Clinical trial NCT06096259: Preventing Injured Knees From osteoArthritis: Severity Outcomes
Official title: Preventing Injured Knees From osteoArthritis: Severity Outcomes (PIKASO)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Post-traumatic Osteoarthritis
ACL Tear
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Arthritis Foundation
First posted: 2023-10-23
Enrollment: 512
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: KOOS Pain Score
timeFrame: Average of 12 and 24 months
measure: Modified MOAKS Cartilage Score
timeFrame: 24 months
Secondary outcomes:
measure: KOOS Pain
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: KOOS Symptoms
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: KOOS Activities of Daily Living (ADL)
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: KOOS Sport and Recreation Function
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: KOOS Quality of Life
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: Marx Activity Rating Scale
timeFrame: baseline, 12 months, 24 months
measure: Work Productivity and Activity Impairment (WPAI)
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: EuroQoL Score
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: Tampa Scale of Kinesiophobia Score
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: MHI-5 Score
timeFrame: baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
measure: Joint Space Narrowing Over Time
timeFrame: baseline, 12 months, 24 months
measure: Cartilage composition assessed with T1rho, T2
timeFrame: baseline, 12 months, 24 months
measure: Severity of Synovitis on Contrast MRI
timeFrame: baseline, 12 months
measure: Knee Range of Motion
timeFrame: 12 and 24 months
measure: 3D Gait Biomechanics
timeFrame: 12 and 24 months
measure: Isokinetic knee flexion/extension strength at 60º/sec
timeFrame: 12 and 24 months
measure: 10m Habitual Walking Speed
timeFrame: 12 and 24 months
measure: Single Leg Hop Test
timeFrame: 12 and 24 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
Study officials:
affiliation: Brigham and Women's Hospital
name: Morgan H Jones, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital
name: Cale A Jacobs, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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citation: 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.
citation: 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.
citation: 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.