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

This study has been completed.
Sponsor:
Information provided by:
Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation
ClinicalTrials.gov Identifier:
NCT00695188
First received: June 9, 2008
Last updated: February 15, 2011
Last verified: August 2009
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: methotrexate
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation:

Primary Outcome Measures:
  • DAS-28 (Disease Activity Score in 28 Joints) [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

    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:
  • HAQ (Health Assessment Questionnaire) [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Enrollment: 19
Study Start Date: May 2008
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Standard dose
Escalating dose
Drug: methotrexate
oral administration Escalating dose (15, 20, 25 mg)
Active Comparator: High dose
25 mg
Drug: methotrexate
25 mg oral administration

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00695188

Locations
Austria
Kaiser-Franz-Josef-Spital
Wien, Austria, 1100
Rheumazentrum Wien Oberlaa
Wien, Austria, 1100
Sponsors and Collaborators
Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation
Investigators
Principal Investigator: Hans Broell, Prof. Dr. Ludwig-Boltzmann-Institut fuer Rheumatologie und Balneologie
  More Information

No publications provided by Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prim. Univ.-Prof. Dr. Hans Broell, Ludwig-Boltzmann Institut fuer Rheumatologie und Balneologie
ClinicalTrials.gov Identifier: NCT00695188     History of Changes
Other Study ID Numbers: PROMTX2007_01, EudraCT: 2007-006288-56
Study First Received: June 9, 2008
Results First Received: December 20, 2010
Last Updated: February 15, 2011
Health Authority: Austria: Agency for Health and Food Safety

Keywords provided by Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation:
rheumatoid arthritis
MTX polyglutamates
clinical outcome

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 18, 2014