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Development of a Novel Clinical Trial Design to Evaluate the Effects of Joint Therapeutics on Cartilage Turnover in Healthy Subjects

Kevin J Ruff, Matthew Back, Dennis Morrison and Sarah A Duncan

Background: Articular joint diseases such as Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are quite prevalent throughout the world, particularly in adults 60 years of age and older, and result in significant costs (both financial and quality-of-life) for those that are afflicted. Owing to the lack of drugs that can halt the progression of arthritis there is an obvious current need for additional joint therapeutics. Various biomarkers have been historically evaluated to better guide the development of new therapeutic interventions. Of these biomarkers, c-terminal Cross- Linked Telopeptide of type-II collagen (CTX-II), a marker of cartilage degradation, has shown the most potential. The purpose of this investigation was to develop a clinical trial design to aid in the evaluation of chondroprotective joint therapeutics by taking advantage of the apparent sensitivity of the articular cartilage of healthy, post-menopausal women to increased exercise-induced joint strain.

Methods: Variables such as the timing of urinary CTX-II clearance and the sensitivity of the CTX-II assay were initially investigated. The sensitivity of CTX-II production to differing levels of exercise strain was then investigated in a non-interventional clinical phase in developing the trial design. The joint therapeutic Natural Eggshell Membrane (NEM^®) was then evaluated in a subsequent open-label clinical phase as a proof of concept.

Results: There appears to be a reproducible initial increase in uCTX-II clearance within the first 2-4 hours following exercise, followed by somewhat of a plateau, with the maximum (or near maximum) level being observed 24 hours post-exercise in the 2nd void of the morning. The CTX-II assay is sensitive enough to measure changes resulting from exercise in obese and OA subjects with a 20.4% to 43.6% increase from resting. There was an obvious trend in the non-interventional clinical phase for the strenuous nature of the exercise (lifting weight>seated step machine>inclined treadmill) to affect the magnitude of the cartilage turnover of the study subjects. NEM^® prevented exercise-induced cartilage turnover in the open-label clinical phase indicating that it is chondroprotective.

Conclusion: This trial design shows great potential to evaluate chondroprotective joint therapeutics including symptomology (i.e. joint pain and stiffness) in healthy individuals, where sparing cartilage may prevent patients from ultimately developing arthritis. By extension, this design may also enable the evaluation of chondroprotective joint therapeutics in an OA population, particularly where cartilage preservation has reached a critical stage.