Study Results
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Basic Information
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COMPLETED
PHASE4
30 participants
INTERVENTIONAL
2022-04-08
2024-05-27
Brief Summary
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Objective: Evaluate if tildrakizumab reverses peripheral blood leukocyte DNA methylation (epigenetic aging) observed in chronic psoriasis.
Number of subjects: 30. Intervention group: 20 (10 men, 10 women) with moderate-to-severe psoriasis. Control group: 10 (5 men, 5 women) with other skin diagnosis.
Population: \>35-year-old subjects will be recruited from Brown Dermatology clinics.
Biological samples: Blood samples will be collected for all subjects at screening, and weeks 16, 28 and 52. Urine pregnancy tests will be performed for females of childbearing potential at weeks 4, 16, and 28. Serum pregnancy test and QuantiFERON test for tuberculosis will be performed at screening visit.
Safety parameters: Adverse events, and screening, week 16, week 28 blood samples laboratory results. Females of childbearing potential: serum pregnancy test at screening visit, urine pregnancy test at weeks 4, 16, and 28. Data Safety Monitoring Board will review data and laboratory flags quarterly.
Study center: Rhode Island Hospital, Providence, RI, USA.
Trial Duration: One year.
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Detailed Description
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Psoriasis is a common, chronic, inflammatory disorder that affects millions of individuals worldwide.1,2 Although psoriasis etiology is still largely unknown and its precision management remains to be improved, advances in understanding the pathogenic cytokine network of psoriasis have led to the development of biologic therapy, such as FDA-approved on-label indication for moderate-to-severe psoriasis of tildrakizumab-asmn (ILUMYA, Sun Pharma Global, Princeton, NJ), an injectable monoclonal antibody that inhibit interleukin (IL)-23, a pro-inflammatory cytokine. Epidemiologic studies have promoted the recognition of psoriasis as a systemic disorder.3 Associations between psoriasis and incident risk of diabetes, cardiovascular disease, Crohn's disease, and gout have been reported in prospective studies.4-7 However, the mechanism underlying the systemic manifestations has been a knowledge gap for research on psoriasis.8
2. Epigenetic aging (DNA methylation)
The complex interplay of genetic and environmental factors in psoriasis may occur through the epigenetic mechanisms. DNA methylation of cytosine followed by guanine residues (CpG dinucleotides), the epigenetic process that participates in the transcriptional regulation and gene expression, has been linked to psoriasis.9 As the precise pathogenesis underlying the development of psoriasis remains largely undefined, further exploration of the role of epigenetics would offer a biologically plausible perspective to clarify psoriasis etiology. Epigenetic epidemiology would serve as a tool to elucidate the susceptibility and to identify novel biomarkers for psoriasis.10 The epigenetic clock is a novel biomarker of aging, developed based on DNA methylation.11-13 The epigenetic clock may capture aspects of "biological age" and older epigenetic age of blood has been associated with all-cause mortality,14,15 obesity,16 and many diseases.17-20 Although whether epigenetic age is associated with psoriasis is not yet known, previous research from our group recently found that average epigenetic age in psoriasis patients was 5 years higher than their corresponding chronological age (data not published), suggesting possible epigenetic age acceleration in psoriasis. Therefore, epigenetic age acceleration may serve as a novel biomarker for psoriasis and its systemic manifestations. It may also potentially be used as an intermediate biomarker assessing the systemic effects of tildrakizumab.
Blood-based measures of epigenetics have the advantage of interrogating the systemic health status or treatment responses and assessing biomarkers across a large variety of disease domains.10,21
Rationale for the study:
Although epigenetic changes are tissue-specific, the connections between epigenetic epidemiology and psoriasis in blood-based epigenetic studies would decipher novel systemic inflammation and immune states of psoriasis and elucidate the effect of tildrakizumab use on the epigenetic age acceleration. Comprehensive assessment of epigenetic age acceleration in blood leukocytes between psoriasis and controls, and the change in epigenetic age acceleration after tildrakizumab initiation may lead to the identification of methylation markers for predicting the systemic risk of psoriasis and the effect of tildrakizumab on psoriasis. If confirmed to be an intermediate marker for the effect of psoriasis therapy with tildrakizumab, epigenetic age may be used to better profile the beneficial role of immunomodulation, promoting the management of psoriasis and its systemic comorbidities.
Psoriasis is an inflammatory disease of the skin and joints and has been recognized as a systemic disorder. In this proposed study, the investigators hypothesize that epigenetic age acceleration may be associated with psoriasis, and tildrakizumab may be able to affect the epigenetic age acceleration associated with psoriasis.
3. Objective
To determine the association between epigenetic age acceleration and risk of psoriasis, and also to evaluate if tildrakizumab can reverse peripheral blood leukocyte DNA methylation (epigenetic aging) associated with chronic psoriasis.
Specific Aim 1: To examine the association between epigenetic age acceleration and psoriasis: by comparing the baseline samples of peripheral blood leukocyte genome-wide DNA methylation assay collected at screening for psoriasis patients and controls.
Specific Aim 2: To evaluate dynamic changes in epigenetic age of the on-label use of tildrakizumab (week 28 vs screening visit). And upon discontinuation (week 28 vs week 52). Assess if epigenetic age could be a marker for the effect of tildrakizumab on psoriasis through psoriasis severity scores.
Specific Aim 3: We will evaluate the transcriptomic impact of ILUMYA therapy in patients with psoriasis and possible correlation/association with Epigenetic changes, psoriasis severity scores, the presence of systemic comorbidities.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
Arm 1 (psoriasis treatment): 20 subjects with moderate-to-severe psoriasis (including 10 men and 10 women).
Arm 2 (non-psoriasis, non-treatment): 10 age and sex matched controls without psoriasis (including 5 men and 5 women).
The blood leukocytes will be collected to evaluate DNA methylation at baseline (week 0) for both arms. The psoriasis treatment arm will undergo blood leukocytes collection during treatment (at week 28) and post-treatment (week 52).
BASIC_SCIENCE
NONE
Study Groups
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PSORIASIS TREATMENT
1 syringe containing 1 mL of 100 mg/mL tildrakizumab-asmn. 100mg delivered by subcutaneous injection at weeks 0, 4, 16 and 28. Total of 20 subjects (10 male, 10 female).
TILDRAKIZUMAB
ILUMYA (tildrakizumab-asmn) is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.
ILUMYA injection for subcutaneous use is a sterile, clear to slightly opalescent, colorless to slightly yellow solution supplied in 1mL single-dose prefilled syringe which contains 100 mg of tildrakizumab-asmn formulated in: L-histidine (0.495 mg), L-histidine hydrochloride monohydrate (1.42 mg), polysorbate 80 (0.5 mg), sucrose (70.0 mg), and Water for Injection, USP with a pH of 5.7-6.3. ILUMYA is supplied in a single-dose prefilled syringe with a glass barrel and 29-gauge fixed, 1/2-inch needle.
NON-PSORIASIS
No intervention. Total of 10 subjects (5 male, 5 female).
No interventions assigned to this group
Interventions
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TILDRAKIZUMAB
ILUMYA (tildrakizumab-asmn) is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.
ILUMYA injection for subcutaneous use is a sterile, clear to slightly opalescent, colorless to slightly yellow solution supplied in 1mL single-dose prefilled syringe which contains 100 mg of tildrakizumab-asmn formulated in: L-histidine (0.495 mg), L-histidine hydrochloride monohydrate (1.42 mg), polysorbate 80 (0.5 mg), sucrose (70.0 mg), and Water for Injection, USP with a pH of 5.7-6.3. ILUMYA is supplied in a single-dose prefilled syringe with a glass barrel and 29-gauge fixed, 1/2-inch needle.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Psoriasis subjects: moderate-to-severe psoriasis: PASI (Psoriasis Area and Severity Index ≥12) and a minimum Body Surface Area (BSA) involvement of 10%.
* Control Subjects: other skin diseases without psoriasis.
Exclusion Criteria
2. Patients with previous skin cancer or other cancers.
3. Women of childbearing potential without effective contraceptive method, or lactating women.
4. Prisoners.
5. Psoriasis patients who have had a severe allergic reaction to ILUMYA or any of its ingredients.
6. Psoriasis patients who have chronic or recurring infections. Positive QuantiFERON upon screening will be exclusionary for this trial (latent tuberculosis).
7. Any condition that, in the opinion of the investigator, may interfere with patient's ability to participate in the study, such as severe cognitive impairment or other comorbidities that would, in the opinion of the investigator, predictably limit compliance with the study plan.
35 Years
ALL
Yes
Sponsors
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Sun Pharmaceutical Industries Limited
INDUSTRY
Brown University
OTHER
Lifespan
OTHER
Ocean State Research Institute, Inc.
OTHER
Carlos Wambier
OTHER
Responsible Party
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Carlos Wambier
Associate Professor of Dermatology, Clinician Educator
Principal Investigators
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Carlos G Wambier, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Department of Dermatology, Warren Alpert Medical School of Brown University
Locations
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Clinical Trials Center for Skin Diseases: Rhode Island Hospital, 593 Eddy Street, Dermatology Research, Jane Brown Building, 1st floor, Room 115
Providence, Rhode Island, United States
Countries
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References
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Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007 Feb 22;445(7130):866-73. doi: 10.1038/nature05663.
Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol. 2009 Feb;60(2):218-24. doi: 10.1016/j.jaad.2008.09.022. Epub 2008 Nov 20.
Li WQ, Cho E, Weinstock MA, Mashfiq H, Qureshi AA. Epidemiological Assessments of Skin Outcomes in the Nurses' Health Studies. Am J Public Health. 2016 Sep;106(9):1677-83. doi: 10.2105/AJPH.2016.303315. Epub 2016 Jul 26.
Li W, Han J, Hu FB, Curhan GC, Qureshi AA. Psoriasis and risk of type 2 diabetes among women and men in the United States: a population-based cohort study. J Invest Dermatol. 2012 Feb;132(2):291-8. doi: 10.1038/jid.2011.319. Epub 2011 Oct 13.
Li WQ, Han JL, Manson JE, Rimm EB, Rexrode KM, Curhan GC, Qureshi AA. Psoriasis and risk of nonfatal cardiovascular disease in U.S. women: a cohort study. Br J Dermatol. 2012 Apr;166(4):811-8. doi: 10.1111/j.1365-2133.2011.10774.x.
Li WQ, Han JL, Chan AT, Qureshi AA. Psoriasis, psoriatic arthritis and increased risk of incident Crohn's disease in US women. Ann Rheum Dis. 2013 Jul;72(7):1200-5. doi: 10.1136/annrheumdis-2012-202143. Epub 2012 Aug 31.
Merola JF, Wu S, Han J, Choi HK, Qureshi AA. Psoriasis, psoriatic arthritis and risk of gout in US men and women. Ann Rheum Dis. 2015 Aug;74(8):1495-500. doi: 10.1136/annrheumdis-2014-205212. Epub 2014 Mar 20.
Ryan C, Korman NJ, Gelfand JM, Lim HW, Elmets CA, Feldman SR, Gottlieb AB, Koo JY, Lebwohl M, Leonardi CL, Van Voorhees AS, Bhushan R, Menter A. Research gaps in psoriasis: opportunities for future studies. J Am Acad Dermatol. 2014 Jan;70(1):146-67. doi: 10.1016/j.jaad.2013.08.042. Epub 2013 Oct 11.
Gudjonsson JE, Krueger G. A role for epigenetics in psoriasis: methylated Cytosine-Guanine sites differentiate lesional from nonlesional skin and from normal skin. J Invest Dermatol. 2012 Mar;132(3 Pt 1):506-8. doi: 10.1038/jid.2011.364.
Nelson HH, Kelsey KT. Epigenetic epidemiology as a tool to understand the role of immunity in chronic disease. Epigenomics. 2016 Aug;8(8):1007-9. doi: 10.2217/epi-2016-0055. Epub 2016 Jul 13. No abstract available.
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi: 10.1186/gb-2013-14-10-r115.
Bocklandt S, Lin W, Sehl ME, Sanchez FJ, Sinsheimer JS, Horvath S, Vilain E. Epigenetic predictor of age. PLoS One. 2011;6(6):e14821. doi: 10.1371/journal.pone.0014821. Epub 2011 Jun 22.
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013 Jan 24;49(2):359-367. doi: 10.1016/j.molcel.2012.10.016. Epub 2012 Nov 21.
Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, Gibson J, Henders AK, Redmond P, Cox SR, Pattie A, Corley J, Murphy L, Martin NG, Montgomery GW, Feinberg AP, Fallin MD, Multhaup ML, Jaffe AE, Joehanes R, Schwartz J, Just AC, Lunetta KL, Murabito JM, Starr JM, Horvath S, Baccarelli AA, Levy D, Visscher PM, Wray NR, Deary IJ. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015 Jan 30;16(1):25. doi: 10.1186/s13059-015-0584-6.
Christiansen L, Lenart A, Tan Q, Vaupel JW, Aviv A, McGue M, Christensen K. DNA methylation age is associated with mortality in a longitudinal Danish twin study. Aging Cell. 2016 Feb;15(1):149-54. doi: 10.1111/acel.12421. Epub 2015 Nov 17.
Horvath S, Erhart W, Brosch M, Ammerpohl O, von Schonfels W, Ahrens M, Heits N, Bell JT, Tsai PC, Spector TD, Deloukas P, Siebert R, Sipos B, Becker T, Rocken C, Schafmayer C, Hampe J. Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15538-43. doi: 10.1073/pnas.1412759111. Epub 2014 Oct 13.
Horvath S, Ritz BR. Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients. Aging (Albany NY). 2015 Dec;7(12):1130-42. doi: 10.18632/aging.100859.
Horvath S, Levine AJ. HIV-1 Infection Accelerates Age According to the Epigenetic Clock. J Infect Dis. 2015 Nov 15;212(10):1563-73. doi: 10.1093/infdis/jiv277. Epub 2015 May 12.
Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S. DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative. Aging (Albany NY). 2015 Sep;7(9):690-700. doi: 10.18632/aging.100809.
Related Links
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Brown Dermatology Clinical Trials Website
Other Identifiers
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20-056
Identifier Type: OTHER
Identifier Source: secondary_id
420620
Identifier Type: -
Identifier Source: org_study_id
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