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Mechanism of Action Study for Psoriasis (MOA)

Primary Purpose

Psoriasis

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Methotrexate
Adalimumab (Humira)
Sponsored by
Tufts Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Psoriasis focused on measuring tumor necrosis factor (TNF) inhibitor, tumor necrosis factor (TNF) blockade, Methotrexate, treatment, mechanism, psoriasis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Tufts Medical Center, Department of Dermatology

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Adalimumab

Methotrexate (MTX)

Arm Description

Dosing will be on day 1 and then weekly. For the injections, dosing will occur according to product recommendations. Patients will receive 80mg adalimumab (2 pre-filled syringes, each with 40mg) on day 1, and then 40mg on week 1 and then every 2 weeks (from week 1 through week 15).

Patients will be dosed according to the CHAMPION study in single weekly doses of methotrexate: 7.5mg at week 0, 10mg at week two, and 15mg at week 4 for all patients. For each subject if the PASI did not decrease by at least 50% from baseline (PASI-50) at week 8, dosing will be increased to 20mg per week; the dose will be maintained at 15mg per week if PASI-50 was achieved at week 8. If PASI-50 was not achieved at week 12, dosing will be increased to 25mg per week; the dose will be maintained at 20mg per week if the PASI-50 was achieved at week 12. All patients on methotrexate will also receive a dietary supplement of oral folate (5mg per week). Methotrexate-treated patients will then receive 16 weeks of adalimumab at the end of study.

Outcomes

Primary Outcome Measures

Biologic Activity Endpoints
Histologic and Immunohistochemistry endpoints; Relative messenger RNA gene expression (normalized to HARP); and Gene Arrays.

Secondary Outcome Measures

Clinical Endpoints for Psoriasis: PASI 75
PASI 75 is the percent of subjects who experience an improvement in PASI (Psoriasis Area and Severity Index) score of at least 75% from their baseline PASI score.
Clinical Endpoints for Psoriasis: Physician's Global Assessment (PGA) Clear or Almost Clear (PGA 0-1)
Clinical Endpoints for Psoriasis: % Body Surface Area
Clinical Endpoints for Psoriasis: Target Lesion Score
The lesion score of a single psoriatic plaque selected at baseline. Total range is 0 - 12 with 0 being clear and 12 representing the most severe disease. The target lesion score is composed of scale, erythema, and induration, each parameter is scored 0 (clear) through 4 (very severe). Totals are summed for target lesion score. S+E+I = TLS
Clinical Endpoints for Psoriasis: Photography Completed

Full Information

First Posted
June 30, 2009
Last Updated
August 1, 2017
Sponsor
Tufts Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT00932113
Brief Title
Mechanism of Action Study for Psoriasis
Acronym
MOA
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

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
May 1, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tufts Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Psoriasis
Keywords
tumor necrosis factor (TNF) inhibitor, tumor necrosis factor (TNF) blockade, Methotrexate, treatment, mechanism, psoriasis

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Adalimumab
Arm Type
Active Comparator
Arm Description
Dosing will be on day 1 and then weekly. For the injections, dosing will occur according to product recommendations. Patients will receive 80mg adalimumab (2 pre-filled syringes, each with 40mg) on day 1, and then 40mg on week 1 and then every 2 weeks (from week 1 through week 15).
Arm Title
Methotrexate (MTX)
Arm Type
Active Comparator
Arm Description
Patients will be dosed according to the CHAMPION study in single weekly doses of methotrexate: 7.5mg at week 0, 10mg at week two, and 15mg at week 4 for all patients. For each subject if the PASI did not decrease by at least 50% from baseline (PASI-50) at week 8, dosing will be increased to 20mg per week; the dose will be maintained at 15mg per week if PASI-50 was achieved at week 8. If PASI-50 was not achieved at week 12, dosing will be increased to 25mg per week; the dose will be maintained at 20mg per week if the PASI-50 was achieved at week 12. All patients on methotrexate will also receive a dietary supplement of oral folate (5mg per week). Methotrexate-treated patients will then receive 16 weeks of adalimumab at the end of study.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Methotrexate (MTX), Folic Acid
Intervention Description
2 cohorts (Randomized 1:1 adalimumab:methotrexate). Subjects will receive treatment on Day 1 (baseline visit) and then weekly or every 2 weeks for 16 weeks. Methotrexate-treated patients will then receive 16 weeks of adalimumab at the end of study.
Intervention Type
Drug
Intervention Name(s)
Adalimumab (Humira)
Other Intervention Name(s)
Humira
Intervention Description
2 cohorts (Randomized 1:1 adalimumab:methotrexate). Subjects will receive treatment on Day 1 (baseline visit) and then weekly or every 2 weeks for 16 weeks.
Primary Outcome Measure Information:
Title
Biologic Activity Endpoints
Description
Histologic and Immunohistochemistry endpoints; Relative messenger RNA gene expression (normalized to HARP); and Gene Arrays.
Time Frame
Weeks 0, 1, 2, 4 and 16
Secondary Outcome Measure Information:
Title
Clinical Endpoints for Psoriasis: PASI 75
Description
PASI 75 is the percent of subjects who experience an improvement in PASI (Psoriasis Area and Severity Index) score of at least 75% from their baseline PASI score.
Time Frame
Weeks 0 and week 16
Title
Clinical Endpoints for Psoriasis: Physician's Global Assessment (PGA) Clear or Almost Clear (PGA 0-1)
Time Frame
Week 0 and Week 16
Title
Clinical Endpoints for Psoriasis: % Body Surface Area
Time Frame
Week 0 and week 16
Title
Clinical Endpoints for Psoriasis: Target Lesion Score
Description
The lesion score of a single psoriatic plaque selected at baseline. Total range is 0 - 12 with 0 being clear and 12 representing the most severe disease. The target lesion score is composed of scale, erythema, and induration, each parameter is scored 0 (clear) through 4 (very severe). Totals are summed for target lesion score. S+E+I = TLS
Time Frame
Week 0 and Week 16
Title
Clinical Endpoints for Psoriasis: Photography Completed
Time Frame
Week 0 and Week 16
Other Pre-specified Outcome Measures:
Title
Additional Gene Analysis (Ongoing)
Description
A single, long-term follow-up visit will be done for all available subjects for additional pharmacogenetic analysis. The goal in collecting DNA from psoriasis patients is to determine if individual subjects have gene variants associated with increased incidence of psoriasis. The investigators plan on analyzing variants using single nucleotide polymorphism (SNP) analysis by high-throughput DNA sequencing. This patient genetic information may allow us to correctly interpret data collected about gene expression levels in affected or non-affected skin. Additionally genetic typing may lead to cogent personalized health care (PHC) strategies for the identification of psoriasis drug responders/non-responders, patients who achieve durable disease remission post-treatment, and/or pharmacodynamic markers, as examples.
Time Frame
long-term follow-up visit 4- 6 years post end of study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alice B. Gottlieb, M.D., PhD.
Organizational Affiliation
Tufts Medical Center, Department of Dermatology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tufts Medical Center, Department of Dermatology
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
17039656
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.
Results Reference
background
PubMed Identifier
17010737
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.
Results Reference
background
PubMed Identifier
16081850
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.
Results Reference
background
PubMed Identifier
17502868
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.
Results Reference
background
PubMed Identifier
15955104
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.
Results Reference
background
PubMed Identifier
18047523
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.
Results Reference
result
PubMed Identifier
25946554
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.
Results Reference
derived

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Mechanism of Action Study for Psoriasis

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