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Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis

Award Number: R01AR076411
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/23/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $726,131 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	5/12/2025	NON-COMPETING CONTINUATION	$726,131
														Subtotal = $726,131

Issue Date FY: 2024 ( Subtotal = $932,667 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	5	6/24/2024	NON-COMPETING CONTINUATION	$895,944
2024	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	005	4	7/18/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,931
2024	2023	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/29/2024	NON-COMPETING CONTINUATION	-$548,123
2024	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	3/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$36,723
2024	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	3/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$548,123
2024	2023	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	3	7/18/2024	NON-COMPETING CONTINUATION	-$136,931
														Subtotal = $932,667

Issue Date FY: 2023 ( Subtotal = $750,087 )
2023	2023	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/5/2023	NON-COMPETING CONTINUATION	$750,087
														Subtotal = $750,087

Issue Date FY: 2022 ( Subtotal = $525,404 )
2022	2022	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/2/2022	NON-COMPETING CONTINUATION	$525,404
														Subtotal = $525,404

Issue Date FY: 2021 ( Subtotal = $627,942 )
2021	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/21/2021	NEW	$627,942
														Subtotal = $627,942

Grand Total All Awards = $3,562,231

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Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis

Award Number: R01AR076411

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/23/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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