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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02903446

Enrollment

Registered

2016-09-16

Start date

2017-02-01

Completion date

2020-03-01

Last updated

2021-11-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Gout

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.

Interventions

DRUGDenosumab

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

30 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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
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.

Countries

United States

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.

Participants by arm

Arm	Count
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	10
Control Standard urate lowering therapy	10
Total	20

Baseline characteristics

Characteristic	Control	Total	Intervention
Age, Continuous	63 years STANDARD_DEVIATION 9.4	65.0 years STANDARD_DEVIATION 12.4	67 years STANDARD_DEVIATION 15
CT Erosion Score (range 0-140 total of 14 bones)	7.0 units on a scale STANDARD_DEVIATION 5.1	6.8 units on a scale STANDARD_DEVIATION 5.1	6.6 units on a scale STANDARD_DEVIATION 5.4
Estimated glomerular filtration rate	72 mL/min/1.73m2 STANDARD_DEVIATION 15.3	74.2 mL/min/1.73m2 STANDARD_DEVIATION 24.5	76.5 mL/min/1.73m2 STANDARD_DEVIATION 32
Health Assessment Questionnaire -Disability Index Total (range from 0-3.0)	0.39 HAQ Score STANDARD_DEVIATION 0.44	0.38 HAQ Score STANDARD_DEVIATION 0.52	0.36 HAQ Score STANDARD_DEVIATION 0.61
Race/Ethnicity, Customized Asian	1 Participants	2 Participants	1 Participants
Race/Ethnicity, Customized European descent	5 Participants	11 Participants	6 Participants
Race/Ethnicity, Customized Maori	2 Participants	2 Participants	0 Participants
Race/Ethnicity, Customized Other	2 Participants	5 Participants	3 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants	0 Participants	0 Participants
Region of Enrollment New Zealand	6 Participants	11 Participants	5 Participants
Region of Enrollment United States	4 Participants	9 Participants	5 Participants
Serum CTX	286.9 pg/mL STANDARD_DEVIATION 111.5	303.4 pg/mL STANDARD_DEVIATION 133	316.6 pg/mL STANDARD_DEVIATION 152.6
Serum Urate	4.2 mg/dL STANDARD_DEVIATION 0.7	4.3 mg/dL STANDARD_DEVIATION 0.6	4.3 mg/dL STANDARD_DEVIATION 0.5
Sex: Female, Male Female	0 Participants	1 Participants	1 Participants
Sex: Female, Male Male	10 Participants	19 Participants	9 Participants
Short Form Survey (SF-12) mental component score (range 0-100)	55.1 SF-12 score STANDARD_DEVIATION 10.4	56.3 SF-12 score STANDARD_DEVIATION 7.8	57.5 SF-12 score STANDARD_DEVIATION 4.2
Short Form Survey (SF-12) physical component score (range 0-100)	43.9 SF-12 score STANDARD_DEVIATION 7.3	43.8 SF-12 score STANDARD_DEVIATION 9.6	43.6 SF-12 score STANDARD_DEVIATION 11.9
Visual Analogue Pain Score (range 0-10)	1.3 visual analog pain scale STANDARD_DEVIATION 1.5	1.8 visual analog pain scale STANDARD_DEVIATION 2.9	2.2 visual analog pain scale STANDARD_DEVIATION 3.7

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 10
other Total, other adverse events	5 / 10	6 / 10
serious Total, serious adverse events	0 / 10	0 / 10

Outcome results

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.