Trial on the Effect of Adalimumab on Vascular Inflammation in Patients With Psoriasis

Study Overview
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Brief Summary
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This study is a double-blinded randomized multicenter placebo controlled trial to determine the effect of adalimumab on vascular inflammation (ascending aorta and carotides) in patients with moderate to severe psoriasis.

Detailed Description
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Patients with moderate to severe psoriasis will be included in this multicenter, double-blind, placebo controlled study. Patients will be randomized (1:1) at Day 0 to receive either adalimumab or placebo. Adalimumab will be administered sub-cutaneously as described in the Canadian product monograph (80mg followed by 40mg at Week 1 and 40mg every other week). At Week 16, all patients will receive two injections of blinded study products. Patients randomized to the placebo group will receive two injections of adalimumab (2 x 40 mg) and patients randomized to adalimumab will receive two injections of placebo. As of Week 17, patients randomized to the placebo group will receive 40 mg adalimumab every other week until Week 67. Patients randomized to the adalimumab group will continue to receive adalimumab 40mg every other week until Week 51. Efficacy will be assessed with 18-FluoroDeoxyGlucose Positron Emission Tomography (FDG-PET) scan and carotid MRI at baseline, Week 16 and Week 52 (or Week 68 for patients randomized to placebo). Safety will be assessed with physical examinations, vital signs, adverse events collection, routine laboratory examinations, pregnancy test, hepatitis B and C serology (screening), Purified Protein Derivative (PPD) or Quantiferon Gold (screening) and Chest X-Ray (CXR) (screening).

Official Title
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Randomized Multicenter Placebo-controlled Trial on the Effect of Adalumumab on Vascular Inflammation in Patient With Moderate to Severe Psoriasis

Conditions
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Psoriasis, Vascular Inflammation, Coronary Atherosclerosis

Intervention / Treatment
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* Biological: Adalimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has plaque psoriasis. Patient has at least a 6 month history of plaque psoriasis.Patient has a Body Surface Area (BSA) covered with psoriasis of 5% or more at Day 0. Patient is a candidate for systemic therapy. Patient is male or female, 18 to 80 years of age at time of consent. Patient's weight at screening is a maximum of 180 kg. Patient using medication to control angina, hypertension, serum lipids and any medication that can have an effect on inflammation must be on a stable dose for at least 8 weeks before Day 0. Patient has an ascending aorta atherosclerotic plaque inflammation target-to-background ratio of 1.6 or more as determined by 18-FDG uptake measured by PET scanning. Patient or patient's partner has been in a menopausal state for at least a year, is surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation or vasectomy), is clinically diagnosed infertile, has a same-sex partner, is abstinent, or is willing to use effective contraceptive method for at least 30 days before Day 0 and at least 6 months after the last study drug administration. Effective contraceptive methods are: Barrier methods such as condom, sponge or diaphragm combined with spermicide in foam, gel or cream; Hormonal contraception (oral, intramuscular, implant or transdermal) which include Depo-Provera, Evra and Nuvaring; Intrauterine device (IUD); Female patients of childbearing potential must have a negative serum pregnancy test at the Screening visit. Patient 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 CXR performed at Screening. Patient will be evaluated for latent TB infection with a PPD or a Quantiferon Gold test and CXR. Patient who demonstrates evidence of latent TB infection (either PPD more than or equal to 5 mm of induration or positive Quantiferon Gold, irrespective of Bacillus Calmette-Guerin (BCG) vaccination status and negative CXR findings for active TB, and/or suspicious CXR findings) will not be allowed to participate in the study. Patient must be able and willing to provide written informed consent and comply with the requirements of this study protocol. Patient must be able and willing to self-administer SC injections or have a qualified person available to administer SC injections. Exclusion Criteria: Patient has spontaneously improving or rapidly deteriorating plaque psoriasis. Patient has other active infections (bacterial, fungal or viral) or skin diseases or skin infections (bacterial, fungal, or viral) that may interfere with evaluation of psoriasis or with patient's safety. Patient has a history of an allergic reaction or significant sensitivity to constituents of study drug, including latex (a component of the pre-filled syringe). Patient has used a non-biological systemic therapy for the treatment of psoriasis less than 30 days before Day 0. Patient has used an investigational chemical or biological agent less than 30 days or 5 half-lives prior to the Day 0 visit (whichever is longer). Patient has used a biological therapy for the treatment of psoriasis less than 90 days before day 0. Patient has used a systemic immnosuppressor (eg. Azathioprine, 6-mercaptopurine) less than 30 days before Day 0. Patient is taking or requires oral or injectable corticosteroids during the study. Inhaled corticosteroids for stable medical conditions are allowed. Patient has used a topical treatment for psoriasis or has used phototherapy within the last 2 weeks prior to Day 0 (at the exception of low potency topical corticosteroids for groin, genitals, face, inflammatory area, palms and soles). Patient has received Anakinra/Kineret within the last 2 weeks prior to the Day 0 visit or is likely to receive Anakinra/Kineret during the course of the study Patient has a poorly controlled medical condition, such as uncontrolled diabetes, documented history of recurrent infections, unstable ischemic heart disease, class III or IV (New York Heart Association Functional Classification; NYHA) congestive heart failure, an ejection fraction of less than 30%, recent stroke (within the past 3 months), chronic leg ulcer or any other condition which, in the opinion of the investigator, would put the patient at risk if participating in the study. Patient has had a myocardial infarction or has been hospitalized for a cardiac condition within the past 12 weeks. Patient has a history of acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass graft, carotid endarterectomy, stent installation or carotid revascularization within 12 weeks of Day 0. Patient has had a percutaneous coronary intervention in the past 12 months. Patient plans for a change in medical treatment for angina, serum lipids, hypertension or any other medication that can have a significant effect on inflammation during the course of the study. Patient has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease (e.g. optic neuritis, visual disturbance, gait disorder/ataxia, facial paresis, apraxia). Patient has history of cancer or lymphoproliferative disease other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix. Patient has a history of listeriosis, treated or untreated Tuberculosis (TB), persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous anti-infectives within 30 days prior to the Day 0 visit or oral anti-infectives within 14 days prior to the Day 0 visit. Patient has received a live attenuated vaccine 28 days or less before Day 0 or plan to receive a live attenuated vaccine during the study and up to 4 months after the last study drug administration.. Patient with hepatitis B or hepatitis C viral infection Patient with any of the following: hemoglobin ≤ 10 g/L, white blood cell count ≤ 3.0 X 109/L, platelet count ≤130 X 109/L, ALT ≥ 2 times the upper limit of normal, AST ≥ 3 times the upper normal limit, total bilirubin ≥ 2 times the upper normal limit or creatinine ≥ 150 µmol/L. Patient currently uses or plans to use anti-retroviral therapy at any time during the study. Patient is known to have immune deficiency or is immunocompromised. Female patient who is pregnant or breast-feeding or considering becoming pregnant during the study or for 6 months after the last dose of study medication. Patient has a history of clinically significant drug or alcohol abuse in the last year. Patient who plans to travel in an area where tuberculosis is endemic during the study and up to 4 months after the last study drug administration. Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group Adalimumab<br>A total of 53 patients with moderate to severe psoriasis will randomized in the adalimumab group. At Day 0 patients will receive adalimumab. It will be administered sub-cutaneously as described in the Canadian product monograph (80mg followed by 40mg at Week 1 and 40mg every other week). At Week 16, all patients will received two injections of placebo. As of Week 17, patients randomized to the adalimumab group will receive 40 mg adalimumab every other week until Week 51. | Biological: Adalimumab<br>* Injection of adalimumab (80 mg followed by 40 mg at week 1 and 40 mg EOW thereafter for 52 weeks). For Adalimibab group and Placebo group.<br>* Other names: Humira;|
| Placebo Comparator: Placebo Group<br>A total of 53 patients with moderate to severe psoriasis will be randomized in the placebo group. At Day 0 these patients will receive the placebo. It will be administered sub-cutaneously as described in the Canadian product monograph of adalimumab. At Week 16, all these patients will received two injections of adalimumab. As of Week 17, patients randomized to the placebo group will receive 40 mg adalimumab every other week until Week 67. | Biological: Adalimumab<br>* Injection of adalimumab (80 mg followed by 40 mg at week 1 and 40 mg EOW thereafter for 52 weeks). For Adalimibab group and Placebo group.<br>* Other names: Humira;Other: Placebo<br>* Injection of placebo that is physicaly identical to adalimumab without the active ingredient at identical intervals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the target (atherosclerotic plaque) to background (blood) ratio (TBR) from the ascending aorta at Week 16 for patients randomized to adalimumab as compared to patients randomized to placebo |  | Baseline, Week 16 and Week 52 or 68 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the TBR from the mean of both carotid arteries at Week 16 for patients randomized to adalimumab as compared to patients randomized to placebo |  | Baseline, Week 16 and Week 52 or 68 | 
| Change from baseline in the TBR from the ascending aorta 52 weeks after the first dose of adalimumab |  | Baseline and Week 52 or 68 | 
| Change from baseline in the TBR from the mean of both carotid arteries 52 weeks after the first dose of adalimumab |  | Baseline and Week 52 or 68 | 
| Change from baseline in carotid wall area at Week 16 as measured by MRI for patients randomized to adalimumab as compared to patients randomized to placebo |  | Baseline and Week 16 | 
| Change from baseline in carotid wall area as measured by Magnetic Resonance Imaging (MRI) 52 weeks after the first dose of adalimumab |  | Baseline and Week 52 or 68 | 
| Change from baseline in hsCRP at Week 16 for patients randomized to adalimumab as compared to patients randomized to placebo |  | Baseline and Week 16 | 
| Change from baseline in serum lipids (total cholesterol, LDL- calc, HDL cholesterol, triglycerides) at Week 16 for patients randomized to adalimumab as compared to patients randomized to placebo |  | Baseline, Week 16 | 
| Correlation between change from baseline in TBR from the ascending aorta at Week 16 and change from baseline in PASI at Week 16 |  | Baseline and Week 16 | 
| Correlation between change from baseline in PASI at Week 16 and change in hsCRP at Week 16 |  | Baseline and week 16 | 
| Correlation between change from baseline in TBR from the ascending aorta at Week 16 and change from baseline in hsCRP at Week 16 |  | Baseline and Week 16 | 
| Correlation between change from baseline in TBR at Week 16 from the ascending aorta and change from baseline in skin inflammation as measured by PET-Scan at Week 16 |  | Baseline and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psoriasis, Vascular Inflammation, Coronary Atherosclerosis, Ascending aorta, Pet scan, MRI