Clinical Trial Finder

Inclusion Criteria:

1. Age 25-45 or Age 18-24 with preoperative KOOS Pain <80 (0-100, 100 best) recorded at least 14 days after the day of ACL injury. 2. ACL tear documented on MRI within 6 months prior to screening. 3. Plan to undergo ACL reconstruction.

Exclusion Criteria:

1. Inflammatory arthritis. 2. Pregnancy and/or lactation, or plans to become pregnant in the next 12 months. 3. Known contraindication to metformin. 4. Current use of metformin or topiramate. 5. Type I diabetes mellitus or diabetic ketoacidosis. 6. Heavy alcohol consumption and/or known hepatic disease. 7. Acute or chronic renal insufficiency. 8. History of ACLR on either knee. 9. Applying for or receiving Workers' Compensation for their knee injury. 10. Joint space narrowing AND definite osteophyte(s) on weightbearing radiograph on index knee. 11. Tibial plateau fracture on index knee. 12. Concomitant avulsion fracture of index knee that will be treated surgically. 13. Concomitant posterior cruciate ligament, medial collateral ligament, or lateral collateral ligament injury on index knee requiring surgical repair/reconstruction. 14. Contraindication to MRI. 15. Unable to speak and understand English. 16. Diagnosis of cognitive impairment or otherwise unable to provide informed consent. 17. Insufficient time for recruitment and drug titration: Surgery scheduled for <14 days from the time of screening. 18. Presence of a condition or abnormality that in the opinion of the surgeon investigator would compromise the safety of the patient or the quality of the data. 19. Plan for allograft at time of consent

Osteoarthritis (OA) is among the most prevalent chronic, disabling conditions, occurring in over 32 million persons in the US. Worldwide, an estimated 240 million persons have symptomatic, activity-limiting OA. OA cases arising from injury are referred to as post-traumatic OA (PTOA). Approximately 12% of cases of lower extremity symptomatic OA are PTOA, often the result of injuries such as anterior cruciate ligament (ACL) rupture or ankle fracture. Four million Americans have PTOA. On average, patients with PTOA develop knee OA 10.4 years earlier than those with primary knee OA. Similarly, individuals with PTOA of the hip and ankle develop OA 9.0 and 14.0 years, respectively, earlier than their primary OA counterparts. Sustaining ACL injury early in adulthood leads to greater lifetime risk as well as earlier onset of knee OA and need for total knee replacement (TKR). The earlier age of onset means that PTOA is often a disorder of working persons, compromising productivity and quality of life. The indirect cost burden of PTOA is estimated to be ~$4.4 billion annually, because individuals are typically affected in their most productive years of employment. Anterior cruciate ligament (ACL) injury is the most common sports-related knee injury, and many patients who wish to return to sporting activities that involve cutting and pivoting will choose to undergo ACL reconstruction (ACLR). Each year, more than 120,000 ACL reconstructions are performed in the US alone. Even though ACLR can allow people to return to sporting activities with a stable knee, there is still an increased risk of PTOA after the ACL injury and subsequent reconstruction. Studies have demonstrated that around 50% of patients who undergo ACL reconstruction develop OA within 10-15 years. Given the large number of ACL injuries and subsequent reconstructions that occur annually, and the strong association between ACL tear/reconstruction and PTOA, developing treatment strategies to delay or prevent PTOA and promote long-term health after ACLR is critical to maintaining the well-being of young, active populations. This study proposes to address these issues by testing the efficacy of metformin, a commonly used and safe drug with promising pre-clinical and clinical evidence of PTOA prevention, in younger adults undergoing ACL reconstruction. PIKASO is a multicenter, double-blind (participants, treating clinicians, and assessors), placebo-controlled, randomized study to establish the efficacy of metformin at delaying the onset of post-traumatic osteoarthritis (PTOA) after anterior cruciate ligament reconstruction. Subjects will be randomized in a 1:1 ratio. Each subject will complete standard-of-care postoperative physical therapy in both arms. The two primary outcomes will be KOOS pain (assessed at 12 and 24 months postoperatively and averaged) and modified MRI Osteoarthritis Knee Score (MOAKS) cartilage score at 24 months postoperatively.

Arms

Experimental: Metformin

3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year

Placebo Comparator: Placebo

3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year

Interventions

Drug: - Metformin

Metformin is an oral anti-hyperglycemic agent widely used as first-line treatment for type II diabetes to improve glycemic control. It is the fourth most commonly prescribed drug in the United States. Participants will receive commercially available extended-release metformin 500mg tablets manufactured by Granules India Limited, Hyderabad, India and then sourced, packaged, and labeled for the study by Sharp Labs. The study will follow standard dosing procedures for extended-release metformin. Participants will begin by taking 1x500 mg pill once a day, and then the dose will be increased in 500 mg/day increments weekly as tolerated, up to a maximum dose of 1500 mg daily.

Drug: - Placebo

The study will use matching placebo tablets that are almost indistinguishable from the 500 mg metformin ER tablets. Participants will begin by taking 1x500 mg pill once a day, and then the dose will be increased in 500 mg/day increments weekly as tolerated, up to a maximum dose of 1500 mg daily.