Vascular Inflammation in Psoriasis Trial (The VIP Trial)

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of adalimumab (Humira), when compared to NB-UVB (narrow-band ultraviolet B) phototherapy or placebo (an inactive substance that may resemble an active substance but has no medical value) injection. The study will compare the effects of each on systemic inflammation and cardiovascular disease risk factors in subjects diagnosed with moderate to severe psoriasis. This study will look for systemic vascular inflammation in subjects with a test called FDG-PET/CT (Fluorodeoxyglucose-positron emission tomography/computed tomography). The study will also look for cardio metabolic (heart disease and metabolic factors such as diabetes) identifiers in the blood. A blood sample will be taken that will look for these markers identifying high cholesterol, cholesterol efflux function (the ability of cholesterol to move in the body), metabolic factors, and inflammation. This study will also assess the effect of adalimumab (Humira), when compared to NB-UVB phototherapy or placebo injection on psoriasis activity and severity. The study will also compare the safety of adalimumab (Humira) to NB-UVB phototherapy or placebo injection. This study will also evaluate subjects' reported outcomes through a questionnaire that will assess quality-of-life in subjects living with psoriasis.

Official Title
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A Trial to Determine the Effect of Psoriasis Treatment on Cardiometabolic Disease

Conditions
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Psoriasis, Cardiovascular Disease

Intervention / Treatment
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* Drug: Adalimumab (Humira)
* Drug: Placebo Injection
* Other: NB-UVB phototherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females 18 years of age and older. Clinical diagnosis of psoriasis for at least 6 months as determined by subject interview of his/her medical history and confirmation of diagnosis through physical examination by Investigator. Stable plaque psoriasis for at least 2 months before Screening and at Baseline (Week 0) as determined by subject interview of his/her medical history. Moderate to severe psoriasis defined by ≥ 10 percent Body Surface Area (BSA) involvement at the Baseline (Week 0) visit. PASI (psoriasis assessment and severity index) score of ≥ 12 at the Baseline (Week 0) visit. Subject is a candidate for systemic therapy or phototherapy and has active psoriasis despite prior treatment with topical agents. Women are eligible to participate in the study if they meet one of the following criteria: Women of childbearing potential who are willing to undergo regular pregnancy testing and agree to use one method of contraception throughout the study are eligible to participate Women who are postmenopausal (for at least one year), sterile, or hysterectomized are eligible to participate Women who have undergone tubal ligation are eligible to participate Women who agree to be sexually abstinent, defined as total abstinence from sexual intercourse, as a form of contraception are eligible to participate in the study. Subject is judged to be in good general health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, and 12-lead electrocardiogram (ECG) performed at screening. Able and willing to give written informed consent and to comply with requirements of this study protocol. Exclusion Criteria: Previous adverse event following exposure to a TNF-alpha antagonist and/or UV phototherapy that led to discontinuation of either of these therapies and contraindicates future treatment. Previous lack of response to a TNF-alpha antagonist and/or UV phototherapy that led to discontinuation of either of these therapies. Diagnosis of erythrodermic psoriasis, generalized or localized pustular psoriasis, medication-induced or medication-exacerbated psoriasis, or new onset guttate psoriasis. Diagnosis of other active skin diseases or skin infections (bacterial, fungal, or viral) that may interfere with evaluation of psoriasis. Cannot avoid UVB phototherapy for at least 14 days prior to the Baseline (Week 0) visit. Cannot avoid psoralen-UVA phototherapy for at least 30 days prior to the Baseline (Week 0) visit and during the study. Cannot discontinue systemic therapies for the treatment of psoriasis, or systemic therapies known to improve psoriasis, during the study: Systemic (investigational or marketed) therapies must be discontinued at least 30 days prior to the Baseline (Week 0) visit except for biologics. All biologics, except ustekinumab, must be discontinued for at least 90 days prior to Baseline (Week 0). The IL-12/IL-23 antagonist ustekinumab (half-life of 45.6 ± 80.2 days) must be discontinued for at least 180 days prior to Baseline (Week 0). Investigational agents must be discontinued at least 30 days or 5 half-lives (whichever is longer) prior to the Baseline (Week 0) visit. Subject is taking or requires oral or injectable corticosteroids during the study. Inhaled corticosteroids for stable medical conditions are allowed. Poorly controlled medical condition, such as unstable ischemic heart disease, congestive heart failure, recent cerebrovascular accidents, psychiatric disease requiring frequent hospitalization, and any other condition, which, in the opinion of the Investigator, would put the subject at risk by participation in the study. History of diabetes mellitus, type 1 or type 2 - note that patients with type 2 diabetes may be enrolled if the duration of diabetes is <10 years and HbA1c is <7.0%) Uncontrolled hypertension, with measured systolic blood pressure >180 mmHg or diastolic blood pressure >90 mmHg History of demyelinating diseases or lupus. Subject has infection or risk factors for severe infections, for example: Positive serology or known history of HIV, hepatitis B or C, or other severe, recurrent, or persistent infections; Excessive immunosuppression or other factors associated with it, including human immunodeficiency virus infection; Active tuberculosis (TB) disease; Evidence of latent TB infection demonstrated by Purified Protein Derivative (PPD) ≥ 5 mm of induration or positive Quantiferon-GOLD results; except if prophylactic treatment for TB, as recommended by local guidelines, is initiated prior to administration of study drug or if there is documentation that the subject has received prophylactic treatment for TB previously. Any other significant infection requiring hospitalization or intravenous (IV) antibiotics in the month prior to Baseline; Infection requiring treatment with oral or parenteral antibiotics within 14 days prior to Baseline; Subject has received vaccination with Bacille Calmette-Guerin (BCG) within 365 days prior to Screening; Subject has received vaccination with a live viral agent 30 days prior to Screening or will require a live vaccination during study participation including up to 30 days after the last dose of study drug. Subject has history of hematological or solid malignancy other than successfully treated basal cell carcinoma, non-metastatic cutaneous squamous cell carcinoma or cervical carcinoma in situ. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study. Screening clinical laboratory analyses showing any of the following abnormal results: Hemoglobin (Hgb) < 10 g/dL in females or <12 g/dL in males; White blood cell (WBC) count <2.5 x 109/L o Subject can be included if WBC count is <2.5 x x 109/L and absolute neutrophil count (ANC) is >1000 cells / mm3. WBC count > 15 x 109/L; Platelet count < 100 x 109/L; Serum aspartate transaminase (AST) or alanine transaminase (ALT) >2.5 upper limits of normal (ULN); Serum total bilirubin ≥2 mg/dL (≥26 µmol/L); or Serum creatinine >1.6 mg/dL (>141 µmol/L). Recent history of substance abuse or psychiatric illness that could preclude compliance with the protocol. History of any substance abuse within 365 days of screening visit Alcohol use >14 drinks per week at the screening visit or within 30 days of the screening period If subject is on cholesterol-lowering medication (e.g. statin), dose and form of medication must be stable for 90 days prior to week 0 and remain stable throughout the duration of the study. History of photosensitivity of medical condition that may be exacerbated by UV exposures such as lupus or dermatomyositis

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adalimumab (Humira)<br>Injection of the active drug Humira. | Drug: Adalimumab (Humira)<br>* Humira will be given at an initial dose of 80mg followed by 40 mg the second week, subsequent doses will be given at 40mg and follow FDA dosing schedule.<br>|
| Placebo Comparator: Placebo Injection<br>Injection of placebo in place of active Humira injection. | Drug: Placebo Injection<br>* Placebo injection will be given according to the same dose and schedule as the active comparator.<br>|
| Active Comparator: NB-UVB phototherapy<br>NB-UVB Phototherapy 3 times per week, no other intervention. | Other: NB-UVB phototherapy<br>* Phototherapy will be given 3 times per week according to the Fitzpatrick scale for skin types.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vascular Inflammation | Change in total vascular inflammation of five aortic segments as assessed on FDG-PET/CT between baseline and week 12. The arterial uptake of FDG is measured by the standardized uptake value (SUV) max divided by the venous SUV mean yielding a target to background ratio (TBR). | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Total Cholesterol | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on total cholesterol. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Cholesterol Efflux | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on cholesterol efflux capacity. The ability to promote cholesterol efflux from macrophages is a classic function of HDL that is thought to be an important mechanism by which HDL protects against atherosclerosis. HDL cholesterol efflux capacity assays are performed based on published methods using J774 cells derived from a murine macrophage cell line (Mehta NN Atherosclerosis 2012). Efflux is calculated as a unitless measure by using the following formula: [(µCi of 3H-cholesterol in media containing apoB-depleted subject plasma - µCi of 3H-cholesterol in plasma-free media) / (µCi of 3H-cholesterol in media containing apoB-depleted pooled control plasma-µCi of 3H-cholesterol in pooled control plasma-free media)]. The pooled plasma was obtained from five healthy volunteers. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Low Density Lipoprotein Particle Total | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on low density lipoprotein particle total. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: High Density Lipoprotein Particle Total | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on high density lipoprotein particle total. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log Insulin | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log insulin. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log Adiponectin | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log adiponectin. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log Leptin | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log leptin. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log C-reactive Protein | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log C-reactive protein (CRP). | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log Tumor Necrosis Factor-alpha | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log Tumor necrosis factor-alpha. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: Log Interleukin 6 | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on log interleukin 6. | Baseline - Week 12 | 
| Change in Cardiometabolic Biomarkers: GlycA | To assess the effects of adalimumab, as compared to NB-UVB phototherapy or placebo, in patients with moderate to severe psoriasis on GlycA | Baseline - Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Psoriasis Activity (PASI-75 and PGA) | Psoriasis activity will be assessed using standard psoriasis measurements, PASI75 and PGA Clear/Almost Clear | Baseline - Week 12 | 
| Change in Patient-reported Outcomes-EuroQol EQ-5D | EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health conditions and treatments. The EQ-5D consists of a descriptive system and the EQ VAS. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression on a scale ranging from 1 (no health state problem) to 3 (extreme health state problems). The EQ VAS records the patient's self-rated health on a vertical visual analogue scale ranging from 0, worst health state, to 100, best health state. A scoring function is used to assign a value (i.e., EQ-5D™ index score) to self-reported health states from a set of population-based preference weights. For the U.S. general population, the possible EQ-5D index scores range from -0.11 to 1.0 where 0.0 = death and 1.0 = perfect health. | Baseline -Week 12 | 
| Change in Patient-reported Outcomes-Dermatology Life Quality Index (DLQI) | Patient reported quality of life outcomes will be assessed using DLQI. The DLQI is calculated by summing the score of 10 questions regarding impact of skin condition on daily life resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. | Baseline - Week 12 | 
| Change in Patient-reported Outcomes-MEDFICTS Dietary Assessment) | Patient reported dietary outcomes will be assessed using MEDFICTS (Meats, Eggs, Dairy, Fried foods, fat In baked goods, Convenience foods, fats added at the Table, and Snacks), a brief dietary assessment instrument for properly assessing cardiovascular diet. The questionnaire yields a continuous score (ranging from 0 to 216), with a score of <40 indicating adherence to the Therapeutic Lifestyle Changes (TLC) diet (intake of <7% of energy from saturated fat, <30% of energy from total fat, and <200 mg dietary cholesterol/day). | Baseline to Week 12 | 
| Change in Patient-reported Outcomes-International Physical Activity Questionnaire (IPAQ) | Patient reported physical activity will be assessed using IPAQ. IPAQ is an instrument designed primarily for population surveillance of physical activity among adults with activity measured in metabolic equivalent (MET)-minutes per week. | Baseline week 4, 8 and 12 | 
| Number of Patients With Adverse Events. | Safety will be assessed by comparing how many patients have adverse events depending on whether they are on adalimumab, as compared to NB-UVB phototherapy or placebo. | Baseline - Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psoriasis, Cardiovascular Disease, FDG/PET-CT, NB-UVB Phototherapy, Vascular Inflammation, Lipid Biomarkers