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

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00695188
• Other study ID #: PROMTX2007_01
• Secondary ID: EudraCT: 2007-00
• Status: Completed
• Phase: Phase 4
• First received: June 9, 2008
• Last updated: February 15, 2011
• Start date: May 2008
• Est. completion date: December 2010

Study information

• Verified date: August 2009
• Source: Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Agency for Health and Food Safety
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 2010
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

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

Locations

Country	Name	City	State
Austria	Kaiser-Franz-Josef-Spital	Wien
Austria	Rheumazentrum Wien Oberlaa	Wien

Sponsors (1)

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

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DAS-28 (Disease Activity Score in 28 Joints)	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	No
Secondary	HAQ (Health Assessment Questionnaire)		16 weeks	No