An Open-label Proof of Concept Study Regarding the Use of Secukinumab (Cosentyx) in Patients With Necrobiosis Lipoidica Diabeticorum (NLD)
Phase: PHASE2
Conditions: Necrobiosis Lipoidica Diabeticorum
Sponsor: Beth Israel Deaconess Medical Center

 
PROTOCOL DOCUMENT WITH STATISTICAL ANALYSIS INCLUDED 
 
 
Title: Secukinumab for NLD (Cosentyx) in Patients With Necrobiosis 
Lipoidica Diabeticorum (NLD) 
 
 
NCT: NCT03791060 
 
 
Document Date: 11-10-2020 

(CCI) Committee on Clinical Investigations 
Page 1 of 19 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
An open-label proof of concept study regarding the use of Secukinumab 
(Cosentyx) in patients with necrobiosis lipoidica diabeticorum (NLD) 
 
Principal Investigator 
Martina Porter, MD 
 
 
 
B1. 
PURPOSE OF PROTOCOL 
The objective of this study is to evaluate whether the IL-17 inhibitor, secukinumab shows evidence of efficacy 
in the treatment of Necrobiosis Lipoidica Diabeticorum (NLD).  
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Background: 
Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous condition of the skin that is over-
represented in patients with diabetes.  Classically, this condition presents with papules and plaques, most 
commonly on the distal extensor lower extremities. These plaques can become atrophic over time displaying a 
characteristic yellow hue, and may subsequently ulcerate. Although in many patients the lesions are not 
painful, in approximately 25% of patients the lesions can be very painful, particularly among patients who 
develop ulcerations.  
 
The nature of the relationship between NLD and diabetes mellitus is poorly understood. The incidence of NLD 
in people with diabetes mellitus is estimated to be 0.3% to 1.2%.  Initial studies from the 1960’s suggested 
that approximately 60% of patients with NLD also had diabetes, however subsequent studies reported lower 
estimates of diabetes in patients with NLD (11%), and further epidemiologic studies have not been performed.  
 
The condition may be challenging to manage, as currently no FDA-approved treatment exists, and no well-
established treatment algorithm has been described. Reports on successful therapeutic interventions have 
generally been small and inconsistent.  
 
The pathogenesis of NLD is poorly understood, however associations with vascular changes and immune 
dysregulation have been explored. Recent literature has suggested a potential role for IL-17 in the 
development of this condition.  In 2012, Wakusawa et al reported a case of a 37 year old woman with NLD and 
insulin dependent diabetes mellitus. Immunohistochemical staining was performed on a biopsy specimen and 
revealed a significant number of IL-17 positive cells present throughout the granuloma. [1] 
 
Kato et al subsequently reported a 66 year old woman with typical clinical and histopathological features of 
NLD without diabetes mellitus. [2] In their report, immunohistochemical staining found IL-17 expression 
present in lymphocytes, macrophages, multinucleated giant cells, and a high density of IL-17 expressing T-cells 
in granulomatous regions and around blood vessels.  Together these cases suggest that NLD may be an 
inflammatory disorder involving TH17 cells and that vessels may be the target of inflammation. This may, in 
part explain, previous reports of patients with NLD who have been successfully treated with TNF-alpha 
antagonists. Finally, Wakatsuki has reported a patient with concurrent NLD and palmoplantar pustulosis (PPP). 
Immunohistochemistry performed on biopsy specimens found IL-17 producing cells densely associated with 
NLD lesions, as well as PPP lesions. 
 
 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
 
Rationale: 
The reports described above suggest a possible role for IL-17 in the pathogenesis of NLD, and raise the 
possibility that blockade of IL-17 may be a potential therapeutic strategy in patients with NLD. Secukinumab is 
a human monoclonal antibody that targets IL-17a, approved by the FDA for the treatment of psoriasis. Several 
phase III studies have found this medication to be largely safe with nasopharyngitis and headache reported as 
the most frequently observed adverse events.  
 
An open-label proof of concept study regarding the use of secukinumab in patients with NLD may be a first 
step in elucidating and defining a definitive treatment for this chronic and potentially debilitating condition for 
which no FDA approved treatment currently exists.  
 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
Study Design 
This study is a non-randomized, open-label, proof of concept study.  Eighteen patients aged 18 and over with 
histopathologically-proven NLD will be included in a prospective non-controlled study. Dosage of Secukinumab 
will be given according to the standard therapy regimen for psoriasis (300 mg q weekly for 5 weeks followed 
by 300 mg q 4 weeks).  The study compromises a 2-week screening period, a 24-week open-label study period, 
and a 12-week follow-up period. The follow-up period consists of a phone call 16 weeks after the last study 
drug dose. 
 
Population 
Patients potentially eligible for this study are at least 18 years of age and have histologically 
confirmed necrobiosis lipoidica diabeticorum. A total of 18 subjects will be enrolled in the study. 
Potential patients will be assessed for eligibility to participate in this clinical study using the criteria 
for inclusion and exclusion listed under “Subject Selection” section.  
 
Methods 
Study Endpoints: 
1. Primary Endpoint 
- 
Proportion of patients achieving remission or clinical improvement based on Investigator 
Global Assessment Score as measured at week 24.  
 
2. Secondary Endpoints 
- 
Proportion of subjects achieving improvement based upon histological score 
- 
Proportion of subjects improving based upon patient-reported outcomes (pain score and 
Dermatology Quality of Life Index Score) 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
Investigator Global Assessment (IGA) of Efficacy Score (See Investigator Global Assessment of 
Efficacy Score) 
(adapted from scoring system for published pyoderma gangrenosum trials) 
Score 
Description 
0 
Completely clear: except for possible residual hyperpigmentation 
1 
Almost clear: very significant clearance (about 90%); however, patchy remnants of 
dusky erythema and/or very small ulcerations 
2 
Marked improvement: significant improvement (about 75%); however, a small 
amount of disease remaining (i.e. remaining ulcers, although have decreased in size, 
minimal erythema and/or active boarder) 
3 
Moderate improvement: intermediate between slight and marked; representing 
about 50% improvement 
4 
Slight improvement: some improvement (about 25%); however, significant disease 
remaining (i.e. remaining ulcers with only minor decrease in size, erythema or 
boarder activity) 
5 
No change from baseline 
6 
Worse 
Scoring system based on the following trial [4]:  
An open-label pilot study of alefacept for the treatment of pyoderma gangrenosum. European 
Academy of Dermatology and Venereology 2008 22, pp943–949 
 
Histological Score 
 
a. 
Inflammatory infiltrate (0, none; 1, slight; 2, moderate; 3, severe) 
b. 
collagen degeneration (0, none; 1, slight; 2, moderate; 3, severe) 
c. 
epithelioid histiocytes, (0, none; 1, slight; 2, moderate; 3, severe) 
d.  
qualitative expression of IL-17 (0, none;  1, slight; 2 moderate; 3, severe) 
 
Scoring system based on the following trial [5]:  
Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study. British 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
Journal of Dermatology 2005 153, pp802–807 
 
Patient-Reported Outcomes 
Pain Score 
 (i) 
Resolved 
(ii) 
Improved 
(iii) 
Stable 
(iv) 
Worsened  
 
Dermatology Life Quality Index (DLQI) 
A Quality of Life Score will be calculated based upon the Dermatology Life Quality Index (DLQI).    
The DLQI is a validated general dermatology questionnaire that consists of 10 items that assess 
subject health-related quality of life (daily activities, personal relationships, symptoms and feelings, 
leisure, work and school, and treatment) (See Dermatology Life Quality Index). [7] It has been 
extensively used in dermatology clinical trials for AD. The DLQI is a psychometrically valid and reliable 
instrument that has been translated into several languages, and the DLQI total scores have been 
shown to be responsive to change. The minimally important difference for the DLQI 
has been estimated as a 2 to 5 point change from baseline.  
 
Other study parameters 
Safety Parameters 
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, and 
clinical laboratory testing (hematology and chemistry) as a measure of safety and tolerability for the entire 
study duration. 
At every visit adverse events will be registered.  
 
Randomization, blinding and treatment allocation 
This is an open-label proof of concept study. There will be no randomization or blinding.  All subjects 
will receive study treatment.   
 
Study Procedures 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
Prior to performing any study related procedures, the investigator will discuss with each subject the 
nature of the study, its requirements and its restrictions. A written informed consent form will be 
obtained from each participant prior to any procedure.   
 
Each subject with a signed informed consent form will be screened at the first visit, to ensure all the 
inclusion criteria are met and none of the exclusion criteria.  
 
Study procedures are described in detail below and an overview of the study procedures during each 
visit. 
Medical history 
• A complete medical history, including history of diabetes, will be taken at screening. The 
subject's medical history will be updated at the Baseline visit. This updated medical history 
will serve as the baseline for clinical assessment. 
 
• Demographic information, including subject self-reported gender, race, age, ethnicity, and 
child-bearing potential will be recorded. 
 
• Nicotine and alcohol history will be obtained 
 
• NLD history: Date of onset of NLD, all previous and current medical and procedural 
treatments for NLD, and reasons for discontinuation or outcomes of previous treatments will 
be obtained. 
 
Vital signs 
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature 
will be obtained at visits as specified in the Overview of Study Procedures.   Blood pressure and pulse 
rate should be measured after the subject has been sitting for at least 3 minutes. 
 
Complete Physical exam, including height and weight.  
Height will be measured at screening only.  Body weight will be measured at all scheduled visits as 
specified in Overview of Study Procedures. The subject will wear lightweight clothing and no shoes 

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Study Description – Part B 
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PI Revision Date: 11-10-2020 
 
during weighing. A complete physical examination, including cutaneous examination to evaluate for 
skin malignancies, will be performed at the designated study visits as specified in Overview of Study 
Procedures. The physical examination performed on Study Day 0 will serve as the baseline physical 
examination for the entire study. If appropriate, a targeted physical exam should be performed at 
any other visit (e.g., to evaluate a reported adverse event). Any significant physical examination 
findings after the first dose will be recorded as adverse events, while any findings prior to the first 
dose will be recorded as medical history. All findings, whether related to an AE or part of each 
subject's medical history, will be captured on the appropriate AE report form. At any time, a 
symptom‐directed physical examination can be performed as deemed necessary by the Investigator. 
 
Efficacy assessment:  
IGA of Disease Severity will be performed by the investigator.  Patient-reported outcomes, including 
DLQI and Pain score, will be administered to subjects as subject questionnaires prior to any 
assessment of disease severity or laboratory testing.  See Overview of Study Procedures for schedule 
and Study Parameters for further details on efficacy assessments. 
 
Laboratory Testing 
Blood samples will be collected at scheduled visits as listed in Overview of Study Procedures.  A 
certified laboratory at Beth Israel Deaconess Medical Center (BIDMC) through the Clinical Research 
Center will be utilized to process and provide results for the clinical laboratory tests. 
Laboratory reference ranges will be obtained prior to the initiation of the study. The Baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug. 
 
Whether action needs to be taken to address notable laboratory values will be decided by the investigator, 
taking into account the overall status of the subject.  
 
The following laboratory tests will be performed according to the study procedures schedule listed in 
Overview of Study Procedures: 
 
• Complete Blood Count (CBC):  automated WBC, RBC, hemoglobin, hematocrit, platelet count 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
and RBC indices 
• Complete Metabolic Panel (CMP):  Sodium, Potassium, Chloride, Bicarbonate, BUN, 
Creatinine, Glucose, Alk Phos, ALT, AST, Total Bilirubin, GGT, Albumin, Albumin/Globulin Ratio 
(calculated), BUN/Creatinine Ratio (calculated), Calcium, Globulin (calculated), Total Protein 
• HIV: HIV1&2 Antibody/Antigen Combo Assay 
• Hepatitis B: Hep B Core Ab (Hep B Cab), Hep B Surface Antigen (Hep B Sag), and Hep B surface 
antibody (Hep B Sab) 
• Hepatitis C: Hepatitis C antibody 
• Tuberculosis: Quantiferon-TB Gold 
Subjects who test positive for TB (quantiferon gold), Hepatitis C antibody, or Hepatitis B Sag or 
Hepatitis B Core antibody will be excluded from the study. Patients with a positive quantiferon gold 
will be referred to ID. If a patient has an indeterminate quantiferon gold that test will be repeated. If 
there are two indeterminate quantiferon gold results, then the patient will be referred to ID. If ID 
thinks the patient (with an indeterminate quant gold) needs to be treated for latent TB, then the patient 
will be treated for latent TB (see below). If ID does not think the patient (with an indeterminate quant 
gold) needs treatment for latent TB then the patient will be eligible to enroll in the clinical trial 
 
After one month of treatment for latent TB, a subject would be considered eligible for participation in 
the trial.  
 
Skin Biopsy 
A 4 mm punch biopsy will be obtained from lesional skin at the baseline and week 26 visit.  Skin 
biopsy location will be determined by the investigator and standard procedures for skin biopsy will 
be employed.  Subjects may have lesions closed with suture or gelfoam, depending on nature of 
lesion and biopsy.   
 
Skin biopsies will be sent to Dermatopathology lab at BIDMC for further Immunohistochemistry 
analysis as below.  Samples will be preserved in formalin jars and sent to the histology lab to be 
processed within 48 hours.   The paraffin blocks will be sectioned and stained at the histology lab, 
and then blocks and slides will be returned to the Dermatopathologist and stored securely at BIDMC, 
Dept of Pathology. Samples are retained for the duration of the project, through publication.  If all 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
members of the study team deem they are no longer needed, they will then be destroyed.  
 
Immunohistochemistry 
Each biopsy will be fixed in formalin, bisected vertically, dehydrated by routine histologic methods, 
and embedded in a paraffin block.  5-µm-thick surface sections will be cut, mounted on glass slides, 
and baked for 60 minutes at 60C.  The first slide will be stained with Hematoxylin and Eosin. The next 
slide will be loaded into the Bond III staining platform and antigen retrieved by immersion in Bond 
Epitope Retrieval 2 for 30 minutes. It will then incubated at room temperature for 30 minutes with 
Anti-Human IL17A antibody [Abcam 4K5F6] at a concentration of 0.5–10 μg/ml.  After appropriate 
washes, antibody detection will be performed using Bond Polymer Refine Detection kit.  Slides will be 
developed in DAB, then dehydrated and coverslipped.  A biopsy of an active psoriatic skin lesion and 
a slide of the case with no antibody applied will be run in parallel as positive and negative controls, 
respectively. 
 
Evaluation of immunohistochemistry 
IL-17A expression levels will be scored as follows:  A three tier stratification threshold for percentage 
of positive lymphocytes will be established after review of the pre-treatment biopsies, and classified 
as absent, low, or high.  Cellular staining intensity will be scored as 0 (no staining), 1 (weak staining), 
2 (moderate staining), or 3 (strong staining). 
Pre- and post-treatment expression levels will be compared using Fisher’s exact test. Pre-treatment 
IL17A expression level will be compared with clinical response parameters and evaluated as a 
possible predictor of response to therapy. 
 
In case of an adverse event or disease progression, patients are instructed to call and/or visit the 
clinic trials unit at Beth Israel Deaconess Medical Center. Any visits will be recorded on source 
documentation as Unscheduled Visits.  Any o fthe procedures may be performed at an unscheduled 
visit at the discretion of the investigator.  
 
Follow up phone call at Week 36 
Study personnel will call subjects to collect information regarding the status of any ongoing AEs/SAEs 
or the occurrence of any new AEs/SAEs since last study visit. 

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Study Description – Part B 
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PI Revision Date: 11-10-2020 
 
 
EARLY TERMINATION VISIT 
If a subject is withdrawn from the study for any reason, including withdrawing informed consent, 
he/she will be asked to return for an early termination visit within 2 weeks of being withdrawn from 
the study.  Procedures performed at Early Termination Visit will be identical to Week 26 visit. 
 
Treatment of Subjects 
Investigational Treatment: Secukinumab (Cosentyx)  
Secukinumab (Cosentyx) is a human monoclonal antibody that targets IL-17a and is FDA-approved for 
the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recent literature expanding 
on the previously poorly understood pathogenesis of NLD has suggested a potential role for IL-17 in 
the development of this condition. Thus blockade of IL-17 may be a potential therapeutic strategy in 
patients with NLD 
Dosage 
Dosage of Secukinumab will be given according to the standard therapy regimen for psoriasis and 
administered for 24 weeks. Each subject will receive 300mg of Secukinumab by using 2 syringes of 
150mg each as a subcutaneous injection at weeks 0,1,2,3,4 then every 4 weeks for a total of 9 doses 
over 24 weeks.  Medication will be administered during scheduled study visits by study personnel. 
Use of Co-intervention 
Co-medication 
A full list of current medication, including over-the counter medicines, will be noted for each subject 
at time of screening visit and will updated at each visit in their medical chart/report form. 
Analgesic Therapy 
If a subject develops more than transient pain or the subject’s pain increases after starting 
treatment, they are allowed to start analgesic therapy. In case of NLD-related pain, the subject will 
be asked to report this at the next visit.  
Exacerbation/Intervention 
In case exacerbations of NLD lesions occur in the treatment areas and an intervention is required, the 
investigator may decide to treat with standard therapies not anticipated to decrease size of active 
areas such as antibiotics.  Use of any of the prohibited treatments listed below could that could 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
confound the efficacy assessment are NOT allowed during the study.  If the subject requires 
treatment with any of the prohibited treatments listed below, the subject should be discontinued 
from the study treatment will proceed to an early termination visit. 
Any medication or surgical treatment that will be used to treat AEs will be recorded on the electronic 
case report forms (eCRF). 
Prohibited Therapy 
The treatments listed below are prohibited for all subjects during the study: 
 
Any investigational agent 
 
Any immunosuppressive systemic therapy started within 28 days prior to baseline, including 
but not limited to oral corticosteroids, adalimumab or other biologic agent, etc. 
 
Surgical intervention on the treatment areas 
Investigational Product/Study Drug 
Secukinumab (Cosentyx) 
Secukinumab (Cosentyx) is a human monoclonal antibody that targets IL-17a and is FDA approved for 
the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis.     
 
COSENTYX injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly 
yellow solution. COSENTYX is supplied in a single-use Sensoready pen with a 27-gauge fixed ½-inch 
needle, or a single-use prefilled syringe with a 27-gauge fixed ½-inch needle. The removable cap of 
the COSENTYX Sensoready pen or prefilled syringe contains natural rubber latex. 
 
Each COSENTYX Sensoready pen or prefilled syringe contains 150 mg of secukinumab formulated in: 
Lhistidine/histidine hydrochloride monohydrate (3.103 mg), L-methionine (0.746 mg), polysorbate 80 
(0.2 mg), trehalose dihydrate (75.67 mg), and Sterile Water for Injection, USP, at pH of 5.8. 
 
Secukinumab will be supplied by the sponsor, Novartis, and will be packaged in quantities sufficient 
to accommodate study design.  Each kit will be labeled per local requirements and this label must 
remain affixed to the kit.  Upon receipt, study drug should be stored as specified on the label in their 
original packaging and kept in a secure location. A temperature log will be maintained for 
documentation in the research pharmacy.  Administration of the study drug will be recorded by study 

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Study Description – Part B 
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PI Revision Date: 11-10-2020 
 
personnel at scheduled study visits.  
Summary of findings from clinical and non-clinical studies 
Secukinumab is a recombinant human monoclonal IgG1/κ antibody that binds specifically to IL-17A. It 
is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. Secukinumab has a molecular 
mass of approximately 151 kDa; both heavy chains of secukinumab contain oligosaccharide chains.  
Please refer to the local label available to you for information regarding the efficacy and safety of this 
product. 
 
Overview of Study Procedures: 
Evaluation Schedule: 
Activity 
Screening  
BASELINE/WK0 
Wk1 
Wk2 
Wk3 
Wk4 
Wk8 
Wk12 
Wk16 
Wk20 
Wk24 Wk26* 
Follow 
Up Call 
(Wk 
36) 
 
 Informed consent 
 
Demographics 
 
 Medical history 
 
 
Nicotine use and alcohol 
history
 
NLD history 
 
Eligibility criteria 
 
 
Prior/concomitant therapy 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
 
Exam, including height and 
weight
 
 
 
 
 
 
 
Adverse event assessment 
 
 
 
 
 
 
 
 
 
 
 
IGA of disease severity 
 
 
 
 
 
 
 
 
 
 
 
Pain Score 
 
 
 
 
 
 
 
 
 
 
 
DLQI 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for 
women of childbearing 
potential 
 
 
 
 
 
 
 
 
 
 
 
CMP & CBC 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B (Hep B Sag, 
Hep B Sab, Hep B Cab) and 
Hepatitis C Screening (Hep 
C ab) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Digital photography of 
l
i
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Description – Part B 
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Skin biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suture removal* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Secukinumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
* = if suture is placed following skin biopsy 
 
Multi-Site: Joslin Diabetes Center 
The Co-Investigator at Joslin Dr. Giulio Romeo will be responsible for generating a list of patient MRNs with 
NLD diagnosis in their records. The list will generate a list of patients seen at Joslin as well as BIDMC. The list 
will be shared with BIDMC study team, who will then contact the patients via letters. Patients will be pre-
screened by BIDMC study team only. Patient study visits will take place at BIDMC and Dr. Romeo will not be 
involved in the study visits at BIDMC. Patients study related records will only be stored at BIDMC and not 
shared with Joslin or Dr. Romeo.  
After study completion follow up call: 
We want to call patients who have completed the study (n=3) and had an early termination (n=1) for a follow 
up call. We will ask them general question about well-being, any side effects, and option to send photos of 
their NLD lesions. Patients can send photo to secure telederm or clinical trials email account.  
B. 
Statistical Considerations 
Sample Size Calculation 
A sample size calculation is not applicable, for this is an early feasibility and tolerability pilot study. 
Data/statistical analysis 
Study Parameters 
The clinical efficacy will be measured by physician assessments and standardized scoring tools as 
noted in Main Study Parameters and Secondary Parameters.  Because of the small number of 
patients in the study, and absence of a control group, primarily descriptive statistics will be used to 
report data from measured endpoints. 
Main Study parameters 
Primary Endpoint 
• 
Proportion of patients achieving remission or clinical improvement based on Investigator Global 
Assessment Score as measured at week 24.  
We will assess the proportion of patients achieving remission or clinical improvement based upon 
the previously published Investigator Global Assessment Score. Remission correlates with a score of 0 
or 1 and clinical improvement correlates with at least a -1 change from baseline.  
 
Secondary study parameters 

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Study Description – Part B 
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PI Revision Date: 11-10-2020 
 
Secondary Endpoints 
Because of the small sample size, primarily descriptive statistics will be used. 
• Proportion of subjects achieving improvement based upon histological score 
• Proportion of subjects achieving improvement based upon patient-reported outcomes (pain 
score and Dermatology Quality of Life Index Score) 
Other study parameter(s) 
Patient characteristics and demographic data will be presented using descriptive statistics. 
Histological Score 
In addition, a histological score will be calculated as a secondary endpoint. The score is calculated by 
adding sub scores as listed below, which will be evaluated by the dermatopathologist.  Average of 
pre and post scores and overall change in score will be calculated and compared using a paired T-
test.  See Secondary Study Parameters for details regarding histologic analysis. 
Pain Score 
A Pain Score will be calculated based upon the Wong-Baker 10-point pain score, which has been 
widely used to rate pain in both children and adults and has also been used in dermatology clinical 
trials.[6] 
Response based on an improvement from baseline in the Wong-Baker pain score at all scheduled 
time points will be calculated. We will compare pre and post treatment pain values and categorize 
patients as  
Dermatology Life Quality Index (DLQI) 
A Quality of Life Score will be calculated based upon the Dermatology Life Quality Index (DLQI).    
 
 
 
 
 
 

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Study Description – Part B 
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PI Revision Date: 11-10-2020 
 
C. 
Subject Selection 
Inclusion Criteria 
A subject must meet all of the following criteria in order to be eligible to participate in this study: 
1. Adults, age 18 and over 
2. Previous diagnosis of biopsy-proven NLD  
3. Active NLD lesions, defined as 
(i) clinical signs of inflammation, for example erythematous margins, sensations of itch, pain, 
dysaesthesia  
(ii) lesions increasing in size or appearance of new lesions within the last 3 months  
(iii) ulcerations 
4. Subjects must be able to understand and communicate with the investigator and comply with 
the requirements of the study and must give a written, signed and dated informed consent 
before any study related activity is performed. 
Exclusion Criteria 
Eligible subjects will be excluded from participation if they meet any of the following criteria: 
1. History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis 
infection as defined by a positive QuantiFERON TB-Gold test at screening.  
2. Are currently pregnant, breastfeeding, or planning to get pregnant during the study. 
3. Previous hypersensitivity reaction to secukinumab or to any of the components.  
4. History of Inflammatory Bowel Disease (Crohn’s Disease or Ulcerative Colitis) 
5. Allergy to Latex  
6. Currently on any other immunosuppressant systemic medication or within 28 days of 
baseline visit 
7. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unwilling to use effective contraception during the study and for 16 
weeks after stopping treatment.  Methods of acceptable birth control are listed below 
under “Women of Childbearing Potential” 
8. Subjects with a serum creatinine level exceeding 176.8 μmol/L (2.0 mg/dL) 
9. Screening total WBC count <2,500/μL, or platelets <100,000/μL or neutrophils <1,500/μL or 
hemoglobin <8.5 g/dL 
10. Known infection with HIV, hepatitis B or hepatitis C at screening or randomization.  Patients 
who are Hepatitis B Core antibody and/or Hep B Surface Antigen positive will be excluded 
from this study.  Patients who are Hepatitis C ab positive will also be excluded from this 
study. 
11. History of lymphoproliferative disease or any known malignancy or history of malignancy of 
any organ system within the past 5 years (except for non-melanoma skin cancer and 
carcinoma in situ of the cervix) 
12. Are participating in another study using an investigational agent or procedure during 
participation in this study or within 28 days prior to baseline visit.  
13. Plans for administration of live vaccines during the study period or 6 weeks prior to randomization 
14. Any other procedural treatment for NLD with 28 days prior to baseline visit, including 
phototherapy, surgical intervention, laser therapy, or cryotherapy. 
15. Any other active skin disease or condition (e.g., bacterial, fungal or viral infection) that may 
interfere with assessment of NLD; 
16. Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, 
pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
opinion of the investigator significantly immunocompromises the subject and/or places the 
subject at unacceptable risk for receiving an immunomodulatory therapy 
Women of Childbearing Potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unwilling to use effective contraception during the study and for 16 weeks after stopping 
treatment. Effective contraception is defined as one of the following: 
• 
Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal) associated with inhibition of ovulation 
• 
Progestogen-only hormonal birth control (oral, injectable, transdermal) associated 
with inhibition of ovulation 
• 
Bilateral tubal occlusion/ligation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS ). 
• 
Vasectomized sexual partner(s) (the vasectomized partner should have received 
medical assessment of the surgical success and is the sole sexual partner of the trial 
participant). 
• 
True abstinence: Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable). 
 
 
 
  
 
 
B4. 
POSSIBLE BENEFITS 
It is not possible to predict whether you will benefit directly from participation in this study.  
However, your participation may help others in the future as a result of knowledge gained from the 
research. 
 
 
 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
RISKS AND DISCOMFORTS 
Summary of known and potential risks and benefits. 
Benefits: there are no FDA-approved treatments for NLD.  Subjects enrolled in this study may 
improve with study treatment.  It is not possible to predict whether subjects will benefit directly from 
participation in this study.  However, subject participation may help others in the future as a result of 
knowledge gained from the research. 
 
Infections  
Cosentyx may increase the risk of infections. In clinical trials, a higher rate of infections was observed 
in Cosentyx treated subjects compared to placebo-treated subjects. In placebo-controlled clinical trials 
in patients with moderate to severe plaque psoriasis, higher rates of common infections such as 

(CCI) Committee on Clinical Investigations 
Page 16 of 19 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and 
mucocutaneous infections with candida (1.2% versus 0.3%) were observed with COSENTYX 
compared with placebo. A similar increase in risk of infection was seen in placebo-controlled trials in 
patients with psoriatic arthritis and ankylosing spondylitis. The incidence of some types of infections 
appeared to be dose-dependent in clinical studies. 
 
We will evaluate patients for tuberculosis (TB) infection prior to initiating treatment with 
COSENTYX. A positive TB test would lead to exclusion from the trial. 
  
Inflammatory Bowel Disease 
Exacerbations of inflammatory bowel disease (IBD), in some cases serious, occurred in COSENTYX 
treated patients during clinical trials in plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. 
In addition, new onset inflammatory bowel disease cases occurred in clinical trials with COSENTYX. 
In an exploratory study in 59 patients with active Crohn’s disease, there were trends toward greater 
disease activity and increased adverse events in the secukinumab group as compared to the placebo 
group.   
 
Patients will be screened prior to inclusion in trial for a history of IBD. Patients who are treated with 
Cosentyx should be monitored for signs and symptoms of inflammatory bowel disease.  
 
Hypersensitivity Reaction 
Anaphylaxis and cases of urticaria occurred in Cosentyx treated patients in clinical trials. If an 
anaphylactic or other serious allergic reaction occurs, administration of Cosentyx should be 
discontinued immediately and appropriate therapy initiated. 
 
Risk of Hypersensitivity in Latex-sensitive Individuals  
The removable cap of the Cosentyx Sensoready pen and the Cosentyx prefilled syringe contains 
natural rubber latex which may cause an allergic reaction in latex-sensitive individuals. The safe use of 
Cosentyx Sensoready pen or prefilled syringe in latex-sensitive individuals has not been studied.  
 
 
Vaccinations  
Patients treated with Cosentyx should not receive live vaccines. Prior to initiating therapy with 
Cosentyx, we will consider completion of all age appropriate immunizations according to current 
immunization guidelines. 
 
Non-live vaccinations received during a course of Cosentyx may not elicit an immune response 
sufficient to prevent disease. 
 
Risks listed in the consent form are the following: 
Common 
• 
Sore throat and stuffy nose (upper respiratory tract infection, nasopharyngitis),  
• 
Runny nose (rhinitis), diarrhea 
• 
Cold sores (oral herpes) 
 
Rare 
• 
Oral thrush (oral candidiasis),  
• 
signs of low levels of white blood cells, such as fever, sore throat or mouth ulcers due 
to infections (neutropenia),  

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
• 
athlete’s foot (tinea pedis),  
• 
infection of the external ear (otitis externa),  
• 
discharge from the eye with itching,  
• 
redness and swelling (conjunctivitis),  
• 
itchy rash (urticaria) 
Other Risks Related to Study Procedures: 
• Blood Tests: The risks and discomforts of blood draws 
• Subcutaneous (SC) Injection: discomfort, infections, and/or pain at the site of the injection.  
Skin Biopsy: bleeding, pain, infection, scar 
 
 
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Dermatologists and Dermatopathologists from Beth Israel Deaconess Medical Center will be 
informed using IRB approved recruitment letters of this study and asked to refer eligible patients to 
our research unit. These letters will explain the purpose of the research, including a brief description 
of the nature and extent of involvement, and the investigator's email and phone number will be 
included.  A research advertisement will also be posted in the dermatology clinic. 
 
A list of potential subjects will be compiled from  all BIDMC Dermatology physicians’ patient 
population using ICD codes for necrobiosis lipoidica diabeticorum. These identified patients will be sent 
recruitment letters informing them of the study and to contact Dr. Porter if they are interested. 
 
The study will also be placed on TrialX as well as skinstudies.com, craigslist, twitter and BU quickie 
jobs. TrialX will use clinicaltrials.gov information; skinstudies.com, craigslist, twitter and BU quickie 
jobs will use the recruitment flyer and language from the targeted provider email.  
 
We will advertise the study on Twitter as well with the following posting: “Do you have necrobiosis 
lipoidica diabeticorum? You may be eligible to participate in a clinical trial. If you are interested visit 
our website skintudies.com, email us at clears@bidmc.harvard.edu or call at 617-667-5834.”  
 
The flyer will also be posted at the Dimock Center.  
 
Joslin will generate a list of patient with NLD diagnosis in their records.  
 
Consent 
Prior to entering the study, a licensed physician investigator will explain to the potential subject the 
nature of the study, its purpose, procedures, expected duration, and the benefits and risks involved 
in study participation.  The licensed physician will explain the main study. 
 
Subjects will be given the opportunity to ask questions and be informed of their right of study 
withdrawal.  After this explanation and before any study-specific procedures have been performed, 
the potential subject may voluntarily sign and date the informed consent form, thereby giving 
permission for the subject to enter the study.  

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Page 18 of 19 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
 
Prior to participation in the study, the subject will receive a copy of the signed and dated written 
informed consent form and any other written information provided to the subject. If, for any reason, the 
subject desires more time to consider the decision, the subject will be given a copy of the unsigned 
consent form for reference and instructed to call the office if they decide to participate in the study. 
 
Subject Protection 
In order to address the issue of patients feeling pressured to participate, a standard approach was 
developed and implemented years ago. This gives the patient the opportunity to actively 
demonstrate their interest before enrolling in the study. If a discussion about the study presents 
itself during a clinical encounter, the patient is offered to take the consent home and read and then 
asked to follow up with the clinic if they are interested. It is also attempted to have a physician who 
is not involved in their clinical care go over their consent form in order to provide further separation.  
 
B7. 
STUDY LOCATION 
 Privacy  
Subject visits will be conducted in the CRC at BIDMC or, rarely, in private patient exam rooms in the 
dermatology clinic if the CRC is not available at the time of subject visits.  Both locations should 
ensure adequate privacy for patients.  Patients will complete all study related procedures in these 
private settings, including questionnaires.  Questionnaires will be in written form and returned 
directly to the investigators or study staff. 
 
Pre-screening telephone calls and subject visits will be limited only to the minimum amount of data 
necessary to accomplish the research purposes.  No sensitive questions will be discussed by 
telephone. 
 
Physical Setting 
 
Subject visits will be conducted in the CRC at BIDMC or, rarely, in private patient exam rooms in the 
dermatology clinic if the CRC is not available at the time of subject visits.  Both locations should 
ensure adequate privacy for patients.  Patients will complete all study related procedures in these 
private settings, including questionnaires. 
 
 
 

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Page 19 of 19 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 11-10-2020 
 
B8. 
DATA SECURITY 
All subjects will be assigned a subject number at their screening visit.  Only investigators and study 
staff at BIDMC will have access to the subject’s identifiable health information. To ensure 
appropriate privacy and confidentiality, any paper source documentation and questionnaires will be 
stored in a locked cabinet.  Only the PI, sub-investigator, and study staff will have access to this 
locked cabinet. This documentation will all be coded.  Subject’s identifiable health information will 
be kept separate from coded documentation.  Any electronic data containing PHI will be stored on a 
password protected computer in a locked office and on a secure server behind the BIDMC firewall.  
 
The Investigator will maintain adequate records for the study, including source documentation, 
Informed Consent documents, drug dispensing and disposition records, information regarding 
participants who discontinued, adverse events, and other pertinent data. All essential documents 
will retained by the Investigators for at least 10 years in a long-term storage facility as arranged 
through the CTO. 
 
 
 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
 
 
 
B10 
Dissemination of Research Results 
 
Subjects will be thanked for their participation in the study immediately following their last visit.  
Because we are not able to anticipate the final completion date of the study, which may take years, 
and because we are not primarily responsible for analyzing and publishing the data, it will not be 
feasible for investigators to provide results to individual subjects.  Subjects may contact the PI 
following their completion of the study to inquire about the final findings of the study, if available to 
the investigators, at that time. 
 
Planned dissemination of research results may include abstract presentations at dermatology 
conferences and submission of data for publication in academic journals as an original research 
article.