Complementary Herbal Approach to Rheumatoid Management Study (CHARMS)

Complementary Herbal Approach to Rheumatoid Management Study (CHARMS)

Rheumatoid Arthritis (RA) is a chronic disease characterised by symmetric, polyarticular pain and swelling, involving small joints of the hands and feet. RA can lead to irreversible joint damage without treatment, causing disability and impacting daily activities and work productivity. Some patients turn to Chinese Herbal Medication (CHM) for treatment. Since there is currently no well designed randomised controlled trial to support the 'real-world' use of Si Miao Xiao Bi Tang with anti-rheumatic drugs, such as methotrexate, the investigators are conducting a 12-week, randomised double-blinded placebo-controlled trial to determine the efficacy, safety and cost effectiveness of a modified Si Miao Xiao Bi Tang, a type of CHM, in the treatment of patients with active RA.

From the Traditional Chinese Medicine (TCM) perspective, RA is part of the Bi Syndrome. Si Miao Xiao Bi Tang is one of the formulas listed in the guidelines for treatment of Damp-Heat syndrome. Till date, few studies have explored use of CHM, in particular Si Miao Xiao Bi Tang, in treating RA. According to past systematic reviews of radnomised controlled trials performed on Chinese herbs in RA patients, most studies were of low methodological quality and small numbers, resulting in lack of generalizability. Studies looking into cost effectiveness are also lacking.

Proposed project is a randomised double-blind placebo-controlled trial to be conducted over a period of three years, anchored to the Consolidated Standards of Reporting Trials (CONSORT) guidelines and CONSORT extension for CHM. Eligible patients will be randomly allocated to receive CHM and methotrexate or methotrexate and placebo on a 1:1 basis via random permuted block randomization.

Intervention group and control group patients receive methotrexate and CHM or methotrexate and placebo respectively for 12 weeks. They will attend rheumatologist reviews at weeks 0, 4, 8, and 12, including physical exams and disease monitoring. Safety is tracked through blood tests, and further tests are ordered as needed. TCM physicians participate by counselling and diagnosing TCM syndrome and monitoring for side effects during study visits at weeks 0, 4, 8 and 12.

American College of Rheumatology 20% improvement criteria (ACR20) at week 8 is the primary outcome. To achieve an ACR20 response, a patient with RA must demonstrate a 20% improvement in both tender and swollen joint counts, and 20% improvement in at least three of the following five criteria: patient's assessment of disease activity, physician's assessment of treatment response, patient's ability to perform daily activities based on Health Assessment Questionnaire-Disability Index (HAQ-DI), pain level, and serum inflammation markers.

Secondary outcomes include ACR20 response ACR50 response, ACR70 response, 28-joint disease activity score using ESR (DAS28-ESR), impact of RA on disability as measured using the Health Assessment Questionnaire Disability Index (HAQ-DI), severity of synovitis as determined using the EULAR-OMERACT ultrasound scoring system, quality of life as measured using the Medical Outcomes Study Short-Form (36-item) Health Survey (SF-36), fatigue level as measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale and safety of the trial.

Exploratory outcome is improvement in ultrasound inflammation at week 8 as compared to baseline, based on EULAR-OMERACT ultrasound scoring system.

Inclusion Criteria:

1. Patients between the ages of 21 and 70 years, and diagnosed with RA by a rheumatologist and fulfilling the 2010 ACR/EULAR classification criteria for RA.

2. Active disease with DAS28 ESR ≥3.2 at screening, with at least 6 swollen joints out of 66 and at least 6 tender joints out of 68.

3. Receiving stable doses of methotrexate therapy for at least 3 months, and on stable dose for at least 4 weeks before trial entry ( ≥10mg per week), either subcutaneous or orally.

4. Stable doses of non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen, or oral corticosteroids (equivalent to prednisone ≤ 10 mg) for at least 4 weeks prior to first dose of study medication.

5. Except for methotrexate, patients must have discontinued all csDMARDs, including, but not limited to: hydroxychloroquine, sulfasalazine, leflunomide prior to first dose of study medication as specified below:

   1. ≥ 4 weeks prior to Baseline Visit for sulfasalazine and hydroxychloroquine
   2. ≥ 8 weeks prior to Baseline Visit for leflunomide if no elimination procedure was followed, or adhere to an elimination procedure (i.e., 11 days with cholestyramine, or 30 days washout with activated charcoal)

6. A negative urine pregnancy test for women of childbearing potential on Day 1 (prior to administration of first dose of study drug).

7. Use of a reliable method of contraception by all female patients of childbearing potential and male patients with procreative capacity during the study and up to 3 months after the last dose of the study medication.

Exclusion Criteria:

1. Not able to provide informed consent.

2. Previous lack of efficacy to Si Miao Xiao Bi Tang.

3. History of inflammatory joint disease other than RA. Secondary Sjogren's Syndrome is permitted.

4. Concurrent use of other immunosuppressant medications, except MTX and protocol allowed doses of steroids.

5. Has been treated with intra-articular, intramuscular, intravenous, trigger point or tender point administration of corticosteroids in the preceding 4 weeks prior to the Baseline Visit.

6. Subject has been treated with any investigational drug within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the Baseline Visit or is currently enrolling in another clinical study.

7. Pregnant or breastfeeding females.

8. Infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses, untreated malignancy, or evidence of active or untreated latent tuberculosis.

9. Receipt of any live vaccine within 1 month prior to the Screening Visit, or expected need of live vaccination during study participation including up to 1 month after the last dose of study drug.

10. History of clinically significant hematologic, pulmonary, renal, hepatic, or psychiatric disease that would interfere with the subject's participation in this study.

11. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Day 1 or oral anti-infectives within 14 days prior to the Baseline Visit.

12. Any uncontrolled clinically significant laboratory abnormality or any of the following laboratory abnormalities:

    1. Evidence of hematopoietic disorder or hemoglobin <9 g/dL
    2. White blood cell count <3.0 x 10^9/L (<3000/mm^3)
    3. Absolute neutrophil count <1.2 x 10^9/L (<1000/mm^3)
    4. Platelet count <100 x 10^9/L (<100,000/mm^3)
    5. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal (ULN)
    6. Estimated glomerular filtration rate of less than 60 mL/min

13. Any arrhythmia on baseline/screening ECG.

14. Females of childbearing potential not willing to use contraceptive methods which, in the opinion of the investigator, are effective and adequate while on the study. Female subjects who are not of childbearing potential must meet at least one of the following criteria: (a) Have undergone a documented hysterectomy and/or bilateral oophorectomy; or (b) Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.

15. Been diagnosed with G6PD deficiency.

16. Subjects who are taking TCM supplements regularly (daily) and not willing to stop intake.