Ignite Creation Date:
2024-05-06 @ 3:15 PM
Last Modification Date:
2024-10-26 @ 1:46 PM
Study NCT ID:
NCT04572256
Status:
RECRUITING
Last Update Posted:
2024-04-30
First Post:
2020-09-25
Brief Title:
MOntelukast as a Potential CHondroprotective Treatment Following Anterior Cruciate Ligament Reconstruction MOCHA Trial
Sponsor:
Austin V Stone
Organization:
University of Kentucky
Study Overview
Official Title:
MOntelukast as a Potential CHondroprotective Treatment Following Anterior Cruciate Ligament Reconstruction MOCHA Trial
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MOCHA
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
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None