A Phase 3 interventional study of Methotrexate and Leflunomide in Rheumatoid Arthritis, sponsored by Jawaharlal Institute of Postgraduate Medical Education & Research. Terminated at 1 site in India. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2021-07-27.
Sponsored by Jawaharlal Institute of Postgraduate Medical Education & Research · Phase 3, Interventional, and Treatment
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)
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.
3,332 studies on the registry are indexed under Arthritis, Rheumatoid; 443 are open to participants now.
This study's enrollment of 136 is above the median of 96 across 2,220 interventional studies indexed under Arthritis, Rheumatoid.
Browse Arthritis, Rheumatoid studies →Jawaharlal Institute of Postgraduate Medical Education & Research is the lead sponsor of 12 studies on the registry; 1 is open to participants now.
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Age >18 years satisfying ACR-EULAR criteria for RA
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 · Drug: Leflunomide · Drug: Hydroxychloroquine · Drug: Prednisolone · Drug: Folic Acid
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 · Drug: Hydroxychloroquine · Drug: Prednisolone · Drug: Folic Acid · Drug: Sulfasalazine
Methotrexate, a structural analogue of folic acid, can be administered orally or parenterally to treat a variety of rheumatic diseases
Also known as: folitrax, MTX
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
Also known as: Arava, Lefno, LEF
Hydroxychloroquine (HCQ) is a well-tolerated DMARD that is commonly used in combination therapy regimens for RA. HCQ is more commonly used than chloroquine.
Also known as: HCQ
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)
Also known as: Steroids, Glucocorticoids
Folic acid is to be given to all patients receiving methotrexate at a dose of 5 mg twice a week.
Also known as: Folvite
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)
Also known as: Saaz, SSZ
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
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
Number of Participants With Adverse Drug Reactions
Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
Time frame: 24 weeks
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
patients were enrolled from OPD (outdoor patient department) of Rheumatology clinic of JIPMER , from September 2016 to March 2018
| Milestone | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Started | 68 | 68 |
| Completed | 59 | 61 |
| Not completed | 9 | 7 |
| Withdrew: Lost to follow-up | 9 | 7 |
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
| participants | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Number of Patients Achieving Good EULAR Response at the End of 12 Weeks | 40 | 37 |
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
| units on a scale | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Disease Activity as Per Ultrasound-7 (US-7) Score | 3.5 (0 to 6) | 4 (0 to 4.5) |
Infections, transaminitis, nausea, vomiting, derranged renal function tests etc
| Participants | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Total number of any adverse events | 15 | 21 |
| Serious adverse events | 0 | 0 |
| Any gastrointestinal adverse reaction | 11 | 16 |
| Nausea | 4 | 6 |
| Diarrhea | 1 | 1 |
| Switch to parenteral Methotrexate | 5 | 14 |
| Raised liver enzymes > 2 times upper limit normal | 1 | 1 |
| Herpes labialis | 0 | 2 |
| upper respiratory tract infection | 5 | 5 |
| urinary tract infection | 1 | 0 |
| Hypertension | 1 | 0 |
| hairfall | 2 | 2 |
| Cytopenia | 0 | 0 |
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
| score on a scale | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Indian Health Assessment Questionnaire (iHAQ) | 0.7 (0.4 to 1) | 0.5 (0.07 to 1.3) |
Collected over 24 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Group 1- MTX+LEF+HCQ | 0/68 (0%) | 0/68 (0%) | 15/68 (22.1%) |
| Group 2- MTX+SSZ+HCQ | 0/68 (0%) | 0/68 (0%) | 21/68 (30.9%) |
| Event | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ |
|---|---|---|
| Gastrointestinal adverse eventsGastrointestinal disorders | 11/68 | 16/68 |
| Switch to parenteral MethotrexateProduct Issues | 5/68 | 14/68 |
| infectionsInfections and infestations | 6/68 | 7/68 |
| HairfallSkin and subcutaneous tissue disorders | 2/68 | 2/68 |
| hypertensionCardiac disorders | 1/68 | 0/68 |
| Raised liver enzymesHepatobiliary disorders | 1/68 | 1/68 |
| Age, Customized(years) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Age (years) | 39 (31 to 47) | 42 (29 to 46) | 40 (30 to 46) |
| Sex: Female, Male(Participants) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Female | 64 | 64 | 128 |
| Male | 4 | 4 | 8 |
| Race and Ethnicity Not Collected(Participants) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
| Disease duration (months)(months) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Median | 12 (6 to 24) | 18 (6 to 24) | 15 (6 to 24) |
| Rheumatoid factor positivity(Participants) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Count of participants | 51 | 44 | 95 |
| Anti- cyclic citrullinated peptide antibody(Participants) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Count of participants | 51 | 54 | 105 |
| DAS28ESR(units on a scale) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Median | 4.3 (4.1 to 5) | 4.2 (3.9 to 4.5) | 4.2 (4.1 to 4.7) |
| Tender joint count (TJ28)(tender joints) | Group 1- MTX+LEF+HCQ | Group 2- MTX+SSZ+HCQ | Total |
|---|---|---|---|
| Median | 4 (2 to 6) | 4 (2 to 5) | 4 (3 to 6) |
6 further baseline measures are reported on the registry.
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Sep 2016 to primary completion in Aug 2018, 23 months.
Results were first posted in Jun 2021, 2 years 10 months after primary completion.
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This study is terminated, as verified in Jul 2021. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Leflunomide · Sulfasalazine
Jawaharlal Institute of Postgraduate Medical Education & Research