Preventing Injured Knees From osteoArthritis: Severity Outcomes

NCT06096259 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2023P002573
• Study Type: interventional
• Target: 512
• Locations: 1 country
• Sites: 9

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.

Conditions

Osteoarthritis, Knee; Post-traumatic Osteoarthritis; ACL Tear

Outcome Measures

Primary Outcomes (2)

• 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.

  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)

  24 months

Secondary Outcomes (18)

• KOOS Pain

  baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months

• KOOS Symptoms

  baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months

• KOOS Activities of Daily Living (ADL)

  baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months

• KOOS Sport and Recreation Function

  baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months

• KOOS Quality of Life

  baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months

Study Arms (2)

Metformin

EXPERIMENTAL

3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year

Drug: Metformin

Placebo

PLACEBO COMPARATOR

3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year

Drug: Placebo

Interventions

Metformin DRUG

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.

Also known as: Glumetza, Fortamet, Glucophage extended release (XR)

Metformin

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Arthritis Foundation: collaborator

Study Sites (9)

Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

RECRUITING

University of Kentucky

Lexington, Kentucky, 40504, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

RECRUITING

Hospital for Special Surgery

New York, New York, 10021, United States

RECRUITING

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 25599, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

The Ohio State University

Columbus, Ohio, 43210, United States

RECRUITING

Related Publications (8)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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. Erratum In: Osteoarthr Cartil Open. 2025 Aug 23;7(4):100665. doi: 10.1016/j.ocarto.2025.100665.

  PMID: 39867299 DERIVED

MeSH Terms

Conditions

Osteoarthritis, Knee; Anterior Cruciate Ligament Injuries

Interventions

Metformin

Condition Hierarchy (Ancestors)

Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Knee Injuries; Leg Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Morgan H Jones, MD, MPH

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

• Cale A Jacobs, PhD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Faith Selzer, PhD

CONTACT

617-525-8617; fselzer@bwh.harvard.edu

Daniel J Betensky, AB

CONTACT

6175259727; dbetensky@bwh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Orthopedic Surgery

Study Record Dates

• First Submitted: October 4, 2023
• First Posted: October 23, 2023
• Study Start: May 6, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 29, 2025

Record last verified: 2025-04

Locations

US (9)