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| Name | Class |
|---|---|
| University of Auckland, New Zealand | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention | Active Comparator | Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care |
|
| Control | No Intervention | Standard urate lowering therapy |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Denosumab | 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 |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35294 | United States |
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Potential study participants were screened for enrollment at rheumatology clinics located at the University of Alabama at Birmingham and the University of Auckland. Participants were recruited between March 2017 and May 2019.
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| ID | Title | Description |
|---|---|---|
| FG000 | Intervention | Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care 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 |
| FG001 | Control | Standard urate lowering therapy |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Intervention | Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | Score on a scale | Baseline, 12 months |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intervention | Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care 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 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial flutter | Cardiac disorders | Medra | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Angelo Gaffo, MD; Associate Professor | UNIVERSITY OF ALABAMA AT BIRMINGHAM | 205-996-6086 | agaffo@uab.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 26, 2017 | Apr 13, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006073 | Gout |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D000070657 | Crystal Arthropathies |
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| ID | Term |
|---|---|
| D000069448 | Denosumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| 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 |
| Control |
Standard urate lowering therapy |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Serum Urate | Mean | Standard Deviation | mg/dL |
|
| Estimated glomerular filtration rate | Mean | Standard Deviation | mL/min/1.73m2 |
|
| CT Erosion Score (range 0-140 total of 14 bones) | 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%, etc. Higher score indicate worsening of erosion. | Mean | Standard Deviation | units on a scale |
|
| Serum CTX | Measure of the amount carboxy-terminal collagen crosslinks (CTX) in serum | Mean | Standard Deviation | pg/mL |
|
| Health Assessment Questionnaire -Disability Index Total (range from 0-3.0) | 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. | Mean | Standard Deviation | HAQ Score |
|
| Short Form Survey (SF-12) physical component score (range 0-100) | The SF-12 measures eight concepts commonly represented in widely used surveys: physical functioning. 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. | Mean | Standard Deviation | SF-12 score |
|
| Short Form Survey (SF-12) mental component score (range 0-100) | 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. | Mean | Standard Deviation | SF-12 score |
|
| Visual Analogue Pain Score (range 0-10) | A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values (0-10) | Mean | Standard Deviation | visual analog pain scale |
|
| OG001 | Control | Standard urate lowering therapy |
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | pg/mL | Baseline, 12 months |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | Difference in HAQ score from baseline | Baseline, 12 months |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | units on a scale | Baseline, 12 months |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | units on a scale | Baseline, 12 months |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | units on a scale | Baseline, 12 months |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 5 |
| 10 |
| EG001 | Control | Standard urate lowering therapy | 0 | 10 | 0 | 10 | 6 | 10 |
| Atrial fibrillation | Cardiac disorders | Medra | Systematic Assessment |
|
| Gastro-esophageal reflux | Gastrointestinal disorders | Medra | Systematic Assessment |
|
| Vomitting | Gastrointestinal disorders | Medra | Systematic Assessment |
|
| Esophageal refulx | Gastrointestinal disorders | Medra | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | Medra | Systematic Assessment |
|
| Joint Pain | Musculoskeletal and connective tissue disorders | Medra | Systematic Assessment |
|
| Cramps | Musculoskeletal and connective tissue disorders | Medra | Systematic Assessment |
|
| Skin Rash | Skin and subcutaneous tissue disorders | Medra | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Medra | Systematic Assessment |
|
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| D012216 |
| Rheumatic Diseases |
| D011686 | Purine-Pyrimidine Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |