Disease-modifying Osteoarthritis Drug Trials Research Articles

Subchondral bone in knee osteoarthritis: bystander or treatment target?

The subchondral bone is an important structural component of the knee joint relevant for osteoarthritis (OA) incidence and progression once disease is established. Experimental studies have demonstrated that subchondral bone changes are not simply the result of altered biomechanics, i.e., pathologic loading. In fact, subchondral bone alterations have an impact on joint homeostasis leading to articular cartilage loss already early in the disease process. This narrative review aims to summarize the available and emerging imaging techniques used to evaluate knee OA-related subchondral bone changes and their potential role in clinical trials of disease-modifying OA drugs (DMOADs). Radiographic fractal signature analysis has been used to quantify OA-associated changes in subchondral texture and integrity. Cross-sectional modalities such as cone-beam computed tomography (CT), contrast-enhanced cone beam CT, and micro-CT can also provide high-resolution imaging of the subchondral trabecular morphometry. Magnetic resonance imaging (MRI) has been the most commonly used advanced imaging modality to evaluate OA-related subchondral bone changes such as bone marrow lesions and altered trabecular bone texture. Dual-energy X-ray absorptiometry can provide insight into OA-related changes in periarticular subchondral bone mineral density. Positron emission tomography, using physiological biomarkers of subchondral bone regeneration, has provided additional insight into OA pathogenesis. Finally, artificial intelligence algorithms have been developed to automate some of the above subchondral bone measurements. This paper will particularly focus on semiquantitative methods for assessing bone marrow lesions and their utility in identifying subjects at risk of symptomatic and structural OA progression, and evaluating treatment responses in DMOAD clinical trials.

A call for screening MRI as a tool for osteoarthritis clinical trials.

Conventional radiography is the most commonly used imaging modality for the evaluation of osteoarthritis (OA) in clinical trials of disease-modifying OA drugs (DMOADs). Unfortunately, radiography has many shortcomings as an imaging technique to meaningfully assess the pathological features of OA. In this perspective paper, we will describe the reasons why radiography is not an ideal tool for structural OA assessment and why magnetic resonance imaging (MRI) should be preferred for such purposes. These shortcomings include a lack of reproducibility of radiographic joint space measurements (if conducted without using a standardized positioning frame), a lack of sensitivity and specificity, an insufficient definition of disease severity, a weak association of radiographic structural damage and pain, a lack of ability to depict many faces of OA, and incapability to depict diagnoses of exclusion. MRI offers solutions to these limitations of radiography. Several different phenotypes of OA have been recognized and it is important to recruit appropriate patients for specific therapeutic approaches in DMOAD trials. Radiography does not allow such phenotypical stratification. We will explain known hurdles for widespread deployment of MRI at eligibility screening and how they can be overcome by technological advances and the use of simplified image assessment.

KELLGREN-LAWRENCE 2 AND 3 KNEES WITH A CARTILAGE-MENISCUS PHENOTYPE SHOW DIFFERENT PATTERNS OF STRUCTRAL PROGRESSION

Purpose: Imaging plays an important role in defining structural disease severity and potential suitability of patients recruited to disease-modifying osteoarthritis drug (DMOAD) trials. Three main structural phenotypes in knee OA have been proposed based on MRI, i.e., inflammation, cartilage-meniscus and subchondral bone. Recently, Rapid OsteoArthritis MRI Eligibility Score (ROAMES1) system has been introduced that allows structural phenotypic stratification based on abbreviated MRI assessment and thus, may potentially be applicable in screening efforts for inclusion into clinical DMOAD trials.

Emerging Concepts of Endotypes/Phenotypes in Regenerative Medicine for Osteoarthritis

Osteoarthritis (OA) represents a broad spectrum of different conditions. Our present understanding of phenotypes and endotypes can explain the differences in clinical manifestations, etiology, and underlying pathophysiology. Although this concept was first applied in choosing the right target population for clinical trials of disease-modifying osteoarthritis drugs (DMOADs), given that the regenerative medicine so far has not delivered uniformly successful results in structural improvement in OA, it merits a consideration to introduce the concept of phenotype/endotype in the regenerative medicine for OA toward an effort to find the right patients for these expensive therapeutics. A better understanding of molecular endotypes facilitates defining clinical phenotypes more clearly. Based on this knowledge, these patients may respond better to treatments that can preserve joints, including regenerative medicine. On the other hand, patients who are not expected to benefit from these treatments may receive earlier total joint replacement surgery. This will result in a reduction of healthcare costs, as well as a more effective approach to new drug development. An understanding of phenotypes/endotypes will contribute to the selection of suitable patients for regenerative treatment of OA.

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

ObjectiveThe 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,...

Test-retest reliability and smallest detectable change (SDC) of MRI-based cartilage thickness analysis in a large multicenter randomized controlled clinical trial of knee osteoarthritis

Test-retest reliability and smallest detectable change (SDC) of MRI-based cartilage thickness analysis in a large multicenter randomized controlled clinical trial of knee osteoarthritis

Subregional anatomical prevalence of cartilage damage in knees with radiographic disease severity Kellgren-Lawrence 2 and 3: the most study

Purpose: Imaging plays an important role in defining structural disease severity and potential suitability of patients recruited to disease-modifying osteoarthritis drug (DMOAD) trials. A common target tissue of DMOADs is cartilage and structural success of a clinical trial is usually defined by reduced cartilage loss or increase in cartilage thickness compared to placebo, commonly in the medial tibio-femoral joint (TFJ). To be eligible for inclusion into a DMOAD trial from a structural perspective, knees with Kellgren-Lawrence (KL) grades 2 and 3 are typically included.

Heterogeneity of cartilage involvement in knees with radiographic disease severity Kellgren-Lawrence 2 and 3: the most study

Purpose: Imaging plays an important role in defining structural disease severity and potential suitability of patients recruited to disease-modifying osteoarthritis drug (DMOAD) trials. A common target tissue of DMOADs is cartilage and structural success of a clinical trial is usually defined by reduced cartilage loss or increase in cartilage thickness compared to placebo, commonly in the medial tibio-femoral joint (TFJ). To be eligible for inclusion into a DMOAD trial from a structural perspective, knees with Kellgren-Lawrence (KL) grades 2 and 3 are typically included.

Imaging of OA - From disease modification to clinical utility.

Multiple disease-modifying osteoarthritis drug (DMOAD) trials were done in the last two decades, but no pharmacological agent has yet been approved by regulatory agencies as an effective therapy to date. Given the fact that we have seen the recent discontinuation of several late-stage drug development trials, a careful strategy is needed in formulating a plan for a successful DMOAD trial - including the various roles of imaging. This narrative review article will summarize how imaging is utilized in osteoarthritis from the perspective of disease modification to clinical utility. We will describe how semi-quantitative and quantitative magnetic resonance imaging approaches have been deployed in DMOAD trials. We will then review the utility of musculoskeletal ultrasound in research and clinical settings. Finally, novel hybrid positron emission tomography/MRI techniques and current research using artificial intelligence will be discussed, focusing on original research. Older publications are included for the discussion of the previous DMOAD trials and other relevant topics where deemed appropriate.

MRI-based screening for structural definition of eligibility in clinical DMOAD trials: Rapid OsteoArthritis MRI Eligibility Score (ROAMES)

Our aim was to introduce a simplified MRI instrument, Rapid OsteoArthritis MRI Eligibility Score (ROAMES), for defining structural eligibility of patients for inclusion in disease-modifying osteoarthritis drug trials using a tri-compartmental anatomic approach that enables stratification of knees into different structural phenotypes and includes diagnoses of exclusion. We also aimed to define overlap between phenotypes and determine reliability. 50 knees from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study, a nested case-control study within the Osteoarthritis Initiative, were selected within pre-defined definitions of phenotypes as either inflammatory, subchondral bone, meniscus/cartilage, atrophic or hypertrophic. A focused scoring instrument was developed covering cartilage, meniscal damage, inflammation and osteophytes. Diagnoses of exclusion were meniscal root tears, osteonecrosis, subchondral insufficiency fracture, tumors, malignant marrow infiltration and acute traumatic changes. Reliability was determined using weighted kappa statistics. Descriptive statistics were used for determining concordance between the a priori phenotypic definition and ROAMES and overlap between phenotypes. ROAMES identified 43 of 50 (86%) pre-defined phenotypes correctly. Of the 50 participants, 27 (54%) had no additional phenotypes other than the pre-defined phenotype. 18 (36%) had one and 5 (10%) had two additional phenotypes. None had three or four additional phenotypes. All features of ROAMES showed almost perfect agreement. One case with osteonecrosis and one with a tumor were detected. ROAMES is able to screen and stratify potentially eligible knees into different structural phenotypes and record relevant diagnoses of exclusion. Reliability of the instrument showed almost perfect agreement.

Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation

ObjectiveTo identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre disease-modifying osteoarthritis drug (DMOAD) study.MethodsKnee osteoarthritis patients from...

Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis

ObjectivesTo explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial...

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations

BackgroundA lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs.ObjectiveTo determine whether inflammatory genetic markers could stratify patients with knee OA...

Subject retention and adherence in a randomized placebo‐controlled trial of a disease‐modifying osteoarthritis drug

To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD). Subjects were obese 45-64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week "faintness-of-heart" (FOH) test, during which she was required to demonstrate reliable appointment keeping and > or =80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls. Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups. The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of > or =2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high.