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Biologic Therapy to Prevent Osteoarthritis After ACL Injury

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ClinicalTrials.gov Identifier: NCT03968913
Recruitment Status : Not yet recruiting
First Posted : May 30, 2019
Last Update Posted : May 30, 2019
Sponsor:
Collaborator:
Orthopedic Research and Education Foundation
Information provided by (Responsible Party):
Thomas Kremen, MD, University of California, Los Angeles

Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE May 30, 2019
Last Update Posted Date May 30, 2019
Estimated Study Start Date  ICMJE September 1, 2019
Estimated Primary Completion Date August 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Biologic Therapy to Prevent Osteoarthritis After ACL Injury
Official Title  ICMJE 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.

Rather than waiting years to observe the sequelae, T1rho MRI technology will be used to compare MRI findings among patients in these 3 treatment groups as well as an uninjured control group. In addition, the investigators will analyze subjects self-reported function and pain scores as well as urinary levels of cartilage breakdown products over time. These MRI, urine and subjective outcome assessments will be obtained prior to surgery and then again at 3, 6, 9, 12 and 24 months post-operatively.

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.

Patients in all 3 groups will be followed longitudinally with repeat MR imaging that includes T1rho sequences being obtained at 3, 6, 12 and 24 months post-operatively (Aim 1). The MRI studies performed in this investigation will be non-arthrogram studies without intra-articular or intravenous contrast.

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 (Aim 2) 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 (Aim 3).

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 and using the same type of needle and syringe. 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. In addition, 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE 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  ICMJE Anterior Cruciate Ligament Injuries
Intervention  ICMJE
  • 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  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 28, 2019)
48
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2022
Estimated Primary Completion Date August 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • malignancy
  • inflammatory/rheumatologic disease
  • immune-compromised state
  • concomitant significant meniscus pathology
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03968913
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Thomas Kremen, MD, University of California, Los Angeles
Study Sponsor  ICMJE University of California, Los Angeles
Collaborators  ICMJE Orthopedic Research and Education Foundation
Investigators  ICMJE Not Provided
PRS Account University of California, Los Angeles
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP