MOntelukast as a Potential CHondroprotective Treatment Following Anterior Cruciate Ligament Reconstruction (MOCHA Trial) (MOCHA)

• ClinicalTrials.gov Identifier: NCT04572256
• Recruitment Status: Not yet recruiting
• First Posted: October 1, 2020
• Last Update Posted: December 2, 2020
• Sponsor: Cale Jacobs, PhD
• Collaborators: Duke University; The Cleveland Clinic; University of California, San Francisco
• Information provided by (Responsible Party): Cale Jacobs, PhD, University of Kentucky

Tracking Information

• First Submitted Date: September 25, 2020
• First Posted Date: October 1, 2020
• Last Update Posted Date: December 2, 2020
• Estimated Study Start Date: January 1, 2021
• Estimated Primary Completion Date: January 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 25, 2020)

• Serum prostaglandin E2 [ Time Frame: Change between Visit 3 (10 days post surgery) and Visit 6 (1 year post surgery) ]
  Prostaglandin E2 is a potential inflammatory mediator, and it is being measured to directly assess whether treatment reduces this systemic inflammatory marker. Greater serum prostaglandin is associated with greater inflammation.
• T1rho relaxation time on MRI [ Time Frame: Change between Visit 4 (4 weeks post surgery) and Visit 6 (1 year post surgery) ]
  T1rho relaxation time is a validated measure of proteoglycan content within the cartilage, and can be assessed on MRI. Increased T1rho relaxation time is associated with increased cartilage degeneration.
• Shape of the medial femoral condyle on MRI [ Time Frame: Change between Visit 4 (4 weeks post surgery) and Visit 6 (1 year post surgery) ]
  The shape of the medial femoral condyle has been previously demonstrated to change after ACL reconstruction and is predictive of later cartilage changes. Flattening and widening of the medial femoral condyle are considered to be indicative of later cartilage changes.
• Knee injury and Osteoarthritis Outcome Score (KOOS) [ Time Frame: Change between Visit 3 (10 days post surgery) and Visit 6 (1 year post surgery) ]
  The KOOS is a patient-reported outcome instrument that is comprised of 5 subscales (Pain, Symptoms, Activities of Daily Living, Sports and Recreation, and Quality of Life) with each scale being scored from 0 to 100 with higher scores being indicative of a superior outcome.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: MOntelukast as a Potential CHondroprotective Treatment Following Anterior Cruciate Ligament Reconstruction (MOCHA Trial)
• Official Title: MOntelukast as a Potential CHondroprotective Treatment Following Anterior Cruciate Ligament Reconstruction (MOCHA Trial)
• Brief Summary: This is a multicenter randomized, placebo-controlled trial to assess whether a 6-month course of oral montelukast after ACL reconstruction reduces systemic markers of inflammation and biochemical and imaging biomarkers of cartilage degradation. This study will specifically target older ACL reconstruction patients with concomitant meniscal injuries as this group is at greatest risk of rapid PTOA progression. Patients will randomly be assigned to receive oral montelukast (10 mg) versus placebo daily for 6 months after surgery.

Detailed Description

After anterior cruciate ligament (ACL) reconstruction, patient-reported outcomes are improved 10 years post-surgery. Cytokine concentrations, however, remain elevated years after surgery; over 80% of patients with combined ACL and meniscus injuries have post-traumatic osteoarthritis (PTOA) within 10-15 years after injury. Since pain nociceptors are not located in the articular cartilage, patient-reported outcomes improve despite progressive, irreversible cartilage loss, thus making PTOA a "silent killer." Because early cartilage loss progresses without pain and dysfunction, the prevalence of PTOA continues to increase. PTOA now represents the most common cause of military disability.

Our recent results illustrate the downstream cytokine and degradative enzyme activity following ACL reconstruction. ACL and meniscus injury initiate a biochemical cascade resulting in cartilage degradation and this process involves an up-regulated pro-inflammatory response with a dysregulated anti-inflammatory response. Single-dose intra-articular anti-inflammatory treatment appears to reduce hyaline cartilage degradation shortly after the time of injury based on synovial fluid measures of type II collagen degradation. The intra-articular inflammatory milieu at the time of surgery appears to predict the patient symptom state two years later; however, the effectiveness of preoperative anti-inflammatory treatments in impacting patient symptoms or slowing long-term PTOA progression is as yet unclear. A lack of efficacy in preoperative interventions may be attributed to a profound inflammatory stimulus from surgical reconstruction of the ACL. The postoperative inflammatory cascade results in articular cartilage and meniscus degradation due to matrix degrading enzymes, especially those which breakdown type II collagen.

PTOA affects the whole joint organ including the cartilage, synovium, and bone. PTOA progression is multifaceted and includes activation of the pro-inflammatory Nuclear Factor Kappa-B (NFkB) pathway, an increase in pro-inflammatory M1 macrophages, cell senescence, and bone remodeling. Limiting the biochemical cascade through an innovative disease modifying treatment to target upstream activity will potentially treat all components of the knee, thereby lessening the inflammatory response, reducing cartilage catabolism, and potentially improving pathologic bony remodeling observed after ACL reconstruction. The early proteomic PTOA response is more similar to inflammatory rheumatoid arthritis than idiopathic OA; thus, long-acting agents which better regulate pro-inflammatory cytokine activity may more successfully limit tissue destruction. By re-purposing approved therapeutics with proven immune efficacy, a readily-available and cost-effective strategy for disease modification may be possible.

Montelukast was first approved for clinical use in 1998 for prophylaxis and chronic treatment of asthma. The drug selectively inhibits the cysteinyl leukotriene receptor 1 (CysLT1). Montelukast blocks the actions of cysteinyl leukotriene D4 (LTD4), which is produced through the arachidonic acid pathway. This pro-inflammatory signal is released from several cells including the inflammatory mast cells and eosinophils. Montelukast also appears to address multiple PTOA mechanisms by inhibiting cysteinyl leukotrienes. Cysteinyl leukotriene inhibition in animal and laboratory models of PTOA resulted in the elimination of senescent cells, reduced NFkB activation, decreased concentrations of pro-inflammatory and catabolic factors and reactive oxygen species (ROS) while increasing expression of anti-inflammatory factors (inducing anti-inflammatory M2 macrophage infiltration), inhibiting osteoclastogenesis and improving bone quality. The novel use of oral montelukast offers the potential of a disease modifying treatment to prevent irreversible cartilage loss after ACL injury.

• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• ACL Injury
• Meniscus Tear
• Post-traumatic Osteoarthritis

Intervention

• Drug: Montelukast
  The novel use of oral montelukast offers the potential of a disease modifying treatment to prevent irreversible cartilage loss after ACL injury. 10mg of oral Montelukast will be taken daily for 6 months post surgery.
  Other Name: Singulair
• Drug: Placebo
  An oral placebo will be taken daily for 6 months post surgery.

Study Arms

• Experimental: Montelukast
  Patients will receive oral montelukast (10 mg) daily for 6 months after surgery.
  Intervention: Drug: Montelukast
• Placebo Comparator: Placebo
  Patients will receive an oral placebo daily for 6 months after surgery.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: September 25, 2020): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 1, 2023
• Estimated Primary Completion Date: January 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Undergoing primary ACL reconstruction
2. Age between 25-50
3. Concomitant meniscus injury

Exclusion Criteria:

1. Undergoing revision procedures
2. Multiple ligament injuries requiring multiple ligament reconstruction/repair
3. Depressive symptoms and/or those who endorse suicidal ideation at the time of enrollment (PHQ-9 score >= 15)
4. Found to not have a meniscus tear at the time of surgery

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04572256
• Other Study ID Numbers: 60266
• 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.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Cale Jacobs, PhD, University of Kentucky
• Study Sponsor: Cale Jacobs, PhD

Collaborators

• Duke University
• The Cleveland Clinic
• University of California, San Francisco

• Investigators: Not Provided
• PRS Account: University of Kentucky
• Verification Date: November 2020