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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

19 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-05-31

Study Completion Date

2010-12-31

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.

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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.

Conditions

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Rheumatoid Arthritis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Standard dose

Escalating dose

Group Type OTHER

methotrexate

Intervention Type DRUG

oral administration Escalating dose (15, 20, 25 mg)

High dose

25 mg

Group Type ACTIVE_COMPARATOR

methotrexate

Intervention Type DRUG

25 mg oral administration

Interventions

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methotrexate

oral administration Escalating dose (15, 20, 25 mg)

Intervention Type DRUG

methotrexate

25 mg oral administration

Intervention Type DRUG

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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No