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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Denosumab In Addition To Intense Urate-Lowering Therapy for Bone Erosions in Gout: A Pilot Study

Conditions
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Gout

Intervention / Treatment
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* Drug: Denosumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention<br>Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care | Drug: Denosumab<br>* 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<br>* Other names: Prolia;|
| No Intervention: Control<br>Standard urate lowering therapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CT Bone Erosion Score | 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. | Baseline, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrease in Bone Reabsorption | 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 | Baseline, 12 months | 
| Change in Subject Reported Functional Status (Disability) | 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. | Baseline, 12 months | 
| Subject Reported Change in Physical Health | 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. | Baseline, 12 months | 
| Subject Reported Change in Mental Health | Subject Reported Change in Mental Health on SF-12 mental component form. Range 0-100 with higher scores representing better self-reported health | Baseline, 12 months | 
| Assessment of Pain | Assessment of pain score by visual analogue scale (VAS) reported from baseline over 12 months. Range 0-10 with higher scores representing more pain. | Baseline, 12 months |