Preventing Injured Knees From osteoArthritis: Severity Outcomes

Официальное название

Preventing Injured Knees From osteoArthritis: Severity Outcomes (PIKASO)

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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. Pa
• Препарат 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.

Первичные конечные точки

• KOOS Pain Score [Срок оценки: Average of 12 and 24 months]
• Modified MOAKS Cartilage Score [Срок оценки: 24 months]

Вторичные конечные точки (12)

• KOOS Pain [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• KOOS Symptoms [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• KOOS Activities of Daily Living (ADL) [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• KOOS Sport and Recreation Function [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• KOOS Quality of Life [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• Marx Activity Rating Scale [Срок оценки: baseline, 12 months, 24 months]
• Work Productivity and Activity Impairment (WPAI) [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• EuroQoL Score [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• Tampa Scale of Kinesiophobia Score [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• MHI-5 Score [Срок оценки: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months]
• Joint Space Narrowing Over Time [Срок оценки: baseline, 12 months, 24 months]
• Cartilage composition assessed with T1rho, T2 [Срок оценки: baseline, 12 months, 24 months]

Критерии участия

Критерии включения

• 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
• Plan to undergo ACL reconstruction within 12 months of injury

Критерии исключения

• Inflammatory arthritis
• Pregnancy and/or lactation, or plans to become pregnant in the next 12 months
• Known contraindication to metformin
• Current use of metformin or topiramate
• Diabetes mellitus or diabetic ketoacidosis
• Acute or chronic renal insufficiency
• History of prior ACL tear on the index knee, with or without reconstruction
• History of ACL tear on the contralateral knee within the past 12 months
• Applying for or receiving Workers' Compensation for their knee injury
• Joint space narrowing AND definite osteophyte(s) on weightbearing radiograph on index knee
• Tibial plateau fracture on index knee
• Concomitant avulsion fracture of index knee that will be treated surgically
• Concomitant posterior cruciate ligament, medial collateral ligament, or lateral collateral ligament injury on index knee requiring surgical repair/reconstruction
• Contraindication to MRI
• Unable to speak and understand English
• Diagnosis of cognitive impairment or otherwise unable to provide informed consent
• Insufficient time for recruitment and drug titration: Surgery scheduled for <14 days from the time of screening
• Date of injury more than 6-months ago, relative to date of screening
• 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
• Plan for allograft at time of consent

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

США · 9 центров

• Emory University — Atlanta
• University of Iowa Hospitals and Clinics — Iowa City
• University of Kentucky — Lexington
• Brigham and Women's Hospital — Boston
• University of Nebraska Medical Center — Omaha
• Hospital for Special Surgery — New York
• The University of North Carolina at Chapel Hill — Chapel Hill
• Cleveland Clinic — Cleveland
• … и ещё 1 центр

Публикации

• 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. PMID 26063472
• 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. PMID 17106388
• 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. PMID 27145096
• 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. PMID 34903114
• 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. PMID 35597372
• 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. PMID 31126352
• 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. PMID 22402434
• 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 PIKAS PMID 39867299

Идентификаторы

NCT: NCT06096259 · 2023P002573

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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