Longitudinal stability of molecular endotypes of knee osteoarthritis patients.

Objective: To assess the longitudinal stability of biomarker-based molecular endotypes of knee osteoarthritis (KOA) participants from APPROACH and to evaluate the consistency of findings in an independent KOA population.

Methods: Nineteen biomarkers were measured longitudinally in 295 KOA participants from the APPROACH cohort. K-means clustering was used to identify the structural damage, inflammation, and low tissue turnover endotypes at the six-, 12-, and 24-month follow-ups.

Unbiased analysis of knee cartilage thickness change over three years after sprifermin vs. placebo treatment - A post-hoc analysis from the phase 2B FORWARD study.

Objective: Post-treatment cartilage morphometry in the FORWARD study was performed without blinding to MRI acquisition order, involving potential reader bias. Here we obtained unbiased estimates of cartilage change post-treatment, reading year (Y)2 and Y5 MRIs with blinding to time point. We studied whether post-treatment cartilage thickness change differed between sprifermin- and placebo-treated knees.

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The term placebo poses challenges in definition, language and use in research and clinical settings. Placebo extends beyond inactive substances, and modern exploration has revealed complex neurobiological, psychological, and social factors influencing placebo mechanisms. With knowledge of the placebo effect, clinicians can assess and enhance the effectiveness of the most optimal treatments.

A phase 2b double-blind placebo-controlled randomized clinical trial of SB-061, an aggrecan mimetic, in patients with symptomatic knee osteoarthritis.

Objectives: To evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee osteoarthritis (OA).

Methods: This was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥20 out of 50 at screening and baseline visits.

The Impact of Weight-bearing Exercise, Non-Weight-bearing Exercise, and Cardiovascular Stress on Biochemical Markers of Cartilage Turnover in Patients With Mild to Moderate Knee Osteoarthritis: A Sequential, Cross-Over, Clinical Study.

Objective: To investigate how running, cycling, and sedentary cardiovascular stress impact biomarkers of cartilage turnover acutely in subjects with knee osteoarthritis (OA).

Design: This was a sequential, cross-over, clinical study. Forty subjects with primary knee OA underwent moderate-to-high-intensity cycling, running, and adrenaline infusion on separate days.

Is detection of disease-modifying osteoarthritis drug treatment more effective when performing cartilage morphometry without blinding to MR image acquisition order?

Objective: We here explore whether observed treatment effects of a putative disease-modifying osteoarthritis drug (DMOAD) are greater when cartilage morphometry is performed with rather than without knowledge of magnetic resonance imaging (MRI) acquisition order (unblinded/blinded to time point).

Methods: In the FORWARD (FGF-18 Osteoarthritis Randomized Controlled Trial with Administration of Repeated Doses) randomized controlled trial, 549 knee osteoarthritis patients were randomized 1:1:1:1:1 to three once-weekly intra-articular injections of placebo, 30 µg sprifermin every 6 or 12 months (M), or 100 µg every 6/12 M. After year 2, cartilage segmentation of BL through 24 M MRIs was performed, with blinding to acquisition order.

The efficacy and safety of a fixed-dose combination of apocynin and paeonol, APPA, in symptomatic knee OA: A double-blind, randomized, placebo-controlled, clinical trial.

Objective: Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA).

Methods: A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2-3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period.

Joint biomarker response to mechanical stimuli in osteoarthritis - A scoping review.

Objective: Arthritic cartilage is primed for mechanical damage. Joint biochemical markers (JBM) could provide insight into the impact of mechanical stimulation on joint tissue turnover in osteoarthritis (OA) of potential use in clinical OA research and practice. However, existing studies of the acute impact of physical activities (PA) on JBM often contain risks of substantial bias.

Impact of monitoring approaches on data quality in clinical trials.

Aims: Source data verification (SDV) has been reported to account for up to 25% of the budget in clinical trials (CT) and cost-benefit of SDV has been questioned. Guidelines for risk-based monitoring (RBM) were published in 2013 by agencies and in 2016, ICH-GCP-E6-(R2) added a requirement for risk-based approaches. This report will perform a comparison of the impact of RBM vs classic monitoring (CM) on data quality (defined as accuracy of data reporting from source data to final trial data) and expected impact on costs of CTs.

Associations between single-question Visual Analogue Scale pain score and weight-bearing and non-weight-bearing domains of Western Ontario and McMaster Universities Arthritis Index pain: data from 2 phase 3 clinical trials.

Introduction: Visual Analogue Scale (VAS) and the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC) are commonly used measuring tools of osteoarthritis (OA) pain.

Objectives: The objective of this cross-sectional study was to explore the associations between single-question VAS pain and the weight-bearing and non-weight-bearing domains of WOMAC pain.

Methods: Data from 2093 patients with OA participating in 2 phase 3 clinical trials were included for post hoc analyses.

An Estimate of Plasma Volume Changes Following Moderate-High Intensity Running and Cycling Exercise and Adrenaline Infusion.

Plasma volume (PV) changes in response to physical activity, possibly as a consequence of adrenergic activation. We estimated changes in PV in response to common exercise modalities; cycling and running as well as adrenaline infusion and control at rest. On separate days, forty circulatory healthy subjects [aged 60 years (range: 42-75)] with knee osteoarthritis underwent moderate-high intensity cycling, running, and intravenous adrenaline infusion to mimic the circulatory response to exercise.

Effect of adrenaline on serum mid-regional pro-atrial natriuretic peptide and central blood volume.

New Findings: What is the central question in this study? Atrial natriuretic peptide (ANP) is secreted in response to atrial wall distension and thus allows for evaluation, albeit indirect, of the central blood volume. Adrenaline has chronotropic and inotropic effects. We evaluated whether the chronotropic and inotropic effects of adrenaline were reflected in mid-regional proANP.

Symptomatic and structural benefit of cathepsin K inhibition by MIV-711 in a subgroup with unilateral pain: post-hoc analysis of a randomised phase 2a clinical trial.

Objectives: Osteoarthritis (OA) development programmes face challenges due to discordance between structural changes and symptoms. A novel cathepsin-K inhibitor, MIV-711, recently reported structural benefits, but did not demonstrate a significant difference from placebo in symptoms. Previous work suggests that pain from non-target joints may confound OA pain outcomes.

The Efficacy and Safety of Multiple Dose Regimens of Kudzu () Root Extract on Bone and Cartilage Turnover and Menopausal Symptoms.

Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from , Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear. This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms.

A biomarker perspective on the acute effect of exercise with and without impact on joint tissue turnover: an exploratory randomized cross-over study.

Purpose: To investigate acute changes in biochemical markers of bone and cartilage turnover in response to moderate intensity exercise with and without joint impact in healthy human subjects.

Methods: A randomized, cross-over, exploratory, clinical study was conducted. Twenty healthy subjects with no history of joint trauma completed 30 min interventions of standardized moderate intensity cycling and running as well as a resting intervention 1 week apart.

Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.

Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months.

Serum C-reactive protein metabolite (CRPM) is associated with incidence of contralateral knee osteoarthritis.

The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA).

The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial.

Objective: To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin.

Methods: Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.

A novel diclofenac gel (AMZ001) applied once or twice daily in subjects with painful knee osteoarthritis: A randomized, placebo-controlled clinical trial.

Purpose: Osteoarthritis Research Society International (OARSI) Expert Consensus Guidelines recommend topical non-steroidal anti-inflammatory drugs as first-line medications for osteoarthritis (OA) knee pain, but several voluminous daily applications are required to achieve efficacy. There is a need to develop new and improved topical analgesics with a faster onset, longer duration of action, and the requirement to apply less gel. This trial investigated the safety and efficacy of a new 3.

Clinical and biochemical factors associated with risk of total joint replacement and radiographic progression in osteoarthritis: Data from two phase III clinical trials.

Objectives: Clinical trials of new disease-modifying treatments for osteoarthritis should demonstrate a positive effect on a functional outcome or reduction in joint failure in order to be considered successful. Total joint replacement (TJR) surgery may be considered as joint failure, but great variation in the incidence of TJR complicates its use as a study endpoint. Factors predicting elevated risk of TJR could potentially be used to enrich such outcome-trials.

Evaluation of serum ARGS neoepitope as an osteoarthritis biomarker using a standardized model for exercise-induced cartilage extra cellular matrix turnover.

Objective: To propose a standardized model for exercise-induced cartilage turnover and investigate residual levels and dynamics of biomarker serum ARGS (sARGS) in primary osteoarthritis (OA) patients and a supportive group of young healthy subjects.

Method: The trial is a randomized, cross-over, exploratory study with interventions of exercise and inactivity. 20 subjects with knee OA, as well as 20 young healthy subjects (mean age 25.

Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis.

Background: Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain categories with levels of uCTX-II and biomarkers of bone resorption and formation.

Incidence of total hip and total knee replacements from the prospective epidemiologic risk factor study: considerations for event driven clinical trial design.

Background: Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study.