An experimental medicine study to investigate the short-term effects of retinoic acid metabolism blockade by oral talarozole on molecular outcomes in the joint tissues of those with hand osteoarthritis (RAMBOH-1): protocol for a double- blind randomi

Abstract Background: Hand osteoarthritis (OA) is one of the most common musculoskeletal conditions. A genetic variant in an enzyme (ALDH1A2) lowers retinoic acid levels and is associated with hand osteoarthritis. A developmental drug class, including the agent talarozole, inhibits the degradation of retinoic acid and reduces inflammatory gene expression in preclinical studies, representing a potential therapeutic for hand osteoarthritis. This experimental medicine study will investigate the effect of talarozole on molecular readouts in the articular cartilage of individuals with hand osteoarthritis who are undergoing a surgical procedure as part of their planned clinical care. Methods: A feasibility study of a double-blind placebo-controlled intervention with 1:1 randomisation to either oral talarozole 2 mg once daily or placebo. The target population is those with symptomatic radiographic thumb joint osteoarthritis undergoing trapeziectomy. The objective is to test whether systemic administration of talarozole decreases inflammatory gene expression in the trapezium articular cartilage compared to placebo. Participants will take the study medication for 10-21 days prior to their surgery. The primary outcome is the difference in mean cartilage expression of a panel of pre-defined inflammatory genes (including, but not limited to ADAMTS4, MMP13 and MMP1) when comparing the intervention and placebo arms. Secondary outcomes include measures of feasibility such as recruitment, safety, acceptability, retinoic acid dependent gene expression and clinical outcomes such as average hand pain. Discussion: Identifying new treatments that improve symptoms and slow progression of hand osteoarthritis remains a top research priority. This study is not definitive but will provide data including mechanistic data on the molecular effects of pharmacological retinoic acid metabolism blockade in participants with hand osteoarthritis. The study will generate data to inform progression criteria to a fully powered randomised controlled efficacy trial. The findings will be published in a peer-reviewed journal and presented at relevant conferences. Trial registration: ISRCTN, ISRCTN16717773. Registered 16 February 2022, https://www.isrctn.com/ISRCTN16717773