Methotrexate Polyglutamate Levels as a Marker for the Clinical Outcome in the Treatment of Rheumatoid Arthritis

Study Overview
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Brief Summary
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The primary objective is to determine whether erythrocyte polyglutamate levels are associated with objective clinical response in patients with rheumatoid arthritis after oral administration of low-dose methotrexate.The secondary aim of this study is to compare the efficacy and safety of standard dose methotrexate versus a higher starting dose.

Detailed Description
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The folate antagonist methotrexate (MTX) is currently one of the most widely used drugs for the treatment of rheumatoid arthritis (RA).Although MTX is very effective and well tolerated, the major drawback is the large interpatient variability in the clinical response.MTX is intracellularly converted by folylpolyglutamate synthetase (FPGS) to methotrexate polyglutamates (MTXPGs), which enhance the intracellular retention of MTX. Furthermore, the γ-linked sequential addition of glutamic acid residues inhibits finals steps in the de novo purine and pyrimidine biosynthesis, resulting in anti-proliferative and anti-inflammatory effects.76 adult, MTX-naive patients who fulfill the American College of Rheumatology criteria (ACR) for RA with a Disease Activity Score in 28 joints (DAS-28) > 3.2 are enrolled at two sites in Vienna (Austria).Clinical status is assessed by the number of joint counts and the Health Assessment Questionnaire (HAQ).Patients are randomly assigned to receive either a standard dose or a higher starting dose of 25 mg orally. In week 5, a subcutaneous dose of 25 mg is administered to each patient to get a reference level (bioavailability of 100%).The patients participate for 16 weeks, in which blood samples are collected at weeks 1, 2, 5, 6, 10 and 11 to perform pharmacokinetic analyses and metabolite measurements.The determination of erythrocyte MTXPG-levels is performed by using a HPLC technique.The primary outcome is the objective clinical response (measured in a rheumatic score, DAS-28), secondary outcome parameters are quality of life and routine laboratory parameters used in rheumatology. This clinical outcome will be correlated with MTX pharmacokinetics in blood, MTXPG kinetics in erythrocytes, and their impact on the folate pathway.

Official Title
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Methotrexate Polyglutamate Levels as a Marker for the Clinical Outcome in the Treatment of Rheumatoid Arthritis A Multicenter, Randomized, Double-blind, Controlled Phase IV Trial

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: methotrexate
* Drug: methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MTX-naive Age > 18 years DAS-28 > 3.2 American College of Rheumatology-criteria for RA Chest-X-ray Informed consent Prednisolon < 10 mg a day Exclusion Criteria: Pregnancy Lactation Renal and hepatic impairment Malignant diseases (last 5 years) Contraindications Human Immunodeficiency Virus (HIV), Hepatitis B and C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard dose<br>Escalating dose | Drug: methotrexate<br>* oral administration Escalating dose (15, 20, 25 mg)<br>|
| Active Comparator: High dose<br>25 mg | Drug: methotrexate<br>* 25 mg oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DAS-28 (Disease Activity Score in 28 Joints) | DAS stands for Disease Activity Score and is a measure of the activity of rheumatoid arthritis. In Europe the DAS is the recognized standard in research and clinical practice. The following parameters are included in the calculation: Number of joints tender to the touch (TEN) Number of swollen joints (SW) Erythrocyte sedimentation rate (ESR) Patient assessment of disease activity (VAS; mm) The DAS-28 is evaluated using a scale: 0 - 3.2: low disease activity 3.2 - 5.1: moderate disease activity > 5.1: severe disease activity | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HAQ (Health Assessment Questionnaire) |  | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, MTX polyglutamates, clinical outcome