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

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT02903446
• Collaborator: University of Auckland, New Zealand (Other)
• Enrollment: 20
• Location: 1
• Arms: 2
• Actual Duration (Months): 36.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Gout	Drug: Denosumab	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Denosumab In Addition To Intense Urate-Lowering Therapy for Bone Erosions in Gout: A Pilot Study
• Actual Study Start Date: Feb 1, 2017
• Actual Primary Completion Date: Mar 1, 2020
• Actual Study Completion Date: Mar 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intervention Denosumab 60 mg administered subcutaneously (SC) every 6 months for a year + urate lowering therapy (ULT) standard of care	Drug: 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; Other Names: Prolia
No Intervention: Control Standard urate lowering therapy

Outcome Measures

Primary Outcome Measures

1. 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

1. 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

2. 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.

3. 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.

4. 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

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham
• University of Auckland, New Zealand

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 26, 2017

More Information

Publications

None provided.

• Responsible Party: Angelo L. Gaffo, Principal Investigator, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT02903446
• Other Study ID Numbers: F160315004
• First Posted: Sep 16, 2016
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Gout; Denosumab

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Intervention	Control	Total
Arm/Group Description	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	Standard urate lowering therapy	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (15)	63 (9.4)	65.0 (12.4)
Sex: Female, Male (Count of Participants)
Female	1 10%	0 0%	1 5%
Male	9 90%	10 100%	19 95%
Race/Ethnicity, Customized (Count of Participants)
European descent	6 60%	5 50%	11 55%
Maori	0 0%	2 20%	2 10%
Asian	1 10%	1 10%	2 10%
Pacific Islander	0 0%	0 0%	0 0%
Other	3 30%	2 20%	5 25%
Region of Enrollment (Count of Participants)
United States	5 50%	4 40%	9 45%
New Zealand	5 50%	6 60%	11 55%
Serum Urate (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	4.3 (0.5)	4.2 (0.7)	4.3 (0.6)
Estimated glomerular filtration rate (mL/min/1.73m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73m2]	76.5 (32)	72 (15.3)	74.2 (24.5)
CT Erosion Score (range 0-140 total of 14 bones) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.6 (5.4)	7.0 (5.1)	6.8 (5.1)
Serum CTX (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	316.6 (152.6)	286.9 (111.5)	303.4 (133.0)
Health Assessment Questionnaire -Disability Index Total (range from 0-3.0) (HAQ Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [HAQ Score]	0.36 (0.61)	0.39 (0.44)	0.38 (0.52)
Short Form Survey (SF-12) physical component score (range 0-100) (SF-12 score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [SF-12 score]	43.6 (11.9)	43.9 (7.3)	43.8 (9.6)
Short Form Survey (SF-12) mental component score (range 0-100) (SF-12 score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [SF-12 score]	57.5 (4.2)	55.1 (10.4)	56.3 (7.8)
Visual Analogue Pain Score (range 0-10) (visual analog pain scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [visual analog pain scale]	2.2 (3.7)	1.3 (1.5)	1.8 (2.9)

Outcome Measures

1. Primary Outcome

Title	CT Bone Erosion Score
Description	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.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [Score on a scale]	6.6 (5.4)	7.0 (5.1)

2. Secondary Outcome

Title	Decrease in Bone Reabsorption
Description	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
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [pg/mL]	177.6 (143.1)	324.1 (113.3)

3. Secondary Outcome

Title	Change in Subject Reported Functional Status (Disability)
Description	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.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [Difference in HAQ score from baseline]	.33 (.30)	.11 (0.24)

4. Secondary Outcome

Title	Subject Reported Change in Physical Health
Description	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.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	45.5 (12.6)	52.3 (1.8)

5. Secondary Outcome

Title	Subject Reported Change in Mental Health
Description	Subject Reported Change in Mental Health on SF-12 mental component form. Range 0-100 with higher scores representing better self-reported health
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	58.7 (6.7)	53.1 (7.6)

6. Secondary Outcome

Title	Assessment of Pain
Description	Assessment of pain score by visual analogue scale (VAS) reported from baseline over 12 months. Range 0-10 with higher scores representing more pain.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	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	Standard urate lowering therapy
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	1.3 (3.1)	1.2 (1.4)

Adverse Events

Time Frame	1 year
Arm/Group Title	Intervention		Control
Arm/Group Description	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		Standard urate lowering therapy
All Cause Mortality
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/10 (50%)		6/10 (60%)
Blood and lymphatic system disorders
Anemia	0/10 (0%)	0	1/10 (10%)	1
Cardiac disorders
Atrial flutter	0/10 (0%)	0	1/10 (10%)	1
Atrial fibrillation	1/10 (10%)	1	0/10 (0%)	0
Gastrointestinal disorders
Gastro-esophageal reflux	0/10 (0%)	0	1/10 (10%)	1
Vomitting	1/10 (10%)	1	0/10 (0%)	0
Esophageal refulx	0/10 (0%)	0	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Back Pain	0/10 (0%)	0	1/10 (10%)	1
Joint Pain	1/10 (10%)	1	1/10 (10%)	1
Cramps	1/10 (10%)	1	0/10 (0%)	0
Skin and subcutaneous tissue disorders
Skin Rash	1/10 (10%)	1	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.