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

Phase 4

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Drug: methotrexate

• Registration Number: NCT00695188
• Lead Sponsor: Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2008-05
• Study First Submitted: 2008-06-09
• Study First Submitted QC: 2008-06-10
• Study First Posted: 2008-06-11
• Status Verified: 2009-08
• Primary Completion: 2010-12
• Study Completion: 2010-12
• Results First Submitted: 2010-12-20
• Results First Submitted QC: 2011-01-19
• Results First Posted: 2011-02-15
• Last Update Submitted: 2011-02-15
• Last Update Posted: 2011-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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

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Exclusion Criteria

• Pregnancy
• Lactation
• Renal and hepatic impairment
• Malignant diseases (last 5 years)
• Contraindications
• Human Immunodeficiency Virus (HIV), Hepatitis B and C

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard dose	methotrexate	Escalating dose
High dose	methotrexate	25 mg

Primary Outcome Measures

Name	Time	Method
DAS-28 (Disease Activity Score in 28 Joints)	16 weeks	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

Secondary Outcome Measures

Name	Time	Method
HAQ (Health Assessment Questionnaire)	16 weeks

Trial Locations

Locations (2)

Rheumazentrum Wien Oberlaa; 🇦🇹 Wien, Austria

Kaiser-Franz-Josef-Spital; 🇦🇹 Wien, Austria