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

• Sponsor: Jawaharlal Institute of Postgraduate Medical Education & Research (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02930343
• Collaborator: (none)
• Enrollment: 136
• Location: 1
• Arms: 2
• Actual Duration (Months): 23
• Patients Per Site Per Month: 5.9

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Methotrexate; Drug: Leflunomide; Drug: Hydroxychloroquine; Drug: Prednisolone; Drug: Folic Acid; Drug: Sulfasalazine	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Patients Achieving Good EULAR Response at the End of 12 Weeks [12 weeks]

   EULAR response criteria for Rheumatoid arthritis includes- estimation of DAS 28 ESR, that includes- Tender joint count 28 Swollen joint count 28 ESR Patient global assessment of health

Secondary Outcome Measures

1. Disease Activity as Per Ultrasound-7 (US-7) Score [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

2. Number of Participants With Adverse Drug Reactions [24 weeks]

   Infections, transaminitis, nausea, vomiting, derranged renal function tests etc

3. Indian Health Assessment Questionnaire (iHAQ) [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Clinical Immunology , Jawaharlal Institute of Post graduate Medical Educationa and Research	Pondicherry		India	605006

Sponsors and Collaborators

• 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

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - May 2, 2016

More Information

Publications

None provided.

• Responsible Party: Dr. Vir Singh Negi, Professor and head of the department, Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education & Research
• ClinicalTrials.gov Identifier: NCT02930343
• Other Study ID Numbers: JIP/IEC/2016/27/893
• First Posted: Oct 12, 2016
• Last Update Posted: Jul 27, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Folic Acid; Hydroxychloroquine; Sulfasalazine; Prednisolone; Methotrexate; Leflunomide; Glucocorticoids

Study Results

Participant Flow

Recruitment Details	patients were enrolled from OPD (outdoor patient department) of Rheumatology clinic of JIPMER , from September 2016 to March 2018

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
Period Title: Overall Study
STARTED	68	68
COMPLETED	59	61
NOT COMPLETED	9	7

Baseline Characteristics

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ	Total
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)	Total of all reporting groups
Overall Participants	68	68	136
Age, Customized (years) [Median (Inter-Quartile Range) ]
Age (years)	39	42	40
Sex: Female, Male (Count of Participants)
Female	64 94.1%	64 94.1%	128 94.1%
Male	4 5.9%	4 5.9%	8 5.9%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Disease duration (months) (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	12	18	15
Rheumatoid factor positivity (Count of Participants)
Count of Participants [Participants]	51 75%	44 64.7%	95 69.9%
Anti- cyclic citrullinated peptide antibody (Count of Participants)
Count of Participants [Participants]	51 75%	54 79.4%	105 77.2%
DAS28ESR (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	4.3	4.2	4.2
Tender joint count (TJ28) (tender joints) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [tender joints]	4	4	4
Swollen joint count (SJ28) (swollen joints) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [swollen joints]	2	2	2
Baseline ESR (mm at the end of 1 hour) (millimeter (mm)) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [millimeter (mm)]	45	40	45
Early morning stiffness (EMS) (minutes) (minutes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [minutes]	60	60	60
patient VAS global health (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	20	20	20
Indian Health assessment questionnaire (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	1.9	1.75	1.8
Ultrasound7 score (US7 score) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	3.5	4	4

Outcome Measures

1. Primary Outcome

Title	Number of Patients Achieving Good EULAR Response at the End of 12 Weeks
Description	EULAR response criteria for Rheumatoid arthritis includes- estimation of DAS 28 ESR, that includes- Tender joint count 28 Swollen joint count 28 ESR Patient global assessment of health
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis was done by intention to treat

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
Measure Participants	68	68
Number [participants]	40 58.8%	37 54.4%

2. Secondary Outcome

Title	Disease Activity as Per Ultrasound-7 (US-7) Score
Description	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
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

intention to treat analysis

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
Measure Participants	68	68
Median (Inter-Quartile Range) [units on a scale]	3.5	4

3. Secondary Outcome

Title	Number of Participants With Adverse Drug Reactions
Description	Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
Measure Participants	68	68
Total number of any adverse events	15 22.1%	21 30.9%
Serious adverse events	0 0%	0 0%
Any gastrointestinal adverse reaction	11 16.2%	16 23.5%
Nausea	4 5.9%	6 8.8%
Diarrhea	1 1.5%	1 1.5%
Switch to parenteral Methotrexate	5 7.4%	14 20.6%
Raised liver enzymes > 2 times upper limit normal	1 1.5%	1 1.5%
Herpes labialis	0 0%	2 2.9%
upper respiratory tract infection	5 7.4%	5 7.4%
urinary tract infection	1 1.5%	0 0%
Hypertension	1 1.5%	0 0%
hairfall	2 2.9%	2 2.9%
Cytopenia	0 0%	0 0%

4. Secondary Outcome

Title	Indian Health Assessment Questionnaire (iHAQ)
Description	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
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1- MTX+LEF+HCQ	Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
Measure Participants	68	68
Median (Inter-Quartile Range) [score on a scale]	0.7	0.5

Adverse Events

Time Frame	24 weeks
Adverse Event Reporting Description	Adverse events were assessed for at each patient visit (clinical assessment and laboratory reports). Also, patients were given the contact number of researcher so that they can contact in case of any adverse reaction.
Arm/Group Title	Group 1- MTX+LEF+HCQ		Group 2- MTX+SSZ+HCQ
Arm/Group Description	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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.		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. Methotrexate: Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases 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. 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) Folic Acid: Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week. 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)
All Cause Mortality
	Group 1- MTX+LEF+HCQ		Group 2- MTX+SSZ+HCQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/68 (0%)
Serious Adverse Events
	Group 1- MTX+LEF+HCQ		Group 2- MTX+SSZ+HCQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/68 (0%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Group 1- MTX+LEF+HCQ		Group 2- MTX+SSZ+HCQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/68 (22.1%)		21/68 (30.9%)
Cardiac disorders
hypertension	1/68 (1.5%)	1	0/68 (0%)	0
Gastrointestinal disorders
Gastrointestinal adverse events	11/68 (16.2%)	11	16/68 (23.5%)	16
Hepatobiliary disorders
Raised liver enzymes	1/68 (1.5%)	1	1/68 (1.5%)	1
Infections and infestations
infections	6/68 (8.8%)	6	7/68 (10.3%)	7
Product Issues
Switch to parenteral Methotrexate	5/68 (7.4%)	5	14/68 (20.6%)	14
Skin and subcutaneous tissue disorders
Hairfall	2/68 (2.9%)	2	2/68 (2.9%)	2

Limitations/Caveats

Early termination resulted in enrollment of 136 patients instead of 140 patients.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.