Hand Osteoarthritis
Conditions
Keywords
denosumab, RANKL-blockade
Brief summary
This is a randomized, double blind placebo controlled one-site proof-of-concept study in subjects with erosive osteoarthritis (OA) of interphalangeal (IP) finger joints. A total of 100 subjects will be enrolled into the study: 48 weeks placebo controlled double-blind phase with denosumab 60mg every 12 weeks, followed by a 48-week open-label phase in which all subjects will receive denosumab.
Detailed description
Investigational therapy: denosumab 60mg subcutaneous injection every 12 weeks. All subjects will receive Calcium/vit D supplementation. Efficacy objectives: The primary objective is to assess the effect of denosumab on the reduction of radiographic erosive progression using the Ghent University Score System (GUSS). The secondary objective is to assess the effect of denosumab on the reduction of radiographic erosive progression as defined by diminishing the appearance of new erosive IP finger joints. The exploratory objective is mainly to assess the effect of denosumab on clinical variables, as well as ultrasonography and dual energy x-ray absorptiometry parameters.
Interventions
DRUGdenosumab
60mg sc
DRUGPlacebo
identical syringe
DIETARY_SUPPLEMENTCalcium/Vit D supplementation
Daily dosage Calcium 1000mg / Vit D 880 IU
Sponsors
Amgen
University Hospital, Ghent
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* • Subjects with hand OA having suffered from transient inflammatory attacks of the interphalangeal finger joints characteristic for what has been termed 'inflammatory' or 'erosive' hand OA. * Subjects with hand OA showing inflammatory signs, either clinically or ultrasonographically, of the interphalangeal finger joints. * Subjects with hand OA in which at least 1 interphalangeal finger joint has the typical appearance on the X-rays of a 'J' or 'E' phase joint as defined by the criteria mentioned above. * Subjects with hand OA where at least 1 interphalangeal finger joint in the 'J' or 'E' phase presents a palpable swelling.
Exclusion criteria
* Patients with known hypersensitivities to mammalian-derived drug preparations. * Patients with clinically significant hypersensitivity to any of the components of Prolia. * Current and/or Prior treatment with any investigational agent within 90 days, or five half-lives of the product, whichever is longer. * Previous administration of denosumab from clinical trials or others (e.g. commercial use). * Vitamin D deficiency \[25(OH) vitamin D level \< 20 ng/mL (\< 49.9 nmol/L)\]. Possibility of replenishment and re-screening. * Subjects with current hypo- or hypercalcemia (normal serum calcium levels: 8.5-10.5 mg/dl or 2.12-2.62 mmol/L). * Patients currently under bisphosphonate (BP) treatment or any use of oral BPs within 12 months of study enrollment or intravenous BPs or strontium ranelate within 5 years of study enrollment * Prior use of any chondroprotective drug within 90 days e.g. chondroitin sulfate, glucosamine, avocado-soybean unsaponifiables, tetracyclins, corticosteroids. * Prior use of any immunomodulating drug with possible effects on proinflammatory cytokine metabolism within 90 days a.o. corticosteroids, methotrexate, sulfasalazine, leflunomide, D-Penicillin, anti-malarials, cytotoxic drugs, tumor necrosis factor (TNF) blocking agents. * History of drug or alcohol abuse in the last year. * Patients suffering from chronic inflammatory rheumatic disease (e.g. rheumatoid arthritis, spondylarthropathy, psoriatic arthritis, gout, chondrocalcinosis or other auto-immune diseases, e.g. systemic lupus erythematosus). * History of cancer or lymphoproliferative disease other than a successfully and completely treated squamous cell or basal cell carcinoma of the skin or cervical dysplasia, with no recurrence within the last two years. * History of any Solid Organ or Bone Marrow Transplant. * Comorbidities: significant renal function impairment (glomerular filtration \< 30 ml/min/1.73m2 or \<50% of normal value), uncontrolled diabetes, unstable ischemic heart disease, congestive heart failure (NYHA III, IV), uncontrolled hypo or hyperparathyroidism, active inflammatory bowel disease, malabsorption, liver failure or chronic hepatic disease (serum aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) levels 3 times above normal), recent stroke (within three months), chronic leg ulcer and any other condition (e.g,. indwelling urinary catheter) which, in the opinion of the investigator, would put the subject at risk by participation in the protocol. * Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures . * Patient who is pregnant or planning pregnancy; if the female subject is of child-bearing age, she must use a valid mean of contraception during the study and for 9 months after last dose of study medication. For males with a partner of childbearing potential: subject refuses to use 1 effective methods of contraception for the duration of the study and for 10 months after the last dose of study medication. * Female subjects who are breast-feeding. * History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction or other unhealed dental surgery; or planned invasive dental work during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Ghent University Scoring System (GUSS) of Target Joints at Week 24 | 24 weeks | The Ghent University Scoring System, GUSS, is quantitative radiographic scoring system and found to be a reliable method to score radiographic change over time in erosive IP OA. It includes assessment of proportions of normal subchondral bone, subchondral plate and joint space over time. Range of score: min: 0 max:300. Change scores are measured where positive changes corresponds with remodeling or repair (better outcome), and negative changes with erosive progression (worse outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New Erosive Joints by Verbruggen and Veys at Week 48 | 48 weeks | These are the number of new erosive IP joints according to the Verbruggen and Veys anatomical scoring system amongst the pre-erosive joints (i.e., N, S, J joints) at 48 weeks. |
| Total Ghent University Scoring System (GUSS) at Week 48 | 48 weeks | The Ghent University Scoring System, GUSS, is quantitative radiographic scoring system and found to be a reliable method to score radiographic change over time in erosive IP OA. It includes assessment of proportions of normal subchondral bone, subchondral plate and joint space over time. Range of score: min: 0 max:300. Change scores are measured where positive changes corresponds with remodeling or repair, and negative changes with erosive progression. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of (Serious) Adverse Events | 48 weeks | Number of patients who have experienced one or more (serious) adverse events throughout the study |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Comparator: Experimental: Denosumab 51 patients were enrolled in this group for a total treatment duration of 24 months (96 weeks): 48 weeks denosumab 60mg sc every 12 weeks followed by a 48-weeks open label phase denosumab 60mg sc every 12 weeks. | 51 |
| Comparator - Placebo 49 patients were enrolled in this group for a total treatment duration of 24 months (96 weeks): 48 weeks placebo sc every 12 weeks followed by a 48-weeks open label phase denosumab 60mg sc every 12 weeks. | 49 |
| Total | 100 |
Baseline characteristics
| Characteristic | Total | Comparator - Placebo | Active Comparator: Experimental: Denosumab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 9 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 82 Participants | 40 Participants | 42 Participants |
| Age, Continuous | 61.3 years STANDARD_DEVIATION 7.8 | 60.6 years STANDARD_DEVIATION 7.9 | 62.0 years STANDARD_DEVIATION 7.7 |
| Australian-Canadian Hand Osteoarthritis index, subscale function | 41.6 units on a scale STANDARD_DEVIATION 23.4 | 42.0 units on a scale STANDARD_DEVIATION 24.9 | 41.3 units on a scale STANDARD_DEVIATION 21.9 |
| Australian-Canadian Hand Osteoarthritis index, subscale pain | 21.2 units on a scale STANDARD_DEVIATION 12.3 | 21.7 units on a scale STANDARD_DEVIATION 13 | 20.7 units on a scale STANDARD_DEVIATION 11.6 |
| Body mass index | 25.3 kg/m² STANDARD_DEVIATION 3.8 | 25.3 kg/m² STANDARD_DEVIATION 4 | 25.3 kg/m² STANDARD_DEVIATION 3.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants | 49 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Functional Index for Hand Osteoarthritis (FIHOA) | 10.4 units on a scale STANDARD_DEVIATION 1 | 10.3 units on a scale STANDARD_DEVIATION 1 | 10.4 units on a scale STANDARD_DEVIATION 0.9 |
| Ghent University scoring system (GUSS) of all joints | 249 units on a scale STANDARD_DEVIATION 67 | 248 units on a scale STANDARD_DEVIATION 67 | 249 units on a scale STANDARD_DEVIATION 66 |
| Ghent University scoring system (GUSS) of target joints | 157.3 units on a scale STANDARD_DEVIATION 58.3 | 158.7 units on a scale STANDARD_DEVIATION 46.8 | 155.9 units on a scale STANDARD_DEVIATION 69.3 |
| Number of radiographically affected joints | 3.8 count STANDARD_DEVIATION 2.2 | 4.0 count STANDARD_DEVIATION 2.2 | 3.6 count STANDARD_DEVIATION 2.2 |
| Pain | 4.8 units on a scale STANDARD_DEVIATION 2.7 | 4.8 units on a scale STANDARD_DEVIATION 2.7 | 4.7 units on a scale STANDARD_DEVIATION 2.5 |
| Sex: Female, Male Female | 78 Participants | 37 Participants | 41 Participants |
| Sex: Female, Male Male | 22 Participants | 12 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 49 |
| other Total, other adverse events | 41 / 51 | 44 / 49 |
| serious Total, serious adverse events | 6 / 51 | 7 / 49 |
Outcome results
Primary
Total Ghent University Scoring System (GUSS) of Target Joints at Week 24
The Ghent University Scoring System, GUSS, is quantitative radiographic scoring system and found to be a reliable method to score radiographic change over time in erosive IP OA. It includes assessment of proportions of normal subchondral bone, subchondral plate and joint space over time. Range of score: min: 0 max:300. Change scores are measured where positive changes corresponds with remodeling or repair (better outcome), and negative changes with erosive progression (worse outcome).
Time frame: 24 weeks
Population: intention-to-treat (ITT) population (i.e., all participants randomly assigned to groups and who attended a baseline visit)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Experimental: Denosumab | Total Ghent University Scoring System (GUSS) of Target Joints at Week 24 | 162.2 units on a scale | Standard Error 2.4 |
| Comparator - Placebo | Total Ghent University Scoring System (GUSS) of Target Joints at Week 24 | 153.3 units on a scale | Standard Error 3.2 |
Comparison: Comparison between groups was done by Generalized Estimation Equations at joint level, accounting for within-patient clustering and adjusted for baseline unbalances. Missing values were imputed according to a predefined imputation model, including randomization group, baseline value and values at other time points available, presence of baseline inflammation, baseline number of affected joints.p-value: 0.02495% CI: [1, 16.9]GEE
Secondary
Number of New Erosive Joints by Verbruggen and Veys at Week 48
These are the number of new erosive IP joints according to the Verbruggen and Veys anatomical scoring system amongst the pre-erosive joints (i.e., N, S, J joints) at 48 weeks.
Time frame: 48 weeks
Population: intention-to-treat (ITT) population (i.e., all participants randomly assigned to groups and who attended a baseline visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Comparator: Experimental: Denosumab | Number of New Erosive Joints by Verbruggen and Veys at Week 48 | 9 joints |
| Comparator - Placebo | Number of New Erosive Joints by Verbruggen and Veys at Week 48 | 38 joints |
p-value: <0.00195% CI: [0.11, 0.5]Regression, Logistic
Secondary
Total Ghent University Scoring System (GUSS) at Week 48
The Ghent University Scoring System, GUSS, is quantitative radiographic scoring system and found to be a reliable method to score radiographic change over time in erosive IP OA. It includes assessment of proportions of normal subchondral bone, subchondral plate and joint space over time. Range of score: min: 0 max:300. Change scores are measured where positive changes corresponds with remodeling or repair, and negative changes with erosive progression.
Time frame: 48 weeks
Population: intention-to-treat (ITT) population (i.e., all participants randomly assigned to groups and who attended a baseline visit)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Experimental: Denosumab | Total Ghent University Scoring System (GUSS) at Week 48 | 163.5 units on a scale | Standard Error 2.9 |
| Comparator - Placebo | Total Ghent University Scoring System (GUSS) at Week 48 | 149.2 units on a scale | Standard Error 3.9 |
Comparison: Comparison between groups was done by Generalized Estimation Equations at joint level, accounting for within-patient clustering and adjusted for baseline unbalances. Missing values were imputed according to a predefined imputation model, including randomization group, baseline value and values at other time points available, presence of baseline inflammation, baseline number of affected joints.p-value: 0.00395% CI: [4.6, 24]GEE
Other Pre-specified
Number of (Serious) Adverse Events
Number of patients who have experienced one or more (serious) adverse events throughout the study
Time frame: 48 weeks