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.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Biologic Activity Endpoints
研究概览
简要总结
The objective of this study is to compare the mechanism of action between adalimumab and methotrexate in subjects with psoriasis.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Adalimumab
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).
干预措施: Adalimumab (Humira) (Drug)
Methotrexate (MTX)
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.
干预措施: Methotrexate (Drug)
Methotrexate (MTX)
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.
干预措施: Adalimumab (Humira) (Drug)
结局指标
主要结局
Biologic Activity Endpoints
时间窗: Weeks 0, 1, 2, 4 and 16
Histologic and Immunohistochemistry endpoints; Relative messenger RNA gene expression (normalized to HARP); and Gene Arrays.
次要结局
- Clinical Endpoints for Psoriasis: % Body Surface Area(Week 0 and week 16)
- Clinical Endpoints for Psoriasis: Photography Completed(Week 0 and Week 16)
- Clinical Endpoints for Psoriasis: PASI 75(Weeks 0 and week 16)
- Clinical Endpoints for Psoriasis: Physician's Global Assessment (PGA) Clear or Almost Clear (PGA 0-1)(Week 0 and Week 16)
- Clinical Endpoints for Psoriasis: Target Lesion Score(Week 0 and Week 16)