Preventing Injured Knees From osteoArthritis: Severity Outcomes

Osteoarthritis, Knee Clinical Trial

— PIKASO  

Official title:

Preventing Injured Knees From osteoArthritis: Severity Outcomes (PIKASO)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06096259
• Other study ID #: 2023P002573
• Status: Recruiting
• Phase: Phase 2
• Start date: May 6, 2024
• Est. completion date: December 2029

Study information

• Verified date: May 2024
• Source: Brigham and Women's Hospital
• Contact: Faith Selzer, PhD
• Phone: 617-525-8617
• Email: fselzer[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 512
• Est. completion date: December 2029
• Est. primary completion date: December 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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. ACL tear documented on MRI within 6 months prior to screening

3. Plan to undergo ACL reconstruction

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. Type I diabetes mellitus or diabetic ketoacidosis

6. Heavy alcohol consumption and/or known hepatic disease

7. Acute or chronic renal insufficiency

8. History of ACLR on either knee

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. 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

19. Plan for allograft at time of consent

Related Conditions & MeSH terms

• ACL Tear
• Osteoarthritis
• Osteoarthritis, Knee
• Post-traumatic Osteoarthritis

Intervention

Drug:
• 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. Participants will begin by taking 1x500 mg pill once a day, and then the dose will be increased in 500 mg/day increments weekly as tolerated, up to a maximum dose of 1500 mg daily.
• 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 weekly as tolerated, up to a maximum dose of 1500 mg daily.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Kentucky	Lexington	Kentucky
United States	Hospital for Special Surgery	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Arthritis Foundation

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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: bone marrow lesions and cysts (score: 0-3, 3 worst); articular cartilage loss (score: 0-3, 3 worst); osteophytes (score: 0-3, 3 worst); synovitis and effusion (score: 0-3, 3 worst); meniscus extrusion and morphology (score: 0-3, 3 worst); ligaments/tendon (0/1, 0=normal, 1=abnormal); periarticular features (0/1, 0=absent, 1=present)	24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 12 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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).	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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: Avoiding physical exertion because of fear of reinjury or worsening of pain (Questions 1, 2, 7, 9, 10, 11, 12); 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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Secondary	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.	baseline, 12 months, 24 months
Secondary	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.	baseline, 12 months, 24 months
Secondary	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.	baseline, 12 months
Secondary	Knee Range of Motion	Assessed via physical examination with a goniometer	12 and 24 months
Secondary	3D Gait Biomechanics	Walking gait will be evaluated using a motion capture system as participants walk at a self-selected speed	12 and 24 months
Secondary	Isokinetic knee flexion/extension strength at 60º/sec	Assessed using an isokinetic dynamometer	12 and 24 months
Secondary	10m Habitual Walking Speed	The time to walk 10 m will be recorded	12 and 24 months
Secondary	Single Leg Hop Test	The maximum distance will be recorded	12 and 24 months