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

Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

Status and phase: Completed; Phase 4

Conditions: Rheumatoid Arthritis

Treatments: Drug: methotrexate

Study type: Interventional

Funder types: Other

Identifiers

NCT00695188

PROMTX2007_01

EudraCT: 2007-006288-56

Details and patient eligibility

About

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.

Full 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.

Enrollment: 19 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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19 participants in 2 patient groups

Standard dose

Other group

Description:

Escalating dose

Treatment:

Drug: methotrexate

Drug: methotrexate

High dose

Active Comparator group

Description:

25 mg

Treatment:

Drug: methotrexate

Drug: methotrexate