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

February 15, 2011 updated by: Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Wien, Austria, 1100
        • Kaiser-Franz-Josef-Spital
      • Wien, Austria, 1100
        • Rheumazentrum Wien Oberlaa

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DAS-28 (Disease Activity Score in 28 Joints)
Time Frame: 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
16 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
HAQ (Health Assessment Questionnaire)
Time Frame: 16 weeks
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2008

Primary Completion (Actual)

December 1, 2010

Study Completion (Actual)

December 1, 2010

Study Registration Dates

First Submitted

June 9, 2008

First Submitted That Met QC Criteria

June 10, 2008

First Posted (Estimate)

June 11, 2008

Study Record Updates

Last Update Posted (Estimate)

February 17, 2011

Last Update Submitted That Met QC Criteria

February 15, 2011

Last Verified

August 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PROMTX2007_01
  • EudraCT: 2007-006288-56

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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