Clinical trial NCT00695188: Methotrexate Polyglutamate Levels as a Marker for the Clinical Outcome in the Treatment of Rheumatoid Arthritis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis
MTX polyglutamates
clinical outcome
Lead sponsor: Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation
Sponsor class: OTHER
First posted: 2008-06-11
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: DAS-28 (Disease Activity Score in 28 Joints)
timeFrame: 16 weeks
Secondary outcomes:
measure: HAQ (Health Assessment Questionnaire)
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Kaiser-Franz-Josef-Spital
city: Wien
country: Austria
facility: Rheumazentrum Wien Oberlaa
Study officials:
affiliation: Ludwig-Boltzmann-Institut fuer Rheumatologie und Balneologie
name: Hans Broell, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hobl EL, Mader RM, Jilma B, Duhm B, Mustak M, Broll H, Hogger P, Erlacher L. A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naive adult patients with rheumatoid arthritis. Clin Ther. 2012 May;34(5):1195-203. doi: 10.1016/j.clinthera.2012.03.059. Epub 2012 Apr 18.