Fluphenazine Decanoate for Psoriasis

Study Overview
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Brief Summary
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We are doing this research study to evaluate the effectiveness and safety of fluphenazine decanoate when injected with a needle into psoriasis lesions in adults. Fluphenazine decanoate is FDA (U.S. Food and Drug Administration) approved for use in people who have schizophrenia and psychotic symptoms. Fluphenazine decanoate is not approved by the FDA for use in psoriasis. Fluphenazine decanoate slows T cell growth in cells in laboratory test tubes. Its usefulness and safety in people with psoriasis will be investigated in this study.

Detailed Description
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Psoriasis is a hyperproliferative, inflammatory, immune-mediated skin disease that affects approximately 2% of the United States and European populations (Tutrone 2001, Kipnis 2005). This disease manifests as red, scaly plaques that are itchy and/or painful. Patients with psoriasis may be socially stigmatized because of their appearance. Currently, there is no cure for this condition. Often, repeated medical treatments are necessary and can become expensive. Treatment with topical corticosteroids is the mainstay therapy for mild to moderate psoriasis. In more severe cases, systemic therapies (e.g., cyclosporine) and phototherapy (e.g., ultraviolet B (UVB) irradiation) are used. These treatments, however, are associated with toxicities or inconvenience. There is anecdotal evidence to suggest that antipsychotic drugs have a beneficial effect on psoriasis (Gupta 2001, 2003). Fluphenazine is a phenothiazine antipsychotic drug. In vitro, fluphenazine kills activated human T cells under conditions that do not affect resting T cells (Immune Control Inc. data not shown). To determine the size of a therapeutic window for human peripheral blood mononuclear cells (PBMC)s, Immune Control Inc. performed the following experiments. First, phytohemagglutinin- (PHA)-activated cells were exposed to 2, 10, or 20 µM fluphenazine for 0, 18, 24, 36, 48, or 72 hours. Second, resting cells were exposed to identical fluphenazine concentrations for identical time periods, after which the drug was washed out of the cells, and the cells activated with PHA. In all cases, deoxyribonucleic acid (DNA) synthesis was measured by exposing the cells to tritiated thymidine, and measuring the incorporated nucleotide by scintillation counting. The data show that exposure of activated cells to 10 µM fluphenazine for 72 hours, or 20 µM fluphenazine for 36 hours, caused the death of virtually all of the activated cells. The ability of the resting cells to initiate DNA synthesis after activation, by contrast, was largely unaffected by these fluphenazine exposures. Although we cannot precisely control intralesional fluphenazine concentrations, we expect that injections of up to 1 mg fluphenazine decanoate will yield local concentrations that exceed 10 µM without significant systemic fluphenazine concentrations. We propose that fluphenazine will suppress proliferating T-lymphocytes in psoriatic plaques in vivo and thus result in healing of plaques. The objective of this study is to assess the safety and biologic activity of intralesional injection of fluphenazine decanoate in adult subjects with psoriasis.

Official Title
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Ascending-Dose, Double-Blind, Placebo-Controlled, Bilateral Study of Intralesional Fluphenazine Decanoate in Psoriasis

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: Fluphenazine Decanoate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18 to 65 years of age with psoriasis, in general good health Must have symmetric target lesions approximately 2-4 cm in diameter on each side of the body (e.g., thighs) with baseline target lesion score of 6 or higher (scale of 0-12) for each target Women of childbearing potential must agree to use two forms of contraception for the duration of the study Exclusion Criteria: Infliximab (Remicade) or alefacept (Amevive) within the past 6 months (24 weeks) Etanercept (Enbrel), efalizumab (Raptiva), adalimumab (Humira), or other tumor necrosis factor- (TNF)-alpha inhibitor within the past 3 months (12 weeks) Other systemic psoriasis therapies (e.g., methotrexate, cyclosporine, acitretin) or PUVA (psoralen plus ultraviolet A) within the past 4 weeks Ultraviolet B (UVB) or topical therapy (other than over the counter (OTC) moisturizers and shampoos) within the past 2 weeks (including topical corticosteroids, vitamin A and D analogues) Receipt of an investigational agent within the past 4 weeks Systemic corticosteroid therapy Inability to understand consent or comply with protocol Pregnancy, lactation, or unwillingness to use adequate birth control during the study Impaired hepatic function Known Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), hepatitis B/C Blood dyscrasia Epilepsy Tardive dyskinesia Excessive alcohol consumption Current use of selective serotonin reuptake inhibitors (SSRI), tricyclic, or norephinephrine reuptake inhibitor antidepressants or use within 6 weeks of beginning the study Concurrent use of anti-seizure drugs, with the exception of gabapentin for treatment of neuropathy Use of phenothiazine antipsychotics or anticholinergics Known allergy to fluphenazine decanoate or other phenothiazines Known allergy to parabens/para-aminobenzoic acid (PABA), benzyl alcohol, sesame oil or sesame seeds Clinically significant mitral valve disease Clinically significant and uncontrolled cardiovascular disease QTc >450 msec, or evidence of a clinically significant dysrhythmia on electrocardiography (ECG) Operator of heavy machinery Pheochromocytoma History of breast cancer History of seizure disorder Occupational exposure to organophosphate insecticides Parkinson's disease and other related movement disorders Lab abnormalities including: Alanine aminotranferease (ALT)/aspartate aminotransferase (AST) ≥ 2X upper limit of reference range Creatinine ≥ 1.5X upper limit of reference range Bilirubin ≥ 2X upper limit of reference range Absolute total lymphocyte or polymorphonuclear leucocyte count ≤ 1000/uL or ≥ 3X upper limit of ref range Platelets ≤ 80,000/uL Hemoglobin ≤ 8.0 g/dL Glucose ≥ 200 mg/dL Fasting blood sugar ≥ 126 mg/dL Concurrent use of drugs listed in Appendix F

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluphenazine treated<br>Treated with fluphenazine | Drug: Fluphenazine Decanoate<br>* Fluphenazine decanoate marketed by APP Pharmaceuticals (25 mg/mL, 5 mL vial) was used in this study. This was an ascending dose study with the first cohort of 5 subjects dosed at 10 µg/mL, followed by 5 subject dosed in the second cohort at 100 µg/mL. Note: APP Pharmaceuticals is the name of the pharmaceutical company; APP is not an acronym.<br>|
| Placebo Comparator: Placebo<br>Treated with Placebo | Drug: Placebo<br>* The sterile placebo (sesame oil with 1.2% (w/v) benzyl alcohol) was prepared at the University of Iowa, Division of Pharmaceutical Services, a FDA registered pharmaceutical manufacturing facility.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Target Lesion Score at Week 4 Compared to Baseline | Change in score from 0-14 of target lesion disease activity based on scaling, erythema, and induration as determined by a physician assessor at week 4 compared to baseline (with 0 being no disease activity and 14 being maximum disease activity). | Baseline to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Target Lesion Pruritus Visual Analog Scale (VAS) at Week 4 Compared to Baseline. | Target lesion pruritus as measured by the Visual Analog Scale (VAS) from 0 to 100 mm at week 4 compared to baseline (with 0 being no pruritis and 100 being maximum pruritis). | Baseline to week 4 |