Leflunomide Versus Sulfasalazine/Methotrexate in Rheumatoid Arthritis:an Ultrasound/Magnetic Resonance Imaging Study

Sponsor

Singapore General Hospital (Other)

Overall Status

Terminated

CT.gov ID

NCT01659242

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

In rheumatoid arthritis patients with active disease despite optimal treatment with methotrexate, the main objective of this pilot study is to use advance imaging tools such as magnetic resonance imaging and ultrasound to evaluate which treatment option is more efficacious: initiating methotrexate/sulfasalazine combination therapy, or switching to leflunomide monotherapy

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Methotrexate plus sulfasalazine Drug: Leflunomide	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

1 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Leflunomide Versus Sulfasalazine/Methotrexate in Rheumatoid Arthritis Patients With Active Disease Despite Methotrexate: an Ultrasound and Magnetic Resonance Imaging Study

Study Start Date :

Jul 1, 2012

Actual Primary Completion Date :

Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methotrexate plus sulfasalazine ARM 1(Methotrexate(MTX) plus Sulfasalazine(SSZ)) SSZ:Oral form, 2g/day, with escalation regime starting from 1g/day for the first week and increase to 1.5g/day in the next week and increasing to 2g/day by the third week. Total treatment period is 16 weeks. After reaching 2g/day, if patients conditions warrants (and no contraindication), SSZ may be increased at 0.5g per clinic visit) up to a maximum of 3g/day. MTX:Kept at the highest optimal dose.	Drug: Methotrexate plus sulfasalazine ARM 1(Methotrexate(MTX) plus Sulfasalazine(SSZ)) SSZ:Oral form, 2g/day, with escalation regime starting from 1g/day for the first week and increase to 1.5g/day in the next week and increasing to 2g/day by the third week. Total treatment period is 16 weeks. After reaching 2g/day, if patients conditions warrants (and no contraindication), SSZ may be increased at 0.5g per clinic visit) up to a maximum of 3g/day. MTX:Kept at the highest optimal dose.
Active Comparator: Leflunomide ARM 2:Leflunomide(LEF) LEF: Oral form, 20mg every other day for first 2 weeks then increasing to 20mg per day by the third week. Total treatment period is 16 weeks. Methotrexate:Off	Drug: Leflunomide ARM 2:Leflunomide(LEF) LEF: Oral form, 20mg every other day for first 2 weeks then increasing to 20mg per day by the third week. Total treatment period is 16 weeks. Methotrexate:Off

Arm

Intervention/Treatment

Active Comparator: Methotrexate plus sulfasalazine

ARM 1(Methotrexate(MTX) plus Sulfasalazine(SSZ)) SSZ:Oral form, 2g/day, with escalation regime starting from 1g/day for the first week and increase to 1.5g/day in the next week and increasing to 2g/day by the third week. Total treatment period is 16 weeks. After reaching 2g/day, if patients conditions warrants (and no contraindication), SSZ may be increased at 0.5g per clinic visit) up to a maximum of 3g/day. MTX:Kept at the highest optimal dose.

Drug: Methotrexate plus sulfasalazine

Active Comparator: Leflunomide

ARM 2:Leflunomide(LEF) LEF: Oral form, 20mg every other day for first 2 weeks then increasing to 20mg per day by the third week. Total treatment period is 16 weeks. Methotrexate:Off

Drug: Leflunomide

ARM 2:Leflunomide(LEF) LEF: Oral form, 20mg every other day for first 2 weeks then increasing to 20mg per day by the third week. Total treatment period is 16 weeks. Methotrexate:Off

Outcome Measures

Primary Outcome Measures

MRI synovitis score [four months]

Secondary Outcome Measures

MRI bone marrow edema score [4 months]
MRI erosion score [4 months]
US synovitis score [4 months]
clinical outcomes [4 months]
Swollen/Tender joint counts, investigator's global assessment of disease activity (0-10), patient's assessment of disease activity (0-10), pain assessment by visual analogue scale (0-10), erythrocyte sedimentation rate, duration (mins) of early morning stiffness, and calculated disease activity indices

Other Outcome Measures

US erosion score [4 months]
US tenosynovitis score [4 months]
MRI tenosynovitis score [4 months]
Adverse events [4 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Male and female patients aged between 21 and 65 years.
Patients with no childbearing potential (For example postmenopausal or sterilised) or have decided not to have offspring(s).
All female patients must consent not to get pregnant/breastfeed, male patients must consent not to father a child and all must consent to practice effective birth control.
Fulfills either the 1987 ACR criteria and/or the 2010 ACR / EULAR RA Classification Criteria.
Seropositivity: Rheumatoid factor (RF) and/or anti -cyclic citrullinated protein antibodies (anti-CCP) must be positive.
MCPJ(s) and/or Wrist(s) joint(s) involvement.
Rheumatoid arthritis patients (less than 5 years duration) who remain at least moderately active based on DAS28 score of > 3.2, following 3 months of therapy with an optimal dose of methotrexate(e.g. at least 15 mg/week).
If patient is on oral corticosteroids, this should not exceeding 10mg prednisolone daily (or oral steroid equivalent) for at least 4 weeks and should be at an unchanged dose for at least 2 weeks before entering study.
If patient is on NSAIDs, this should be at an unchanged dose for at least 2 weeks before entering study.
Glomerular filtration rate > 60 mls/min/1.73m2.

Exclusion Criteria

Patient known to have the following medical condition(s) will be excluded:
Other autoimmune disease /inflammatory joint disease/connective tissue disease ( e.g. lupus, seronegative spondylarthropathy (e.g. ankylosing spondylitis/psoriatic arthropathy ), reactive arthritis, overlap syndrome, primary sjogren syndrome and mixed connective tissue disease.)
Inflammatory arthritis with onset before 18 years old.
Current or previous history of cancer or lymphoproliferative disease.
HIV positive status, Hepatitis B/C positive status.
Persistent and/or severe infection in the previous 12 weeks.
Major traumatic injury, terminal illness, or other medical condition(s)that could place the patient at risk to participate in the study.
Clinically relevant cardiovascular (e.g unstable ischemic heart disease), neurological (e.g recent stroke), gastroenterology (e.g active peptic ulcer disease), renal (e.g chronic renal failure), hepatic (e.g alcoholic liver disease, fatty liver) and any other major systemic disease that could i) place the patient at risk to participate in the study; or ii) make protocol implementation difficult; or iii) make study results interpretation difficult.
Presence of any known condition(s)/circumstance(s) which would negatively impact compliance or study completion.
Impaired laboratory parameters:
Hemoglobin less than 10.5 g/dl, white blood count less than 4 x 10 (9)/L , platelet count less than 150 x 10(9)/L.
Deranged Liver function test: e.g. elevated AST/ALT.
Wants to consume alcohol while taking the study medications.
Body weight that is less than 45 kg.
Pregnancy/Breastfeeding/Male patient wishing to father children.
Patients with the following medication history will be excluded:
History of Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency.
Known allergy to: i) study medications; or ii) contrast; or iii) drugs whose chemical structures are similar (e.g. sulphonamides, salicylates, etc).
On anticoagulation for any reasons.
Previous treatment (within the last 4 weeks) with: i) oral corticosteroid greater than prednisolone equivalent of 10mg/day; or ii) parenteral/intra-articular corticosteroid injection.
Previous treatment (within the last 12 weeks) with: i) other DMARDs such as sulfasalazine,hydroxychloroquine,chloroquine,gold salts, etc; or ii) investigational drug(s); or iii) other immunosuppressive agents such as cyclophosphamide,cyclosporin,azathioprine and any biologic agents, e.g. anti-TNF.
Previous treatment(any duration) with i) Leflunomide; or ii) Sulfasalazine used together with methotrexate
Contraindication to MRI (e.g. pacemakers, metallic implants/stents, claustrophobia).