Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial.

Background: Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis.

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.

[Not Available].

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.

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.

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.

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.

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.

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.

Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial.

Importance: Sprifermin is under investigation as a disease-modifying osteoarthritis drug.

Objective: To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis.

Design, Setting, And Participants: FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites.

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.

Protein biomarkers associated with pain mechanisms in osteoarthritis.

Osteoarthritis (OA) is the most common arthritic disease in the world, leading to debilitating pain and destruction of joint tissues. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. OA pain is multifactorial and may arise from multiple distinct or concurrent mechanisms, and may thus present as different pain sub-types.

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women.

Acute myocardial infarction (AMI) is often underdiagnosed in women. It is therefore of interest to identify biomarkers that indicate increased risk of AMI and thereby help clinicians to have additional focus on the difficult AMI diagnosis. Type I Collagen, a component of the cardiac extracellular matrix, is cleaved by matrix metalloproteinases (MMPs) generating the neo-epitope C1M.

Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis.

Background: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC).

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes.

The impact of clinical trial monitoring approaches on data integrity and cost--a review of current literature.

Purpose: Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost.