Clinical trial NCT00932113: Mechanism of Action Study for Psoriasis
Official title: An Investigator-Initiated, Assessor Blinded, Randomized Study Comparing the Mechanism of Action of Adalimumab to Methotrexate in Subjects With Moderate to Severe Chronic Plaque Psoriasis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Psoriasis
Keywords: tumor necrosis factor (TNF) inhibitor
tumor necrosis factor (TNF) blockade
Methotrexate
treatment
mechanism
psoriasis
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
First posted: 2009-07-03
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The objective of this study is to compare the mechanism of action between adalimumab and methotrexate in subjects with psoriasis.

Detailed description: Both methotrexate and adalimumab are FDA-approved drugs for the treatment of moderate to severe psoriasis. The two treatments, methotrexate and adalimumab, both show efficacy for psoriasis, however their profiles differ. In the CHAMPION Study, more adalimumab-treated, moderate to severe psoriasis patients achieved a PASI 75 after 16 weeks compared to those treated with methotrexate (80% vs. 36%). The reason for this difference is poorly understood. No direct comparative mechanism of action studies in psoriasis patients between methotrexate and adalimumab (or any tumor necrosis factor blocker) has been reported.

With etanercept, another tumor necrosis factor blocker, the in vivo mechanism has been studied with some scientific rigor. These studies demonstrate that etanercept down regulates multiple pro-inflammatory pathways (as shown in Table 1 of the protocol).

To date, there are no similar studies with adalimumab or methotrexate.

In order to understand the molecular and cellular basis for the differential clinical efficacy of adalimumab and methotrexate, it is essential to compare their mechanisms of action in psoriatic plaques. Biopsies will be performed, and we will study biomarkers in this proposal with immunohistochemistry, real-time polymerase chain reaction, and gene arrays.

Eligibility criteria: Inclusion Criteria:

* Adults 18-85 years of age with moderate to severe psoriasis, in general good health as determined by the PI based upon the results of medical history, laboratory profile, and physical examination, and who are candidates for systemic or phototherapy
* Presence of a psoriatic plaque of \>2cm in an area which can be biopsied repeatedly.
* Men must agree to avoid impregnating a woman while on this study.
* Women are eligible to participate in the study if they meet one of the following criteria:

  * Women who are postmenopausal (\>1 year), sterile, or hysterectomized
  * Women of childbearing potential must undergo monthly pregnancy testing during the study and agree to use two of the following methods of contraception throughout and for 60 days after the last dose of study drug:

    * Oral contraceptives
    * Transdermal contraceptives
    * Injectable or implantable methods
    * Intrauterine devices
    * Barrier methods (diaphragm or condom with spermicide)
    * Abstinence and Tubal Ligation are also considered a form of Birth control

Exclusion Criteria:

* Patients \<18 or \>85 years old
* Absence of a psoriatic plaque \>2cm in diameter
* Active guttate, erythrodermic, or pustular psoriasis at the time of the screening visit
* Evidence of skin conditions at screening (e.g. eczema) that would interfere with evaluations of the effect of study medication
* Inability to understand the consent process
* Receipt of any investigational drugs, psoralen+ultraviolet A or oral systemic treatments within 4 weeks of study drug initiation
* Biologics within 3 months of study initiation
* Topical steroids, topical vitamin A or D analog preparations, Ultraviolet B therapy or anthralin within 2 weeks of study drug initiation. (Exception-stable regimen of class I-II topical steroids on scalp, axillae, and groin)
* Methotrexate within 6 weeks of study initiation
* History of treatment with adalimumab
* History of primary non-response to methotrexate, infliximab or etanercept
* History of discontinuation of methotrexate or tumor necrosis factor (TNF) blocker for a safety-related reason that makes it unwise to restart either type of drug
* Any internal malignancy within 5 years (excluding fully excised cutaneous basal cell or squamous cell carcinoma)
* Pregnancy, not practicing effective birth control, or inability to practice safe sex during the length of the study
* Lactation
* Subjects who have known hypersensitivity to adalimumab or methotrexate or any of its components or who is known to have antibodies to etanercept
* History of alcohol or drug abuse one year before and during the study
* Known HIV-positive status or any other immune-suppressing disease
* Presence of a grade 3 or 4 infection \<30 days prior to the screening visit, between the screening visit and the first day of treatment on study, or any time during the study that in the opinion of the PI would preclude participation in the study
* Any grade 3 or 4 adverse event, or laboratory toxicity, at the time of the screening visit or at any time during the study, which in the opinion of the PI would, preclude participation in the study

  * Serum creatinine \>3.0 mg/dL (265 micromoles/L)
  * Serum potassium \<3.5 mmol/L or \> 5.5 mmol/L
  * Serum alanine aminotransferase or aspartate aminotransferase \>3 times the upper limit of normal for the lab
  * Platelet count \<100,000/mm3
  * White blood cell count \<3,000/mm3
  * Hgb, Hct, or red blood cell outside 30% of the upper or lower limits of normal for the Lab
* Receipt of live vaccines 1 month prior to or while on study
* History of tuberculosis, and/or a positive PPD skin test/chest x-ray at screening without appropriate treatment-treatment of latent tuberculosis (for those with positive PPD tests) must be initiated prior to therapy with adalimumab or methotrexate
* Chronic hepatitis B or C infection, history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy

Primary outcomes:
measure: Biologic Activity Endpoints
timeFrame: Weeks 0, 1, 2, 4 and 16
Secondary outcomes:
measure: Clinical Endpoints for Psoriasis: PASI 75
timeFrame: Weeks 0 and week 16
measure: Clinical Endpoints for Psoriasis: Physician's Global Assessment (PGA) Clear or Almost Clear (PGA 0-1)
timeFrame: Week 0 and Week 16
measure: Clinical Endpoints for Psoriasis: % Body Surface Area
timeFrame: Week 0 and week 16
measure: Clinical Endpoints for Psoriasis: Target Lesion Score
timeFrame: Week 0 and Week 16
measure: Clinical Endpoints for Psoriasis: Photography Completed
timeFrame: Week 0 and Week 16
Other outcomes:
measure: Additional Gene Analysis (Ongoing)
timeFrame: long-term follow-up visit 4- 6 years post end of study
Locations:
city: Boston
country: United States
facility: Tufts Medical Center, Department of Dermatology
state: Massachusetts
Study officials:
affiliation: Tufts Medical Center, Department of Dermatology
name: Alice B. Gottlieb, M.D., PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Malaviya R, Sun Y, Tan JK, Magliocco M, Gottlieb AB. Induction of lesional and circulating leukocyte apoptosis by infliximab in a patient with moderate to severe psoriasis. J Drugs Dermatol. 2006 Oct;5(9):890-3.
citation: Malaviya R, Sun Y, Tan JK, Wang A, Magliocco M, Yao M, Krueger JG, Gottlieb AB. Etanercept induces apoptosis of dermal dendritic cells in psoriatic plaques of responding patients. J Am Acad Dermatol. 2006 Oct;55(4):590-7. doi: 10.1016/j.jaad.2006.05.004. Epub 2006 Jul 3.
citation: Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 2005 Aug 15;175(4):2721-9. doi: 10.4049/jimmunol.175.4.2721.
citation: Tan JK, Aphale A, Malaviya R, Sun Y, Gottlieb AB. Mechanisms of action of etanercept in psoriasis. J Investig Dermatol Symp Proc. 2007 May;12(1):38-45. doi: 10.1038/sj.jidsymp.5650037.
citation: Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, Gottlieb AB. Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol. 2005 Jun;124(6):1275-83. doi: 10.1111/j.0022-202X.2005.23735.x.
citation: Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, Unnebrink K, Kaul M, Camez A; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008 Mar;158(3):558-66. doi: 10.1111/j.1365-2133.2007.08315.x. Epub 2007 Nov 28.
citation: Goldminz AM, Suarez-Farinas M, Wang AC, Dumont N, Krueger JG, Gottlieb AB. CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial. JAMA Dermatol. 2015 Aug;151(8):837-46. doi: 10.1001/jamadermatol.2015.0452.