Success of Long-acting Anti-inflammatories After Anterior Cruciate Ligament and Meniscal Injury (SLAM)

The purpose of this study is to determine if extended-release triamcinolone acetonide treatment alters the progressive changes in bone shape previously demonstrated after anterior cruciate ligament (ACL) reconstruction with partial meniscectomy or meniscal repair.

Study Overview

• Status: Terminated
• Conditions: Anterior Cruciate Ligament Tear; Tibial Meniscus Injuries; Tibial Meniscus Tears; Tibial Meniscus, Torn
• Intervention / Treatment: Drug: Zilretta; Other: Placebo

Detailed Description

Anterior cruciate ligament (ACL) injury initiates a biochemical cascade that leads to cartilage degradation and the development of posttraumatic osteoarthritis (PTOA). ACL and acute traumatic meniscus tears have been linked to the development and progression of PTOA. As such, there is an unmet need to identify treatments that may alter the progression of PTOA following ACL meniscus injury. The overarching hypothesis of this project is that intraarticular administration of long-acting anti-inflammatory agents will alter the progression of PTOA following ACL reconstruction.

The current standard of care for patients with combined ACL and meniscus injuries consists of surgical treatment often with a short course of postoperative physical therapy. However, the current mechanically-based standard of care does not address the persistent inflammatory process that promotes cartilage degradation and PTOA progression. The pro-inflammatory stimulation of meniscus cells increases matrix metalloproteinase (MMP) and cytokine activity, and the combination of pro-inflammatory cytokines and compressive loading like what may be seen during sporting and high demand activities further results in degradative enzyme activity and increased production of pro-inflammatory mediators. In this way, the meniscus plays an active role in promoting the cycle of articular cartilage degradation and PTOA progression after ACL reconstruction.

Reducing MMP and cytokine activity after ACL and meniscus injury may alter the progression of PTOA for this at-risk patient population. After ACL injury and reconstruction demonstrate triamcinolone acetonide effectively reduces cartilage degradation, the inflammatory cascade and corresponding cartilage degradation are reinitiated after surgery, hyaluronate treatment 1 week after surgery unsuccessfully mitigates the inflammatory and catabolic processes, and pain and persistent postsurgical cytokine activity at 4 weeks were predictive of inferior knee biomechanics 6 months after surgery. In addition, long-acting agents may provide a greater treatment effect as temporal regulation of cytokine activity may more successfully alter the pro-inflammatory environment than shorter-duration treatments. These results identify that long-acting anti-inflammatory treatment is needed to alter the path of PTOA following meniscus injury and administration 8 weeks after surgery may offer the optimal timing of treatment.

The model whereby femoral shape change and cytokine activity are mediated by a long-acting anti-inflammatory agent (extended-release triamcinolone acetonide) will be tested. Femoral shape changes have been demonstrated after ACL injury and reconstruction, with shape changes in the first 6 months after surgery correlating with subsequent MRI evidence of cartilage degradation and inferior patient-reported outcomes 3 years postoperatively. A Phase 2a, double-blind, placebo-controlled, randomized controlled trial will be performed. The trial will determine if a long-acting anti-inflammatory agent (extended-release triamcinolone acetonide) improves patient-reported outcomes and/or lessens progressive bone shape changes or cartilage breakdown when compared to placebo (saline). Saline was chosen as the placebo as saline has few potential risks and rare adverse events and is the most commonly used placebo treatment option used in knee osteoarthritis research.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • UK Healthcare at Turfland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written consent to participate in the study
2. Male or female greater than or equal to 18 years of age and less than 40 years of age
3. Has been consented to undergo arthroscopic ACL reconstruction with partial meniscectomy or meniscal repair
4. Ambulatory and in good general health
5. Willing and able to comply with the study procedures and visit schedules and able to follow verbal and written instructions.
6. Willing to abstain from use of protocol-restricted medications during the study
7. Females and males who have reproductive potential: Must use highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation (10 weeks; 4 to 14 weeks after surgery)
8. Demonstrate persistent inflammation defined as synovial fluid IL-1a concentration greater than or equal to 5 pg/mL at the time of surgery

Exclusion Criteria:

1. Known allergic reactions to components of the extended-release triamcinolone acetonide (Zilretta®)
2. Reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease
3. History of infection in either knee joint
4. Clinical signs and symptoms of active knee infection or crystal disease in either knee within 1 month of Screening
5. Other surgery or arthroscopy of either knee within 6 months of Screening
6. Intraarticular treatment of any joint with any of the following agents within six (6) months of Screening: any corticosteroid preparation or any biologic agent (e.g., platelet rich plasma (PRP) injection, stem cells, prolotherapy, amniotic fluid injection; investigational or marketed).
7. Intraarticular treatment in either knee with hyaluronic acid (investigational or marketed) within 6 months of Screening
8. Parenteral or oral corticosteroids (investigational or marketed) within 3 months of Screening
9. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of Screening
10. Females who are pregnant or nursing or plan to become pregnant during the study; men whose female partner plans to conceive during the study
11. Radiographic osteoarthritic changes defined as Kellgren-Lawrence grade 2 or greater (as determined by PI from patient's preoperative X-rays)
12. Inability to read and understand English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; The experimental group will receive a single 32 mg Zilretta injection approximately 8 weeks after meniscus surgery.	Drug: Zilretta; ZILRETTA is an injectable suspension that delivers 32 mg of triamcinolone acetonide. It is supplied as a single-dose kit containing one vial of ZILRETTA microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter.; Other Names: Extended release triamcinolone acetonide
Placebo Comparator: Placebo; The placebo group will receive a single 5 mL injection of normal saline approximately 8 weeks after meniscus surgery.	Other: Placebo; 5 mL normal saline; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bone Shape (Baseline to 4 Months)	Using manual segmentation, the volume of the medial femoral condyle will be quantified from 3-Tesla magnetic resonance imaging (MRI) scans performed before and 4 months after the study injection. Medial condyle volume will be expressed as cm3.	Baseline, 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IKDC (Baseline to 4 Months)	The International Knee Documentation Committee (IKDC) scores range from 0-100 with greater scores being indicative of greater self-reported function and reduced pain.	Baseline, 4 months, 1 year, 2 years
Change in IKDC (Baseline to 1 Year)	The International Knee Documentation Committee (IKDC) scores range from 0-100 with greater scores being indicative of greater self-reported function and reduced pain.	Baseline, 4 months, 1 year, 2 years
Change in IKDC (Baseline to 2 Years)	The International Knee Documentation Committee (IKDC) scores range from 0-100 with greater scores being indicative of greater self-reported function and reduced pain.	Baseline, 4 months, 1 year, 2 years
Change in KOOS Global (Baseline to 4 Months)	The Knee injury and Osteoarthritis Outcome Score (KOOS) Global scores range from 0-100 with greater scores being indicative of greater self-reported knee function and reduced pain and symptoms.	Baseline, 4 months, 1 year, 2 years
Change in KOOSglobal (Baseline to 1 Year)	The Knee injury and Osteoarthritis Outcome Score (KOOS) Global scores range from 0-100 with greater scores being indicative of greater self-reported knee function and reduced pain and symptoms.	Baseline, 4 months, 1 year, 2 years
Change in KOOSglobal (Baseline to 2 Years)	The Knee injury and Osteoarthritis Outcome Score (KOOS) Global scores range from 0-100 with greater scores being indicative of greater self-reported knee function and reduced pain and symptoms.	Baseline, 4 months, 1 year, 2 years
Change in ICOAP (Baseline to 4 Months)	The Intermittent and Constant Osteoarthritis Pain (ICOAP) Score is a valid and reliable tool to assess osteoarthritis-related pain. Scores range from 0 to 100, with greater scores indicating worse pain.	Baseline, 4 months, 1 year, 2 years
Change in ICOAP (Baseline to 1 Year)	The Intermittent and Constant Osteoarthritis Pain (ICOAP) Score is a valid and reliable tool to assess osteoarthritis-related pain. Scores range from 0 to 100, with greater scores indicating worse pain.	Baseline, 4 months, 1 year, 2 years
Change in ICOAP (Baseline to 2 Years)	The Intermittent and Constant Osteoarthritis Pain (ICOAP) Score is a valid and reliable tool to assess osteoarthritis-related pain. Scores range from 0 to 100, with greater scores indicating worse pain.	Baseline, 4 months, 1 year, 2 years
Change in CTXII (Baseline to 4 Months)	C-terminal cross-linked telopeptides (CTX); CTXII levels measured by ELISA. CTXII is a biomarker of type II collagen breakdown	Baseline, 4 months

Collaborators and Investigators

• Sponsor: Austin V Stone
• Investigators: Study Director: Austin Stone, MD, PhD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2020
• Primary Completion (Actual): July 11, 2022
• Study Completion (Actual): July 11, 2022

Study Registration Dates

• First Submitted: July 27, 2019
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): April 2, 2020

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Anterior cruciate ligament; Knee; Anti-inflammatory; Meniscectomy; Meniscus Repair
• Additional Relevant MeSH Terms: Leg Injuries; Knee Injuries; Wounds and Injuries; Anterior Cruciate Ligament Injuries; Tibial Meniscus Injuries; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Triamcinolone diacetate
• Other Study ID Numbers: 53136

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

With the participant's approval and as approved by local Institutional Review Boards (IRBs), de-identified biological samples will be stored at the University of Kentucky Orthopedic Biomarker Repository. These samples could be used to research the causes of osteoarthritis after meniscus injury, its complications and other conditions for which individuals with meniscus injuries are at increased risk, and to improve treatment.

Before sharing biomarker samples, we will ensure that the participant has given previous consent to the sharing of the information or samples. When we confirm that the previously provided consent is still in effect we will remove identifiers such as (e.g., name, medical record number, or date of birth). We will use a secure electronic log to track information shared without releasing the individual participant's identity.

• IPD Sharing Time Frame: Access to individual participant data will be available 1 year after the final study follow-up has been completed, and will be available until 5 years after the final study follow-up has been completed.
• IPD Sharing Access Criteria: The researchers requesting access to participant information or samples must complete a questionnaire describing why they need information or samples for their research and how they will use the information or samples. The researchers who receive the information or samples will sign an agreement to use the data responsibly.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• 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.: Yes