Leflunomide EfficAcy Response Related to Dosing Regimen in Early Rheumatoid Arthritis (LEADER)

Assessment of the Early Efficacy Response Rate of Leflunomide According to the Initial Dosing Regimen in the Treatment of Naive-DMARD (Disease Modifying Anti-Rheumatic Drug) Early RA (Rheumatoid Arthritis)-Patients

To assess the efficacy response rate at 3-months of two dosing regimen of leflunomide in DMARDs-naive patients presenting an early-RA using American College of Rheumatology 20% response rate.

To assess the clinical efficacy at 1-month and 3-month using complementary efficacy criteria (ACR 50, ACR 70, DAS 28) in each group of treatment, To assess the clinical and biological safety using standard blood monitoring, TEAED and SAE in each group of treatment, To evaluate treatment modifications; particularity leflunomide and concomitant use of AINS and corticoids.

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: leflunomide

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Italy
  • Milan, Italy
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Romania
  • Bucuresti, Romania
    • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of active rheumatoid arthritis in the previous 6 months (according to the ACR guidelines)
• Must have active disease to be initiated by DMARDs (Disease Modifying Anti-Rheumatic Drugs)

Exclusion Criteria:

• Patient presenting or having a history of other inflammatory joint disease
• Patient with ongoing or previous Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme
• Patient with significantly impaired bone marrow function or significant anaemia, leucopenia or thrombocytopenia due to causes or other than active rheumatoid arthritis
• Persistent infection or severe infection within 3 months before enrollment,
• Uncontrolled hypertension, uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, terminal illness or other medical condition which, in the opinion of the investigator, would put the patient at risk to participate in the study,
• Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult
• Severe hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin < 3.0 g/dl
• Moderate or severe impairment of renal function, as known by serum creatinine > 133 mcmol/L (or 1.5 mg/dl)
• Patient with history of recent and clinically significant drug or alcohol abuse
• Impairment of liver function or persisting ALT (SGPT) elevations of more than 2-fold the upper limit of normal
• Pregnancy
• Breastfeeding
• Women of childbearing potential, except if they fulfill specific conditions,
• Men wishing to father children during the course of the study or within the 24 months thereafter (or 3 month with the washout procedure)
• Patient with a congenital or acquired severe immuno-deficiency, a history of cancer or lymphoproliferative disease, or any patient who has received total lymphoid irradiation
• Known HIV positive status
• Known positive serology for hepatitis B or C
• Patient with hypersensitivity to any of the excipients in the tablets of leflunomide

• Previous therapy at any time with:

  • any DMARD including methotrexate, oral or injectable gold salts, chloroquine, hydroxychloroquine, ciclosporin, azathioprine, methotrexate, sulfasalazine
  • D penicillamine
  • alkylating agents, e.g., cyclophosphamide, chlorambucil, biological agents, e.g., interferon, monoclonal antibodies, growth factor, cytokines
  • any investigational drug
  • any antimetabolites
  • any opiates

• Therapy within the previous 4 weeks with:

  • oral corticosteroids exceeding a prednisolone equivalent of 10 mg/day
  • parenteral or intra-articular corticoid injection

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; 100 mg of leflunomide	Drug: leflunomide; 20 or 100 mg per os, Film coated tablet, for 3 days + matching placebo, then 20 mg once daily for 3 months
Active Comparator: 2; 20 mg of leflunomide	Drug: leflunomide; 20 or 100 mg per os, Film coated tablet, for 3 days + matching placebo, then 20 mg once daily for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinical efficacy response rate using ACR 20 criteria in each initial dosing regimen group	at 3 month

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical efficacy response rate using ACR 50, ACR 70, DAS 28 efficacy criteria in each group of treatment	at 1 and 3 months
Clinical and biological safety using standard blood monitoring, TEAED and SAE in each group of treatment	From the Informed Consent Form (ICF) signature to the end of the study
Measure of acute phase response (ESR, CRP)	At 1 and 3 months
Patient and physician global assessment	At 1 and 3 months
SF-36 questionnaire	At 1 and 3 months

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Cutolo M, Bolosiu H, Perdriset G; LEADER Study Group. Efficacy and safety of leflunomide in DMARD-naive patients with early rheumatoid arthritis: comparison of a loading and a fixed-dose regimen. Rheumatology (Oxford). 2013 Jun;52(6):1132-40. doi: 10.1093/rheumatology/kes321. Epub 2013 Feb 11.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: January 4, 2008
• First Submitted That Met QC Criteria: January 4, 2008
• First Posted (Estimate): January 16, 2008

Study Record Updates

• Last Update Posted (Estimate): October 13, 2010
• Last Update Submitted That Met QC Criteria: October 11, 2010
• Last Verified: October 1, 2010

More Information

Terms related to this study

• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Leflunomide
• Other Study ID Numbers: LEFLU_R_01143; Eudract#: 2007-000886-40