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

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.

Study Overview

• Status: Recruiting
• Conditions: Post-traumatic Osteoarthritis; ACL Injury; Meniscus Tear
• Intervention / Treatment: Drug: Montelukast; Drug: Placebo

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
• Enrollment (Estimated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Austin Stone, MD, PhD; Phone Number: 859.218.3065; Email: austin.stone@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • Recruiting
      • UK Healthcare at Turfland
      • Contact: Austin Stone, MD, PhD; Phone Number: 859-218-3065; Email: austin.stone@uky.edu
      • Sub-Investigator: Cale Jacobs, PhD
      • Principal Investigator: Austin Stone, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

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: Montelukast; Patients will receive oral montelukast (10 mg) daily for 6 months after surgery.	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 Names: Singulair
Placebo Comparator: Placebo; Patients will receive an oral placebo daily for 6 months after surgery.	Drug: Placebo; An oral placebo will be taken daily for 6 months post surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum prostaglandin E2	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.	Change between Visit 3 (10 days post surgery) and Visit 6 (1 year post surgery)
T1rho relaxation time on MRI	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.	Change between Visit 4 (4 weeks post surgery) and Visit 6 (1 year post surgery)
Shape of the medial femoral condyle on MRI	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.	Change between Visit 4 (4 weeks post surgery) and Visit 6 (1 year post surgery)
Knee injury and Osteoarthritis Outcome Score (KOOS)	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.	Change between Visit 3 (10 days post surgery) and Visit 6 (1 year post surgery)

Collaborators and Investigators

• Sponsor: Austin V Stone
• Collaborators: The Cleveland Clinic; Duke University; University of California, San Francisco
• Investigators: Principal Investigator: Austin Stone, MD, PhD, University of Kentucky

Publications and helpful links

General Publications

• Jacobs CA, Conley CEW, Kraus VB, Lansdown DA, Lau BC, Li X, Majumdar S, Spindler KP, Lemaster NG, Stone AV. MOntelukast as a potential CHondroprotective treatment following Anterior cruciate ligament reconstruction (MOCHA Trial): study protocol for a double-blind, randomized, placebo-controlled clinical trial. Trials. 2022 Jan 31;23(1):98. doi: 10.1186/s13063-021-05982-3.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: September 25, 2020
• First Submitted That Met QC Criteria: September 25, 2020
• First Posted (Actual): October 1, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: osteoarthritis; knee ligament
• Additional Relevant MeSH Terms: Wounds and Injuries; Leg Injuries; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Knee Injuries; Osteoarthritis; Anterior Cruciate Ligament Injuries; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Montelukast
• Other Study ID Numbers: 60266

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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