Zoledronic Acid in Rheumatoid Arthritis (AZAR)

Randomized Clinical Trial on the Prevention of Radiographic Progression With Zoledronic Acid in Patients With Early Rheumatoid Arthritis and Low Disease Activity

The progression of structural joint damage is the leading cause of disability and socioeconomic costs associated with rheumatoid arthritis (RA). Remission and low clinical activity not always imply absence of progression of structural damage. The main objective of this study is to evaluate the progression of radiological damage in early RA patients currently treated with disease modifying anti-rheumatic drugs (DMARDs) and low disease activity to which treatment with zoledronic acid is added.

The investigators propose a randomized clinical trial in 94 patients with RA of less than 2 years of evolution that, being treated with DMARDs, present criteria of low disease activity (DAS28 < 3.2).

Patients will be randomized into two branches: zoledronic acid and no treatment. 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; the secondary variables: radiographic progression after one year, serum bone biomarkers (OPG, RANKL, DKK-1 and sclerostin) and adverse effects. In a subgroup of patients, the investigators shall evaluate the change in the size of hand erosions by multislice computed tomography and the evolution of periarticular osteoporosis and systemic bone mass by dual X-ray absorptiometry (DXA).

Study Overview

• Status: Terminated
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: Zoledronic acid

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • A Coruña, Spain, 15006
    • Complexo Hospitalario Universitario A Coruña
  • Barcelona, Spain, 08036
    • Hospital Clinic I Provincial de Barcelona
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Sevilla, Spain, 41071
    • Hospital Virgen Macarena
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge
    • Sant Joan Despí, Barcelona, Spain, 08970
      • Hospital de Sant Joan Despí Moisès Broggi
    • Sant Pere de Ribes, Barcelona, Spain, 08810
      • Hospital Residència Sant Camil
    • Viladecans, Barcelona, Spain, 08840
      • Hospital de Viladecans
  • Bilbao
    • Barakaldo, Bilbao, Spain, 48903
      • Hospital Universitario de Cruces
  • Mallorca
    • Palma de Mallorca, Mallorca, Spain, 07120
      • Hospital Universitari Son Espases

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:

1. Age equal or greater than 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. In case of premenopausal women, commitment to make contraceptive treatment up to 3 years after the last dose of zoledronic acid
7. Signed informed consent

Exclusion Criteria:

1. Previous or current treatment with biological drugs used for the treatment of RA (infliximab, adalimumab, etanercept, certolizumab, golimumab, rituximab, abatacept, tocilizumab)

2. Pretreatment with:

   1. Bisphosphonates in the 5 years prior to the onset of RA
   2. Calcitonin, raloxifene, bazedoxifene, strontium ranelate, teriparatide and denosumab in the year before the onset of RA

3. Contraindication to treatment with zoledronic acid:

   1. Hypersensitivity to bisphosphonates
   2. Hypocalcemia
   3. Glomerular filtration rate <35 mL / min
   4. Pregnant (negative pregnancy test) and lactating women
   5. Poor oral hygiene
   6. Pending invasive dental procedure
4. Serum levels of calcidiol lower than 25 nmol/L (10 ng/mL).
5. Simultaneous participation in another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No intervention
Active Comparator: Zoledronic acid; Zoledronic acid: 5 mg/year x 2 years	Drug: Zoledronic acid; Zoledronic acid: 5 mg/year x 2 years; Other Names: Aclasta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sharp van der Heijde index	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, after two years.	Two years

Collaborators and Investigators

• Sponsor: Carmen Gómez-Vaquero
• Investigators: Principal Investigator: Carmen Gómez-Vaquero, MD, PhD, Hospital Universitari de Bellvitge; Study Director: Silvia Pérez-Pujol, PhD, UCICEC-Hospital Universitari de Bellvitge

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: April 23, 2014
• First Submitted That Met QC Criteria: April 24, 2014
• First Posted (Estimate): April 25, 2014

Study Record Updates

• Last Update Posted (Actual): February 22, 2019
• Last Update Submitted That Met QC Criteria: February 21, 2019
• Last Verified: February 1, 2019

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; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: CGV222