Biologic Therapy to Prevent Osteoarthritis After ACL Injury

NCT03968913 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: 19-000724
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Anterior Cruciate Ligament Injuries

Keywords

Osteoarthritis; ACL; Anakinra

Outcome Measures

Primary Outcomes (2)

• Cytokine level analysis of synovial fluid

  Synovial fluid samples will be analyzed for a change in the level of interleukin-1 and interleukin-1 receptor antagonist levels using enzyme-linked immunosorbent assays (ELISA).

  Synovial fluid will be collected within 2 weeks of injury and at approximately 3 to 5 days after the initial injection, at the time of surgery and approximately 10 days after surgery.

• Cartilage biomarker analysis of synovial fluid

  Synovial fluid samples will be analyzed for a change in the level of cartilage breakdown metabolites using enzyme-linked immunosorbent assays (ELISA). Specifically we will test for cartilage tissue breakdown products according to Osteoarthritis Research Society International guidelines including testing for type II Collagen Helical Peptide, C-telopeptide of type II collagen breakdown, sulfated glycosaminoglycan, cartilage oligomeric matrix protein, matrix metalloproteinases 1, 3 and 9 (MMP-1, MMP-3, and MMP-9), and tumor necrosis factor-inducible gene 6.

  Synovial fluid will be collected within 2 weeks of injury and at approximately 10 days after ACL injury, at the time of surgery and approximately 10 days after surgery.

Secondary Outcomes (2)

• Patient-reported knee pain and function

  Surveys will be obtained prior to surgery and then at 3, 6, 9, 12 and 24 months following surgery

• Cartilage biomarker analysis of urine

  Urine samples will be collected within 2 weeks of injury and at the time of surgery. Then urine will be collected at 3, 6, 9, 12 and 24 months after injury.

Other Outcomes (1)

• MRI

  MRI images will be obtained at 12 and 24 months following surgery, optional MRIs will also be obtained pre-operatively.

Study Arms (2)

Control

PLACEBO COMPARATOR

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

Procedure: sterile saline injection

Two doses Anakinra

ACTIVE COMPARATOR

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

Drug: Anakinra injection

Interventions

Anakinra injection DRUG

anakinra 150mg in 5milliliters of sterile saline will be injected into the knee joint

Also known as: Kineret

Two doses Anakinra

sterile saline injection PROCEDURE

5 milliliters of sterile saline will be injected into the knee joint

Control

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• patients age 18 to 35 years with closed growth plates as visualized on plain radiographs who participate in cutting and pivoting activities.
• we will enroll an equal number of men and women in each treatment group (16 total per group; 8 men, 8 women).
• study participants must have an MRI-confirmed ACL injury within 2 weeks of presentation
• must elect to undergo bone-patellar tendon-bone (BTB) autograft ACL reconstruction within 45 days of injury
• no clinical or MRI evidence of posterior cruciate ligament injury
• no more than grade 1 medial collateral ligament injury
• no concurrent posterolateral corner injury to the ipsilateral knee

You may not qualify if:

• injury occurring more than 2 weeks prior to enrollment
• previous ipsilateral knee injury
• multi-ligamentous knee injury
• pre-existing or concurrent grade 3 or 4 chondral (cartilage) injuries
• previous ipsilateral knee surgery (meniscus tear, ACL tear, chondral injury, etc.)
• active infection
• known allergy or adverse reaction to anakinra
• intra-articular cortisone injection into either knee within 3 months of injury
• prior exposure to IL-1Ra
• participation in another clinical drug trial within the 4 weeks before injury
• history of any coagulopathy or current anti-coagulation therapy
• current malignancy
• current inflammatory/rheumatologic disease
• current immune-compromised state
• current renal failure

Sponsors & Collaborators

• Orthopedic Research and Education Foundation: collaborator
• University of California, Los Angeles: lead

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

RECRUITING

Related Publications (1)

• Kraus VB, Birmingham J, Stabler TV, Feng S, Taylor DC, Moorman CT 3rd, Garrett WE, Toth AP. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage. 2012 Apr;20(4):271-8. doi: 10.1016/j.joca.2011.12.009. Epub 2012 Jan 10.

  PMID: 22273632 BACKGROUND

MeSH Terms

Conditions

Anterior Cruciate Ligament Injuries; Osteoarthritis

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Central Study Contacts

Adreanne Rivera

CONTACT

310.794.0213; adreannerivera@mednet.ucla.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: single blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, placebo controlled study with 2 treatment groups: 1) to doses of placebo only and 2) two doses of study medication

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: May 30, 2019
• Study Start: September 15, 2021
• Primary Completion (Estimated): January 30, 2027
• Study Completion (Estimated): January 30, 2027
• Last Updated: January 26, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)