Comparison of Disease Modifying Antirheumatic Drugs Therapy in Patients With RA Failing Methotrexate Monotherapy

NCT ID: NCT02930343

Last Updated: 2021-07-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 136 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-30
• Study Completion Date: 2018-08-31

Brief Summary

RA (Rheuatoid arthritis) is a multisystem disease that mainly involves joints resulting in destructive arthritis if not treated rapidly. Inspite of various advances in field of early diagnosis and treatment of RA, there is still a need for better understanding of the efficacy and safety of various combinations of conventional DMARDS, and to rank them in order accordingly, so as to give a clearer vision for further management of RA once MTX monotherapy fails, so as to achieve remission as soon as possible. The study will be conducted at the Department of Clinical Immunology, JIPMER (Jawaharlal Institute of Postgraduate Medical Education & Research). patients who fail methotrexate monotherapy will be randomised to 2 treatment arms - either a combination of Sulfasalazine (SSZ), Hydroxychloroquine (HCQ) and Methotrexate (MTX) or Leflunomide (LEF), Hydroxychloroquine (HCQ) and Methotrexate (MTX)

Detailed Description

Patients aged ≥18 years, fulfilling the 2010 ACR EULAR criteria for RA (symptom duration less than two years) , having more than 4 joints involved & having moderate to severe disease activity (DAS28≥3.2) will be invited to participate. After providing written informed consent, eligible patients will be first started on MTX monotherapy & only patients who have persistant moderate disease activity (DAS28 ESR > 3.2) will be randomized into two groups. Block randomization will be done to generate random allocation sequence

Group 1 - will receive MTX+LEF+HCQ Group 2- will receive MTX+SSZ+HCQ

DMARD dosages used are: MTX 25 mg/week orally (dosage after 6 weeks),SSZ 2g/d (after 4 weeks) LEF 20 mg/day (dosage after 2 weeks) and HCQ 200 mg/day. Glucocorticoids will be given in an oral tapering scheme. All patients will be prescribed folic acid (10 mg/week) during MTX prescription.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

group 1- MTX+LEF+HCQ

Active Comparator: Combination of Methotrexate (up to 25 mg per week), Leflunomide (20 mg once a day) and Hydroxychloroquine (200-400 mg once at night). All drugs are to be taken orally. Duration of therapy is for 3 months. All patients will receive folic acid (5 mg twice a week) along with methotrexate. Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop) will be given as bridging therapy.

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases

Leflunomide

Intervention Type: DRUG

Leflunomide inhibits pyrimidine synthesis, resulting in blockade of T-cell proliferation. Leflunomide is used in patients with moderate to severe active rheumatoid arthritis with early or late disease

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.

Prednisolone

Intervention Type: DRUG

Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop)

Folic Acid

Intervention Type: DRUG

Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.

group 2- MTX+SSZ+HCQ

Combination of Methotrexate (up to 25 mg per week), Sulfasalazine (2g per day) and Hydroxychloroquine (200-400 mg once at night). All drugs are to be taken orally. Duration of therapy is for 3 months. All patients will receive folic acid (5 mg twice a week) along with methotrexate. Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop) will be given as bridging therapy.

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.

Prednisolone

Intervention Type: DRUG

Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop)

Folic Acid

Intervention Type: DRUG

Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.

Sulfasalazine

Intervention Type: DRUG

5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine; the specific mechanism of action of 5-ASA is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF)

Interventions

Methotrexate

Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases

Intervention Type: DRUG

Leflunomide

Leflunomide inhibits pyrimidine synthesis, resulting in blockade of T-cell proliferation. Leflunomide is used in patients with moderate to severe active rheumatoid arthritis with early or late disease

Intervention Type: DRUG

Hydroxychloroquine

Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.

Intervention Type: DRUG

Prednisolone

Low dose prednisolone (weeks 1-2: 7.5 mg/day, weeks 2-4: 5 mg/day, weeks 4-6: 5 mg on alternate day and then stop)

Intervention Type: DRUG

Folic Acid

Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.

Intervention Type: DRUG

Sulfasalazine

5-aminosalicylic acid (5-ASA) is the active component of sulfasalazine; the specific mechanism of action of 5-ASA is unknown; however, it is thought that it modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF)

Intervention Type: DRUG

Other Intervention Names

folitrax, MTX; Arava, Lefno, LEF; HCQ; Steroids, Glucocorticoids; Folvite; Saaz, SSZ

Eligibility Criteria

Inclusion Criteria

Age >18 years satisfying ACR-EULAR criteria for RA

1. Polyarthritis (>4 joints)

2. Disease duration of less than 2 years

3. Patients with moderate to severe disease activity (DAS28>3.2)

4. Patients who have failed to respond to initial Methotrexate monotherapy

Exclusion Criteria

1. End stage disease (deformed fixed joints)

2. Patients with vasculitis, extra-articular features like interstitial lung disease8

3. Contraindications to DMARD therapy (Chronic Alcoholism, Chronic liver disease, Evidence of acute/chronic infection, Chronic kidney disease, Patients with leucopenia (<3.0×109/l), thrombocytopenia (<150×109/l), AST/ALT>2× upper normal value and creatinine clearance <30ml/minute )

4. Pregnant, lactating women ; patients (both men and women) of reproductive age group unwilling for contraceptive use who have not completed the family

5. Patients unable to come for regular follow up

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jawaharlal Institute of Postgraduate Medical Education & Research

OTHER_GOV

Sponsor Role: lead

Responsible Party

Dr. Vir Singh Negi

Professor and head of the department, Department of Clinical Immunology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vir S Negi, DM

Role: PRINCIPAL_INVESTIGATOR

Jawaharlal Institute of Postgraduate Medical Education & Research

Pooja Belani, MD

Role: STUDY_CHAIR

Jawaharlal Institute of Postgraduate Medical Education & Research

Locations

Department of Clinical Immunology , Jawaharlal Institute of Post graduate Medical Educationa and Research

Puducherry, , India

Countries

India

References

Belani PJ, Kavadichanda CG, Negi VS. Comparison between leflunomide and sulfasalazine based triple therapy in methotrexate refractory rheumatoid arthritis: an open-label, non-inferiority randomized controlled trial. Rheumatol Int. 2022 May;42(5):771-782. doi: 10.1007/s00296-021-04994-1. Epub 2021 Sep 29.

Reference Type: DERIVED

PMID: 34586472 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

JIP/IEC/2016/27/893

Identifier Type: -

Identifier Source: org_study_id