Targeting mitochondrial quality control in osteoarthritis with GrpE-like 1-loaded synovial mesenchymal stromal/stem cell small extracellular vesicles

Table 2 Phase II signal-finding endpoint framework mapped to Outcome Measures in Rheumatology-Osteoarthritis Research Society International

OMERACT-OARSI domain	Endpoint (suggested measure)	Time-points	Role in trial	Rationale
Pain	WOMAC pain (or KOOS pain)	Baseline, week 12, week 24	Primary	Core domain; sensitive to change
Function	KOOS-ADL (or WOMAC function)	Baseline, week 12, week 24	Key secondary	Functional relevance; limits multiplicity
Patient global	Patient global assessment	Baseline, week 12, week 24	Secondary	Complements pain/function per core set
Structural progression	MRI cartilage thickness (pre-specified compartment/ROI)	Baseline, 12-24 months (exploratory in phase II)	Exploratory (or key secondary if powered)	Supported by FNIH analyses; pre-register analysis
Safety	Local/systemic AEs; labs	Visit-aligned	Required	IND-appropriate safety set

OMERACT: Outcome Measures in Rheumatology; OARSI: Osteoarthritis Research Society International; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; KOOS: Knee injury and Osteoarthritis Outcome Score; ADL: Activities of daily living; MRI: Magnetic resonance imaging; ROI: Region of interest; FNIH: Foundation for the National Institutes of Health; AEs: Adverse events; IND: Investigational New Drug.