Denosumab for treating periprosthetic osteolysis; study protocol for a randomized, double-blind, placebo-controlled trial

A randomized, double-blind, placebo-controlled trial will be conducted. Patients will be randomized in a 1:1 ratio to placebo or denosumab using concealed envelopes. A randomly assigned batch size of 4 to 10 (in increments of 2; thus 4, 6, 8, or 10) will be used. Osteolytic lesion volume (<10 cm³/≥10 cm³) at screening and physical activity according to Johnston [27] (<4-low activity level/≥4-high activity level) are clear risk factors for progression of volume size and will therefore be used as stratification to ensure that these are evenly distributed between the two groups [13, 27, 28]. The patients and all staff and investigators will be blinded to treatment. The study will be carried out from 2015 to 2021 at the Orthopaedic Department of Danderyd Hospital in collaboration with the Karolinska Institute. The Ethics Committee of the Karolinska Institute and the Swedish Medical Products Agency approved the study. The trial is initiated, designed, and performed as an academic investigation and registered at ClinicalTrials.gov (NCT02299817). The guidelines of the CONSORT Statement will be followed [29].

Patients with titanium press-fit acetabular components with polyethylene liners will be screened for osteolytic lesions using three-dimensional computed tomography (3D-CT). The patients had their primary surgery more than 7 years before the screening and were all operated because of osteoarthritis of the hip. This time period is sufficient for osteolytic lesions to appear. In this patient group we expect that approximately 30 % of screened patients will have an osteolytic lesion. These patients with screening-detected lesions as well as patients with previously known osteolytic lesions will be eligible for inclusion in the study (Fig. 1). We will include asymptomatic patients, aged 40–85 years, with a primary THA performed due to osteoarthritis or congenital dysplasia of the hip ≥ 7 years before inclusion and who have a osteolytic lesion of at least 4 cm³ and at most 40 cm³ around an uncemented acetabular component with a polyethylene liner. Exclusion criteria includes pain from the hip (VAS ≥3), any surgery of the hip after index operation, ever use of bisphosphonates and inflammatory arthritis. A detailed inclusion and exclusion list is presented in Table 1. The inclusion period is planned from 2015 to 2016. End of study (EOS) will be at the last included patient’s last visit.

Half of the patients will receive a 1 ml subcutaneous injection of denosumab 60 mg on day one and every 6 months with last treatment at 30 months (day 1, 6 mos., 12 mos., 18 mos., 24 mos., 30 mos.), total 6 times. The other half will receive placebo injections as above. The selected dose 60 mg is established in clinical routine for treatment of osteoporosis. The syringes are to be stored at 2-8 °C in a locked, temperature controlled refrigerator. All used syringes must be saved and stored in a cabinet to be checked by the monitor. Study supplies will be documented by completion of drug accountability forms. They will include details of the quantities of IMP/placebo received, administered, stored and dispatched or destroyed. Calcium and Vitamin D (500 mg + 400 IE) twice daily will be given from day 1 to 3 years to all patients. All personnel involved in the study will be blinded. Code envelopes will be stored at the investigator’s office to be used for emergency reasons. In case of a suspected serious adverse drug reaction (SADR) during the study, the PI will determine if unblinding of the study drug is necessary. This decision will be taken by the PI within 24 h of his knowledge of the event. If the PI, for some reason, is unavailable, one of the co-investigators will handle the decision of unblinding.

Patients with serious adverse events (SAE’s) with a direct impact on the periprosthetic region studied will be withdrawn from treatment. Examples of such SAE’s are periprosthetic fractures after accidents, deep infections with revision surgery or any kind of surgery in the hip studied. Should a subject request or decide to withdraw from the study, all efforts will be made to complete and report the observations as thoroughly as possible up to the date of withdrawal. For withdrawn subjects the last post-baseline observation will be carried forward. If the subject withdraws consent or is excluded from the study a 3D-CT will be performed and serological bone turnover markers will be collected (SCTx and P1NP). If implants are to be revised during the study, a CT will be done before surgery and serological bone turnover markers will be collected (SCTx and P1NP). In a case of withdrawal of full consent, the subject will be followed according to the routine standard follow-up of THA patients at our institution, including regular clinical examinations and radiographic follow-up visit at the operating surgeon every 2–3 years.

The primary endpoint variable will be the change in volume of the osteolytic lesion over 3 years (measured with 3D-CT in cm³):

Secondary endpoints include change in volume of the osteolytic lesion over 2 years, percentage change of the lesion over the study period, clinical outcome scores and bone turnover measurements (Table 2). Depending on the outcome parameters, measurements will take place at screening, 6, 12, 18, 24, 30 and 36 months (Fig. 1).

We will use a high-resolution three dimensional computed tomography (3D-CT) at inclusion to detect and measure the volume of the osteolysis according to Howie et al. [13, 30]. The scan will be repeated at 2 and 3 years. Osteolysis will be defined as a demarcated nonlinear osteolytic lesion >3 mm. The measurements will be performed by a technician otherwise not involved in the study and blinded to treatment and who is trained in quantitative CT analysis. 3D-CT has been shown to have an 80 % sensitivity and a 100 % specificity in detecting osteolytic lesions [12] around uncemented acetabular components. Once detected the volume of the lesion can be measured with an error of mean (SD) 7.1 % ±24.1 % (0.3 ± 1.1 cm³) [12].

Plain x-rays of the hip and femur will be taken at baseline and at 3 years to measure wear of the polyethylene. The two-dimensional (2-D) linear head penetration rate will be measure measured from the postoperative examination and inclusion examination using the software Hip Analysis Suite™ (University of Chicago, Chicago, Illinois, USA) version 8.0.4.1 [31] This method uses conventional AP radiographs and the software uses image analysis techniques, determination of bone landmarks and edge detection algorithms to determine the 2-D penetration value change in the position of the femoral head centre with respect to the acetabular component centre. The radiographs will also be examined at 3 years for signs of atypical femoral fractures. There are three reported cases of atypical femoral fractures after denosumab treatment but all of those had, prior to denosumab treatment, been treated with long-term bisphosphonate treatment [32‐34]. Bone mineral density (BMD) of the lumbar spine (vertebrae L1 through L4) will be measured at inclusion and at 3 years using dual x-ray absorptiometry (DXA) (DPX-L; Lunar, Madison, Wisconsin, USA) The BMD will be categorized according to the World Health Organization (WHO) classification for osteoporosis.

Adverse events (AEs) are defined 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. Adverse events include serious adverse events (SAEs), adverse drug reactions (ADRs), serious adverse drug reactions (SADRs) and will be assessed throughout the study period for all patients (Table 3). In case of an adverse event, or serious adverse events, treatment and follow-up will be performed according to clinical routine. The investigator will ensure that all events observed by the investigator or reported by the subject that occur throughout the trial period, starting from the time when a subject has signed the informed consent through to 30 days after the last dose of IP or the EOS (excluding the long-term follow-up period) which ever is longer, are reported using the applicable CRF and properly captured in the patients’ medical records. The investigator will record and grade all adverse events according to Table 3. The investigator will assess whether the adverse event is possibly related to the IP. This relationship is indicated by a response to the question: “Is there a reasonable possibility that the event may be related to a study activity”? The investigator will review laboratory test results and determining whether an abnormal value in a trial subject represents a change from the subject’s baseline values. Abnormal laboratory findings without clinical significance (based on the investigator’s judgment) will not be recorded as adverse events. A patient may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse event. If either of these situations arises, the patient should be strongly encouraged to undergo an end-of-study assessment and be under medical supervision until symptoms cease or the condition becomes stable.

The Harris hip score (HHS) and WOMAC score will be used to assess patient-reported functional hip status, and physical activity [35, 36]. Health-related quality of life will be assessed by the EQ-5D (EuroQoL), which uses five dimensions: mobility, self-care, usual activity, pain/discomfort and anxiety/depression [37]. Each dimension is divided into three levels as follows: 1, no problems; 2, some problems; and 3, extreme problems. This generates 243 different ‘health states’ and the EQ-5D index score. Pain from the hip will be recorded using the Pain Numeric Rating Scale (PNRS), which is an 11-point (0 to 10) scale, in which 0 denotes no pain and 10 unbearable pain [38].

The study progress and study conduct will be monitored before, during and after the study to ensure that ICH-GCP, regulatory requirements, and all aspects of the protocol are followed. The medical records and other documents will be reviewed for verification of agreement with data on the Case Report Forms (CRFs). The subject has a right for a protection against invasion of privacy. All study data will be collected and managed in a digital CRF using REDCap electronic data capture tools hosted at Karolinska Institutet [39]. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. In this study, each subject will receive a unique identification number, which will be linked to the CRF. The data will then be blinded correspondingly in all data analyses. However, the study monitor, auditor, representative from any Regulatory Authority, as well as the appropriate Ethical Committee are permitted to review the subject’s primary medical records including laboratory test result reports, ECG reports, admission and discharge summaries, AE and SAE reports occurring during the study.

The analyses will be performed on the basis of the intention-to-treat principle, and all patients who receive at least one injection of either denosumab or placebo will be included in the final analysis. We will use the unpaired Student’s t-test and Levene’s test for comparison of change in osteolysis volume at 2 and 3 years. Descriptive statistics (means and standard deviations) will be used to describe the patient characteristics and outcome variables at the measurement points. An analysis of covariance (ANCOVA) of the primary endpoint including terms for treatment group, stratification factors and with age and sex as confounders will be performed. ANCOVA will also be used for numeric secondary outcome variables such as progression of osteolysis at 2 years, change in vertebrae 1–4 BMD and the contralateral hip and biochemical markers of bone turnover. For hip-specific outcomes score (Harris hip score, WOMAC) and health-related quality of life (EQ-5D) we will use non-parametric tests. For subjects that withdrawn from the study before year 3 the data from the last observation will be carried forward (imputed). Safety data will be summarized with descriptive statistics.