nature.com
This monocentric, randomized, placebo-controlled, double-blind, parallel-group, phase 2a study in patients with erosive hand OA (EU Clinical Trials Registry, identifier 2015-003223-53) was carried out at the rheumatology outpatient clinic of the Ghent University Hospital in Belgium. The trial protocol was approved by the local ethics committee of the hospital and was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. See Supplementary Note 1 for a list of members of the ethical committee. The study protocol is shown in the Appendix. We used the CONSORT checklist when writing our report38. See Supplementary Note 1 for a list of data monitoring committee members.
Patients aged ≥30 years and diagnosed with erosive hand OA were considered eligible. Patients were recruited from the rheumatology outpatient clinic of the Ghent University Hospital in Belgium. Erosive hand OA was defined as radiographic presence of ≥1 IP joint in the J or E phase according to the Verbruggen and Veys anatomical phase scoring system13. Key inclusion criteria included the presence of ≥1 IP joint with partial or complete loss of joint space (that is, ‘J’ phase of the anatomical phase scoring system) or with central erosions (that is, ‘E’ phase according to the anatomical phase scoring system) and with local inflammatory signs, defined both clinically (that is, presence of soft tissue swelling) and by ultrasound (that is, presence of effusion and/or synovial hyperproliferation at least grade 1 on ultrasound); suffering from transient inflammatory attacks of the IP joints, as referred to as inflammatory or erosive hand OA; an age over 30 years; and providing written informed consent and willing to comply to all requirements according to the protocol. Key exclusion criteria included previous denosumab use; intake of oral bisphosphonates during the past 12 months; oral strontium ranelate or intravenous bisphosphonates during the past 5 years; recent use of chondroprotective molecules or disease modifying drugs as summarized in the protocol during the past 90 days; vitamin D deficiency; current hypo- or hypercalcemia; important comorbidities, cancers or chronic infectious diseases; underlying conditions that compromise the ability to provide written informed consent or to comply to all requirements; history of osteonecrosis of the jaw, recent tooth extraction (within past 3 months) or other unhealed dental procedure; planned invasive dental procedures during the study; history of solid organ or bone marrow transplantation; known hypersensitivity to the study medication or its components; history of alcohol or drug abuse during the past year; breastfeeding; and pregnancy or wishing to be pregnant. Patients suffering from chronic inflammatory rheumatic diseases such rheumatoid arthritis, spondyloarthropathy, psoriatic arthritis, gout, chondrocalcinosis or other auto-immune disease (for example, systematic lupus erythematosus) were excluded. Serology screening was performed if appropriate. The sex of participants was determined on the basis of self-report (male or female). All patients provided written informed consent.
Eligible patients were randomly assigned, in a 1:1 ratio, to receive in a blinded fashion denosumab (Amgen) or placebo during the placebo-controlled double-blind phase of the study, by use of a randomization scheme with a fixed block size of four. The randomization list was generated by a coworker independent of the study and not involved in any procedure during the study. The study medication was provided by the pharmacy department. The medication and placebo syringes were identical in terms of color and shape and labeled with an unique sample number and study patient identification number. Patients and investigators retained unaware of the initial allocation during the entire trial, including the open-label extension.
Denosumab 60 mg or placebo was administered subcutaneously by a dedicated (blinded) nurse or physician at site every 12 weeks for 48 weeks, followed by open-label denosumab 60 mg every 12 weeks for an additional 48 weeks (Extended Data Fig. 1). Since earlier studies in rheumatoid arthritis revealed dose-dependent structural inhibitory capacities of denosumab22,23, we anticipated to use a higher dosing interval than as approved for use in osteoporosis. The medication and placebo syringes were identical. All patients received daily oral calcium (1,000 mg elemental calcium) and vitamin D3 (880 IU). Medication intake, use of rescue medication or changes in concomitant medication was registered throughout the entire study. The patients were allowed to take analgesics and nonsteroidal anti-inflammatory drugs as rescue medication at stable dosages during the first 12 weeks. The intake of corticosteroids was prohibited.
A posteroanterior hand radiograph of both hands were taken at baseline, weeks 24 and 48. All 16 IP joints (the second to fifth distal and proximal IP joints) were evaluated by two experienced rheumatologists (G.V. and R.W.). The first IP was excluded due to reduced visibility on radiographs. Two radiographic scoring systems were used to assess the structural changes of the finger joints13,14. Both readers independently scored paired images with the known time sequence but were blinded for randomization, patient identity and clinical information. The GUSS14 includes three subdomains to assess changes in the subchondral bone, subchondral plate and joint space loss. Details of the GUSS are extensively described in the protocol, and an educational atlas is available14. In summary, each subdomain ranges from 0 to 100 and the total GUSS score is the composite score of the three subscales with equal weight. The total GUSS score ranges from 0 to 300, with the lowest scores representing severe erosive joint destruction and the highest scores representing no damage or complete subchondral and cartilage repair. For each (target) joint, a total GUSS score is computed. The second radiographic scoring system, the anatomical phase scoring system by Verbruggen and Veys, is based on the natural history of joints throughout the erosive OA process13. The Verbruggen and Veys anatomical score system differentiates normal joints (N) from pre-erosive phases (S phase, that is, stationary phase with minimal degenerative features such as subchondral sclerosis, joint space narrowing and presence of small osteophytes, and J phase, with partial or complete loss of joint space), erosive phase (E) and phases of remodeling (R, that is, signs of repair such as reappearance of subchondral plate and joint space width, disappearance of erosions at the subchondral bone and development of osteophytes at joint margins, and F, fused joint as extreme sign of remodeling). Inter- and intrareader reliability analysis was performed. The final radiographic scores were the agreement scores amongst the two readers. In case of no absolute agreement, a consensus score was made.
Ultrasound was performed by an experienced sonographer (R.W.), with more than 10 years of experience, at baseline and weeks 12 and 48. Synovial proliferation (0–3), effusion (0–3), power Doppler signal (0–3) and erosions (present/absent) in proximal IP and distal IP joints 2–5 were recorded.
Pain was questioned (“How would you rate the pain in the finger joints of both hands during the past 24 hours?”) and rated on a NRS from 0 to 10, with 0 corresponding to no pain and 10 maximal pain, at every visit, together with questionnaires of functional outcome, the FIHOA (0–30)37 and the AUSCAN (0–150)38. At each visit after baseline, patients were asked how effective they found the administered treatment (on a NRS from 0 to 10, with 0 corresponding to no effect and 10 to the best effect). Dual energy X-ray absorptiometry was performed at baseline and week 48. An overview of assessments is shown in Extended Data Fig. 1. Deindentified raw data collected through week 48 are available as Supplementary Information.
The primary efficacy endpoint was the change in total GUSS14 from baseline to week 24. The scoring system can change in positive (that is, more remodeling) or negative direction (that is, more erosive progression). Target joints were defined as all proximal and/or distal IP joints in the J or E phase on baseline radiographs (except IP 1) with presence of inflammatory activity, defined by both clinical soft tissue swelling and ultrasonographic inflammation (that is, either synovial proliferation or effusion). If several target joints were available, all were included for efficacy analysis.
The secondary endpoints were the total GUSS changes from baseline to week 48 and the percentage of new erosive joints (J/E) by Verbruggen and Veys13 among the baseline pre-erosive joints (that is, baseline N, S and J joints) per patient at week 48.
Exploratory clinical endpoints and patient-reported outcomes were NRS pain, NRS global assessment of efficacy by patient, tender joint count, swollen joint count and AUSCAN and FIHOA at weeks 24 and 48 (refs. 37,38). In analogy with rheumatoid arthritis, where denosumab showed to reduce structural damage while having no effect on signs and symptoms23, it was anticipated that in erosive hand OA, no clinical effect could be expected in the first year of treatment, and therefore, no pain scales or patient-related outcome measures were considered as primary endpoints. Changes in ultrasound scores at week 12 for effusion, synovial proliferation, synovitis score and power Doppler signal, and for erosions at week 48, and percentage changes from baseline in bone mineral density at the femoral neck and lumbar spine at week 48 were other exploratory outcomes.
Safety endpoints included the number of (serious) adverse events, withdrawal because of adverse events and changes in laboratory data throughout the study.
A sample size of 46 patients in each treatment arm was required to detect a difference in the mean change GUSS of 20 units between the placebo and treated group at week 24, attaining a power of 90%, assuming that the standard deviation was 29 using a t-test with a two-sided 0.05 level of significance (α). Taking into account an attrition rate of 8%, 100 patients were included.
Primary efficacy analyses were performed in an ITT approach (that is, all participants randomly assigned to groups and who attended a baseline visit). Changes in the GUSS were analyzed at joint level with generalized estimating equations (GEE), accounting for within-patient clustering and adjusted for baseline unbalances. Robust standard errors were used, and the working correlation structure specified exchangeable. The independent variables included in the model were the treatment group, visit number (categorical), interaction between treatment group and visit number and baseline value of the dependent variable (continuous). Missing values were imputed according to a predefined imputation model, including the randomization group, baseline value and values at other time points available, presence of baseline inflammation and baseline number of affected joints. As there was only one primary outcome, no adjustments for multiple testing were performed.
Secondary and exploratory outcomes were done in the ITT population and measured at patient level (except for total GUSS at week 48). Primary and secondary efficacy analyses were presented by least squares means and standard error of the mean, a point estimate of the difference between the treatment groups or ORs with a 95% CI and the two-sided P value. Missing values were replaced by the baseline observations.
A first sensitivity analysis of the primary endpoint was performed by using a more conservative approach to handle missing values by replacing these with the baseline observations. A second sensitivity analysis, three-level linear mixed model with patient and joint as random effects and total GUSS baseline, treatment, time (week 24 and week 48) and the interaction between time and treatment as fixed effects was performed.
For the primary outcome measure, a subgroup analysis for inflammatory activity in the joint (yes/no) was done. The interaction between the presence of baseline inflammation and treatment effect on change in the GUSS scores over 24 weeks was tested. For the primary outcome measure, another efficacy analysis was performed, extending the target joints to all joints showing any progression to the J, E or E/R phase throughout the study that were not defined as J or E at baseline.
For the analyses from the open-label extension phase, similar GEE logistic regression models were used with treatment groups based on the initial randomization code from the placebo-controlled phase (that is, patients having received placebo versus denosumab).
A P value below 0.05 was considered statistically significant. All statistical calculations were performed using R version 3.6.1 and IBM SPSS Statistics for Windows, version 25. The statistical analysis plan, which was written before breaking the randomization code, is available in the Appendix.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.