Secukinumab for NLD (Cosentyx) in Patients With Necrobiosis Lipoidica Diabeticorum (NLD)

Study Overview
=================
Brief Summary
-----------------
This study investigates the efficacy of secukinumab in necrobiosis lipoidica diabeticorum (NLD).

Detailed Description
-----------------
Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous condition of the skin often presenting with papules and eventually atrophic plaques, most commonly on the distal extensor lower extremities, which can be painful and disfiguring. 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. 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. Secukinumab (Cosentyx) is a human monoclonal antibody that targets IL-17a and is FDA approved for the treatment of psoriasis. This 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 treatment for this chronic and potentially debilitating condition for which no FDA approved treatment currently exists.

Official Title
-----------------
An Open-label Proof of Concept Study Regarding the Use of Secukinumab (Cosentyx) in Patients With Necrobiosis Lipoidica Diabeticorum (NLD)

Conditions
-----------------
Necrobiosis Lipoidica Diabeticorum

Intervention / Treatment
-----------------
* Drug: Secukinumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults, age 18 and over Previous diagnosis of biopsy-proven NLD Active NLD lesions, defined as clinical signs of inflammation, for example erythematous margins, sensations of itch, pain, dysaesthesia lesions increasing in size or appearance of new lesions within the last 3 months ulcerations 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: 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. Are currently pregnant, breastfeeding, or planning to get pregnant during the study. Previous hypersensitivity reaction to secukinumab or to any of the components. History of Inflammatory Bowel Disease (Crohn's Disease or Ulcerative Colitis) Allergy to Latex Currently on any other immunosuppressant systemic medication or within 28 days of baseline visit 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. Subjects with a serum creatinine level exceeding 176.8 μmol/L (2.0 mg/dL) Screening total WBC count <2,500/μL, or platelets <100,000/μL or neutrophils <1,500/μL or hemoglobin <8.5 g/dL 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. 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) Are participating in another study using an investigational agent or procedure during participation in this study or within 28 days prior to baseline visit. Plans for administration of live vaccines during the study period or 6 weeks prior to randomization Any other procedural treatment for NLD with 28 days prior to baseline visit, including phototherapy, surgical intervention, laser therapy, or cryotherapy. Any other active skin disease or condition (e.g., bacterial, fungal or viral infection) that may interfere with assessment of NLD; Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Secukinumab Subcutaneous Injection<br>300 mg q weekly for 5 weeks followed by 300 mg q 4 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. | Drug: Secukinumab<br>* Secukinumab is selective for human IL-17A and potently neutralizes the bioactivity of this cytokine. IL-17A is the central cytokine in multiple autoimmune and inflammatory processes. It is being recognized as one of the principal pro-inflammatory cytokines in autoimmune diseases such as psoriasis, PsA and AS, uveitis and is thought to play a role in other inflammatory conditions.<br>* Other names: cosentyx;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator Global Assessment Score | Proportion of patients achieving remission or clinical improvement based on Investigator Global Assessment Score as measured at week 24. Score Description 0. Completely clear: except for possible residual hyperpigmentation Almost clear: very significant clearance (about 90%); however, patchy remnants of dusky erythema and/or very small ulcerations 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) Moderate improvement: intermediate between slight and marked; representing about 50% improvement Slight improvement: some improvement (about 25%); however, significant disease remaining (i.e. remaining ulcers with only minor decrease in size, erythema or boarder activity) No change from baseline Worse | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histology | Proportion of subjects achieving improvement based upon histological score. The score is calculated by adding subscores 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. Inflammatory infiltrate (0, none; 1, slight; 2, moderate; 3, severe) collagen degeneration (0, none; 1, slight; 2, moderate; 3, severe) epithelioid histiocytes, (0, none; 1, slight; 2, moderate; 3, severe) qualitative expression of IL-17 (0, none; 1, slight; 2 moderate; 3, severe) | 26 weeks | 
| Pain Score | Self-reported pain and stinging intensity during and directly after treatment with Secukinumab injections 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. 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 (i) Resolved (ii) Improved (iii) Stable (iv) Worsened | Assessed at week 1, 2, 3, 4, 8, 12, 16, 20, 25 | 
| Dermatology Life Quality Index | Proportion of subjects improving based upon patient-reported outcomes 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) 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. | Assessed at week 1, 2, 3, 4, 8, 12, 16, 20, 25 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NLD, Necrobiosis lipoidica