Official Title: “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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Dose Comparison, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: May 2011

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 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.

Intervention(s) in this Clinical Trial

• Drug: methotrexate
  • oral administration Escalating dose (15, 20, 25 mg)
• Drug: methotrexate
  • 25 mg oral administration

Arms, Groups and Cohorts in this Clinical Trial

• Other: Standard dose
  • Escalating dose
• Active Comparator: High dose
  • 25 mg

Primary Measures

• DAS-28
  • Time Frame: 16 weeks
    Safety Issue?: No

Secondary Measures

• HAQ
  • Time Frame: 16 weeks
    Safety Issue?: No

Inclusion Criteria:

• MTX-naive
• Age > 18 years
• DAS-28 > 3.2
• ACR-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
• HIV, Hep. B and C

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

Overall Clinical Trial Officials and Contacts

Hans Broell, Prof. Dr. Principal Investigator Ludwig-Boltzmann-Institut fuer Rheumatologie und Balneologie  

Overall Contact: Eva-Luise Hobl, Mag. pharm.  eva-luise.hobl@meduniwien.ac.at

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00695188

Study ID Number: PROMTX2007_01

ClinicalTrials.gov Identifier: NCT00695188

Health Authority: Austria: Agency for Health and Food Safety