Denosumab In Addition To Intense Urate-Lowering Therapy for Bone Erosions

NCT ID: NCT02903446

Last Updated: 2021-11-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-01
• Study Completion Date: 2020-03-01

Brief Summary

Bone erosions are a common manifestation and feature of structural damage in severe/chronic tophaceous gout. Management of this destructive and often debilitating gout complication has focused exclusively on urate-lowering therapy (ULT) to reduce frequency of gout attacks, but little attention has been given to prevention or reversal of gout related bone erosions and other structural damage to bone caused by gout. Since there is no known effective treatment to attenuate or improve structural damage caused by gout, we propose a pilot, controlled, proof-of-concept study in which denosumab, an FDA approved medication for the treatment of bone loss, will be added to standard ULT in 20 patients with erosive gout.

Detailed Description

A recently published clinical trial with zoledronic acid failed to show an effect in improving bone erosions among individuals with chronic tophaceous gout, despite improvements in bone mineral density (BMD) and bone turnover markers. However, it is known that increased numbers of osteoclasts (cells that absorb bone tissue during growth and healing) in patients with tophaceous gout are most likely a result of enhanced osteoclast activity as these patients also have higher circulating levels of the protein receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL has been identified to affect the immune system and control bone regeneration and remodeling.

Furthermore, peripheral blood cells and synovial fluid cells taken from patients with erosive gout preferentially formed osteoclast-like cells in the presence of RANKL. The number of osteoclasts formed significantly correlates with the number of tophi in gout patients.

Denosumab (Prolia®) is a fully human monoclonal antibody with a high affinity for RANKL that can bind and neutralize the activity of human RANKL. Given the relevance of RANKL in the mechanism of gouty erosions,a central hypothesis of this pilot study is that denosumab is more likely to precisely target RANKL and the mechanism of gouty erosions than zoledronic acid.

Conditions

Gout

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intervention

Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care

Group Type: ACTIVE_COMPARATOR

Denosumab

Intervention Type: DRUG

Participants will be randomized (1:1) allocation to denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + ULT standard of care OR ULT standard of care therapy

Control

Standard urate lowering therapy

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Denosumab

Participants will be randomized (1:1) allocation to denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + ULT standard of care OR ULT standard of care therapy

Intervention Type: DRUG

Other Intervention Names

Prolia

Eligibility Criteria

Inclusion Criteria

• Age 30 years or older and able to provide informed consent
• Diagnosis of gout according to the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria
• Radiographic foot bone erosion attributable to gout and confirmed by a radiologist
• Serum urate of ≤ 5 mg/dL (300 µmol/L) or less*

Exclusion Criteria

• Treatment with bisphosphonates in the preceding 2 years
• Any prior treatment with denosumab
• Women of childbearing potential, who are not currently using birth control, are pregnant, planning to become pregnant, or are breast-feeding
• Men planning to conceive in the next 12 months
• Unstable systemic medical condition
• Uncontrolled hyperthyroidism
• Uncontrolled hypothyroidism
• History of Addison disease
• History of osteomalacia
• History of osteonecrosis of the jaw (ONJ)
• History of atypical femur fracture
• History of tooth extraction, jaw surgery, dental implants, or other dental surgery within the prior 6 months
• History of anorexia nervosa, bulimia (by history or physical) or obvious malnutrition.
• Invasive dental work planned in the next 2 years
• History of Paget's disease of bone
• Other bone diseases which affect bone metabolism
• Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)]†
• Hypercalcemia
• Elevated transaminases ≥ 2.0 x upper limit of normal (ULN)
• Elevated total bilirubin > 1.5x ULN
• History of any solid organ or bone marrow transplant
• Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma)
• Hypocalcemia
• Poorly tolerant of ULT including allopurinol, febuxostat, or probenecid
• Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2
• Current use of any biological therapy (eg. infliximab, etanercept, adalimumab, etc.)
• Treatment history with pegloticase or another recombinant uricase
• Recipient of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Auckland, New Zealand

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Angelo L. Gaffo

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

F160315004

Identifier Type: -

Identifier Source: org_study_id