Biologic Therapy to Prevent Osteoarthritis After ACL Injury

• ClinicalTrials.gov Identifier: NCT03968913
• Recruitment Status: Not yet recruiting
• First Posted: May 30, 2019
• Last Update Posted: December 10, 2020
• 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

Tracking Information

• First Submitted Date: May 24, 2019
• First Posted Date: May 30, 2019
• Last Update Posted Date: December 10, 2020
• Estimated Study Start Date: January 2, 2021
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

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).

Original Primary Outcome Measures (submitted: May 28, 2019)

MRI [ Time Frame: MRI images will be obtained at 3, 6, 9, 12 and 24 months following surgery ]

Change in cartilage signal intensity on magnetic resonance imaging

Current Secondary Outcome Measures (submitted: December 7, 2020)

• 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
• 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.
• 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.

Original Secondary Outcome Measures (submitted: May 28, 2019)

• Patient-reported knee 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 function over time
• Patient-reported knee pain [ 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 over time
• 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.
• 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).
• 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.

Current Other Pre-specified Outcome Measures (submitted: December 7, 2020)

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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Biologic Therapy to Prevent Osteoarthritis After ACL Injury
• Official Title: Biologic Therapy to Prevent Osteoarthritis After ACL Injury

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 as well as an uninjured control group. These urine, subjective outcome measure assessments will be obtained prior to surgery and then again at 3, 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.

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, 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 3, 6, 12 and 24 month post-operatively.

Patients in all 3 groups will be also be followed longitudinally with repeat MR imaging that includes cartilage-sensative 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.

In addition, investigators will compare the imaging findings of ACL injured patients at the time points outlined above to a cohort of healthy volunteers with uninjured knees (patients whom have had no history of knee injury, knee surgery or knee injection procedure). This will result in a control group (Group 4) that will only undergo MR imaging using cartilage-sensative sequences (T1rho) at one point in time, however, this group will not receive any intervention (i.e. no injection of saline, no injection of anakinra, no urine sample collection and no arthrocentesis sample collection). The imaging findings from this control group will be used to compare to those obtained from patients enrolled in the study. This cohort will be identified based on age, sex, BMI and activity level (Tegner score) after the 48 study patients (groups 1, 2 and 3) are enrolled into the study as previously described in the research study plan. This will facilitate the cohorts being matched by age, sex, BMI and activity level allowing for an appropriate comparison group even if cartilage-sensative MRI (T1rho) images are not obtained among study patients at the early time points.

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 Type: Interventional
• Study Phase: Early Phase 1

Study Design

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

• Condition: Anterior Cruciate Ligament Injuries

Intervention

• Drug: Anakinra injection
  anakinra 150mg in 5milliliters of sterile saline will be injected into the knee joint
  Other Name: Kineret
• Procedure: sterile saline injection
  5 milliliters of sterile saline will be injected into the knee joint

Study Arms

• Placebo Comparator: Control
  Subjects will receive two injections of sterile saline after ACL injury, prior to surgery
  Intervention: Procedure: sterile saline injection
• 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
  Intervention: Drug: Anakinra injection
• Active Comparator: Two doses Anakinra
  Subjects will receive two injections of anakinra after ACL injury, prior to surgery
  Intervention: Drug: Anakinra injection

• 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.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: May 28, 2019): 48
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2023
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Eligibility 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
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 35 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03968913
• Other Study ID Numbers: 19-000724
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Thomas Kremen, MD, University of California, Los Angeles
• Study Sponsor: University of California, Los Angeles
• Collaborators: Orthopedic Research and Education Foundation
• Investigators: Not Provided
• PRS Account: University of California, Los Angeles
• Verification Date: December 2020