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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]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Rheumatoid arthritis

Condition category

Condition code

Inflammatory and Immune System

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]

Treatment: Drugs

Comparator / control treatment

No comparator.

Control group

Active

Outcomes

Primary outcome [1]

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]

Blood will be collected at each clinic visit

Secondary outcome [1]

Association between MTX PGs, response to MTX and genetic polymorphisms of the enzymes involved in MTX metabolism.

Timepoint [1]

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?

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]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Health Research Council of New Zealand

Address [1]

P.O. Box 5541
Wellesley Street
Auckland
New Zealand 1141

Country [1]

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]

Individual

Name [1]

Lisa Stamp

Address [1]

P.O.Box 4345
Christchurch 8014

Country [1]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Upper South B Ethics Committee

Ethics committee address [1]

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

Approval date [1]

01/09/2005

Ethics approval number [1]

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

Prof Lisa Stamp

Address

Department of Medicine
PO Box 4345
Christchurch

Country

New Zealand

Phone

+6433640953

Fax

[email protected]

Contact person for public queries

Name

Lisa Stamp

Address

Department of Medicine
P.O.Box 4345
Christchurch

Country

New Zealand

Phone

64-3-3640953

Fax

[email protected]

Contact person for scientific queries

Name

Lisa Stamp

Address

Department of Medicine
P.O.Box 4345
Christchurch

Country

New Zealand

Phone

64-3-3640953

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

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