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

Psoriasis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01722214
• Other study ID #: Inno-6025
• Status: Completed
• Phase: Phase 4
• First received: November 2, 2012
• Last updated: September 8, 2016
• Start date: November 2012
• Est. completion date: January 2016

Study information

• Verified date: September 2016
• Source: Innovaderm Research Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: January 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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:

1. Barrier methods such as condom, sponge or diaphragm combined with spermicide in foam, gel or cream;

2. Hormonal contraception (oral, intramuscular, implant or transdermal) which include Depo-Provera, Evra and Nuvaring;

3. 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Atherosclerosis
• Coronary Artery Disease
• Coronary Atherosclerosis
• Inflammation
• Myocardial Ischemia
• Psoriasis
• Vascular Inflammation

Intervention

Biological:
• Adalimumab
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.

Other:
• Placebo
Injection of placebo that is physicaly identical to adalimumab without the active ingredient at identical intervals.

Locations

Country	Name	City	State
Canada	Lynderm Research Inc.	Markham	Ontario
Canada	Innovaderm Research Inc	Montreal	Quebec
Canada	Montreal Healt Institute	Montreal	Quebec
Canada	Clinique Médicale Dr Isabelle Delorme	St-Hyacinthe	Quebec
Canada	Windsor Clinical Research Inc.	Windsor	Ontario

Sponsors (3)

Lead Sponsor	Collaborator
Innovaderm Research Inc.	Abbott, Montreal Heart Institute

Country where clinical trial is conducted

Canada, 

References & Publications (18)

Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, Torp-Pedersen C, Hansen PR. Prognosis following first-time myocardial infarction in patients with psoriasis: a Danish nationwide cohort study. J Intern Med. 2011 Sep;270(3):237-44. doi: 10.1111/j.1365-2796.2011.02368.x. Epub 2011 Mar 24. — View Citation

Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, van de Kerkhof P, Ståhle M, Nestle FO, Girolomoni G, Krueger JG. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010 Jul;130(7):1785-96. doi: 10.1038/jid.2010.103. Epub 2010 May 6. Review. Erratum in: J Invest Dermatol. 2010 Oct;130(10):2517. Jörg, Prinz C [corrected to Prinz, Jörg C]. — View Citation

Dixon WG, Symmons DP. What effects might anti-TNFalpha treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFalpha in cardiovascular pathophysiology. Ann Rheum Dis. 2007 Sep;66(9):1132-6. Epub 2007 Jan 24. Review. — View Citation

Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007 Sep;56(9):2905-12. — View Citation

Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new retinoid. Dermatologica. 1978;157(4):238-44. — View Citation

Gelfand JM, Dommasch ED, Shin DB, Azfar RS, Kurd SK, Wang X, Troxel AB. The risk of stroke in patients with psoriasis. J Invest Dermatol. 2009 Oct;129(10):2411-8. doi: 10.1038/jid.2009.112. Epub 2009 May 21. — View Citation

Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006 Oct 11;296(14):1735-41. — View Citation

Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21;352(16):1685-95. Review. — View Citation

Jacobsson LT, Turesson C, Gülfe A, Kapetanovic MC, Petersson IF, Saxne T, Geborek P. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005 Jul;32(7):1213-8. — View Citation

Ko H-S, M.D. Medical Officer, Division of Dermatologic and Dental Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda MD. Clinical Design for Psoriasis [presentation]. Dermatologic and Ophthalmic Drugs Advisory Committee 49th Meeting Open Session (Volume II); Gaithersburg, MD. 1998 March 20.

Marks R, Barton SP, Shuttleworth D, Finlay AY. Assessment of disease progress in psoriasis. Arch Dermatol. 1989 Feb;125(2):235-40. Review. — View Citation

Mehta NN, Yu Y, Saboury B, Foroughi N, Krishnamoorthy P, Raper A, Baer A, Antigua J, Van Voorhees AS, Torigian DA, Alavi A, Gelfand JM. Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study. Arch Dermatol. 2011 Sep;147(9):1031-9. doi: 10.1001/archdermatol.2011.119. Epub 2011 May 16. — View Citation

Miyasaka Y, Barnes ME, Petersen RC, Cha SS, Bailey KR, Gersh BJ, Casaclang-Verzosa G, Abhayaratna WP, Seward JB, Iwasaka T, Tsang TS. Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a community-based cohort. Eur Heart J. 2007 Aug;28(16):1962-7. Epub 2007 Apr 25. — View Citation

Moubayed SP, Heinonen TM, Tardif JC. Anti-inflammatory drugs and atherosclerosis. Curr Opin Lipidol. 2007 Dec;18(6):638-44. Review. — View Citation

Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009 Jun;145(6):700-3. doi: 10.1001/archdermatol.2009.94. — View Citation

Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis. 2007 Jan;66(1):70-5. Epub 2006 Jul 28. — View Citation

van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford). 2008 Jan;47(1):3-7. Epub 2007 Aug 16. Review. — View Citation

Wu F. The effect of tumor necrosis factor-alfa inhibitors on the risk of myocardial infarction in patients with psoriasis. E-poster session presented at the 69th American Academy of Dermatology, Abstract P400; 4-8 Feb 2011; New Orleans, USA.

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from baseline in hsCRP protein levels at 52 weeks after the first dose of adalimumab		Baseline and Week 52 or 68	No
Other	Change from baseline in serum lipids (total cholesterol, LDL- calc, HDL cholesterol, triglycerides) 52 weeks after the first dose of adalimumab		Baseline and Week 52 or 68	No
Primary	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	No
Secondary	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	No
Secondary	Change from baseline in the TBR from the ascending aorta 52 weeks after the first dose of adalimumab		Baseline and Week 52 or 68	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	Change from baseline in hsCRP at Week 16 for patients randomized to adalimumab as compared to patients randomized to placebo		Baseline and Week 16	No
Secondary	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	No
Secondary	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	No
Secondary	Correlation between change from baseline in PASI at Week 16 and change in hsCRP at Week 16		Baseline and week 16	No
Secondary	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	No
Secondary	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	No