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

July 25, 2021 updated by: Dr. Vir Singh Negi, Jawaharlal Institute of Postgraduate Medical Education & Research

Comparison of Sulfasalazine Versus Leflunomide Based Combination Disease Modifying Anti-rheumatic Drug Therapy (DMARD) in Patients With Rheumatoid Arthritis Failing Methotrexate Monotherapy : A Randomized Control Trial

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)

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

136

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
      • Pondicherry, India, 605006
        • Department of Clinical Immunology , Jawaharlal Institute of Post graduate Medical Educationa and Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 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.
Drug: Methotrexate
Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases
Other Names:
  • folitrax, MTX
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
Other Names:
  • Arava, Lefno, LEF
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.
Other Names:
  • HCQ
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)
Other Names:
  • Steroids, Glucocorticoids
Drug: Folic Acid
Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.
Other Names:
  • Folvite
Active Comparator: 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.
Drug: Methotrexate
Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases
Other Names:
  • folitrax, MTX
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.
Other Names:
  • HCQ
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)
Other Names:
  • Steroids, Glucocorticoids
Drug: Folic Acid
Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.
Other Names:
  • Folvite
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)
Other Names:
  • Saaz, SSZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients Achieving Good EULAR Response at the End of 12 Weeks
Time Frame: 12 weeks

EULAR response criteria for Rheumatoid arthritis includes- estimation of DAS 28 ESR, that includes-

  1. Tender joint count 28
  2. Swollen joint count 28
  3. ESR
  4. Patient global assessment of health
12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Activity as Per Ultrasound-7 (US-7) Score
Time Frame: 12 weeks
Ultrasound 7 score (US-7) Calculates ultrasound score in 7 joints using greyscale and power doppler to evaluate for disease activity (synovitis, tenosynovitis) and damage (erosions) Score minimum value= 0 Maximum value = 108 Higher score indicates worse disease
12 weeks
Number of Participants With Adverse Drug Reactions
Time Frame: 24 weeks
Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
24 weeks
Indian Health Assessment Questionnaire (iHAQ)
Time Frame: 12 weeks
Indian version of Health assessment Questionnaire (iHAQ) Comprises of 12 questions relating to functional activity iHAQ score ranges from 0 to 3 (minimum 0, maximum 3) Higher scores indicate more disability
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jawaharlal Institute of Postgraduate Medical Education & Research

Investigators

  • Principal Investigator: Vir S Negi, DM, Jawaharlal Institute of Postgraduate Medical Education & Research
  • Study Chair: Pooja Belani, MD, Jawaharlal Institute of Postgraduate Medical Education & Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2016

Primary Completion (Actual)

August 1, 2018

Study Completion (Actual)

August 1, 2018

Study Registration Dates

First Submitted

September 13, 2016

First Submitted That Met QC Criteria

October 9, 2016

First Posted (Estimate)

October 12, 2016

Study Record Updates

Last Update Posted (Actual)

July 27, 2021

Last Update Submitted That Met QC Criteria

July 25, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JIP/IEC/2016/27/893

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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