Background
Methods/design
Study design
Study population
Inclusion criteria | Exclusion criteria |
---|---|
Age 40–85 years | For women of childbearing potential: Subject refuses to use 1 highly effective method of contraception (contraceptive pill, intra uterine contraceptive device) for the duration of the study and for 10 months after the last dose of study medication. |
Short Portable Mental Status Questionnaire (SPMSQ) also named Pfeiffertest ≥7 | For males with a partner of childbearing potential: Subject refuses to use 1 highly effective method of contraception for the duration of the study and for 10 months after the last dose of study medication. |
Male and females | For males with a partner who is pregnant: Subject refuses to use a condom for the duration of the study and for 10 months after the last dose of study medication. |
The primary THA performed between 7 to 20 years before inclusion. | Pain in the operated hip (because the presence of hip pain in combination with an osteolytic lesion is an indication for revision surgery). VAS >3 |
The primary THA performed due to osteoarthritis or congenital dysplasia of the hip. | Previous revision surgery of the hip i.e. exchange of any inplant after the primary surgery |
Uncemented cup fixation | Inflammatory arthritis |
Baseline osteolytic lesion of at least 4 cm3 and at most 40 cm3around an uncemented acetabular component with a polyethylene liner. | Previous participation in clinical trials with denosumab or administration of commercial denosumab (Prolia™ or Xgeva™) |
Participant is willing and able to follow study protocol and has provided informed consent prior to any study specific procedures. | Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial (s), or subject is receiving other investigational agent (s). |
Treatment with any intravenous bisphosphonate, fluoride (except for dental treatment) or strontium ranelate within 5 years prior to inclusion. | |
Treatment with any oral bisphosphonate within 1 year prior to inclusion. | |
Treatment with cortisol or cytostatic drugs within 6 months prior to inclusion. | |
Administration of any of the following treatments 3 months prior to screening: | |
For women of childbearing potential: Subject refuses to use 1 highly effective method of contraception (contraceptive pill, intra uterine contraceptive device) for the duration of the study and for 10 months after the last dose of study medication. | |
For males with a partner of childbearing potential: Subject refuses to use 1 highly effective method of contraception for the duration of the study and for 10 months after the last dose of study medication. | |
For males with a partner who is pregnant: Subject refuses to use a condom for the duration of the study and for 10 months after the last dose of study medication. | |
Pain in the operated hip (because the presence of hip pain in combination with an osteolytic lesion is an indication for revision surgery). VAS >3 | |
Previous revision surgery of the hip i.e. exchange of any inplant after the primary surgery | |
Inflammatory arthritis | |
Previous participation in clinical trials with denosumab or administration of commercial denosumab (Prolia™ or Xgeva™) | |
Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial (s), or subject is receiving other investigational agent (s). | |
Treatment with any intravenous bisphosphonate, fluoride (except for dental treatment) or strontium ranelate within 5 years prior to inclusion. | |
Treatment with any oral bisphosphonate within 1 year prior to inclusion. | |
Treatment with cortisol or cytostatic drugs within 6 months prior to inclusion. | |
Administration of any of the following treatments 3 months prior to screening: | |
Anabolic steroids or testosterone | |
Glucocorticosteroids (≥5 mg prednisone equivalent per day for more than 10 days or a total cumulative dose of ≥ 50 mg) | |
Calcitonin | |
Calcitriol or vitamin D derivatives [vitamin D contained in supplements or multivitamins is allowed] | |
Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin | |
Chronic systemic ketoconazole, ACTH (adrenocorticotrophic hormone), cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists. | |
Androgen deprivation therapy | |
Hypocalcaemia. | |
Bone metabolic disorders (such as OI, PHPT, Paget) | |
History of osteonecrosis of the jaw and/or recent tooth extraction or dental surgery; or planned invasive dental proceedures during the study | |
Serum 25-OH D <20 ng/ml | |
Significant malabsorption including Celiac Disease, Short Bowel Syndrome, Crohn’s Disease, Previous Gastric Bypass. | |
Active cancer and/or malignancy in last 5 years (except cervical carcinoma in situ or basal cell carcinoma) | |
History of solid organ or bone marrow transplant. | |
Hypersensitivity to any components of study drug. | |
Intolerance to calcium supplements. | |
Pregnancy and/or currently lactating. | |
Significantly impaired renal function as determined by a derived glomerular filtration rate (GFR) using Cockcroft Gault formula of ≤ 30 mL/min/1.73 m2 | |
Elevated transaminases ≥ 2.0 × upper limit of normal (ULN); Elevated total bilirubin (TBL) > 1.5 × ULN. | |
Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the safety of the subject. | |
Hypocalcaemia. | |
Bone metabolic disorders (such as OI, PHPT, Paget) | |
History of osteonecrosis of the jaw and/or recent tooth extraction or dental surgery; or planned invasive dental proceedures during the study | |
Serum 25-OH D <20 ng/ml | |
Significant malabsorption including Celiac Disease, Short Bowel Syndrome, Crohn’s Disease, Previous Gastric Bypass. | |
Active cancer and/or malignancy in last 5 years (except cervical carcinoma in situ or basal cell carcinoma) | |
History of solid organ or bone marrow transplant. | |
Hypersensitivity to any components of study drug. | |
Intolerance to calcium supplements. | |
Pregnancy and/or currently lactating. | |
Significantly impaired renal function as determined by a derived glomerular filtration rate (GFR) using Cockcroft Gault formula of ≤ 30 mL/min/1.73 m2 | |
Elevated transaminases ≥ 2.0 × upper limit of normal (ULN); Elevated total bilirubin (TBL) > 1.5 × ULN. | |
Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the safety of the subject. |
Treatments
When and how to withdraw subjects from the trial treatment
Endpoints and follow-up
No. | Outcome measurement | Follow-up time |
---|---|---|
1 | Baseline data including height, weight, medical history, physical examination | Screening |
2. | Screening, 12, 24, 36 months | |
3. | Screening, 12, 24, 36 months | |
4a | Percent change from baseline in BMD in vertebrae L1-L4 measured with dual-energy x-ray absorptiometry (DXA) | Screening, 36 months |
5. | Screening, 12, 24, 36 months | |
6. | Correlation between change in serum concentrate values for RANKL and Osteoprogesterin (OPG) and progression of osteolysisb. | Screening, 24,36 months |
7. | Occurrence of adverse events | 6, 12, 18, 24, 30, 36 months |
8. | Radiological analysis plain x-ray | Screening, 36 months |
Osteolysis assessment
Radiological and bone densitometric assessment
Clinical safety assessments and withdrawal from study
No. | Type | Definition |
---|---|---|
1. | Adverse event (AE) | An adverse event is defined in the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.” (ICH E6:1.2). The investigator is responsible for reviewing laboratory test results and determining whether an abnormal value in an individual study subject represents a change from values before the study. In general, abnormal laboratory findings without clinical significance (based on the investigator’s judgment) should not be recorded as adverse events; however, laboratory value changes requiring therapy or adjustment in prior therapy are considered adverse events. |
2. | Serious adverse event (SAE) | A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following criteria: a) fatal, b) life threatening (places the subject at immediate risk of death), c) requires in-patient hospitalization or prolongation of existing hospitalization, d) results in persistent or significant disability/incapacity or congenital anomaly/birth defect e) other significant medical hazard. A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital admission that includes a minimum of an overnight stay in a health care facility. Any adverse event that does not meet one of the definitions of serious (e.g., emergency room visit, outpatient surgery, or requires urgent investigation) may be considered by the investigator to meet the “other significant medical hazard” criterion for classification as a serious adverse event. Examples include allergic bronchospasm, convulsions, and blood dyscrasias. |
3. | Adverse drug reaction (ADR) | All untoward and unintended responses to a medicinal product related to any dose administered. The phrase “responses to a medicinal product” means that a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. |
4. | Serious adverse drug reaction (SADR) | A serious ADR (SADR) is an ADR that meets the definition of SAE |
5. | AE attributes | The investigator will assign the following adverse event attributes: |
Adverse event diagnosis or syndrome (s), if known (if not known, signs or symptoms) | ||
Dates of onset and resolution | ||
Severity | ||
Assessment of relatedness to IP | ||
Action taken. | ||
6 | AE grading | The following adverse events severity grading scale used in the trial. |
MILD: Aware of sign or symptom, but easily tolerated | ||
MODERATE: Discomfort enough to cause interference with usual activity | ||
SEVERE: Incapacitating with inability to work or do usual activity | ||
LIFE-THREATENING: Refers to an event in which the patient was, in the view of the investigator, at risk of death at the time of event. | ||
FATAL |