion 
GPG score at Week 16 with a constant p=0.10. Clopper-Pearson 90% confidence interval 
will be estimated.   
Analysis of Secondary Endpoints
Effective Date: 2/27/2024
End Date:8/14/2024

23

One sided Clopper-Pearson 90% confidence intervals will be estimated for the 
proportion of patients achieving re-epithelization (GPG Severity Score of 0) at Visits  
3, 4, 5 , 6, 7, 8, and 9 

We will apply a two-sided paired t-test to evaluate significance of the mean 
difference of GPG score at Week 16 versus Week 0.

Mean patient reported scores of pain (Pain VAS) and quality of life (DLQI) at 
baseline will be compared to those at Week 16 and treatment termination using the 
student’s t- test to compare between subject’s pre and post-treatment scores. 

One sided Clopper-Pearson 90% confidence intervals will be estimated for the 
proportion of patients with recurrence or worsening of PG lesions from point of 
complete re-epithelization or spesolimab cessation at end of treatment visit (Week 
28 or Week 26 depending on dosing frequency). 
Interim Analysis
An interim analysis will be performed after the first 10 subjects complete Week 16. We will 
continue enrollment during this time. Proportion of patients achieving one-point GPG score 
decrease will be reported. Changes from baseline at Week 16 in the PG lesions (number, 
size, GPG score) will be evaluated and reported. Enrolled subjects  will continue to receive 
treatments during this time.  
Data Transfer and Management
Data including the patient info, demographics, clinical scores will be stored in password-
protected files that will be shared only with investigators and a biostatistical team, if 
necessary. Data will be stored on secure Mount Sinai servers that may only be accessed 
by investigators listed on this protocol. 
Analysis of Safety and Tolerability
Safety will be evaluated by tabulations of adverse events (AEs) and will be presented with 
descriptive statistics at each visit. AEs will be coded using the CTCAE, Common 
Terminology Criteria for Adverse Events, V 4.0 and MedDRA. The number and percentage 
of subjects/lesions experiencing an AE/SAE will be stratified by system organ class, or a 
preferred term, and/or severity of the adverse event, and recorded and tabulated overall 
by each sub-strata. Each subject will be counted only once within a system organ class or 
a preferred term using the adverse events with the highest severity within each category. 
All information pertaining to adverse events noted during the study will be listed by subject, 
detailing verbatim given by the investigator, preferred term, system organ class, date of 
onset, date of resolution, severity, and relationship to treatment. A tabulation of AEs will 
be provided by subject. 
Effective Date: 2/27/2024
End Date:8/14/2024

24
Table 3. Schedule of Events Q4 Week Dosing Through Week 28
Visit Week
(Up to -28 
Days 
before 
Baseline
0
4
8
12
16
20
24
28
4 wk 
post-
spesoli-
mab last 
dose
8 wk 
post- 
spesoli-
mab last 
dose
12 wk 
post- 
spesoli=
mab last 
dose
16 wk 
post- 
spesoli-
mab last 
dose
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Type
Screen=
ing
Baseline
TX
TX
TX
TX
TX
TX
TX
F/Up
F/Up
F/Up
F/Up
Early Term 
(ET)
Additional 
Treatment 
Visits
Informed 
Consent
X
Inclusion/ 
Exclusion 
Criteria
X
X
Demographics/ 
Medical Hx1 
X
Limited 
Physical Exam
X
X
Vitals2
X
X
X
X
X
X
X
X
X
X
X
Serum Preg 
Test
X
Urine Preg Test
X
X
X
X
X
X
X
X
X
X
CBC 
w/differential, 
CMP and CRP
X
X
X
X
X
X
X
X
X
X
X
Screening for 
TB 
(Quantiferon 
Gold, or PPD), 
HIV, HepB and 
HepC
X
PG Clinical 
Assessments 
(including 
number 
location and 
measurements)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Global PG 
(GPG) Severity 
Score
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject PG 
Questionnaire 
and DLQI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Effective Date: 2/27/2024
End Date:8/14/2024

25
Visit Week
(Up to -28 
Days 
before 
Baseline
0
4
8
12
16
20
24
28
4 wk 
post-
spesoli-
mab last 
dose
8 wk 
post- 
spesoli-
mab last 
dose
12 wk 
post- 
spesoli=
mab last 
dose
16 wk 
post- 
spesoli-
mab last 
dose
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Type
Screen=
ing
Baseline
TX
TX
TX
TX
TX
TX
TX
F/Up
F/Up
F/Up
F/Up
Early Term 
(ET)
Additional 
Treatment 
Visits
Standardized 
Photographs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record and 
changes 
related to 
associated 
conditions 
(such as IBD, 
RA, etc) if 
applicable
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Cytokine 
Profile O-Link 
Inflammatory 
Panel
X
X
X
X
X
X
X
Pharmaco-
kinetics, 
ADA, NAb
X
X
X
X
X
Dispense Drug
X
X
X
X
X
X
X
X
Concomitant 
Medications
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
    1 Includes current and past medical conditions in addition to personal and family history of inflammatory bowel disease, rheumatoid arthritis, and autoimmune  
       conditions as well as history of myeloproliferative disorders and malignancy
2  Includes height and weight (only at screening), blood pressure, and pulse
3  Pre-dose PK, ADA, NAb samples will be obtained at selected visits (Visit 2, 4, 6, and 9 or ET). At Week 0/Visit 2, a post-dose PK samples will also be obtained    
   approximately 5 mins after end of i.v. infusion. 
  4  Record all concomitant medications at each visit, and at screening also collect any  medications taken within the last 30 days, and previous therapies/treatments  
      for PG  (including systemic and topical treatments, and invasive treatment such as surgery,  radiation and cryotherapy).
Effective Date: 2/27/2024
End Date:8/14/2024

26
Table 4. Schedule of Events Q4 Week Dosing through Week 8 Followed by Q3 Week Dosing Through Week 26 
Visit Week
(Up to -28 
Days 
before 
Baseline
0
4
8
11
14
16
17
20
23
26
4 wk 
post-
spesoli-
mab last 
dose
8 wk 
post- 
spesoli-
mab last 
dose
12 wk 
post- 
spesoli=
mab last 
dose
16 wk 
post- 
spesoli-
mab last 
dose
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Visit Type
Screen=
ing
Baseline
TX
TX
TX
TX
TX
TX
TX
TX
F/Up
F/Up
F/Up
F/Up
Early 
Term (ET)
Additional 
Treatment 
Visits
Informed 
Consent
X
Inclusion/ 
Exclusion 
Criteria
X
X
Demographics/ 
Medical Hx1 
X
Limited 
Physical Exam
X
X
Vitals2
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Preg 
Test
X
Urine Preg Test
X
X
X
X
X
X
X
X
X
X
X
X
CBC 
w/differential, 
CMP and CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening for 
TB 
(Quantiferon 
Gold, or PPD), 
HIV, HepB and 
HepC
X
PG Clinical 
Assessments 
(including 
number 
location and 
measurements)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Global PG 
(GPG) Severity 
Score
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject PG 
Questionnaire 
and DLQI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Effective Date: 2/27/2024
End Date:8/14/2024

27
Visit Week
(Up to -28 
Days 
before 
Baseline
0
4
8
11
14
16
17
20
23
26
4 wk 
post-
spesoli-
mab last 
dose
8 wk 
post- 
spesoli-
mab last 
dose
12 wk 
post- 
spesoli=
mab last 
dose
16 wk 
post- 
spesoli-
mab last 
dose
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Visit Type
Screen=
ing
Baseline
TX
TX
TX
TX
TX
TX
TX
TX
F/Up
F/Up
F/Up
F/Up
Early 
Term (ET)
Additional 
Treatment 
Visits
Standardized 
Photographs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record and 
changes 
related to 
associated 
conditions 
(such as IBD, 
RA, etc) if 
applicable
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Cytokine 
Profile O-Link 
Inflammatory 
Panel
X
X
X
X
X
X
X
Pharmaco-
kinetics, 
ADA, NAb 3
X
X
X
X
X
Dispense Drug
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
    1 Includes current and past medical conditions in addition to personal and family history of inflammatory bowel disease, rheumatoid arthritis, and autoimmune  
       conditions as well as history of myeloproliferative disorders and malignancy
2  Includes height and weight (only at screening), blood pressure, and pulse
3  Pre-dose PK, ADA, NAb samples will be obtained at selected visits (Visit 2, 4, 7 and 11, or ET). At Week 0/Visit 2, a post-dose PK samples will also be obtained    
   approximately 5 mins after end of i.v. infusion. 
  4  Record all concomitant medications at each visit, and at screening also collect any  medications taken within the last 30 days, and previous therapies/treatments  
      for PG  (including systemic and topical treatments, and invasive treatment such as surgery,  radiation and cryotherapy).
Effective Date: 2/27/2024
End Date:8/14/2024

28
Figure 3. Flow Diagram for Participants 
Effective Date: 2/27/2024
End Date:8/14/2024

29
REFERENCES
1 Alavi, A., French, L. E., Davis, M. D., Brassard, A., & Kirsner, R. S. (2017). Pyoderma 
gangrenosum: an update on pathophysiology, diagnosis and treatment. American journal of clinical 
dermatology, 18(3), 355-372.
2 Xu, A., Balgobind, A., Strunk, A., Garg, A., & Alloo, A. (2020). Prevalence estimates for pyoderma 
gangrenosum in the United States: an age-and sex-adjusted population analysis. Journal of the 
American Academy of Dermatology, 83(2), 425-429.
3 Cozzani, E., Gasparini, G., & Parodi, A. (2014). Pyoderma gangrenosum: a systematic review. G 
Ital Dermatol Venereol, 149(5), 587-600.
4 Langan, S. M., Groves, R. W., Card, T. R., & Gulliford, M. C. (2012). Incidence, mortality, and 
disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort 
study. Journal of investigative dermatology, 132(9), 2166-2170.
5 Koo, K., Brem, H., & Lebwohl, M. (2006). Pyoderma gangrenosum versus chronic venous 
ulceration: comparison of diagnostic features. Journal of Cutaneous Medicine and Surgery, 10(1), 
26-30.
6 Jockenhöfer, F., Wollina, U., Salva, K. A., Benson, S., & Dissemond, J. (2019). The 
PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. British Journal of 
Dermatology, 180(3), 615-620.
7 Min, M. S., Kus, K., Wei, N., Kassamali, B., Faletsky, A., Mostaghimi, A., & Lebwohl, M. G. 
(2022). Evaluating the role of histopathology in diagnosing pyoderma gangrenosum using Delphi 
and PARACELSUS criteria: a multicentre, retrospective cohort study. British Journal of 
Dermatology.
8 Henry, C. M., Sullivan, G. P., Clancy, D. M., Afonina, I. S., Kulms, D., & Martin, S. J. (2016). 
Neutrophil-derived proteases escalate inflammation through activation of IL-36 family 
cytokines. Cell reports, 14(4), 708-722
9 Schuppe, H. C., Homey, B., Assmann, T., Martens, R., & Ruzicka, T. (1998). Topical tacrolimus 
for pyoderma gangrenosum. The Lancet, 351(9105), 832.
10 Lebwohl, M. G., Heymann, W. R., Berth-Jones, J., & Coulson, I. (2013). Treatment of skin 
disease E-Book: comprehensive therapeutic strategies. Elsevier Health Sciences.
11 Brooklyn, T. N., Dunnill, M. G. S., Shetty, A., Bowden, J. J., Williams, J. D., Griffiths, C. E., ... & 
Probert, C. (2006). Infliximab for the treatment of pyoderma gangrenosum: a randomised, double 
blind, placebo-controlled trial. Gut, 55(4), 505-509.
12 Pomerantz, R. G., Husni, M. E., Mody, E., & Qureshi, A. A. (2007). Adalimumab for treatment of 
pyoderma gangrenosum. British Journal of Dermatology, 157(6), 1274-1275.
13 McGowan, J. W., Johnson, C. A., & Lynn, A. (2004). Treatment of pyoderma gangrenosum with 
etanercept. Journal of drugs in dermatology: JDD, 3(4), 441-444.
14 Spesolimab Package Insert, Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc, 2022.
15 Bachelez, H., Choon, S. E., Marrakchi, S., Burden, A. D., Tsai, T. F., Morita, A., ... & Lebwohl, M. 
G. (2021). Trial of spesolimab for generalized pustular psoriasis. New England Journal of 
Medicine, 385(26), 2431-2440.
16 Miller, J., Yentzer, B. A., Clark, A., Jorizzo, J. L., & Feldman, S. R. (2010). Pyoderma 
gangrenosum: a review and update on new therapies. Journal of the American Academy of 
Dermatology, 62(4), 646-654.
17 Ormerod, A. D., Thomas, K. S., Craig, F. E., Mitchell, E., Greenlaw, N., Norrie, J., ... & Williams, 
H. C. (2015). Comparison of the two most commonly used treatments for pyoderma gangrenosum: 
results of the STOP GAP randomised controlled trial. bmj, 350.
Effective Date: 2/27/2024
End Date:8/14/2024

30
18 Carrier, Y., Ma, H. L., Ramon, H. E., Napierata, L., Small, C., O'toole, M., ... & Medley, Q. G. 
(2011). Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications 
in psoriasis pathogenesis. Journal of Investigative Dermatology, 131(12), 2428-2437.
19 Yuan, Z. C., Xu, W. D., Liu, X. Y., Liu, X. Y., Huang, A. F., & Su, L. C. (2019). Biology of IL-36 
signaling and its role in systemic inflammatory diseases. Frontiers in immunology, 10, 2532.
20 Vigne, S., Palmer, G., Martin, P., Lamacchia, C., Strebel, D., Rodriguez, E., ... & Gabay, C. 
(2012). IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of 
naive CD4+ T cells. Blood, The Journal of the American Society of Hematology, 120(17), 3478-
3487.
21 Harusato, A., Abo, H., Ngo, V. L., Yi, S. W., Mitsutake, K., Osuka, S., ... & Denning, T. L. (2017). 
IL-36γ signaling controls the induced regulatory T cell–Th9 cell balance via NFκB activation and 
STAT transcription factors. Mucosal immunology, 10(6), 1455-1467.
22 Kolios, A. G. A., Maul, J. T., Meier, B., Kerl, K., Traidl‐Hoffmann, C., Hertl, M., ... & French, L. E. 
(2015). Canakinumab in adults with steroid‐refractory pyoderma gangrenosum. British Journal of 
Dermatology, 173(5), 1216-1223.
Effective Date: 2/27/2024
End Date:8/14/2024

31
Appendix 1. Clinician Assessment of Pyoderma Gangrenosum 
At each visit, the following assessments will be performed:
1. Photographs of target PG ulcer (and other PG ulcers present) 
2. Measure length, width, and depth target lesion
The following tools/questions have been adapted from various clinical studies for pyoderma 
gangrenosum and other dermatological conditions22-24.
Global Pyoderma Gangrenosum (GPG) Severity Score 
Assess subject GPG severity of target lesion at each visit by using below categories
I.
INFLAMMATION (adapted from Foss, C. et al 2008)1
Ulcer Border Erythema 
Point Value 
None; possible residual hyperpigmentation 
0
Slight: Pink to red color 
1
Mild: Red color  
2
Moderate: Deep red color
3
Severe: Violaceous/Grey 
4
Ulcer Border Elevation  
Point Value 
None; flat border in plane with surrounding skin 
0
Slight: border slightly elevated, <1 mm above ulcer base
 
1
Mild: Border noticeably elevated (1-2 mm) above ulcer 
base and surrounding skin 
2
Moderate: Border significantly elevated above ulcer base 
(2-5mm) 
3
Severe: Significant, rolled border >5 mm in any part of 
ulcer
4
Ulcer Purulence  
Point Value
None: dry ulcer base  
0
Slight Purulence 

minimal to no purulent drainage

dressing is dry at presentation and dabbing lesion 
with 4x4 gauze does not appreciably wet the 
gauze.

 No drops of purulence appreciated. 
1
Effective Date: 2/27/2024
End Date:8/14/2024

32
Mild Purulence 

Few 
drops 
purulence 
appreciated 
upon 
examination.

Dressings are damp at presentation and dabbing 
the wound with a 4x4 gauze wets the first layer of 
the gauze.
2
Moderate Purulence 

Ulcer bed covered with purulent drainage 

Dressings are wet at presentation and ulcer bed 
significantly wets a 4x4 gauze upon presentation. 
3
Severe Purulence 

Necrotic tissue may be present

Extensive purulent drops present on ulcer bed

Dressings soaked at presentation and soaks 4x4 
gauze when cleaned (can wet multiple 4x4 
gauzes). 
4
II.
RE-EPITHELIZATION 
% Active Ulcer Base
Point Value
0% Active Ulcer  
0
1%-25% Active Ulcer 
1
26-50 % Active Ulcer
2
51-75% Active Ulcer
3
76-100% Active Ulcer
4
% Granulation Tissue 
Point Value
Re-epithelization evident with cribiform scarring   
0
More than 90% granulation tissue with some re-
epithelization of skin evident 
1
Mostly granulation tissue without any evidence of re-
epithelization 
2
Some evidence of granulation tissue; mostly purulent ulcer 
3
No evidence of granulation tissue
4
III.
PG ULCER Diameter  
PG Ulcer Size  
Point Value
No ulcer
0
Lesion measures greater than 0 cm and less than or equal 
to 2 cm
1
Lesion measures greater than 2 cm and less than or equal 
to 4 cm
2
Lesion measures greater than 4 cm and less than or equal 
to 6 cm 
3
Lesion measures greater than 6 cm and less than or equal 
to 8 cm
4
Lesion measures greater than 8 cm and less than or equal 
to 10 cm 
5
Lesion measures greater than 10 cm 
6
Effective Date: 2/27/2024
End Date:8/14/2024

33
Final Calculation  
Sum of Points   
Target Lesion GPG Severity Score & Ulcer Description 
0-5
Completely Clear: 0

evidence of cribriform scarring, re-epithelization and 
possible residual hyperpigmentation. 0% ulceration 
apparent and lesion is dry
6-10
Almost Clear: 1

<25% of active ulceration present; more than 90% 
granulation tissue present with mild pink, slightly elevated 
borders. Some evidence of re-epithelization. Minimal to no 
purulent drainage at presentation; dressing is dry at 
presentation and dabbing lesion with 4x4 gauze does not 
appreciably wet the gauze. No drops of purulence 
appreciated. 
11-15
Mild: 2

<50% of active ulceration with perceptible border elevation 
with mild red border. Evidence of granulation tissue without 
any re-epithelization of skin. Few drops purulence 
appreciated upon examination. Dressings are damp at 
presentation and dabbing the wound with a 4x4 gauze wets 
the first layer of the gauze.
16-20
Moderate: 3

<75% active ulceration with marked red, rolled borders and 
significant purulence. Some evidence of granulation tissue 
with multiple purulent drops and significant purulence on 
ulcer bed at presentation. Dressings are wet at presentation 
and ulcer bed significantly wets a 4x4 gauze upon 
presentation. 
21-26   
Severe: 4

100% active ulcer with violaceous, raised rolled borders.  
Necrotic tissue may be present. No evidence of granulation 
tissue. Extensive purulent drops present on ulcer bed. 
Dressings soaked at presentation and soaks 4x4 gauze 
when cleaned (can wet multiple 4x4 gauzes). 
Effective Date: 2/27/2024
End Date:8/14/2024

34
Appendix 2. Patient Pyoderma Gangrenosum Questionnaires
The following tools/questions have been adapted from various clinical studies for pyoderma 
gangrenosum and other dermatological conditions22.
Patient Reported- “Ooze” or Purulence Measure 24
1. How often do you need to change your wound dressings in the past 4 weeks (circle the 
response that best applies to you)?
a. Multiple times per day 
i. How many times? ________
b. Daily
c. Every other day 
d. Every 3 days 
e. Once a week 
f.
I do not use dressings
i. If you no longer require dressings, how many days after treatment did you stop 
placing dressings on your lesion (in days)? ______
ii. I have never used dressings for the ulcers 
g. Other: ________
Patient Pain Visual Analogue Scale (VAS)  22 
Patients will be asked to report pain scores at each visit. Patients will report scores on a scale of 0 
to 10.
0 signifies no pain and 10 signifies the worst pain imaginable. Choose an integer whole number. 
Effective Date: 2/27/2024
End Date:8/14/2024

35
https://assessment-module.yale.edu/im-palliative/visual-analogue-scale
DLQI (Dermatology Life Quality Index)
The DLQI is a validated questionnaire consisting of 10 questions that has been used in many 
randomized controlled trials in dermatology. 22,22
Scoring
The scoring of each question is as follows:
Very much
scored 3
A lot
scored 2
A little
scored 1
Not at all
scored 0
Not relevant
scored 0
Question unanswered
scored 0
The DLQI is calculated by summing the score of each question. The maximum score is 30 and 
minimum score is 0. Higher score represents a quality of life that is more impaired.
Definition of DLQI Scores
0-1 = no effect at all on patient's life 
2-5 = small effect on patient's life 
6-10 = moderate effect on patient's life 
11-20 = very large effect on patient's life 
Effective Date: 2/27/2024
End Date:8/14/2024

3 6
2 1- 3 0 = e xtr e m el y l ar g e eff e ct o n p ati e nt' s lif e
A c h a n g e i n D L QI s c or e of at l e a st 4 p oi nt s i s c o n si d er e d cli ni c all y i m p ort a nt 2 2 . S u c h c h a n g e 
s u g g e st s t h at t h er e h a s a ct u all y b e e n a m e a ni n gf ul c h a n g e i n t h at p ati e nt' s q u alit y of lif e si n c e t h e 
pr e vi o u s m e a s ur e m e nt of hi s/ h er/t h eir D L QI s c or e s.
D er m at ol o g y Lif e Q u alit y I n d e x
T h e ai m of t hi s q u e sti o n n air e i s t o m e a s ur e h o w m u c h y o ur s ki n pr o bl e m h a s aff e ct e d 
y o ur lif e O V E R T H E L A S T W E E K.  Pl e a s e c h e c k o n e b o x f or e a c h q u e sti o n.
1.
O v er t h e l a st w e e k, h o w it c h y, s or e , p ai nf ul  or sti n gi n g  h a s y o ur 
s ki n b e e n ?
V er y m u c h
A l ot
A littl e
N ot at all




2.
O v er t h e l a st w e e k, h o w e m b arr a s s e d  or s elf c o n s ci o u s  h a v e y o u 
b e e n b e c a u s e of y o ur s ki n ?
V er y m u c h
A l ot
A littl e
N ot at all




3.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n i nt erf er e d wit h y o u 
g oi n g s h o p pi n g  or l o o ki n g aft er y o ur h o m e  or y ar d ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
4.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n i nfl u e n c e d t h e cl ot h e s  
y o u w e ar ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
5.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n aff e ct e d a n y s o ci al  or 
l ei s ur e a cti viti e s ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
6.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n m a d e it diffi c ult f or y o u 
t o d o a n y s p ort ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
Eff e cti v e D at e: 2/ 2 7/ 2 0 2 4
E n d D at e: 8/ 1 4/ 2 0 2 4

3 7
O v er t h e l a st w e e k, h a s y o ur s ki n pr e v e nt e d y o u fr o m w or ki n g  or 
st u d yi n g ?
y e s
n o


N ot r el e v a nt 
7.
If " N o", o v er t h e l a st w e e k h o w m u c h h a s y o ur s ki n b e e n a pr o bl e m at 
w or k  or st u d yi n g ?
A l ot
A littl e
N ot at all 
 


8.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur  
s ki n cr e at e d pr o bl e m s 
wit h y o ur p art n er  or a n y of y o ur cl o s e fri e n d s or r el ati v e s? 
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
9.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur  
s ki n c a u s e d a n y s e x u al 
diffi c ulti e s ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
1 0.
O v er t h e l a st w e e k, h o w m u c h of a pr o bl e m h a s t h e tr e at m e nt f or 
y o ur s ki n b e e n, f or e x a m pl e b y m a ki n g y o ur h o m e m e s s y, or b y 
t a ki n g u p ti m e ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
A p p e n di x 3 – A m e n d m e nt s
A m e n d m e nt # 1 A u g u st 1 0, 2 0 2 3
P a g e 1- A m e n d m e nt 1 J u n e 1 3, 2 0 2 3 a d d e d.
P a g e 2 – T a bl e of C o nt e nt s a d d e d A p p e n di x 1 A m e n d m e nt s p a g e 3 1 a n d r e vi s e d R ef er e n c e s t o 
p a g e 3 3
P a g e 8 a n d 9 – St u d y D e si g n O v er vi e w

Cl arifi e d l e n gt h of d o si n g p eri o d:
“ S u bj e ct s will r e c ei v e 9 0 0 m g of s p e s oli m a b i ntr a v e n o u sl y (I V) o v er 9 0 mi n ut e s e v er y 3 
w e e k s u ntil r e- e pit h eli z ati o n ( G P G S e v erit y S c or e 0) a n d r e gr e s si o n of t ar g et l e si o n, or 
t hr o u g h W e e k 1 5, w hi c h e v er i s s o o n er. S u bj e ct s will r e c ei v e tr e at m e nt f or a m a xi m u m of 1 5 
w e e k s.”

Cl arifi e d w hi c h s u bj e ct s will b e m o nit or e d d uri n g t h e F oll o w- U p P eri o d:
“ S u bj e ct s w h o r e a c h e d G P G s c or e 0 will t h e n b e m o nit or e d f or r e c urr e n c e of l e si o n s f or 4 
m o nt h s s u b s e q u e nt t o tr e at m e nt c e s s ati o n."
P a g e 1 3, 1 4 a n d 1 5 – Pr o c e d ur e s

Cl arifi e d l e n gt h of d o si n g p eri o d:
“ S u bj e ct s will r e c ei v e 9 0 0 m g I V s p e s oli m a b e v er y 3 w e e k s u ntil r e- e pit h eli z ati o n of s ki n 
a n d/ or G P G s e v erit y s c or e 0, or t hr o u g h W e e k 1 5, w hi c h e v er i s s o o n er. S u bj e ct s w h o 
a c hi e v e d G P G s c or e 0 will t h e n b e m o nit or e d o n c e a m o nt h, f or 4 m o nt h s aft er tr e at m e nt 
c e s s ati o n t o m o nit or r e c urr e n c e of l e si o n s a n d a d v er s e e v e nt s.”
Eff e cti v e D at e: 2/ 2 7/ 2 0 2 4
E n d D at e: 8/ 1 4/ 2 0 2 4

38

Clarified which subjects will be monitored during the Follow-Up Period:
o
If patient has seen full-epithelization of skin (GPG Score 0), patient will continue with 
follow-up phase of study.
o
If patient has not experienced any improvement or has experienced worsening of 
condition (rise in GPG score), patient will be considered a non-responder and be 
discontinued from the study
o
If patient has experienced a decrease in GPG score but not full-epithelization of skin 
(GPG Score 0), patient will be a partial responder and will be discontinued from the 
study, however, they may seek additional infusions outside of this study.  

Clarified that Week 16 is Visit 8

Revised Follow-Up period numbers to Visits 9-12 and added month 3. 
Page 20 Table 1: Total Volume of Blood Collected During the Study – Updated table with corrected 
visits and volume amounts. 
Page 22 Investigational Drug Supply – added that drug will be supplied for up to a total of 6 infusions. 
 
Amendment #2 December 21, 2023
Throughout document: Replaced “Guenin” with “Global”
Page 1- Amendment 2 October 19, 2023 added; Updated investigators
Page 2- Table of Contents revised paginations
Page 3- Background: corrected PARACELSUS score definition to subject with a score greater than 
or equal to 10 points instead of greater than 10 points 
Page 8- Objectives: removed time point of Week 16 
Page 8 – Endpoints: 

clarified primary endpoint one point decrease in GPG severity score at Visit 8 – one week 
post 6th infusion instead of week 16 . 

Removed references to Weeks and added only references to Visits. 

Added secondary endpoint Time to worsening (1 or more GPG point increase) of target PG 
lesion from spesolimab cessation 
Page 9. Study Design Overview:

Changed spesolimab dosing from every 3 weeks to every 4 weeks. Added a potential dose 
switch at week 8 if subject does not show improvement. Updated section with only Visits 
and not Weeks to reflect variable dosing schedules. 

Revised who will be discontinued from treatment: Only if subject significantly worsens while 
on treatment will they be removed from study and not receive the full 6 infusions. 

Added the collection of Pharmacokinetics, NAb, and ADA
Page 9 Inclusion Criteria:
Effective Date: 2/27/2024
End Date:8/14/2024

39

Corrected inclusion criteria PARACELSUS score must be greater than or equal to 10, 
instead of greater than 10 
Page 13 Procedures:

Clarified that all subjects will receive infusions of spesolimab every 4 weeks until Visit 4, at 
which time frequency can be increased to every 3 weeks for the remainder of the treatment 
period. All subjects will receive 6 infusions regardless of full-reepithelization, unless they 
experience worsening. Clarified that all responders will enter the 4-month follow-up period. 
Only patients who experience disease progression will be removed from the study and/or 
follow-up period to receive standard of care of PG. Clarified that  patients benefiting from 
treatment at week 28 but need more therapy to achieve wound closure may be eligible to 
continue on treatment (on case-by-case basis) to a maximum of 52 week after discussion with 
Boehringer Ingelheim trial team.

Screening: Added review of PARACELSUS criteria and determination of PARACELSUS 
score in screening Visit 1.

Screening:Added HIV screening and added an option to perform PPD in lieu of quantiferon 
gold.  

Visit 2: Added PK, ADA and NAb collections; removed the double entry of “vitals”

Visit 3 thru 7: removed references to “Weeks”; added urine pregnancy tests for females of 
child bearing potential; added PK, ADA and NAb collections

Visit 9: Clarified those that will enter follow-up (anyone who has not worsened)

Visit 10-13: Added assessment of associated comorbidities; added that subjects who 
worsen will be discontinued from Follow-Up.

Early Termination: Added urine pregnancy test for FOCBP; added assessment of 
associated comorbidities.
Page 20 Table 2 Total Volume of Blood Collected

Removed references to Week #s; split Visits 3-6 to Visits 3, 5, 7, 8, 9 and Visit 4 and Visit 6; 
updated the total amount of blood collected at Baseline and Visit 8; updated follow up visits 
to Visits 10-13. 
Page 20 Discontinuation of Treatment: 

Defined subject disease worsening as a reason for discontinuation of treatment. 
Page 22 Investigational Drug Supply: 

Added language to include dose frequency switch possibility at week 8 for patients who 
experience progression of disease. 

Added that drug will be supplied by Boehringer Ingelheim
Page 22-23 Statistical considerations:

Updated section to match revised endpoints.

Removed references to Weeks and included only Visits
Changed secondary endpoint week numbers to reflect dosing frequency change from every 
3 to every 4 weeks with potential to switch after week 8 to every 3 week. 
Revised “Patients” to “Subjects”

Included explanation of power analysis in sample size section

Updated description of descriptive statistics section
Effective Date: 2/27/2024
End Date:8/14/2024

40

Updated Primary and Secondary endpoints sections to include description of paired t-test, 
CI and p-value. 
Page 23 Analysis of Secondary Endpoints

Updated to include Visit #’s 
Page 25-28 Schedule of Events Table(s)

Added second schedule of events table: ‘Table 4 Schedule of Events Q4 Week Dosing 
through Week 8 Followed by Q3 Week Dosing Through Week 26’

Updated Week #s. 

Added HIV at Screening

Added option of PPD at screening in lieu of quantiferon gold. 

Removed urine pregnancy tests during follow-up

Added PK, ADA, and NAb sample collections at Baseline, and Visits 4, 6 and 9 (Table 3) or 
at Baseline and Visits 4, 7 and 11 (Table 4). 

Replaced “Guenin” with “Global”

Added footnote regarding PKs, ADA and NAb for Table 3: “Pre-dose PK, ADA, NAb 
samples will be obtained at selected visits (Visit 2, 4, 6, and 9 or ET). At Week 0/Visit 2, a 
post-dose PK samples will also be obtained approximately 5 mins after end of i.v. infusion.” 
and for Table 4: “Pre-dose PK, ADA, NAb samples will be obtained at selected visits (Visit 2, 
4, 7 and 11, or ET). At Week 0/Visit 2, a post-dose PK samples will also be obtained 
approximately 5 mins after end of i.v. infusion.”
Page 29: Corrected Figure 3 with “Visits” and updated outcome measures 
Page 26: updated description of GPG
Page 32 Appendix 1:

Updated GPG Severity score name from ‘Guenin’ to ‘Global’

Updated last category of final calculation sum of points
Effective Date: 2/27/2024
End Date:8/14/2024