# Cumulative Damage and Disease Activity Metrics as Prognostic Enrichment Imaging Biomarkers for Knee Osteoarthritis Trials

> **NIH FDA U01** · TUFTS MEDICAL CENTER · 2020 · $249,087

## Abstract

The FDA recognizes osteoarthritis as a serious disease that has few effective treatments and none accepted to
reduce its structural progression. Barriers to developing these therapies include failure to enrich study samples
with people likely to progress, an absence of standard definitions of disease progression, and a lack of
structural measures that reliably predict clinically meaningful outcomes. Magnetic resonance (MR) imaging has
great potential to address the gaps impeding drug testing. However, no-one has developed an MR-based
quantitative composite outcome that reflects multiple structural aspects (“whole-knee”) of knee osteoarthritis
(KOA) progression, is sensitive to change, and is prognostic of clinically meaningful outcomes. To tackle these
barriers, we developed and tested parsimonious semi-automated MR analysis methods to quantify knee
cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis. Next, we used an iterative process to
combine these measures and validated 2 composite metrics reflecting separate domains. The first is
cumulative damage, which reflects whole knee cartilage damage. The second is disease activity, which is
based on BML and effusion-synovitis volumes and relates to joint symptoms. These composite metrics were
accepted into the FDA CDER Biomarker Qualification Program with a proposed prognostic context of use for
the enrichment of KOA clinical trials. The critical next steps are to determine the thresholds for KOA cumulative
damage and disease activity metrics (cross-sectional and longitudinal change) that optimize their prognostic
performance in predicting knee arthroplasty. We will also explore how these composite metrics perform in
predicting knee arthroplasty compared with standard structural measures (e.g., joint space width, cartilage
thickness) and each component measure of the composite metrics (13 measures of cartilage damage, BML
volume, and effusion-synovitis). We will also explore the consistency of these prognostic measures across
varying acquisition periods (1, 2, and 3 years). We will accomplish this by leveraging the resources of the
Osteoarthritis Initiative, which was designed to develop KOA biomarkers. Specifically, we will use a matched
nested case-control design with a sample of case knees that received a total knee arthroplasty and then
perform ROC analyses. This proposal will further the development of cumulative damage and disease activity
as prognostic enrichment imaging biomarkers for long-term KOA progression. These prognostic biomarkers
will be made publicly available to enrich study samples for a clinical trial. They may also be used in early phase
trials to demonstrate the therapeutic potential of an intervention to advance to Phase 3 trials.

## Key facts

- **NIH application ID:** 10146024
- **Project number:** 1U01FD007002-01
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Jeffrey B Driban
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2020
- **Award amount:** $249,087
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146024

## Citation

> US National Institutes of Health, RePORTER application 10146024, Cumulative Damage and Disease Activity Metrics as Prognostic Enrichment Imaging Biomarkers for Knee Osteoarthritis Trials (1U01FD007002-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146024. Licensed CC0.

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