The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial.

Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18-45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 ​mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.