Biologic Therapy to Prevent Osteoarthritis After ACL Injury

• ClinicalTrials.gov Identifier: NCT03968913
• Recruitment Status: Recruiting
• First Posted: May 30, 2019
• Last Update Posted: May 6, 2021
• Sponsor: University of California, Los Angeles
• Collaborator: Orthopedic Research and Education Foundation
• Information provided by (Responsible Party): Thomas Kremen, MD, University of California, Los Angeles

Study Description

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 injection of IL-1 inhibitor (IL-1Ra) into the knee joint of patients suffering recent ACL injury will decrease the incidence of cartilage damage.

After appropriate IRB approval, a total of 48 active patients will be randomized into one of three treatment groups. Group 1 will receive removal of the knee joint fluid (aspiration of hemarthrosis) using a needle and syringe within 1 week 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 10 days post-injury. 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 7 days of ACL injury. In addition, a second knee aspiration and injection of 5mls of sterile saline into the injured knee joint will be performed at 10 days post-injury. Group 3 patients will receive aspiration of the knee hemarthrosis and injection of anakinra as described in group 2 as well as a second intra-articular knee injection of anakinra (150mg, ~5mls) on post-injury day 10. 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 3 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 earlier time points are optional.

Condition or disease	Intervention/treatment	Phase
Anterior Cruciate Ligament Injuries	Drug: Anakinra injection; Procedure: sterile saline injection	Early Phase 1

Detailed Description:

After appropriate IRB approval at total of 48 active patients who meet the inclusion criteria listed above will be randomized into three treatment groups: Group 1 (n = 16) will undergo ultrasound guided arthrocentesis of the knee hemarthrosis at the time of presentation in clinic. Following aspiration of the knee joint hemarthrosis, an injection of 5 milliliters (mls) of 0.9% sodium chloride solution (sterile saline) will be administered as a placebo control. In addition, a second aspiration of knee joint fluid and injection of sterile saline into the injured knee joint will be performed at 10 days post-injury. Group 2 (n = 16) will undergo arthrocentesis as described in group 1 as well as intra-articular administration of 150mg (~5mls) of anakinra (rhIL-1Ra) within 7 days of ACL injury. In addition, repeat knee joint fluid aspiration and a second injection of 5mls of sterile saline into the injured knee joint will be performed at 10 days post-injury. Group 3 patients will receive arthrocentesis and injection of anakinra as described in group 2 as well as a second knee joint aspiration and intra-articular knee injection of anakinra (150mg, ~5mls) on post-injury day 10. Thus, all patients will undergo two ultrasound guided knee aspiration and injection procedures prior to surgery. The first injection will be after the arthrocentesis procedure to remove the hemarthrosis associated with acute ACL injury. To minimize pain and discomfort the same needle stick will be used to aspirate the hemarthrosis and to inject the saline or anakinra depending on the patient's treatment group. The second knee arthrocentesis and injection in each patient will also be performed under ultrasound-guidance at 10 days after injury. Some patient's injuries may fall on a day where performing these aspiration and injection procedures exactly 10 days after injury is not possible due to constraints of the work week (i.e. Monday through Friday). In this case the procedures will be performed on the next consecutive work day closest to the 10 days post-injury time point. An additional arthrocentesis procedure will be performed at the time of surgery.

Study patients in all 3 groups will undergo pre-operative collection of urine and knee joint fluid as described above. These time points include: i) at the time of enrollment into the study (within 7 days of injury), ii) at 10 days after injury, iii) on the day of surgery (within 30 days of injury). In addition, urine and knee joint fluid collection will be performed at the initial post-operative visit (approximately 10 days after surgery) followed by collection of urine alone at 3, 6, 9, 12 and 24 months post-operatively in all treatment groups. Urine and arthrocentesis samples will be analyzed for the presence of inflammatory cytokines and cartilage breakdown biomarkers according to Osteoarthritis Research Society International guidelines (see cytokine and biomarker assays section below for further details). Given, that multiple studies have demonstrated resolution of cytokine abnormalities by 2 to 4 weeks after ACL injury, urine assessments of cytokine assays (IL-1, etc.) will not be conducted beyond 3 months post-operatively. However, ELISAs for cartilage biomarkers will be performed on urine collected at each time point throughout the duration of the study. Validated patient reported outcome assessments (KOOS, VAS and PROMIS) will be completed at initial presentation as well as at 6, 9, 12 and 24 month post-operatively.

Patients in all 3 groups will be also be followed longitudinally with repeat MR imaging that includes cartilage sensitive sequences (T1rho). These will be obtained at 12 and 24 months post-operatively. Additional MRI studies at earlier time points are optional for study participants. The MRI studies performed in this investigation will be non-arthrogram studies without intra-articular or intravenous contrast. The injured and contralateral uninjured knee will be imaged with MRI at 12 and 24 months after surgery.

This study will be a single-blinded design and all aspects of the study design will be disclosed to subjects during the informed consent process. Given that anakinra needs to be ordered by the physician from the pharmacy on the day of injection, the physician performing the injection will not be blinded to which patients receive anakinra treatments. However, the patients will be blinded regarding which treatment they receive. All patients will receive injections of the same volume, same color and using the same type of needle and syringe. The synovial fluid and urine biomarker data will be analyzed in a coded fashion in conjunction with a statistician to avoid bias in the statistical analysis. In addition, the radiologist interpreting the MRI studies will be blinded to which treatment the patients receive. The physician administering the injections into the joint will not be involved in interpreting the MRI findings and will not be present when subjects complete the patient-reported outcome measures.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, placebo controlled study with 3 treatment groups: 1) placebo only, 2) one dose of study medication, 3) two doses of study medication
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: single blinded
• Primary Purpose: Treatment
• Official Title: Biologic Therapy to Prevent Osteoarthritis After ACL Injury
• Estimated Study Start Date: May 10, 2021
• Estimated Primary Completion Date: May 30, 2023
• Estimated Study Completion Date: May 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Control; Subjects will receive two injections of sterile saline after ACL injury, prior to surgery	Procedure: sterile saline injection; 5 milliliters of sterile saline will be injected into the knee joint
Active Comparator: One dose Anakinra, one dose placebo; Subjects will receive one injection of sterile saline and one injection of anakinra after ACL injury, prior to surgery	Drug: Anakinra injection; anakinra 150mg in 5milliliters of sterile saline will be injected into the knee joint; Other Name: Kineret
Active Comparator: Two doses Anakinra; Subjects will receive two injections of anakinra after ACL injury, prior to surgery	Drug: Anakinra injection; anakinra 150mg in 5milliliters of sterile saline will be injected into the knee joint; Other Name: Kineret

Outcome Measures

Primary Outcome Measures :

1. Cytokine level analysis of synovial fluid [ Time Frame: Synovial fluid will be collected within 7 days of injury and at approximately 10 days after ACL injury, at the time of surgery and approximately 10 days after surgery. ]
   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).

Secondary Outcome Measures :

1. Patient-reported knee pain and function [ Time Frame: Surveys will be obtained prior to surgery and then at 3, 6, 9, 12 and 24 months following surgery ]
   Patients will complete questionnaires reading change in their knee pain and function over time
2. Cartilage biomarker analysis of synovial fluid [ Time Frame: Synovial fluid will be collected within 7 days of injury and at approximately 10 days after ACL injury, at the time of surgery and approximately 10 days after surgery. ]
   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.
3. Cartilage biomarker analysis of urine [ Time Frame: Urine samples will be collected within 1 week of injury and at the time of surgery. Then urine will be collected at 3, 6, 9, 12 and 24 months after injury. ]
   Change in urine cartilage biomarker levels will be assessed. 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.

Other Outcome Measures:

1. MRI [ Time Frame: MRI images will be obtained at 12 and 24 months following surgery, optional MRIs will also be obtained pre-operatively as well as at 3, 6 and 9 months following surgery ]
   Change in cartilage single intensity on magnetic resonance imaging

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• 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 7 days of presentation
• must elect to undergo bone-patellar tendon-bone (BTB) autograft ACL reconstruction within 30 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

Exclusion Criteria:

• injury occurring more than 7 days prior to enrollment
• previous ipsilateral knee injury, multi-ligamentous knee injury
• significant (>1cm full-thickness) meniscus tear
• pre-existing or concurrent grade 3 or 4 chondral (cartilage) injuries
• previous ipsilateral knee surgery
• previous contralateral meniscal or ligamentous knee injury
• 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
• malignancy
• inflammatory/rheumatologic disease
• immune-compromised state
• concomitant significant meniscus pathology
• renal failure

Contacts and Locations

Contacts

Contact: Adreanne Rivera; 310.794.0213; adreannerivera@mednet.ucla.edu

Locations

United States, California

University of California, Los Angeles; Recruiting

Los Angeles, California, United States, 90095

Contact: Thomas J. Kremen, M.D. 424-259-9856 tjkremen@mednet.ucla.edu

Contact: Adreanne Rivera 310-794-0213 adreannerivera@mednet.ucla.edu

Sponsors and Collaborators

University of California, Los Angeles

Orthopedic Research and Education Foundation

More Information

Publications:

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.

• Responsible Party: Thomas Kremen, MD, Principal Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT03968913
• Other Study ID Numbers: 19-000724
• First Posted: May 30, 2019
• Last Update Posted: May 6, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Thomas Kremen, MD, University of California, Los Angeles:

Osteoarthritis; ACL; Anakinra

Additional relevant MeSH terms:

Osteoarthritis; Wounds and Injuries; Anterior Cruciate Ligament Injuries; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Knee Injuries; Leg Injuries; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents