Purpose: Osteoarthritis (OA) is a chronic, degenerative disease that burdens millions. Novel OA treatments are needed as no regimen has been approved that halts or reverses disease progression. Here we conducted a review of Disease Modifying Osteoarthritis Drug (DMOAD) clinical trials in order to inform future trial design.
Methods: Between June and Oct. 2020, 12 DMOADs were identified on clinicaltrials.gov, totaling 49 registered trials. The collected data were organized into five parts: trial background, inclusion-exclusion criteria, methods, outcomes and results with a focus on trial design trends.
Results: Only two candidates are currently in phase III; seven other trials stand at phase II, and three remain in phase I. Structural endpoints measured change in cartilage thickness with MRI, joint space width with X-ray, and change in bone density with CT. Subjective measures included WOMAC, KOOS, and OMERACT-OARSI. Pain was measured using VAS, NRS, PGA and medication use. Pharmacokinetics was used as a secondary outcome in 87% of the drugs. While the majority of the drugs were intra-articular injectables, only three measured synovial drug levels. Many trials found no correlation between structural changes and patient-reported clinical improvement. Most objective or subjective improvement measures lacked significance, with many showing contradicting outcomes. Absence of well-established minimal clinically important differences (MCID) challenged validity of outcomes and comparison of drugs.
Conclusions: Analysis revealed a lack of correlation between symptomatic and structural improvements, variable trial designs and distinct analysis techniques. Future DMOAD trial designs must ensure the validity of clinical endpoints, optimize patient selection and provide evidence-based control for placebo effects to improve trial success. Development of additional reliable objective outcome measures-both functional and structural-is essential for successful development of disease modifying drugs for OA.
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