The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial

doi:10.1016/j.ocarto.2024.100563

The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial

College of Medicine

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Abstract

Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18–45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.

Original language	English
Article number	100563
Journal	Osteoarthritis and Cartilage Open
Volume	7
Issue number	1
DOIs	https://doi.org/10.1016/j.ocarto.2024.100563
State	Published - Mar 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Funding

Funding was provided by the Arthritis Foundation Osteoarthritis Clinical Trial Network. Arthritis Foundation representatives (Jason Kim, Michelle McLeod) contributed to study design and writing of the manuscript. The funding source will not be involved with data collection, analysis or interpretation, or the decision to submit the manuscript for publication. ☆ Supported by the Arthritis Foundation Osteoarthritis Clinical Trial Network. The PIKASO trial is led by two co-Principal Investigators, an orthopedic sports medicine surgeon (MHJ) and a clinical orthopaedic researcher (CAJ). They are advised by the Arthritis Foundation’s Osteoarthritis Clinical Trials Network (OA-CTN) Steering Committee, which includes clinician-scientists, biostatisticians, and laboratory scientists, as well as several core coordinating centers (led by DTF). The Data Coordinating Center (DCC) at Mass General Brigham (led by EL and JC) oversees day-to-day operations of the trial, including monitoring screening and recruitment, randomization, organizing staff training, facilitating adherence monitoring, coordinating central resources, and providing reports to the independent Data and Safety Monitoring Board (DSMB). The Imaging Coordinating Center at Cleveland Clinic (led by CSW and XL) manages and coordinates the imaging at each site to ensure uniformity of MRI protocols and image quality and perform centralized image reading and processing. The Biomechanics Coordinating Center at the University of North Carolina at Chapel Hill (led by BP and CL) provides guidance on postoperative physical therapy recommendations and oversees collection, data transmission, and analysis of the biomechanical study outcomes. The Biospecimen Coordinating Center at Duke University School of Medicine (led by VBK and MO) provides oversight for proper collection and analysis of all biological specimens obtained through the study. Finally, the study is supported by an endocrinologist who has performed metformin-related clinical trials in both diabetic and non-diabetic populations, and through active participation from the study sponsor (the Arthritis Foundation). During project preparation, several study groups, including a study-wide operations committee and a clinical committee of the enrolling study surgeons, met regularly to finalize study details.

Funders
Arthritis Foundation Osteoarthritis Clinical Trial Network
Arthritis Foundation representatives
Arthritis Foundation

Keywords

Anterior cruciate ligament reconstruction
Metformin
Post-traumatic osteoarthritis
Synovitis

ASJC Scopus subject areas

Biomedical Engineering
Orthopedics and Sports Medicine
Rehabilitation

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10.1016/j.ocarto.2024.100563

Cite this

@article{db05fde8bea84aaf8cceb906c62ab2e3,

title = "The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial",

abstract = "Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18–45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.",

keywords = "Anterior cruciate ligament reconstruction, Metformin, Post-traumatic osteoarthritis, Synovitis",

author = "Jacobs, \{Cale A.\} and Jones, \{Morgan H.\} and Collins, \{Jamie E.\} and Waddell, \{Lily M.\} and Xiaojuan Li and Winalski, \{Carl S.\} and Brian Pietrosimone and Kraus, \{Virginia Byers\} and Miguel Otero and Elizabeth Wellsandt and Schmitt, \{Laura C.\} and Spindler, \{Kurt P.\} and Anderson, \{Donald D.\} and Rodeo, \{Scott A.\} and Magnussen, \{Robert A.\} and Wolf, \{Brian R.\} and Hart, \{Joe M.\} and Stone, \{Austin V.\} and Conley, \{Caitlin E.\} and Golightly, \{Yvonne M.\} and Myer, \{Gregory D.\} and Lynn Snyder-Mackler and Lotz, \{Martin K.\} and Kim, \{Jason S.\} and McLeod, \{Michelle M.\} and Huebner, \{Janet L.\} and Caroline Lisee and Faith Selzer and Katz, \{Jeffrey N.\} and Kyna Long and Frier, \{Kelly C.\} and Betensky, \{Daniel J.\} and Felson, \{David T.\} and Elena Losina",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = mar,

doi = "10.1016/j.ocarto.2024.100563",

language = "English",

volume = "7",

journal = "Osteoarthritis and Cartilage Open",

issn = "2665-9131",

publisher = "Elsevier Ltd.",

number = "1",

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T1 - The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes)

T2 - Rationale and design features for a randomized controlled trial

AU - Jacobs, Cale A.

AU - Jones, Morgan H.

AU - Collins, Jamie E.

AU - Waddell, Lily M.

AU - Li, Xiaojuan

AU - Winalski, Carl S.

AU - Pietrosimone, Brian

AU - Kraus, Virginia Byers

AU - Otero, Miguel

AU - Wellsandt, Elizabeth

AU - Schmitt, Laura C.

AU - Spindler, Kurt P.

AU - Anderson, Donald D.

AU - Rodeo, Scott A.

AU - Magnussen, Robert A.

AU - Wolf, Brian R.

AU - Hart, Joe M.

AU - Stone, Austin V.

AU - Conley, Caitlin E.

AU - Golightly, Yvonne M.

AU - Myer, Gregory D.

AU - Snyder-Mackler, Lynn

AU - Lotz, Martin K.

AU - Kim, Jason S.

AU - McLeod, Michelle M.

AU - Huebner, Janet L.

AU - Lisee, Caroline

AU - Selzer, Faith

AU - Katz, Jeffrey N.

AU - Long, Kyna

AU - Frier, Kelly C.

AU - Betensky, Daniel J.

AU - Felson, David T.

AU - Losina, Elena

PY - 2025/3

Y1 - 2025/3

N2 - Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18–45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.

AB - Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease. Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18–45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs. placebo in decreasing the rate of structural knee changes and pain. Participants will be asked to take up to 1500 mg/day of either metformin or placebo as tolerated. The primary outcomes are Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale scores averaged between 12 and 24 months after randomization, and MRI derived cartilage structural change at 24 months. The trial will be deemed successful if at least one of the two primary outcomes reaches the preplanned effect size with sufficient statistical certainty. In this paper, we describe PIKASO elements according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Results: Our multidisciplinary team developed the methods and statistical analysis plan for a placebo controlled, randomized clinical trial to determine whether metformin alters pain and early osteoarthritic changes after ACLR. Discussion: This manuscript outlines the rationale, study design, and implementation of the PIKASO trial aiming to prevent the onset of PTOA after ACLR. Trial registration: clinicaltrials.gov NCT06096259.

KW - Anterior cruciate ligament reconstruction

KW - Metformin

KW - Post-traumatic osteoarthritis

KW - Synovitis

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UR - https://www.scopus.com/pages/publications/85214090461#tab=citedBy

U2 - 10.1016/j.ocarto.2024.100563

DO - 10.1016/j.ocarto.2024.100563

M3 - Article

AN - SCOPUS:85214090461

SN - 2665-9131

VL - 7

JO - Osteoarthritis and Cartilage Open

JF - Osteoarthritis and Cartilage Open

IS - 1

M1 - 100563

ER -

The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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