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Trial registered on ANZCTR


Registration number
ACTRN12606000275561
Ethics application status
Approved
Date submitted
28/06/2006
Date registered
3/07/2006
Date last updated
19/09/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Pharmacokinetics and pharmacogenetics of methotrexate in rheumatoid arthritis
Scientific title
Pharmacokinetics and pharmacogenetics of methotrexate (MTX) in rheumatoid arthritis (RA)
Secondary ID [1] 283037 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid arthritis 1250 0
Condition category
Condition code
Inflammatory and Immune System 1336 1336 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Recruitment: Patients seen by the Christchurch Hospital Rheumatology service will be recruited. Patients fulfilling the inclusion/exclusion criteria will be invited to participate.

Treatment of non-responders Patients who are deemed MTX non-responders (DAS>3.2) will have the oral dose of MTX increased to the maximum tolerable dose or 20mg weekly. Lower doses may be used in patients with significant renal impairment at the discretion of the investigator.

If their RA remains active (DAS>3.2) at the maximum dose the route of MTX administration will be changed to subcutaneous (SC) injection. Patients changed to SC MTX will be seen at weeks 8, 16 and 24 to determine disease activity and side effects to MTX. Red blood cell (RBC) methotrexat polyglutamate (MTXPGs) concentrations will be determined weekly until steady state concentrations are reached then at each follow-up visit.

Patients starting or stopping MTX (Pharmacokinetic/clearance studies)
Ten patients with RA starting MTX will be recruited. Each patient will be seen at weeks 0, 8, 16 and 24. Disease activity will be assessed as outlined above. Blood samples will be taken weekly to determine RBC MTXPG concentrations until a steady concentration is reached. This is expected to take between 8 to 16 weeks. More or less frequent blood tests may be required depending on the initial data.

Ten patients with RA stopping MTX will be recruited. Each patient will be seen once when the MTX is stopped, then at weeks 8, 16 and 24. Blood samples will be taken weekly until concentrations of RBC MTXPGs are undetectable. This is expected to take 8-16 weeks. More or less frequent blood tests may be required depending on the initial data.
Intervention code [1] 1175 0
Treatment: Drugs
Comparator / control treatment
No comparator.
Control group
Active

Outcomes
Primary outcome [1] 1822 0
Correlation between Methotrexate polyglutamates and disease activity and or toxicity associated with MTX

Disease activity assessment
Disease activity will be assessed using standard clinical parameters comprising: swollen joint count, tender joint count, physicians global score (visual analogue scale), modified Health Assessment Questionnaire (mHAQ), patient pain and fatigue visual analogue scales, and standardised questions related to side effects from MTX

This data will be used to calculate a Disease Activity Score (DAS28). Using this validated score patients will be defined as a MTX responder (DAS<3.2) or MTX non-responder (DAS>3.2).

Laboratory assessment:
1. Markers of inflammation - full blood count, erythrocyte sedimentation rate, C-reactive protein
2. Assessment of MTX toxicity – full blood count, liver function tests, creatinine
3. Intracellular effects of MTX - serum B12, serum and red cell folate
Timepoint [1] 1822 0
Blood will be collected at each clinic visit
Secondary outcome [1] 3189 0
Association between MTX PGs, response to MTX and genetic polymorphisms of the enzymes involved in MTX metabolism.
Timepoint [1] 3189 0
One off visit

Eligibility
Key inclusion criteria
I. Patients with RA (ARA ’87 Criteria, (Arnett et al. 1988). II Methotrexate therapy either as monotherapy or combination therapy for at least three months. The dose of methotrexate must be at a stable dose of 5-20 mg/weekly over the preceding four weeks.III Patients whom the treating Rheumatologist wishes to start or stop MTX.IV Able and willing to give written informed consent and to comply with the requirements of the study.
Minimum age
18 Years
Maximum age
Not stated
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
I. A change in dose or introduction of another disease modifying anti-rheumatic drug, nonsteroidal anti-inflammatory agent or oral steroid within the preceding month.II. Intra-articular steroid injections within one month prior to enrolment.III. Evidence of serious uncontrolled chronic concomitant disease.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/10/2005
Actual
26/10/2005
Date of last participant enrolment
Anticipated
Actual
17/11/2008
Date of last data collection
Anticipated
Actual
Sample size
Target
200
Accrual to date
Final
200
Recruitment outside Australia
Country [1] 370 0
New Zealand
State/province [1] 370 0

Funding & Sponsors
Funding source category [1] 1461 0
Charities/Societies/Foundations
Name [1] 1461 0
Health Research Council of New Zealand
Country [1] 1461 0
New Zealand
Primary sponsor type
Individual
Name
Lisa Stamp
Address
Department of Medicine
University of Otago, Christchurch
P.O.Box 4345
Christchurch
NZ
Country
New Zealand
Secondary sponsor category [1] 1290 0
Individual
Name [1] 1290 0
Lisa Stamp
Address [1] 1290 0
P.O.Box 4345
Christchurch 8014
Country [1] 1290 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 2841 0
Upper South B Ethics Committee
Ethics committee address [1] 2841 0
Ethics committee country [1] 2841 0
New Zealand
Date submitted for ethics approval [1] 2841 0
Approval date [1] 2841 0
01/09/2005
Ethics approval number [1] 2841 0
URB/05/07/079

Summary
Brief summary
Low dose oral methotrexate (MTX) is used widely in the treatment of rheumatoid arthritis (RA). The dose individual patients require varies and is largely unpredictable. Differences in dose requirements are at least partially due to differences in the pharmacokinetics of methotrexate. Genetic differences in the enzymes that metabolise MTX may be important. Methotrexate is metabolised to form methotrexate polyglutamates (MTXPGs), which are stored in circulating red blood cells (RBC) and white blood cells. MTXPG concentrations can be measured in these cells. There is evidence that the higher the RBC MTXPG concentration, the greater the likelihood a patient’s arthritis will respond to methotrexate. We wish to investigate MTXPG concentrations and clinical response in patients taking MTX for RA. This will involve studying patients that are starting or stopping MTX, as well as those on a stable dose of MTX. We will investigate the relationship between RBC MTXPG concentrations and clinical response to MTX. Patients who are not responding adequately to oral MTX are often changed to subcutaneous (SC) injections of MTX. In this group we will examine whether there is any improvement in clinical response and the relationship of response to RBC MTXPG concentrations after the change in route of administration. In order to explain individual variations in clinical response to MTX and variations in MTXPG concentrations we will investigate for differences in genes for enzymes or drug transporters that might influence concentrations.
Trial website
Trial related presentations / publications
1. Stamp LK, Barclay ML, O’Donnell JL, Zhang M, Drake J, Frampton CMA, Chapman PT. Effects of changing from oral to subcutaneous methotrexate on RBC MTX polyglutamate concentrations and disease activity in patients with RA. J Rheumatol 2011;38(12):2540-7.
2. LK Stamp, PT Chapman, JL O’Donnell, M Zhang, J James, C Frampton, ML Barclay, MA Kennedy, RL Roberts. Polymorphisms within the folate pathway predict folate concentrations but are not with associated disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet Genomics 2010 Jun;20(6):367-76.
3. Stamp LK, O’Donnell JL, Chapman PT, Zhang M, James J, Frampton C, Barclay ML. Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients on long-term MTX therapy. Arthritis Rheum 2010; 62(2);359-368.
4. White D, Chapman PT, O’Donnell JL, James J, Frampton C, Stamp LK. Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving methotrexate for rheumatoid arthritis. Int Med J 2010;40 561-565.
5. Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Frampton C, James J, Barclay ML. Determinants of red blood cell methotrexate polyglutamate concentrations in patients with rheumatoid arthritis on long-term MTX Arthritis Rheum 2009;60(8); 2248-2256
6. LK Stamp, JL O’Donnell, PT Chapman, ML Barclay, MA Kennedy, CMA Frampton, RL Roberts. Lack of association between HLA-G 14bp insertion-deletion polymorphism and response to long-term therapy with methotrexate response in rheumatoid arthritis. Ann Rheum Dis 2009;68 154-155.
7. Dalrymple J, Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of Oral Methotrexate in Patients with Rheumatoid Arthritis. Arthritis Rheum 2008;58(11); 3299-3308
Public notes

Contacts
Principal investigator
Name 35177 0
Prof Lisa Stamp
Address 35177 0
Department of Medicine
PO Box 4345
Christchurch
Country 35177 0
New Zealand
Phone 35177 0
+6433640953
Fax 35177 0
Email 35177 0
[email protected]
Contact person for public queries
Name 10364 0
Lisa Stamp
Address 10364 0
Department of Medicine
P.O.Box 4345
Christchurch
Country 10364 0
New Zealand
Phone 10364 0
64-3-3640953
Fax 10364 0
Email 10364 0
[email protected]
Contact person for scientific queries
Name 1292 0
Lisa Stamp
Address 1292 0
Department of Medicine
P.O.Box 4345
Christchurch
Country 1292 0
New Zealand
Phone 1292 0
64-3-3640953
Fax 1292 0
Email 1292 0
[email protected]

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