Biologic Therapy for Osteoarthritis Prevention After ACL Injury

Overseen By Adreanne Rivera

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of California, Los Angeles

Must not be taking: Cortisone, Anticoagulants, others

Disqualifiers: Multi-ligament injury, Infection, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 3-5 days

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Anterior cruciate ligament (ACL) injuries are extremely common. On average, 50% of individuals suffering an ACL injury will develop radiographic osteoarthritis (OA) 10 to 20 years after injury. Unfortunately, ACL reconstruction does not prevent risk of future OA. Interleukin-1 (IL-1) levels in the human knee joint increase transiently after an ACL injury. In animal experiments, if interleukin-1 levels are increased in the joint, this alone causes arthritis to occur. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1. However, in ACL injuries the balance of these two proteins is disturbed transiently after injury, with the effects of IL-1 dominating this balance. In a large animal model of ACL injury, injection of IL-1Ra into the knee joint after ACL injury significantly decreased the amount of arthritis that was later observed. Thus, the investigators hypothesize that early injection of IL-1 inhibitor (IL-1Ra) into the knee joint of patients suffering recent ACL injury will decrease the incidence of cartilage damage later in life. After appropriate IRB approval, a total of 32 active patients will be randomized into one of two treatment groups. Group 1 will receive removal of the knee joint fluid (aspiration of hemarthrosis) using a needle and syringe within 1 to 2 weeks of injury. Following aspiration of the knee joint, an injection of 5 milliliters (mls) of sterile saline (as a placebo control) will be administered. In addition, a second knee aspiration procedure and an injection of 5mls of sterile saline into the injured knee joint will be performed at 3 to 5 days after the initial injection. Group 2 will receive aspiration of the knee hemarthrosis as described in group 1 as well as intra-articular administration of 150mg (\~5mls) of anakinra (rhIL-1Ra) within 1 to 2 weeks of ACL injury. In addition, a second knee aspiration and intra-articular administration of 150mg (\~5mls) of anakinra (rhIL-1Ra) will be performed at 3 to 5 days after the initial injection. Thus, all patients in this randomized placebo-controlled trial will undergo two injection procedures prior to surgery. Investigators will analyze subjects self-reported function and pain scores as well as urinary levels of cartilage breakdown products over time. Additionally, MRI studies will be used to compare MRI findings among patients in these 2 treatment groups. Urine samples will be obtain prior to surgery, at the time of surgery and at multiple time points after surgery (3, 6, 9, 12 and 24 months after surgery). Subjective outcome measure assessments (surveys) will be completed by participants prior to surgery and then again at 6, 9, 12 and 24 months post-operatively. MRI studies will be obtained at 1 year and 2 years following surgery. Additional, MRI studies at time points are optional and highly encouraged. These additional MRIs are at no cost to the patient.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on anti-coagulation therapy or have had a cortisone injection in the knee within 3 months, you may not be eligible to participate.

Is anakinra (Kineret) generally safe for humans?

Anakinra (Kineret) is generally considered safe and well-tolerated in humans, with the main side effect being skin reactions at the injection site. These reactions are common but usually manageable, and the safety profile is consistent across various studies, including those involving patients with rheumatoid arthritis. ^{1 2 3 4 5}

How is the drug Anakinra unique in treating osteoarthritis after ACL injury?

Anakinra is unique because it targets interleukin-1 (IL-1), a protein involved in inflammation, by blocking its receptor, which can help reduce inflammation and swelling in the knee after ACL injury. This approach is different from other treatments like physical therapy or corticosteroids, which do not specifically target IL-1. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Anakinra (Kineret) for preventing osteoarthritis after ACL injury?

The study titled 'Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury' suggests that using IL-1 receptor antagonist (similar to Anakinra) may be effective for ACL injuries, which could help in preventing osteoarthritis. ^{6 8 10 11 12}

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-35 with a recent ACL injury who plan to have ACL reconstruction surgery within 45 days. They must not have severe knee injuries besides the ACL, no history of certain diseases or conditions, and no prior treatments that could interfere with the study.

Inclusion Criteria

My knee injury is minor.

I am between 18 and 35 years old and engage in sports that involve sudden direction changes.

I understand the trial seeks an equal number of men and women.

Exclusion Criteria

I have multiple torn ligaments in my knee.

My injury happened over 2 weeks ago.

You have had a bad reaction or allergy to anakinra in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive two knee aspiration and injection procedures prior to surgery, with either saline or anakinra

3-5 days

2 visits (in-person)

Surgery

Participants undergo surgery for ACL injury, with additional arthrocentesis procedure performed

Within 45 days of injury

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including urine and synovial fluid analysis, MRI, and patient-reported outcomes

24 months

Multiple visits (in-person and virtual) at 3, 6, 9, 12, and 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Anakinra

Trial Overview The trial tests if injecting Anakinra (a biologic therapy) into the knee after an ACL injury can prevent osteoarthritis. Participants are randomly placed in two groups: one gets Anakinra injections, while the other receives placebo saline injections before their surgery.

How Is the Trial Designed?

Group I: Two doses Anakinra Active Control 1 Intervention

Subjects will receive two injections of anakinra after ACL injury, prior to surgery

Group II: Control Placebo Group 1 Intervention

Subjects will receive two injections of sterile saline after ACL injury, prior to surgery

Anakinra is already approved in European Union, United States for the following indications:

Approved in European Union as Kineret for:

• Rheumatoid arthritis
• Cryopyrin-associated periodic syndromes
• Deficiency of interleukin-1 receptor antagonist
• COVID-19

Approved in United States as Kineret for:

• Rheumatoid arthritis
• Deficiency of interleukin-1 receptor antagonist
• Neonatal-onset multisystem inflammatory disease (NOMID)
• COVID-19

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Orthopedic Research and Education Foundation

Collaborator

Trials

23

Recruited

6,200+

Published Research Related to This Trial

A systematic review of 23 studies on biologic agents for ACL healing found that while platelet-rich plasma (PRP) is commonly used, its benefits are mainly limited to improved graft maturation rather than significant clinical outcomes or integration.

There is a lack of clinical trials on the use of stem cells for ACL healing, indicating a need for more research to understand their potential role in treating both partial and complete ACL tears.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic agents for anterior cruciate ligament healing: A systematic review. Di Matteo, B., Loibl, M., Andriolo, L., et al.[2020]

Anakinra (Kineret) is an effective treatment for rheumatoid arthritis that works by blocking the inflammatory effects of interleukin-1, but it requires daily self-injections due to its short half-life.

While Kineret is generally safe and well tolerated, it can cause injection-site reactions, which are common and may require management strategies to improve patient comfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations. Kaiser, C., Knight, A., Nordström, D., et al.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). [2016]

2. Germany pubmed.ncbi.nlm.nih.gov

The Use of Biologic Agents in Athletes with Knee Injuries. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Biologic agents for anterior cruciate ligament healing: A systematic review. [2020]

4. Italy pubmed.ncbi.nlm.nih.gov

Role of interleukin-10 in the synovial fluid of the anterior cruciate ligament injured knee. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Association of anterior cruciate ligament injury with knee osteoarthritis and total knee replacement: A retrospective cohort study from the Taiwan National Health Insurance Database. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Clinical benefits of intra-articular anakinra for arthrofibrosis. [2010]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Kineret: efficacy and safety in daily clinical practice: an interim analysis of the Kineret response assessment initiative (kreative) protocol. [2013]

11. Germany pubmed.ncbi.nlm.nih.gov

Clinical benefits of intra-articular anakinra for persistent knee effusion. [2019]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Interleukin-1 receptor antagonist inhibits arthrofibrosis in a post-traumatic knee immobilization model. [2021]