Preventing Injured Knees From osteoArthritis: Severity Outcomes

Phase 2RecruitingNCT06096259

Brigham and Women's Hospital512 enrolled

Overview

This study is being done to find out if metformin is effective at reducing pain by delaying the onset of post-traumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) reconstruction. This research study will compare metformin to placebo. The placebo tablet looks exactly like metformin, but contains no metformin. Placebos are used in research studies to see if the results are due to the study drug or due to other reasons. Metformin is approved by the U.S. Food and Drug Administration (FDA) to treat type II diabetes. Notably, it also has anti-inflammatory effects, suggesting it could benefit people who have an ACL injury and are undergoing ACL reconstruction.

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.

Interventions

MetforminDRUG

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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.

PlaceboDRUG

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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

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. Plan to undergo ACL reconstruction within 12 months of injury 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. Diabetes mellitus or diabetic ketoacidosis 6. Acute or chronic renal insufficiency 7. History of prior ACL tear on the index knee, with or without reconstruction 8. History of ACL tear on the contralateral knee within the past 12 months 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. Date of injury more than 6-months ago, relative to date of screening 19. 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 20. Plan for allograft at time of consent

Locations (9)

Emory University

Atlanta, Georgia, United States

RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

RECRUITING

University of Kentucky

Lexington, Kentucky, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, United States

RECRUITING

University of Nebraska Medical Center

Omaha, Nebraska, United States

RECRUITING

Hospital for Special Surgery

New York, New York, United States

RECRUITING

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, United States

RECRUITING

The Ohio State University

Columbus, Ohio, United States

RECRUITING

Outcomes

Primary Outcomes

KOOS Pain Score

To determine whether metformin leads to reduced pain as measured by the KOOS pain subscale compared to placebo between 12 and 24 months postoperatively. Knee Injury and Osteoarthritis Outcome Score (KOOS) is a questionnaire designed to assess short and long-term patient-relevant outcomes following knee injury. The KOOS pain subscale contains 9 items and is scored on a 0-100 scale, 100 being best.

Time frame: Average of 12 and 24 months

Modified MOAKS Cartilage Score

To determine whether metformin leads to reduced structural degeneration at 24 months postoperatively compared to placebo. The MOAKS score (MRI Osteoarthritis Knee Score) is a semi-quantitative whole joint assessment of knee osteoarthritis with very good to excellent reliability used to score knee osteoarthritis. In MOAKS the knee is divided into 14 articular subregions for scoring articular cartilage and bone marrow lesions (BMLs) and in addition the subspinous region is added for BML scoring. For each region, the following features are assessed independently: 1. bone marrow lesions and cysts (score: 0-3, 3 worst) 2. articular cartilage loss (score: 0-3, 3 worst) 3. osteophytes (score: 0-3, 3 worst) 4. synovitis and effusion (score: 0-3, 3 worst) 5. meniscus extrusion and morphology (score: 0-3, 3 worst) 6. ligaments/tendon (0/1, 0=normal, 1=abnormal) 7. periarticular features (0/1, 0=absent, 1=present)

Time frame: 24 months

Secondary Outcomes

KOOS Pain

Assessed via questionnaire. Knee Injury and Osteoarthritis Outcome Score (KOOS) is a questionnaire designed to assess short and long-term patient-relevant outcomes following knee injury. The KOOS is self-administered and includes 42 items across 5 subscales: pain, symptoms, ADLs, sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The pain subscale contains 9 items.