Study of Different Doses of Folic Acid in Combination With Methotrexate in Rheumatoid Arthritis (FOLVARI)

Randomized Trial of 10 mg Versus 30 mg Per Week of Folic Acid in Combination With Methotrexate in Rheumatoid Arthritis

Introduction: Methotrexate is the sheet anchor for the treatment of rheumatoid arthritis. Folic acid supplementation is usually given at a dose of 5-30 mg per week to ameliorate adverse effects. Patients at our center are usually on the higher dose. However, it is unclear if higher doses are required, recent international recommendations suggest 5-10 mg per week only.

Objectives: To randomize rheumatoid patients being being started on Methotrexate into 2 groups- one on 5mg for 6 days a week (30mg per week) of folic acid and the other 5 mg twice a week (10 mg per week) for 24weeks. To look at difference in

1. Adverse effects due to methotrexate

   a. Minor adverse effects: By symptom chart

   a. Major adverse effects: Cytopenia (predefined) and transaminitis.

2. Disease activity using Disease activity score 28 joints (3 variable) and functional status by health assessment questionnaire
3. RBC folic acid levels Methodology: Randomised controlled trial, double blinded, placebo controlled. Sample size 50 in each group. One group of patients will receive folic acid 5 mg twice a week with placebo for 4 days and the other group will receive folic acid 5 mg 6 days a week for 24 weeks.

Patients will be administered adverse effects proforma, assessed for having cytopenias and transaminitis (pre defined) and disease activity will be calculated at every visit, ie., in the beginning at then at 8,16 and 24 weeks. In addition will look at the functional status and RBC folate levels at 0 and 24 weeks. Statistical analysis using chi-square test for proportions and t test for continuous variables.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Folic Acid; Drug: Placebo

Detailed Description

THIS TRIAL WILL INCLUDE NEW RHEUMATOID ARTHRITIS PATIENTS These patients will then be randomized into two groups - one which continues to take the same folic acid dose and one which is shifted to folic acid 10 mg per week.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • New OPD, #3035, Level 3, Rheumatology Clinic, Tuesday and Friday

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-75 years
• Patients fulfilling the 1987 American College of Rheumatology Rheumatoid arthritis criteria

Exclusion Criteria:

• Hb less than 8 g per dl or TLC less than 3500 or Platelet less than 1 lac or SGOT or SGPT more than 60 U/L
• Serious concomitant medical illnesses such as cancer, liver or renal disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Folic acid 30 mg per week; Patients will be administered 5 mg folic acid for 6 days a week, no tablet on the day they take methotrexate (5 mg x 6 days = 30 mg per week)	Drug: Folic Acid; Folic acid tablets 5 mg
Active Comparator: Folic acid 10 mg; Patients will be given folic acid 5 mg for two days per week and placebo tablets for four days a week, no tablet on the day they take methotrexate (Folic acid 5mg x 2 days = 10mg per week)	Drug: Folic Acid; Folic acid tablets 5 mg; Drug: Placebo; Matched placebo to folic acid 5 mg tables, to be given for 4 days a week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse effects	i. Minor: Two Symptom charts: Those AEs related temporally to methotrexate and those not temporally related. ii. Major: Hemoglobin (Hb), Platelet, Total leucocyte count or white blood count (TLC), Differential leukocyte count (DLC), Serum glutamic oxaloacetate transaminase (SGOT)/ serum glutamic pyruvate transaminase (SGPT) will be done at 3 months. Patients having Hb≤6, TLC ≤ 3500, Platelet ≤99000, SGOT or SGPT ≥80 IU/L	24 weeks
disease activity	Using disease activity score 28 joints 3 variables(DAS 28-3v) : uses evaluation of tender joint count (TJC28), Swollen joint count (SJC28) and the erythrocyte sedimentation rate (ESR) using Westergren method.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RBC folic acid:	This will be done by chemiluminescence assay, to compare folic acid levels at baseline and at 24 weeks	24 weeks
Function	Look at the function by Indian Health assessment questionnaire	24 weeks

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Varun Dhir, MD, DM, PGIMER, Chandigarh, India

Publications and helpful links

General Publications

• Dhir V, Sandhu A, Kaur J, Pinto B, Kumar P, Kaur P, Gupta N, Sood A, Sharma A, Sharma S. Comparison of two different folic acid doses with methotrexate--a randomized controlled trial (FOLVARI Study). Arthritis Res Ther. 2015 Jun 11;17(1):156. doi: 10.1186/s13075-015-0668-4.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: March 15, 2012
• First Submitted That Met QC Criteria: April 21, 2012
• First Posted (Estimate): April 24, 2012

Study Record Updates

• Last Update Posted (Estimate): February 7, 2014
• Last Update Submitted That Met QC Criteria: February 5, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: rheumatoid arthritis; methotrexate; folic acid
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Folic Acid
• Other Study ID Numbers: P-124