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Osteoarthritis, KneePhase 2PIKASONCT06096259

Preventing Injured Knees From osteoArthritis: Severity Outcomes

A Phase 2 study testing Metformin in people with Osteoarthritis, Knee and Post-traumatic Osteoarthritis, run by Brigham and Women's Hospital at 9 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 45 years
What is being tested?
Metformin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
512 participants
Where
9 sitesUnited States
Study dates
6 May 2024to Dec 2030
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 20Show fewer
  • 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

Trial locations and contacts

9 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Faith Selzer, PhD contact

617-525-8617

fselzer@bwh.harvard.edu

Daniel J Betensky, AB contact

6175259727

dbetensky@bwh.harvard.edu

9 sites in 1 country

United States9 sites, 9 recruiting

  • Emory University

    Atlanta, Georgia, 30322

    Gregory D Myer, PhD

    Recruiting

  • Brigham and Women's Hospital

    Boston, Massachusetts, 02115

    Rachel Lovejoy, 6177326934, rlovejoy@bwh.harvard.edu

    Morgan H Jones, MD, MPH

    Recruiting

  • The University of North Carolina at Chapel Hill

    Chapel Hill, North Carolina, 25599

    Joe M Hart, PhD

    Brian G Pietrosimone, PhD

    Recruiting

  • Cleveland Clinic

    Cleveland, Ohio, 44195

    Kurt Spindler, MD

    Recruiting

  • The Ohio State University

    Columbus, Ohio, 43210

    Laura C Schmitt, PT, PhD

    Robert A Magnussen, MD

    Recruiting

  • University of Iowa Hospitals and Clinics

    Iowa City, Iowa, 52242

    Don D Anderson, PhD

    Brian R Wolf, MD

    Recruiting

  • University of Kentucky

    Lexington, Kentucky, 40504

    Austin V Stone, MD, PhD

    Recruiting

  • Hospital for Special Surgery

    New York, New York, 10021

    Scott A Rodeo, MD

    Miguel Otero, PhD

    Recruiting

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

    Elizabeth A Wellsandt, PT, PhD

    Yvonne Golightly, PT, PhD

    Recruiting

Other trials in United States

About this study

Official title: Preventing Injured Knees From osteoArthritis: Severity Outcomes (PIKASO)

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.

Read the 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.

Being tested
Metformin, Placebo
Medical subject headings
Osteoarthritis, Knee, Anterior Cruciate Ligament Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    Also called Glumetza, Fortamet, Glucophage extended release (XR)

    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.

  • PlaceboDrug

    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.

Study groups in NCT06096259
Study groupRoleWhat they receive
MetforminExperimental3x500mg metformin hydrochloride (HCl) extended-release (ER) tablets taken orally once a day for 1 year
Receives: Drug: Metformin
PlaceboPlacebo comparator3x metformin placebo tablets matching metformin extended-release taken orally once a day for 1 year
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Average of 12 and 24 months

  2. 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)

    Measured: 24 months

Secondary outcomes (18)

  1. KOOS Pain

    Assessed via questionnaire.

    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 is self-administered and includes 42 items across 5 subscales: pain, symptoms, ADLs, sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The pain subscale contains 9 items.

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

  2. KOOS Symptoms

    Assessed via questionnaire.

    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 is self-administered and includes 42 items across 5 subscales: pain, symptoms, ADLs, sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The symptoms subscale contains 7 items.

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

  3. KOOS Activities of Daily Living (ADL)

    Assessed via questionnaire.

    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 is self-administered and includes 42 items across 5 subscales: pain, symptoms, activities of daily living (ADLs), sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The ADL subscale contains 17 items.

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

  4. KOOS Sport and Recreation Function

    Assessed via questionnaire.

    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 is self-administered and includes 42 items across 5 subscales: pain, symptoms, ADLs, sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The sports and recreation subscale contains five items.

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

  5. KOOS Quality of Life

    Assessed via questionnaire.

    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 is self-administered and includes 42 items across 5 subscales: pain, symptoms, ADLs, sports/recreation, and quality of life. KOOS is scored on a 0-100 scale, 100 being best. The quality of life subscale contains four items.

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

  6. Marx Activity Rating Scale

    Assessed via questionnaire

    The Marx Scale consists of four questions concerning running, cutting, deceleration, and pivoting. The patient is asked to report on the frequency with which they performed the activity in their healthiest state within the past year. It is most often used in physically active adults aged 18-50 with knee problems.

    Measured: baseline, 12 months, 24 months

  7. Work Productivity and Activity Impairment (WPAI)

    Assessed via questionnaire

    The Work Productivity and Activity Impairment (WPAI) questionnaire is a 6-item instrument to measure impairments in both paid work and unpaid work. It measures impairments in paid work and other activity because of health problems during the past seven days.

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

  8. EuroQoL Score

    Assessed via questionnaire

    The 5-level EuroQol score (EQ-5D-5L) is a quality of life measure that includes two components: the EQ descriptive system (EQ-5D) and the EQ visual analogue scale (EQ VAS).

    The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The scores for the five dimensions can be combined into a 5-digit number that describes the patient's health state (5-25, 25 worst). The EQ VAS records the patient's self-rated health on a visual analogue scale (0-100, 100 best).

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

  9. Tampa Scale of Kinesiophobia Score

    Assessed via questionnaire

    The Tampa Scale of Kinesiophobia (TSK) is a 17-item questionnaire with a 4-point Likert scale to assess one's fear of movement or reinjury. Two subscales make up the scale:

    1. Avoiding physical exertion because of fear of reinjury or worsening of pain (Questions 1, 2, 7, 9, 10, 11, 12)
    2. Somatic Focus - the idea that there are underlying, major medical issues involved (Questions 3, 4, 5, 6, 8)

    Individual item scores range from 1-4 (4 worst), with the negatively worded items (4, 8, 12, 16) having a reverse scoring (4-1, 1 worst). The 17 item TSK total scores range from 17 to 68 where the lowest 17 means no kinesiophobia, and the higher scores indicate an increasing degree of kinesiophobia. Scores above 37 are generally considered to indicate kinesiophobia.

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

  10. MHI-5 Score

    Assessed via questionnaire

    The Mental Health Inventory-5 (MHI-5) is a brief, valid, and reliable international instrument for assessing mental health status in adults. The MHI-5 has 5 items and is scored on a scale from 0-100, where 100 indicates optimal mental health.

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

  11. Joint Space Narrowing Over Time

    Joint space narrowing will be measured in mm and assessed via X-Ray and MRI. Greater joint space narrowing indicates more severe structural osteoarthritis.

    Measured: baseline, 12 months, 24 months

  12. Cartilage composition assessed with T1rho, T2

    Assessed via compositional MRI with T1rho and T2 weighted sequences, which are being investigated for their usefulness in musculoskeletal imaging, particularly for examining cartilage.

    Measured: baseline, 12 months, 24 months

  13. Severity of Synovitis on Contrast MRI

    Assessed via optional contrast MRI. Dynamic contrast enhanced MR images will be analyzed to quantify variables including maximum enhancement, number of enhanced voxels, and derived variables (e.g. maximum enhancement times number of enhanced voxels) for evaluating severity of synovitis.

    Measured: baseline, 12 months

  14. Knee Range of Motion

    Assessed via physical examination with a goniometer

    Measured: 12 and 24 months

  15. 3D Gait Biomechanics

    Walking gait will be evaluated using a motion capture system as participants walk at a self-selected speed

    Measured: 12 and 24 months

  16. Isokinetic knee flexion/extension strength at 60º/sec

    Assessed using an isokinetic dynamometer

    Measured: 12 and 24 months

  17. 10m Habitual Walking Speed

    The time to walk 10 m will be recorded

    Measured: 12 and 24 months

  18. Single Leg Hop Test

    The maximum distance will be recorded

    Measured: 12 and 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Oct 2023
  2. Study start6 May 2024
  3. Primary completionDec 2029 (estimated)
  4. Study completionDec 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
512 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06096259
Sponsor's protocol ID
2023P002573
Acronym
PIKASO
Status last verified
Oct 2026
First submitted
4 Oct 2023
Last updated
15 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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 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.

    PubMed 39867299

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Metformin in people with Osteoarthritis, Knee and Post-traumatic Osteoarthritis, run by Brigham and Women's Hospital at 9 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 15 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Faith Selzer, PhD (617-525-8617, fselzer@bwh.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

KOOS Pain Score (time frame: Average of 12 and 24 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06096259, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2026.

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