Osteoarthritis Clinical Trials Research Articles

Latest advancements in imaging techniques in OA.

The osteoarthritis (OA) research community has been advocating a shift from radiography-based screening criteria and outcome measures in OA clinical trials to a magnetic resonance imaging (MRI)-based definition of eligibility and endpoint. For conventional morphological MRI, various semiquantitative evaluation tools are available. We have lately witnessed a remarkable technological advance in MRI techniques, including compositional/physiologic imaging and automated quantitative analyses of articular and periarticular structures. More recently, additional technologies were introduced, including positron emission tomography (PET)-MRI, weight-bearing computed tomography (CT), photon-counting spectral CT, shear wave elastography, contrast-enhanced ultrasound, multiscale X-ray phase contrast imaging, and spectroscopic photoacoustic imaging of cartilage. On top of these, we now live in an era in which artificial intelligence is increasingly utilized in medicine. Osteoarthritis imaging is no exception. Successful implementation of artificial intelligence (AI) will hopefully improve the workflow of radiologists, as well as the level of precision and reproducibility in the interpretation of images.

Detection and Evaluation of Serological Biomarkers to Predict Osteoarthritis in Anterior Cruciate Ligament Transection Combined Medial Meniscectomy Rat Model.

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage’s integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date.

Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved disease-modifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

Use of an activity tracker as a measurement tool in a knee osteoarthritis clinical trial (active-oa trial) – update of results

Purpose: In osteoarthritis (OA) clinical trials, reliable and responsive outcome measures to document improvements in function are limited. Current measures predominately rely on self-reported function tests, but they are poorly responsive, subject to misreporting and the placebo response. Functional measures such as observed timed-up-and-go test (TUG) and six-minute walk test (6MWT) are advocated, but their relevance may be limited in the context of a patient’s real-world functional capabilities.

The “placebo effect” in osteoarthritis clinical trials: challenging the narrative

Purpose: The Results of randomized controlled trials of potential disease-modifying osteoarthritis drugs (DMOADs) often show a precipitous decline in the estimated mean pain score for the active treatment arm and the placebo arm during follow-up. The decrease in the mean pain score in the placebo arm is often attributed to the placebo effect, which has been defined as “a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment”.

Characterization and implications of daily pain variability and response to treatment in osteoarthritis clinical trials

Purpose: Purpose: It is well known that high inter- and intra-patient variability is observed in chronic pain, including in osteoarthritis (OA) patients. Pain fluctuations over time may have an influence in the response to treatments, particularly in clinical trials. However, most interventional pain studies rely on pain reports from single time points and do not take in consideration the dynamic effects of daily pain variations on the response to treatment. In this study we evaluated daily between- and within-subject OA pain variability to evaluate how this information can be predictive of response to treatment in clinical trials.

Proof-of-concept for the detection of early osteoarthritis pathology by clinically applicable endomicroscopy and quantitative AI-supported optical biopsy

Clinical trials for osteoarthritis (OA), the leading cause of global disability, are unable to pinpoint the early, potentially reversible disease with clinical technology. Hence, disease-modifying drug candidates cannot be tested early in the disease. To overcome this obstacle, we asked whether early OA-pathology detection is possible with current clinical technology. We determined the relationship between two sensitive early OA markers, atomic force microscopy (AFM)-measured human articular cartilage (AC) surface stiffness, and location-matched superficial zone chondrocyte spatial organizations (SCSOs), asking whether a significant loss of surface stiffness can be detected in early OA SCSO stages. We then tested whether current clinical technology can visualize and accurately diagnose the SCSOs using an approved probe-based confocal laser-endomicroscope and a random forest (RF) model. We demonstrated a correlation between AC surface stiffness and the SCSO (rrm=-0.91; 95%CI:-0.97,-0.73), and an extensive loss of surface stiffness specifically in those ACs with early OA-typical SCSO (95%CIs: string SCSO: 269-173kPa, double string SCSO: 77-46kPa). This established the SCSO as a visualizable, functionally relevant surrogate marker of early OA AC surface pathology. Moreover, SCSO-based stiffness discrimination worked well in each patient's AC. We then demonstrated feasibility of visualizing the SCSO by clinical laser-endomicroscopy and, importantly, accurate SCSO diagnosis using RF. We present the proof-of-concept of early OA-pathology detection with available clinical technology, introducing a future-oriented, AI-supported, non-destructive quantitative optical biopsy for early disease detection. Operationalizing SCSO recognition, this approach allows testing for correlations between local tissue architectures with other experimental and clinical read-outs, but needs clinical validation and a larger sample size for defining diagnostic thresholds.

Emerging Technologies and Platforms for the Immunodetection of Multiple Biochemical Markers in Osteoarthritis Research and Therapy.

Biomarkers, especially biochemical markers, are important in osteoarthritis (OA) research, clinical trials, and drug development and have potential for more extensive use in therapeutic monitoring. However, they have not yet had any significant impact on disease diagnosis and follow-up in a clinical context. Nevertheless, the development of immunoassays for the detection and measurement of biochemical markers in OA research and therapy is an active area of research and development. The evaluation of biochemical markers representing low-grade inflammation or extracellular matrix turnover may permit OA prognosis and expedite the development of personalized treatment tailored to fit particular disease severities. However, currently detection methods have failed to overcome specific hurdles such as low biochemical marker concentrations, patient-specific variation, and limited utility of single biochemical markers for definitive characterization of disease status. These challenges require new and innovative approaches for development of detection and quantification systems that incorporate clinically relevant biochemical marker panels. Emerging platforms and technologies that are already on the way to implementation in routine diagnostics and monitoring of other diseases could potentially serve as good technological and strategic examples for better assessment of OA. State-of-the-art technologies such as advanced multiplex assays, enhanced immunoassays, and biosensors ensure simultaneous screening of a range of biochemical marker targets, the expansion of detection limits, low costs, and rapid analysis. This paper explores the implementation of such technologies in OA research and therapy. Application of novel immunoassay-based technologies may shed light on poorly understood mechanisms in disease pathogenesis and lead to the development of clinically relevant biochemical marker panels. More sensitive and specific biochemical marker immunodetection will complement imaging biomarkers and ensure evidence-based comparisons of intervention efficacy. We discuss the challenges hindering the development, testing, and implementation of new OA biochemical marker assays utilizing emerging multiplexing technologies and biosensors.

Fibroblast growth factor signalling in osteoarthritis and cartilage repair.

Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis.

Multi-classifier prediction of knee osteoarthritis progression from incomplete imbalanced longitudinal data

Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class classification task, with classes based on clinically relevant measures of progression (over a time scale typical for clinical trials). Using data from two long-term knee osteoarthritis studies OAI and CHECK, we tested multiple algorithms and learning process configurations (including multi-classifier approaches, cost-sensitive learning, and feature selection), to identify the best performing machine learning models. We examined the behaviour of the best models, with respect to prediction errors and the impact of used features, to confirm their clinical relevance. We found that the model-based selection outperforms the conventional inclusion criteria, reducing by 20–25% the number of patients who show no progression. This result might lead to more efficient clinical trials.

Use of an activity tracker as a measurement tool in a knee osteoarthritis clinical trial (active-oa trial)

Purpose: In osteoarthritis (OA) clinical trials, reliable and responsive outcome measures to document improvements in function are limited. Current measures predominately rely on self-reported function tests, but they are poorly responsive, subject to misreporting and the placebo response. Functional measures such as observed timed-up-and-go test (TUG) and six-minute walk test (6MWT) are advocated, but their relevance may be limited in the context of a patient’s real-world functional capabilities. Using physical activity tracking devices/wearables as a way to measure improvements in function in day-to-day life is potentially an attractive and easily available alternative to conventional OA trial outcome measures. Consumer-level activity monitors have shown high validity for measurement of steps when compared with research-grade devices. The aim of this study is to assess if the use of an activity tracker in an OA clinical trial is a responsive measurement tool. Secondary objectives include the assessment of the feasibility of an activity tracker use and validity of an activity tracker in an OA clinical trial. Methods: This was a prospective cohort study nested in the Platelet-rich Plasma as a Symptom and Disease-Modifying Treatment for Knee Osteoarthritis - the RESTORE trial (ACTRN12617000853347). Consecutive participants recruited to the RESTORE trial were invited to join this study. Participants ≥ 50 years old with painful knee OA and Kellgren and Lawrence (KL) grade 2-3 were included. Participants were asked to wear an activity tracker (Fitbit Flex (2), Fitbit Inc, San Francisco, CA, USA) for seven consecutive days at the time of baseline assessment (week 0, before their injection therapies), and at the 2-month follow-up assessment. The primary outcome was mean steps per day calculated from a seven-day wear of an activity tracker. To determine the responsiveness of the activity tracker, the standardised response mean (SRM) was calculated for mean steps per day between baseline and 2 months; dividing the mean change scores by the standard deviation of the mean change scores. To investigate validity, correlation coefficient (r) was used to examine the relationship between change in the mean steps per day between baseline and 2 months and participant-perceived global ratings of change (global improvement in function) at 2 months. The relationship of change in mean steps per day and change in secondary outcomes between baseline and 2 months was examined: global improvement (pain and overall improvement), 6MWT, TUG, numeric rating scale (NRS) for pain, knee osteoarthritis outcome score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC). Correlation coefficients were estimated for continuous variables. The activity tracker wear was deemed feasible if >70% of patients comply with wearing the trackers at least six out of seven days for each measurement period. Results: 65 participants were recruited (mean age = 61.3 years; 46% female; mean BMI 28.7 kg/m2; 41.5% KLG 2 and 58.5% KLG 3). 8 participants dropped out or had activity tracker misuse/failure at the 2-month follow-up. The SRM was -0.02 (95% CI -0.38 to 0.35) for mean steps per day between baseline and 2 months. The proportion of participants who wore the trackers for six out of seven days was 98% at baseline and 100% at 2-months follow-up. The correlation with change in mean steps per day at baseline and 2 months and outcome measures are detailed in table 1. Conclusions: The use of an activity tracker in a real-world OA clinical trial demonstrated small correlations between change in steps at baseline and 2 months follow-up with global improvement overall and WOMAC function. The use of a tracker is a feasible option with demonstration of good compliance amongst the trial participants. This study has not shown significant responsiveness or validity of the activity trackers in comparison with other regularly utilised outcome measures in OA clinical trials. However, the main challenge of this study is the lack of a gold standard outcome measure to validate against. Due to the complex nature of pain, perceived quality of life, and the interplay between these factors and measured function, a lack of correlation does not necessarily represent a failed validation in this context.

Clinical trial data analysis of the placebo effect in osteoarthritis

Purpose: Despite an increasing awareness of the placebo effect in clinical trials in osteoarthritis (OA), there remains a need to better account for this effect in clinical trial analyses. The placebo effect is not a random process, but has been shown to be strongly influenced by quantifiable characteristics of the patient and the clinical context. We have analysed available placebo data in order to model a placebo response with consideration of the different types of therapy used in the clinical trials.

Urinary CTX-II predicts the risk of total joint replacement in postmenopausal women: a 18-year longitudinal study

Purpose: Identifying objective risk-factors for total joint replacement (TJR) is useful to enrich population at high risk in osteoarthritis (OA) clinical trials. In this study, we investigated the value of urinary CTX-II, a biochemical marker of cartilage breakdown, to predict TJR in postmenopausal women.

Is the Pelvis-Thorax Coordination a Valuable Outcome Instrument to Assess Patients With Hip Osteoarthritis?

Objective: The evaluation of the disease severity in hip osteoarthritis (OA) patients being currently based on subjective instruments. It would be of interest to develop more objective instruments, for example based on gait analysis. The aims of this study were to explore if pelvis-thorax coordination parameters could be valuable instrument outcomes to achieve this evaluation by assessing their reliability, discriminant capacity and responsiveness.Methods: Three groups of subjects; healthy, hip OA patients with severe disease (defined as indication to surgery), hip OA patients with less severe disease (no indication to surgery) were included. Hip OA patients with severe disease were evaluated before and 6 months after surgery. Subjects had to perform a gait analysis at comfortable speed, and pelvis-thorax coordination was evaluated. The correlations with clinical and structural parameters, as well as reliability, discriminant capacities and responsiveness, were assessed.Results: The pelvis-thorax coordination in the coronal plane during walking was correlated to clinical and to structural severity in hip OA patients (R2 = 0.13). The coronal plane coordination allowed to discriminate healthy subjects from all hip OA patients (sensibility = 0.86; specificity = 0.59). Moreover, when comparing OA patients only, coronal plane coordination allows to discriminate patients with indication of surgery from those with no indication of surgery (sensibility = 0.72; specificity = 0.72). Moreover, the pelvis-thorax coordination demonstrated an excellent reliability and a good responsiveness.Conclusion: Changes in the pelvis-thorax coordination might refer to different mechanisms, from analgesia to motor control plasticity, and might be a possible explanation for the weak correlation between structure and symptoms in hip OA patients. Moreover, such parameter might be used as an objective outcome in hip OA clinical trials.Clinical Trials Registration: www.ClinicalTrials.gov, identifier: NCT02042586 and NCT01907503.

Osteoartrozda yeni tedavi yöntemleri

Osteoartroz (OA) en yaygın artrit şeklidir. OA'da klinik çalışmaların sunduğu birçok zorluğa rağmen, hastalık patogenezi, hastalık süreci ve ağrının tedavisinin yanı sıra altta yatan hastalığın tedavisinde birçok yeni farmakolojik tedaviler ve klinik araştırmalar vardır. Yeni farmakolojik ajanlar ile klinikte OA'da semptomların ve hastalık sürecinin iyileştirilmesine yönelik fırsatlar ufukta görünmektedir.

Serum Levels of Coll2-1, a Specific Biomarker of Cartilage Degradation, Are Not Affected by Sampling Conditions, Circadian Rhythm, and Seasonality

To assess intraindividual biological variability of serum cartilage specific biomarker Coll2-1 and define the best standardized conditions for blood sampling. Blood samples were taken from 116 subjects with knee osteoarthritis (OA) at a single time point (PRODIGE study) and from 15 healthy subjects under various conditions, including fasting condition, sampling time and season, blood treatment, and type of blood collection tube (COVAR study). Type II collagen-specific biomarker Coll2-1 was directly measured in serum using an immunoassay. There was no significant difference on Coll2-1 values between samples collected at any of the 5 sampling times or at any of the sampling days measured. None of the sampling parameters tested had a significant impact on Coll2-1 value (clotting time, clotting temperature and temperature of blood centrifugation, type of tube). On the contrary, differences were found in between subjects and between subjects with knee OA and healthy subjects. Coll2-1 measurement is not affected by sampling specific conditions, circadian rhythm or seasons but was found elevated in subject with knee OA indicating that Coll2-1 serum variation is not linked to the study environment, but to cartilage degradation in OA. Coll2-1 assay is sufficiently robust for use in OA clinical trials.

Identifying predictors of placebo response in osteoarthritis clinical trials of three agents with different routes of delivery: A meta-analysis using individual patient data

Identifying predictors of placebo response in osteoarthritis clinical trials of three agents with different routes of delivery: A meta-analysis using individual patient data

The OMERACT-OARSI Core Domain Set for Measurement in Clinical Trials of Hip and/or Knee Osteoarthritis.

To update the 1997 OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) core domain set for clinical trials in hip and/or knee osteoarthritis (OA). An initial review of the COMET database of core outcome sets (COS) was undertaken to identify all domains reported in previous COS including individuals with hip and/or knee OA. These were presented during 5 patient and health professionals/researcher meetings in 3 continents (Europe, Australasia, North America). A 3-round international Delphi survey was then undertaken among patients, healthcare professionals, researchers, and industry representatives to gain consensus on key domains to be included in a core domain set for hip and/or knee OA. Findings were presented and discussed in small groups at OMERACT 2018, where consensus was obtained in the final plenary. Four previous COS were identified. Using these, and the patient and health professionals/researcher meetings, 50 potential domains formed the Delphi survey. There were 426 individuals from 25 different countries who contributed to the Delphi exercise. OMERACT 2018 delegates (n = 129) voted on candidate domains. Six domains gained agreement as mandatory to be measured and reported in all hip and/or knee OA clinical trials: pain, physical function, quality of life, and patient's global assessment of the target joint, in addition to the mandated core domain of adverse events including mortality. Joint structure was agreed as mandatory in specific circumstances, i.e., depending on the intervention. The updated core domain set for hip and/or knee OA has been agreed upon. Work will commence to determine which outcome measurement instrument should be recommended to cover each core domain.

Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy.

The objective of this study was to describe in life methods by which osteoarthritis can be staged in order to time therapeutic interventions that are relevant to osteoarthritis (OA) clinical trials. Twenty-two sheep underwent arthroscopic meniscal destabilization to induce OA. Serial computed tomography (CT) imaging and arthroscopy were used to monitor osteoarthritis progression at 3-month intervals over 9 months. Eleven sheep received 1 intra-articular injection of hyaluronate 3 months after OA induction and another group of 11 received saline. A linear mixed model was used to define the trajectory of shape change in the medial joint compartment. Ordinal logistic regression was used to investigate the association between morphological changes and sclerosis. Three months after meniscal destabilization there were early bipolar chondral lesions in the medial compartment of the knee, as well as osteophytes and bone remodeling. Superficial fissures and cartilage cracks progressed to discrete areas of cartilage thinning and fibrillation on the medial tibial plateau by 6 months that became cartilage erosions by nine months. A linear mixed effect model demonstrated significant change in medial compartment length and width with over time (P < 0.05) for both groups. A significant association between severity of sclerosis and medial compartment morphology was also observed. The induction of osteoarthritic lesions with meniscal release model can be followed using noninvasive and minimally invasive procedures allowing for real-time decisions about redosing therapies, or other changes such as extending trial timelines without sacrificing animals to conduct assessments.

Change in activity following administration of a lateral wedge insole: analysis from the Inrespond trial

Change in activity following administration of a lateral wedge insole: analysis from the Inrespond trial