Randomized clinical trial on the prevention of radiographic progression with zoledronic acid in patients with early rheumatoid arthritis and low disease activity

INTERVENTION: Trade Name: Zoledronic acid Product Name: Zoledronic acid Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: ZOLEDRONIC ACID CAS Number: 118072‐93‐8 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 0.8‐ CONDITION: Rheumatoid arthritis ; MedDRA version: 16.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: To assess the progression of radiographic damage in patients with early RA in current treatment with DMARDs and low disease activity to which treatment with zoledronic acid is added, compared to a no treatment control population. Primary end point(s): The primary study endpoint is the progression of radiological damage assessed in a blinded way by the difference in the Sharp‐van der Heijde index (SHI) in radiographs of hands and feet after two years. Secondary Objective: a. To assess the progression of radiological damage after one year ; b. To compare the loss of periarticular bone mass by DXA bone densitometry of the hands at two years ; c. To compare general bone loss by DXA bone densitometry of lumbar spine and proximal femur at two years ; d. To determine the size variation of carpal and metacarpophalangeal joints erosions by high resolution computed tomography (CT), at two years ; e. To assess the predictive value of response to previous targets of serum OPG, RANKL, DKK‐1 and sclerostin assets at the beginning. ; f. To determine the proportion of patients that eventually require the addition of biological treatment for presenting sustained disease activity. ; g. To determine the proportion of patients that eventually require the addition of biological treatment for presenting radiological progression. ; h. To study the safety of zoledronic acid. Timepoint(s) of evaluation of this end point: Baseline and after two years SECONDARY OUTCOME: Secondary end point(s): In patients with early RA in current treatment with DMARDs and low disease activity to whom zoledronic acid or no treatment is added:; a. To assess the progression of radiological damage after one year ; b. To compare the loss of periarticular bone mass by DXA bone densitometry of the hands at two years ; c. To compare general bone loss by DXA bone densitometry of lumbar spine and proximal femur at two years ; d. To determine the size variation of carpal and metacarpophalangeal joints erosions by high resolution computed tomography (CT), at two years ; e. To assess the predictive value of response to previous targets of serum OPG, RANKL, DKK‐1 and sclerostin assets at the beginning of the study treatments. ; f. To determine the proportion of patients that eventually require the addition of biological treatment for presenting sustained disease activity. ; g. To determine the proportion of patients that eventually require the addition of biological treatment for presenting radiological progression. ; h. To study the safety of zoledronic acid. Timepoint(s) of evaluation of this end point: Timepoints are specified for every secondary endpoint in section E.5.2. INCLUSION CRITERIA: 1. Age ? 18 years 2. Patients with RA of less than 2 years of evolution 3. DMARD therapy (methotrexate alone or methotrexate, leflunomide or methotrexate within COBRA strategy) on stable dose for at least 6 weeks prior to study entry 4. Patients not treated with glucocorticoids or under stable dose of prednisone up to 5 mg / day or equivalent dose of another glucocorticoid 5. Low disease activity (DAS28 <3.2) 6. Im case of premenopausal women, commitment to make contraceptive treatment up to 3 years after the last dose of zoledronic acid 7. Signed informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 62 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 32