A Study to Evaluate the Safety and Tolerability of PCS499 for the Treatment of Necrobiosis Lipoidica
Condition: Necrobiosis Lipoidica
MeSH terms: Necrobiosis Lipoidica; Necrobiotic Disorders
Intervention: PCS499
Intervention description: PCS499 900mg twice a day with food
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      This is an open-label study that will evaluate the safety of PCS499 for the treatment of
      necrobiosis lipoidica (NL) and will inform the design of future studies. Approximately 12 NL
      patients (6-9 patients without ulceration and 3-6 patients with ulceration) who also meet
      other inclusion/exclusion criteria will be enrolled in the study. The primary objective of
      this study is to evaluate the safety and tolerability profile of PCS499 in patients with
      Necrobiosis Lipoidica.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients age 18 to 80 years of age, inclusive, at Screening.

          2. Biopsy-confirmed diagnosis of NL. Biopsies of continually active lesions performed
             outside of this clinical study will need to be reviewed and the diagnosis confirmed by
             the study pathologist. For patients with no previous history of biopsy, no biopsy
             within the previous 5 years, a biopsy that is not confirmed to be NL, or newly active
             lesion, a biopsy to confirm a diagnosis of NL will be performed at the Screening
             visit.

          3. Reference NL lesion with a score of 2 or greater on the Investigator Global
             Assessment: Necrobiosis Lipoidica (IGA:NL) Activity scale AND surface area with
             minimum size of 10 cm2. If more than one lesion is present, the reference lesion area
             is the lesion with the highest disease severity.

          4. Women of childbearing potential must have a negative serum pregnancy test at the
             Screening Visit and a negative urine pregnancy test at Baseline before dosing.

          5. Women of childbearing potential must use one of the following acceptable methods of
             contraception throughout the study: oral contraceptive medication, intrauterine device
             (IUD), hormonal implants, injectable contraceptive medications, double-barrier
             methods, or tubal ligation.

          6. Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months and
             increased follicle-stimulating hormone [FSH] > 40 mIU/mL. If necessary to confirm
             postmenopausal status, an FSH will be drawn at Screening) or who have undergone
             hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.

          7. Male patients must be willing to use appropriate contraceptive measures and refrain
             from sexual activity with any female who is pregnant or lactating.

          8. Patient must be willing and able to swallow whole tablets.

          9. Patient must be willing and able to comply with study procedures.

         10. Patient must be willing and able to provide signed, informed consent.

        Exclusion Criteria:

          1. Current or previous (within 4 weeks of Baseline) treatment with:

               1. Oral, topical, or intralesional corticosteroids;

               2. Systemic pentoxifylline, theophylline, or cilostazol

               3. Oral or topical retinoid;

               4. Other systemic or topical immunosuppressant drugs, including but not limited to
                  calcineurin inhibitors (e.g., tacrolimus), thalidomide, apremilast,
                  anti-malarials (e.g., hydroxychloroquine, chloroquine), cyclosporine,
                  mycophenolate mofetil, azathioprine, methotrexate, etc.

          2. Current or previous (within 12 weeks of Baseline) treatment with any biologic therapy
             (e.g., adalimumab, etanercept, infliximab, anakinra, etc.).

          3. Phototherapy/photochemotherapy (NBUVB, UVB, PUVA) within 6 weeks prior to Baseline

          4. Skin grafting, or other surgical procedure (other than debridement) within 6 weeks
             prior to Baseline.

          5. History of drug allergy, including but not limited to pentoxifylline or other xanthine
             derivatives, or other allergy, which in the opinion of the Investigator,
             contraindicates participation.

          6. Anticipated concurrent use of a strong CYP1A2 inhibiting drug, including but not
             limited to cimetidine and/or fluvoxamine, during the course of the study (after
             Screening).

          7. Fever (>38°C), or chronic, persistent, or recurring infection(s) at Screening or
             Baseline.

          8. Any infection requiring oral antimicrobial therapy within 2 weeks prior to Baseline or
             any infection requiring parenteral antibiotics or hospitalization within 12 weeks
             prior to Baseline. Any treatment for such infections must have been completed and the
             infection cured for at least 2 weeks prior to Baseline.

          9. History of sarcoidosis, pyoderma gangrenosum, or any other disorder (in the judgment
             of the Investigator) that would interfere with the evaluation of NL or require
             protocol prohibited medication.

         10. History of any life threatening infection or sepsis within 12 months of Baseline:

         11. Clinically significant cardiac disease including but not limited to unstable angina,
             acute myocardial infarction within 6 months of Baseline, and arrhythmia requiring
             therapy.

         12. Patient has QTc interval ≥ 480 milliseconds on Screening Electrocardiogram (ECG); a
             second Screening ECG may be done at investigator's discretion but the average of the
             two QTc screening intervals must not be ≥ 480 milliseconds.History of cerebral
             hemorrhage, cerebrovascular accident, transient ischemic attack, gastrointestinal
             bleeding, or retinal hemorrhage within 6 months of Baseline.

         13. History of cerebral hemorrhage, cerebrovascular accident, transient ischemic attack,
             gastrointestinal bleeding, or retinal hemorrhage within 6 months of Baseline.

         14. Patient has active or history of neoplastic disease (except for adequately treated
             non-invasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the
             cervix) within the past 5 years prior to Baseline.

         15. Presence of clinically significant medical condition(s) including but not limited to:
             renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary,
             neurological, psychiatric, substance abuse, and/or any other clinically significant
             disease or disorder, which in the opinion of the Investigator (by its nature or by
             being inadequately controlled), may put the patient at risk due to participation in
             the study, influence the results of the study, and/or affect the patient's ability to
             complete the study.

         16. History of or current diagnosis of active tuberculosis (TB); undergoing treatment for
             latent TB infection (LTBI); untreated LTBI (as determined by documented results within
             3 months of the Screening Visit of a positive TB skin test with purified protein
             derivative with induration >= 5 millimeter (mm), or a positive QuantiFERON-TB test or
             positive or borderline T-Spot [Elispot] test); or positive TB test at Screening.
             Subjects with documented completion of appropriate LTBI treatment would not be
             excluded and are not required to be tested.

         17. Vaccination with live or live-attenuated virus vaccine within 1 month prior to
             Baseline.

         18. The results of the following laboratory tests performed at the central laboratory at
             Screening meet any of the criteria below:

               1. Hemoglobin < 8.0 g/dL (International System of Units (SI): < 80 g/L);

               2. White blood cells < 3.0 x 10^3 cells/mm^3 (SI: < 3.0 x 10^9 cells/L);

               3. Neutrophils < 1.0 x 10^3 cells/mm^3 (SI: < 1.0 x 10^9 cells/L);

               4. Lymphocytes < 0.5 x 10^3 cells/mm^3 (SI: < 0.5 x 10^9 cells/L);

               5. Platelets < 100 x 10^3 cells/mm^3 (SI: < 100 x 10^9 cells/L)

               6. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or alkaline
                  phosphatase (ALP) ≥ 2 x upper limit of normal (ULN);

               7. Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with
                  Gilbert's disease and this is clearly documented;

               8. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 based on the
                  Modification of Diet in Renal Disease (MDRD) formula.

               9. Positive HIV serology

              10. Evidence of active Hepatitis B Virus (HBV) infection

              11. Evidence of active Hepatitis C Virus (HCV) infection

         19. Women who are pregnant or breastfeeding.

         20. Patient unwilling or unable to swallow tablets whole.

         21. Any other medical condition, serious intercurrent illness, or extenuating circumstance
             that, in the opinion of the Investigator, would preclude participation in the study.

         22. Use of any investigational product within 30 days prior to Baseline or currently
             enrolled in another study that involves clinical investigations.