Safety Study of Clinical and Immune Effects of Phosphodiesterase 4 (PDE-4) Inhibitor in Cutaneous Lupus Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine the clinical and immunological effects of the phosphodiesterase type 4 inhibitor, CC-10004, on skin inflammation associated with cutaneous lupus erythematosus.

Detailed Description
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Discoid cutaneous lupus is the most common cutaneous manifestation of lupus erythematosus, a chronic, immune mediated disease of unknown etiology. The immune processes underlying cutaneous lupus remain largely unexplored, but recent evidence suggests a role for dendritic cells (DCs), type 1 interferons (IFN) and Th1-type immune processes. Treatment of cutaneous lupus remains limited primarily to anti-malarials, with thalidomide an effective secondary agent. However, side effects associated with these treatments are potentially problematic with chronic use. Phosphodiesterases (PDE) are critical enzymes that degrade cAMP. In particular, PDE type 4 (PDE4) activity is found in inflammatory and immune cells, including DCs. The immune modulator CC-10004 is a PDE4 inhibitor with demonstrated low toxicity in phase I and II clinical studies with potential efficacy in cutaneous lupus. CC-10004 is a well-tolerated, selective PDE4 inhibitor with demonstrated inhibitory effects on Th1-type cytokines and other inflammatory mediators and is under development for the treatment of inflammatory and immune mediated conditions. Prior studies include pilot trials in psoriasis and exercise-induced asthma, with results suggesting clinical efficacy in the former study. This open label, pilot study of 16 weeks duration will explore the clinical and immune-modulating effects of CC-10004 in 10 cutaneous discoid lupus patients. Patients meeting study criteria will receive the drug for 12 weeks, followed by a 4-week washout period. Study visit time points will include weeks 0, 1, 2, 4, 6, 8, 10, 12 and 16, during which we will measure outcomes for clinical, immunological and safety parameters. To investigate early immunological changes occurring in response to treatment, we will also perform skin punch biopsies of lesional sites at week 0 and week 4 for immunohistochemical and molecular analysis.

Official Title
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Clinical and Immune-modulating Effects of CC-10004 in Discoid Lupus Erythematosus

Conditions
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Discoid Lupus Erythematosus

Intervention / Treatment
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* Drug: CC-10004


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of cutaneous discoid lupus by clinical and histopathological exam Exclusion Criteria: Systemic lupus involving the internal organs Systemic vasculitis History of other clinically significant disease process History of HIV, hepatitis B or C Concurrent use of immune modulating therapy Evidence of incompletely treated tuberculosis Pregnant or lactating female

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apremilast<br>CC-10004 20 mg twice daily by mouth for 12 weeks, followed by a 4 week washout period and final assessment | Drug: CC-10004<br>* 20 mg twice daily by mouth for 12 weeks, followed by a 4 week washout period and final assessment<br>* Other names: Apremilast;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cutaneous LE Diseases Area and Severity Index (CLASI) Score Based on Extent of Symptoms | To evaluate the clinical response of cutaneous lupus patients to CC-10004. From J Invest Dermatol. 2005 Nov; 125(5): 889-894.doi: 10.1111/j.0022-202X.2005.23889.x: The CLASI consists of two scores. One summarizes the activity of the disease on a scale from 0 to 30, higher score translates to more severe disease. The second is a measure of the damage done by the disease on a scale form 0 to 30, higher score translates to more severe disease. Activity is scored on the basis of erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss and non-scarring alopecia. Damage is scored in terms of dyspigmentation and scarring, including scarring alopecia. Each score is reported separately. Outcome measures are reported for each time point for each subject due to the low numbers of enrollment. | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dermatology Quality of Life Index (DQLI) | To evaluate the clinical safety of CC-10004 in cutaneous lupus patients To determine the effect of CC-10004 on immune parameters in the skin To determine the effect of CC-10004 on immune parameters in the blood in vivo in vitro To determine the effect of CC-10004 on QOL and psychological outcome measures | 16 Weeks | 
| Common Terminology Criteria for Adverse Events v3.0 (CTCAE) | To evaluate the clinical safety of CC-10004 in cutaneous lupus patients To determine the effect of CC-10004 on immune parameters in the skin To determine the effect of CC-10004 on immune parameters in the blood in vivo in vitro To determine the effect of CC-10004 on QOL and psychological outcome measures | Weeks 1, 2, 4, 6, 8, 10, 12, 16 | 
| Dermal and Circulating Blood Plasmacytoid Dendritic Cell Levels |  | Weeks 0, 4 (dermal and circulating); week 12 (circulating only) | 
| Dermal and Circulating Blood T Regulatory Cell Levels | To evaluate the clinical safety of CC-10004 in cutaneous lupus patients To determine the effect of CC-10004 on immune parameters in the skin To determine the effect of CC-10004 on immune parameters in the blood in vivo in vitro To determine the effect of CC-10004 on QOL and psychological outcome measures | Weeks 0, 4 (dermal and blood); Week 12 (blood only) | 
| Plasma Cytokine Levels | To evaluate the clinical safety of CC-10004 in cutaneous lupus patients To determine the effect of CC-10004 on immune parameters in the skin To determine the effect of CC-10004 on immune parameters in the blood in vivo in vitro To determine the effect of CC-10004 on QOL and psychological outcome measures | Weeks 0, 4, 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous lupus, Intervention, Discoid lupus, Phosphodiesterase 5 inhibitor