Metformin for Osteoarthritis After ACL Surgery

(PIKASO Trial)

Recruiting at 8 trial locations

Overseen By Daniel J Betensky, AB

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Metformin, Topiramate

Disqualifiers: Inflammatory arthritis, Pregnancy, Type I diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 15

Duration: 52 weeks

512 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if metformin, a common diabetes medication with anti-inflammatory properties, can reduce pain and delay the onset of post-traumatic osteoarthritis (PTOA) after ACL surgery. Participants will receive either metformin or a placebo (a pill without active medication) to assess metformin's effectiveness compared to no treatment. Ideal candidates are those planning ACL reconstruction within a year of their injury and experiencing significant knee pain from the injury. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using metformin or topiramate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that metformin is generally safe for people. The FDA has already approved it for treating type II diabetes, indicating its safety is well-understood. Studies suggest it might also help with osteoarthritis, a joint condition, by reducing pain and improving joint health.

In one study, after six months, participants taking metformin reported a significant decrease in knee pain. This finding indicates that the treatment is not only effective but also well-tolerated. These studies have reported no major safety concerns, which is encouraging for those considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for osteoarthritis?

Unlike the standard treatments for osteoarthritis, which often involve pain relievers and anti-inflammatory drugs, metformin is unique because it targets inflammation and potentially slows joint degeneration. Metformin, commonly known for managing diabetes, is being explored for its anti-inflammatory properties, which can be crucial in treating osteoarthritis after ACL surgery. Researchers are excited about metformin because it offers a novel mechanism of action—beyond just pain relief—potentially addressing the underlying causes of osteoarthritis progression. This could lead to more effective long-term outcomes for patients recovering from ACL surgery.

What evidence suggests that metformin might be an effective treatment for post-traumatic osteoarthritis?

This trial will compare the effects of Metformin with a placebo in managing osteoarthritis symptoms after ACL surgery. Research has shown that Metformin may help reduce pain from post-traumatic osteoarthritis (PTOA) following ACL surgery. It can slow cartilage damage, a major cause of osteoarthritis. In one study, patients reported a significant decrease in knee pain on a 100-point scale after six months of taking Metformin. Additionally, those who used Metformin after knee surgery were less likely to need further surgery compared to those taking other diabetes drugs. These findings suggest that Metformin could help manage osteoarthritis symptoms after ACL reconstruction. ^{1 3 4 6 7}

Who Is on the Research Team?

Morgan H Jones, MD, MPH

Principal Investigator

Brigham and Women's Hospital

Cale A Jacobs, PhD

Principal Investigator

Brigham and Women's Hospital

Are You a Good Fit for This Trial?

This trial is for adults aged 25-45, or those 18-24 with significant preoperative knee pain, who have an ACL tear confirmed by MRI and plan to undergo reconstruction. It's not for individuals with inflammatory arthritis, kidney issues, heavy alcohol use, hepatic disease, pregnancy plans within a year, current metformin users or those with certain other knee injuries.

Inclusion Criteria

I am between 25-45 years old, or 18-24 with significant knee pain after an ACL injury.

An MRI scan within the last 6 months has confirmed that you have a tear in your ACL.

I am planning to have ACL reconstruction surgery.

Exclusion Criteria

Applying for or receiving Workers' Compensation for their knee injury

Pregnancy and/or lactation, or plans to become pregnant in the next 12 months

I have inflammatory arthritis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either metformin or placebo for 1 year post-ACL reconstruction

52 weeks

Regular visits for assessments at baseline, 3, 6, 9, 12, 18, and 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including KOOS and MRI scores

12 months

Assessments at 12 and 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Metformin
• Placebo

Trial Overview

The study tests if metformin can reduce pain and delay post-traumatic osteoarthritis after ACL surgery compared to a placebo (a pill without the drug). Metformin is known as a diabetes medication but may help due to its anti-inflammatory properties.

How Is the Trial Designed?

Group I: Metformin Experimental Treatment 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

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

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Arthritis Foundation

Collaborator

Trials

36

Recruited

46,500+

Published Research Related to This Trial

Metformin is a first-line treatment for type 2 diabetes due to its effectiveness in reducing insulin resistance without causing weight gain or hypoglycemia, making it a safe option for patients.

Recent studies have shown that metformin also has cardiovascular benefits and may help in conditions beyond diabetes, such as insulin resistance and potentially tumor suppression, highlighting its broader therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin therapy and clinical uses. Scarpello, JH., Howlett, HC.[2022]

In a study of over 41,000 individuals with type 2 diabetes, metformin treatment was associated with a 24% reduced risk of developing osteoarthritis (OA) compared to those treated with sulfonylureas.

While metformin showed a significant reduction in OA risk, there was no significant difference in the risk of joint replacement between the two treatment groups, suggesting that while metformin may help prevent OA, it does not necessarily affect the need for joint replacement surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Osteoarthritis in Adults With Type 2 Diabetes Treated With Metformin vs a Sulfonylurea. Baker, MC., Sheth, K., Liu, Y., et al.[2023]

Metformin is an effective oral medication for treating non-insulin-dependent diabetes mellitus (type II diabetes) and does not cause hypoglycemia, which is a common side effect of other diabetes medications like sulfonylureas.

The drug is considered safe when proper precautions are taken, including monitoring liver and kidney function, and it has gained widespread use internationally, recently receiving FDA approval under the brand name Glucophage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin: a biguanide. Tanja, JJ., Langlass, TM.[2013]

This study will evaluate the efficacy of metformin in reducing knee pain over 6 months in 102 overweight or obese participants with symptomatic knee osteoarthritis, using a randomized, double-blind, placebo-controlled design.

The primary outcome is the reduction of knee pain measured by a Visual Analogue Scale, with secondary outcomes including overall function and quality of life, ensuring a comprehensive assessment of metformin's effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial. Lim, YZ., Wang, Y., Urquhart, DM., et al.[2023]

In a study of 862 participants with knee osteoarthritis, diabetes, and/or obesity, regular use of metformin was associated with a significantly reduced risk of total knee arthroplasty (TKA), with a prevalence ratio of 0.26, indicating a strong protective effect.

Metformin use also correlated with a reduction in knee pain severity, showing a decrease of 0.48 on the numeric rating scale, suggesting it may help manage symptoms in patients with metabolic-associated osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between Metformin Use and Risk of Total Knee Arthroplasty and Degree of Knee Pain in Knee Osteoarthritis Patients with Diabetes and/or Obesity: A Retrospective Study. Chen, S., Ruan, G., Zeng, M., et al.[2023]

In a study of 196,930 diabetic patients aged 45 and older, regular metformin users (93,330 patients) had a 19% lower risk of needing total knee replacement (TKR) compared to non-users, suggesting a protective effect against knee osteoarthritis progression.

The study found a dose-response relationship, indicating that higher usage of metformin correlates with a greater reduction in TKR incidence, highlighting its potential role in managing knee OA in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study. Lai, FTT., Yip, BHK., Hunter, DJ., et al.[2022]

In a study of 818 obese individuals with knee osteoarthritis, metformin users experienced significantly less medial cartilage volume loss over 4 years compared to non-users, suggesting a protective effect on knee joint health.

Metformin use was also associated with a trend towards a reduced risk of total knee replacement over 6 years, indicating potential long-term benefits for obese patients with knee osteoarthritis, although further randomized controlled trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. Wang, Y., Hussain, SM., Wluka, AE., et al.[2020]

In a 26-week study involving 1,091 participants with type 2 diabetes, liraglutide significantly reduced A1C levels compared to placebo, with reductions of up to 1.0% for higher doses, while also promoting weight loss of 1.8-2.8 kg.

Liraglutide had a similar incidence of minor hypoglycemia (around 3%) compared to placebo, which was much lower than the 17% incidence seen with glimepiride, indicating a safer profile for liraglutide in combination with metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Nauck, M., Frid, A., Hermansen, K., et al.[2023]

In a study of 40,028 Danish patients with type 2 diabetes, DPP-4 inhibitors combined with metformin showed a significantly lower risk of all-cause mortality (RR 0.65) and cardiovascular mortality (RR 0.57) compared to metformin with sulphonylurea, indicating a safer profile for this combination.

GLP-1 agonists also demonstrated a favorable safety profile, although their risk reductions were less pronounced, suggesting that incretin-based therapies may be beneficial for cardiovascular risk management in type 2 diabetes patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus--a retrospective nationwide study. Mogensen, UM., Andersson, C., Fosbøl, EL., et al.[2022]

A systematic review of 15 studies (10 pre-clinical and 5 human) found that metformin may have beneficial effects in treating knee osteoarthritis, showing chondroprotective, immunomodulatory, and pain-reducing properties, primarily through the activation of AMPK (adenosine monophosphate-activated protein kinase).

While pre-clinical studies consistently demonstrated these effects, human studies also supported the findings, although more high-quality clinical trials are needed to confirm metformin's potential as a disease-modifying treatment for osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Lim, YZ., Wang, Y., Estee, M., et al.[2022]

Metformin is a key medication for managing type 2 diabetes, effective both alone and in combination with other diabetes drugs, and it does not cause weight gain or hypoglycemia, making it a safer option for patients.

While mild gastrointestinal side effects are common, they can be managed by starting with a low dose and taking the medication with food; serious complications like lactic acidosis are rare when prescribing guidelines are followed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin: a review. Strack, T.[2019]

Metformin demonstrated protective effects against knee osteoarthritis (OA) in both normal diet and high-fat diet mice, with more significant improvements observed in the high-fat diet group after 10 weeks of treatment, as indicated by reduced OARSI and synovitis scores.

The mechanism of action for metformin includes decreasing apoptosis and matrix-degrading enzyme expression in chondrocytes, as well as reducing the infiltration and pro-inflammatory polarization of synovial macrophages, particularly in obese mice where it also lowers leptin secretion from adipose tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes. Li, D., Ruan, G., Zhang, Y., et al.[2023]

Metformin, a diabetes medication, shows promise in treating osteoarthritis (OA) by reducing inflammation caused by M1 macrophages, which are linked to cartilage degeneration.

In laboratory and mouse studies, metformin not only prevented the secretion of harmful cytokines from M1 macrophages but also mitigated cartilage loss and inflammation, suggesting it could be a beneficial therapy for OA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis. Zheng, M., Zhu, Y., Wei, K., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06096259?cond=Osteoarthritis&intr=metformin&rank=2

Preventing Injured Knees From osteoArthritis : Severity ...

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 ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11305807/

Metformin: pioneering a path forward in knee osteoarthritis ...

The results showed that metformin effectively mitigated cartilage degeneration by modulating the AMPK/mTOR signalling pathway. These findings ...

3.

oarsijournal.com

oarsijournal.com/article/S1063-4584(23)00254-6/fulltext

Comparative Effectiveness Of Metformin In Preventing ...

Metformin users undergoing ACL or meniscal surgery had lower odds of experiencing all OA and TKR outcomes than users of sulfonylureas.

4.

rheumnow.com

rheumnow.com/news/metformin-effective-osteoarthritis

Metformin Effective in Osteoarthritis

After 6 months of treatment, those on metformin scored their knee pain a mean 31.3 points lower than at baseline on a 100-point scale, compared ...

5.

trials.arthritis.org

trials.arthritis.org/trials/NCT06096259

Preventing Injured Knees From osteoArthritis: Severity ...

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 ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12022862/

Metformin for Knee Osteoarthritis in Patients With Overweight ...

Animal studies consistently showed a benefit of metformin for pain and joint structural outcomes in OA, with supporting data from human studies.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12449045/

Sodium–glucose co-transporter-2 inhibitors vs metformin in ...

Prior studies exhibited the association between metformin use and a lower risk of total joint arthroplasty., Additionally, a recent study showed ...