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

Phase 2

Completed

Conditions: Gout

Interventions: Drug: Denosumab

Registration Number: NCT02903446

Lead Sponsor: University of Alabama at Birmingham

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
CT Bone Erosion Score	Baseline, 12 months	Change in the foot CT bone erosion score from baseline to 12 months. A total of 14 bones of the foot are scored. Each bone of the scored separately on a scale from 0 to 10, based on the proportion of eroded bone compared with the 'assessed bone volume', judged on all available images-0: no erosion; 1: 1-10% of bone eroded; 2: 11-20% bone eroded; 3:21-30% of bone eroded; 4: 31-40% of bone eroded; 5: 51-60% bone eroded; 7:61-70% of bone eroded; 8: 71-80% of bone eroded; 9: 81-90% bone eroded; 10:\>=91% of bone eroded. Higher score indicates worsening of erosion. Score ranges from 0 to 140.

Secondary Outcome Measures

Name	Time	Method
Subject Reported Change in Mental Health	Baseline, 12 months	Subject Reported Change in Mental Health on SF-12 mental component form. Range 0-100 with higher scores representing better self-reported health
Subject Reported Change in Physical Health	Baseline, 12 months	Subject reported change in physical and mental health by Short Form Health Survey (SF-12) scores assessed from baseline over 12 months. Range 0-100 with higher scores representing better self-reported health.
Decrease in Bone Reabsorption	Baseline, 12 months	Change in bone reabsorption as measured by serum carboxy-terminal collagen crosslinks (CTX) levels (pg/mL) over 12 months. Lower values represent varying degrees of suppression of normal bone turnover. The reference ranges for C-terminal telopeptide in serum are as follows: Female (premenopausal): 40-465 pg/mL Female (postmenopausal): 104-1008 pg/mL Male: 60-700 pg/mL
Change in Subject Reported Functional Status (Disability)	Baseline, 12 months	Change in subject reported functional status (disability) by Health Assessment Questionnaire (HAQ) will be assessed from baseline over 12 months. 0 to 1 are generally considered to represent mild to moderate difficulty, 1 to 2 moderate to severe disability, and 2 to 3 severe to very severe disability.
Assessment of Pain	Baseline, 12 months	Assessment of pain score by visual analogue scale (VAS) reported from baseline over 12 months. Range 0-10 with higher scores representing more pain.