RANKL-blockade for the Treatment of Erosive Osteoarthritis (OA) of Interphalangeal Finger Joints

Randomized, Double Blind, Placebo-controlled Study to Evaluate the Efficacy of Denosumab 60mg sc Every 3 Months in Patients With Erosive Osteoarthritis of the Interphalangeal (IP) Finger Joints

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.

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.

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.