Losartan to Improve Outcomes After Multiligament Knee Injury (LION Trial)

Losartan to Improve Outcomes after multi-ligament kNee injury (LION Trial) Background: Whether the result of military training, a sports injury, or trauma, multi-ligament knee injuries (MLKIs) can be devastating events. MLKI treatment is complex and 38% of all patients report postoperative complications. Loss of knee range of motion (ROM) is the most common complication and is significantly associated with military separation. There are long-term ramifications of ROM loss, as we recently reported that the need for motion-restoring surgery after MLKI was a significant predictor of physician-diagnosed osteoarthritis within 5 years of surgery. An individual’s ability to perform both activities of daily living and higher demand physical activities is thus frequently impaired both in the short and long term, and less than half of military personnel are able to return to active duty following MLKI. In civilian populations, only 61% of those with MLKIs are able to return to work with little or no limitations and between 22% and 33% are able to return to high-level sport. By repurposing an FDA-approved medication to improve a person’s ability to return to physical activity in the first year after surgery, the proposed LION Trial directly addresses the FY24 PRORP Clinical Translational Research Award Focus Area 2b. Retention Strategies-Return to Duty. Losartan, an angiotensin receptor blocker, is an FDA-approved treatment for hypertension but because of its multiple mechanisms of action, this low-cost and widely available medication could be repurposed to improve outcomes after MLKI. Mechanistically, by inhibiting TGF-β signaling, losartan reduces pain, myofibroblast activity, synovitis, fibrosis, and cartilage degeneration in multiple animal models. In a clinical study of more than 100,000 total knee arthroplasty patients, losartan significantly reduced the incidence of manipulation under anesthesia, a common treatment for ROM loss (OR=0.80, p=0.007). Clinically, orthopaedic surgeons are increasingly prescribing losartan in the early postoperative period after MLKI procedures for those they perceive at increased risk of stiffness, yet to date no clinical translational studies have been performed to determine if the promising mechanistic and pre-clinical results will translate to improved outcomes after MLKI. Hypothesis/Objectives: The purpose of this study is to determine if a 30-day course of oral losartan will improve a person’s ability to return to duty or sport within 12 months post-surgery, improve range of motion and strength, and reduce synovitis and capsular thickening after MLKI. Our provocative hypothesis is that by directly targeting the underlying mechanisms of postoperative pain and fibrosis, a 30-day course of oral losartan will 1) improve a person’s pain, knee function, and the ability to return to work or sport and improve pain, 2) result in more symmetric knee ROM and quadriceps strength, and 3) reduce the number of people with ultrasound evidence of persistent synovitis and synovial thickening. Specific Aims and Study Design: We propose a double-blind, translational RCT to compare the losartan versus placebo with the primary outcome variable being Cincinnati Occupational Rating Scale (CORS) scores 12 months after surgery. Ninety patients enrolled at Mass General Brigham, the University of Kentucky, and Walter Reed National Military Medical Center will be randomized to take either 25 mg/day of losartan or oral placebo for the first 30 days after surgery. Assessments will include patient-reported outcomes, time to return to duty/sport, knee ROM, isokinetic strength testing, and quantitative ultrasound assessments of synovitis and capsular thickening. Data will be collected at 4 time points: preoperative, after completing the 30-day course of study medication, and 6 months and 12 months after surgery. The FDA has granted the LION Trial an IND exemption (PIND 167593). We propose the following specific aims: Aim 1: Determine if a 30-day postoperative course of losartan improves the ability to return to duty or sports and patient-reported outcomes when compared to placebo following MLKI. Aim 2: Assess whether losartan results in more symmetric knee range of motion and quadriceps strength following MLKI when compared to placebo. Aim 3: Compare ultrasound measures of capsular thickening and synovitis between groups treated with losartan versus placebo following surgical treatment of MLKI. Impact and Military Benefit: The risk of knee ligament injury is more than 10 times greater for military service members than their civilian counterparts, and less than half of military service members return to active duty following MLKI. If effective, repurposing the widely available and low-cost losartan offers a scalable intervention with a well-established safety profile to improve MLKI outcomes. The results of the proposed in this military-civilian collaborative trial will create a paradigm shift in the treatment of MLKI with the ultimate deliverable being the creation of an effective treatment strategy to improve postoperative outcomes and quality of life for this high-risk patient population.