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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

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.


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

  Show Detailed Description

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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 : September 1, 2019
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : August 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis
Drug Information available for: Anakinra

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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).

  5. 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.



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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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03968913


Locations
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United States, California
University of California, Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Thomas Kremen, M.D.    310-825-7077    tjkremen@mednet.ucla.edu   
Contact: Gloria Gutierrez    3102675585    gskiel@mednet.ucla.edu   
Sponsors and Collaborators
University of California, Los Angeles
Orthopedic Research and Education Foundation

Publications:
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Responsible Party: Thomas Kremen, MD, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03968913     History of Changes
Other Study ID Numbers: 19-000724
First Posted: May 30, 2019    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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