Rheumatoid Arthritis
Conditions
Keywords
rheumatoid arthritis, MTX polyglutamates, clinical outcome
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.
Interventions
DRUGmethotrexate
oral administration Escalating dose (15, 20, 25 mg)
Sponsors
Ludwig-Boltzmann Institut fuer Rheumatologie, Balneologie und Rehabilitation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DAS-28 (Disease Activity Score in 28 Joints) | 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 |
Secondary
| Measure | Time frame |
|---|---|
| HAQ (Health Assessment Questionnaire) | 16 weeks |
Countries
Austria
Participant flow
Recruitment details
Patients were included at the outpatient unit of the Kaiser-Franz-Josef-Hospital, Department for Rheumatology, if they fulfilled the inclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose Escalating dose (Start with 15 mg MTX/week, escalating dose until 25 mg/week, administered orally) | 10 |
| High Dose Start with 25 mg MTX per week, administered orally | 9 |
| Total | 19 |
Baseline characteristics
| Characteristic | High Dose | Standard Dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 6 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 9 Participants |
| Age Continuous | 62 years STANDARD_DEVIATION 7 | 51 years STANDARD_DEVIATION 15 | 56 years STANDARD_DEVIATION 13 |
| Region of Enrollment Austria | 9 participants | 10 participants | 19 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 10 | 4 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
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
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose | DAS-28 (Disease Activity Score in 28 Joints) | 2.87 Units on a Scale | Standard Deviation 0.93 |
| High Dose | DAS-28 (Disease Activity Score in 28 Joints) | 2.66 Units on a Scale | Standard Deviation 0.11 |
Secondary
HAQ (Health Assessment Questionnaire)
Time frame: 16 weeks