Rheumatoid Arthritis
Conditions
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.
Interventions
DRUGMethotrexate
Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases
DRUGLeflunomide
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
DRUGHydroxychloroquine
Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.
DRUGPrednisolone
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)
DRUGFolic Acid
Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.
DRUGSulfasalazine
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)
Sponsors
Jawaharlal Institute of Postgraduate Medical Education & Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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- 1. Tender joint count 28 2. Swollen joint count 28 3. ESR 4. Patient global assessment of health |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Number of Participants With Adverse Drug Reactions | 24 weeks | Infections, transaminitis, nausea, vomiting, derranged renal function tests etc |
| 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 |
Countries
India
Participant flow
Recruitment details
patients were enrolled from OPD (outdoor patient department) of Rheumatology clinic of JIPMER , from September 2016 to March 2018
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 68 |
| 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.
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) | 68 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 9 | 7 |
Baseline characteristics
| Characteristic | Total | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|---|
| Age, Customized Age (years) | 40 years | 39 years | 42 years |
| Anti- cyclic citrullinated peptide antibody | 105 Participants | 51 Participants | 54 Participants |
| Baseline ESR (mm at the end of 1 hour) | 45 millimeter (mm) | 45 millimeter (mm) | 40 millimeter (mm) |
| DAS28ESR | 4.2 units on a scale | 4.3 units on a scale | 4.2 units on a scale |
| Disease duration (months) | 15 months | 12 months | 18 months |
| Early morning stiffness (EMS) (minutes) | 60 minutes | 60 minutes | 60 minutes |
| Indian Health assessment questionnaire | 1.8 units on a scale | 1.9 units on a scale | 1.75 units on a scale |
| patient VAS global health | 20 units on a scale | 20 units on a scale | 20 units on a scale |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Rheumatoid factor positivity | 95 Participants | 51 Participants | 44 Participants |
| Sex: Female, Male Female | 128 Participants | 64 Participants | 64 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 4 Participants |
| Swollen joint count (SJ28) | 2 swollen joints | 2 swollen joints | 2 swollen joints |
| Tender joint count (TJ28) | 4 tender joints | 4 tender joints | 4 tender joints |
| Ultrasound7 score (US7 score) | 4 units on a scale | 3.5 units on a scale | 4 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 68 |
| other Total, other adverse events | 15 / 68 | 21 / 68 |
| serious Total, serious adverse events | 0 / 68 | 0 / 68 |
Outcome results
Primary
Number of Patients Achieving Good EULAR Response at the End of 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
Time frame: 12 weeks
Population: Analysis was done by intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1- MTX+LEF+HCQ | Number of Patients Achieving Good EULAR Response at the End of 12 Weeks | 40 participants |
| Group 2- MTX+SSZ+HCQ | Number of Patients Achieving Good EULAR Response at the End of 12 Weeks | 37 participants |
Secondary
Disease Activity as Per Ultrasound-7 (US-7) Score
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
Population: intention to treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1- MTX+LEF+HCQ | Disease Activity as Per Ultrasound-7 (US-7) Score | 3.5 units on a scale |
| Group 2- MTX+SSZ+HCQ | Disease Activity as Per Ultrasound-7 (US-7) Score | 4 units on a scale |
Secondary
Indian Health Assessment Questionnaire (iHAQ)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1- MTX+LEF+HCQ | Indian Health Assessment Questionnaire (iHAQ) | 0.7 score on a scale |
| Group 2- MTX+SSZ+HCQ | Indian Health Assessment Questionnaire (iHAQ) | 0.5 score on a scale |
Secondary
Number of Participants With Adverse Drug Reactions
Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
Time frame: 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Hypertension | 1 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | hairfall | 2 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Total number of any adverse events | 15 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Serious adverse events | 0 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Any gastrointestinal adverse reaction | 11 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Nausea | 4 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Diarrhea | 1 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Switch to parenteral Methotrexate | 5 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Raised liver enzymes > 2 times upper limit normal | 1 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Herpes labialis | 0 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | upper respiratory tract infection | 5 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | urinary tract infection | 1 Participants |
| Group 1- MTX+LEF+HCQ | Number of Participants With Adverse Drug Reactions | Cytopenia | 0 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | upper respiratory tract infection | 5 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Hypertension | 0 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Switch to parenteral Methotrexate | 14 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Cytopenia | 0 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Total number of any adverse events | 21 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Raised liver enzymes > 2 times upper limit normal | 1 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Serious adverse events | 0 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | urinary tract infection | 0 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Any gastrointestinal adverse reaction | 16 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Herpes labialis | 2 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Nausea | 6 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | hairfall | 2 Participants |
| Group 2- MTX+SSZ+HCQ | Number of Participants With Adverse Drug Reactions | Diarrhea | 1 Participants |