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

NCT ID: NCT04331002

Last Updated: 2023-07-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-21
• Study Completion Date: 2022-07-11

Brief Summary

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.

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.

Conditions

Tibial Meniscus Injuries; Tibial Meniscus Tears; Tibial Meniscus, Torn; Anterior Cruciate Ligament Tear

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Experimental

The experimental group will receive a single 32 mg Zilretta injection approximately 8 weeks after meniscus surgery.

Group Type: EXPERIMENTAL

Zilretta

Intervention Type: DRUG

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.

Placebo

The placebo group will receive a single 5 mL injection of normal saline approximately 8 weeks after meniscus surgery.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

5 mL normal saline

Interventions

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.

Intervention Type: DRUG

Placebo

5 mL normal saline

Intervention Type: OTHER

Other Intervention Names

Extended release triamcinolone acetonide; Saline

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Austin V Stone

OTHER

Sponsor Role: lead

Responsible Party

Austin V Stone

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Austin Stone, MD, PhD

Role: STUDY_DIRECTOR

University of Kentucky

Locations

UK Healthcare at Turfland

Lexington, Kentucky, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

53136

Identifier Type: -

Identifier Source: org_study_id