Preventing Injured Knees From osteoArthritis: Severity Outcomes
NCT ID: NCT06096259
Last Updated: 2025-04-29
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2
512 participants
INTERVENTIONAL
2024-05-06
2029-12-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
QUADRUPLE
Study Groups
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Metformin
3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year
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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.
Placebo
3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year
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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.
Interventions
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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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.
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 every 5 days as tolerated, up to a maximum dose of 1500 mg daily.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Plan to undergo ACL reconstruction within 12 months of injury
Exclusion Criteria
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
18 Years
45 Years
ALL
No
Sponsors
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Arthritis Foundation
OTHER
Brigham and Women's Hospital
OTHER
Responsible Party
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Morgan H. Jones, MD, MPH
Assistant Professor of Orthopedic Surgery
Principal Investigators
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Morgan H Jones, MD, MPH
Role: PRINCIPAL_INVESTIGATOR
Brigham and Women's Hospital
Cale A Jacobs, PhD
Role: PRINCIPAL_INVESTIGATOR
Brigham and Women's Hospital
Locations
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Emory University
Atlanta, Georgia, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
University of Kentucky
Lexington, Kentucky, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
University of Nebraska Medical Center
Omaha, Nebraska, United States
Hospital for Special Surgery
New York, New York, United States
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Cleveland Clinic
Cleveland, Ohio, United States
The Ohio State University
Columbus, Ohio, United States
Countries
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Central Contacts
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Facility Contacts
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References
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Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Aug 22;386(9995):743-800. doi: 10.1016/S0140-6736(15)60692-4. Epub 2015 Jun 7.
Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006 Nov-Dec;20(10):739-44. doi: 10.1097/01.bot.0000246468.80635.ef.
Thomas AC, Hubbard-Turner T, Wikstrom EA, Palmieri-Smith RM. Epidemiology of Posttraumatic Osteoarthritis. J Athl Train. 2017 Jun 2;52(6):491-496. doi: 10.4085/1062-6050-51.5.08. Epub 2016 May 4.
Brinlee AW, Dickenson SB, Hunter-Giordano A, Snyder-Mackler L. ACL Reconstruction Rehabilitation: Clinical Data, Biologic Healing, and Criterion-Based Milestones to Inform a Return-to-Sport Guideline. Sports Health. 2022 Sep-Oct;14(5):770-779. doi: 10.1177/19417381211056873. Epub 2021 Dec 13.
Lim YZ, Wang Y, Estee M, Abidi J, Udaya Kumar M, Hussain SM, Wluka AE, Little CB, Cicuttini FM. Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Osteoarthritis Cartilage. 2022 Nov;30(11):1434-1442. doi: 10.1016/j.joca.2022.05.005. Epub 2022 May 18.
Wang Y, Hussain SM, Wluka AE, Lim YZ, Abram F, Pelletier JP, Martel-Pelletier J, Cicuttini FM. Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. Arthritis Res Ther. 2019 May 24;21(1):127. doi: 10.1186/s13075-019-1915-x.
Adams D, Logerstedt DS, Hunter-Giordano A, Axe MJ, Snyder-Mackler L. Current concepts for anterior cruciate ligament reconstruction: a criterion-based rehabilitation progression. J Orthop Sports Phys Ther. 2012 Jul;42(7):601-14. doi: 10.2519/jospt.2012.3871. Epub 2012 Mar 8.
Jacobs CA, Jones MH, Collins JE, Waddell LM, Li X, Winalski CS, Pietrosimone B, Kraus VB, Otero M, Wellsandt E, Schmitt LC, Spindler KP, Anderson DD, Rodeo SA, Magnussen RA, Wolf BR, Hart JM, Stone AV, Conley CE, Golightly YM, Myer GD, Snyder-Mackler L, Lotz MK, Kim JS, McLeod MM, Huebner JL, Lisee C, Selzer F, Katz JN, Long K, Frier KC, Betensky DJ, Felson DT, Losina E; for PIKASO Team. The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial. Osteoarthr Cartil Open. 2024 Dec 23;7(1):100563. doi: 10.1016/j.ocarto.2024.100563. eCollection 2025 Mar.
Other Identifiers
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2023P002573
Identifier Type: -
Identifier Source: org_study_id
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