Denosumab In Addition To Intense Urate-Lowering Therapy for Bone Erosions in Gout: A Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- CT Bone Erosion Score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 30 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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*
排除标准
- •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
研究组 & 干预措施
Intervention
Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care
干预措施: Denosumab (Drug)
结局指标
主要结局
CT Bone Erosion Score
时间窗: 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.
次要结局
- Subject Reported Change in Mental Health(Baseline, 12 months)
- Subject Reported Change in Physical Health(Baseline, 12 months)
- Decrease in Bone Reabsorption(Baseline, 12 months)
- Change in Subject Reported Functional Status (Disability)(Baseline, 12 months)
- Assessment of Pain(Baseline, 12 months)
研究者
Angelo L. Gaffo
Principal Investigator
University of Alabama at Birmingham