R01AR076411

Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis - The United States Food and Drug Administration (FDA) recognizes osteoarthritis as a serious disease with an unmet need for therapies that slow, stop, or reverse joint damage. A challenge to testing new therapies is the lack of a comprehensive definition of disease progression that incorporates multiple structural changes.

Another challenge is not knowing how much change in a structural measure would reflect meaningful benefit or worsening to a patient. Magnetic resonance (MR) imaging has great potential to address these critical gaps. However, no-one has developed an MR-based composite outcome that reflects multiple structural aspects (“whole-knee”) of knee osteoarthritis progression and is sensitive to change. This remains a critical technological obstacle to testing and developing new therapies.

We recently tackled these barriers and found that structural measures of knee osteoarthritis progression can be summarized as: 1) cumulative damage (quantitative articular cartilage damage throughout a knee; relates to radiographic progression), and 2) disease activity (quantitative bone marrow lesions and effusion-synovitis volumes; relates to pain progression).

The critical next steps are to demonstrate these outcomes are valid and useful predictive biomarkers of KOA progression by determining 1) how much change in each measure translates to indicators of clinically meaningful improvement or worsening and 2) the discriminative performance of each composite measure. We will accomplish this by assessing annual MR images in 3 nested case-control samples to determine the magnitude of change in cumulative damage and disease activity that predict changes in patient-reported outcomes (Aim 2) and walking speed (Aim 3), and knee replacement (Aim 4) across biological factors (e.g., sex).

To achieve our goal, we will quantify 1- or 2-year change in articular cartilage as well as bone marrow lesions and effusion-synovitis volume on MR images for 5,270 knee visits. We will then determine the amount of change in cumulative damage or disease activity that relates to these outcomes during the same time period. We will also test how much change in these measures differentiates adults who will receive a knee replacement.

Finally, we will test whether cumulative damage and disease activity will reliably predict changes in patient-centered outcomes across sex, body mass index, radiographic severity, and duration of observation period. This study will support an application for approval of these structural endpoints as predictive biomarkers for KOA progression, which could greatly improve the chance of success for clinical trials testing disease-modifying therapies for knee osteoarthritis.

University Of Massachusetts Medical School

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

Research Grants Using the Resources from the Osteoarthritis Initiative (OAI) (R01) - Clinical Trial Not Allowed (PA-18-409)

Amendment Since initial award the total obligations have increased 467% from $627,942 to $3,562,231.