Multi-ligament knee injuries (MLKIs) can occur during military training, sports injuries, or traumatic events such as motor vehicle accidents and can be devastating events. These complex injuries involving disruption of 2 or more ligaments often coincide with injuries to arteries, nerves, tendons, menisci, and/or fractures and can be devastating events. MLKIs often require complex treatments nearly 2 in 5 patients suffer complications after surgery. Loss of knee range of motion is the most common complication and is associated with military separation. There are also long-term effects of motion loss, as the need for motion-restoring surgery after MLKI is associated with an increased risk of osteoarthritis within 5 years of surgery. A person's ability to perform both activities of daily living and higher demand physical activities is often impaired both in the short and long term. In fact, only 1 in 3 people return to high-level sport after MLKI. The purpose of this translational randomized clinical trial is to determine if a 30-day course of oral Losartan improves a person's ability to return to work or sport, range of motion and strength, and reduce knee inflammation in the first year after surgical treatment of an MLKI.

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 effects of ROM loss, as 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. 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.

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.

Specific Aims and Study Design: The LION Trial is a double-blind Randomized Controlled Trial to compare the losartan versus placebo with the primary outcome variable being Cincinnati Occupational Rating Scale scores 12 months after surgery. Ninety patients enrolled and 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 investigators will test 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.

Inclusion Criteria:

• Multi-ligament knee injury defined as a complete grade III injury of 2 or more ligaments
• At least one ligament surgically reconstructed or repaired
• Willingness to comply with the study protocol and assessments

Exclusion Criteria:

• Allergic to any active or inactive ingredient of losartan
• Pregnant, planning to become pregnant, or sexually active females choosing not to use effective means of contraception during the 30-day course of losartan
• Those at increased risk of losartan related side effects including those with severe renal insufficiency, hepatic disease, hypotension, and/or hyperkalemia
• Have a history of prior knee ligament surgery of the involved knee
• Undergoing staged surgical procedures in the treatment of MLKI
• Have a traumatic brain injury that limits their ability to participate in their postoperative care or any condition that would preclude the ability to comply with postoperative rehabilitation
• Have a concomitant injury or underwent a surgical procedure that will preclude the ability to perform range of motion exercises (i.e. surgery for extensor mechanism rupture or avulsion, vascular graft surgery)

IPD from this project will be made available to the research community and to the public at large. Data will be shared through the Harvard Dataverse data repository. A rich dataset will be created which will include patient demographic information, patient-reported outcomes, isokinetic strength, range of motion, and ultrasound assessments of knee synovitis. Demographic information will include patient age, sex, race, ethnicity, body mass index, injury history, intraoperative findings, and surgical treatment. Patient-reported outcomes will include the Cincinnati Occupational Rating Scale (CORS) scores, International Knee Documentation Committee (IKDC) scores, and VAS pain scores

IPD will be made available after data analysis has been completed and the primary study manuscript has been accepted for publication (anticipated March 2030), and will remain available for a minimum of 7 years (anticipated March 2037).

The project team will make their data available as widely and as freely as possible while safeguarding the privacy of participants and protecting confidential and proprietary data. Furthermore, any research resources will be shared in line with the policies adopted by DOD for the purposes of this grant. Data will be made publicly available, and requestors will be required to complete a data-sharing agreement with Brigham and Women's Hospital. The purpose of the data-sharing agreement is to ensure data security at the recipient site and clarify that manipulating the data for the purposes of identifying subjects is strictly prohibited. No limits or caveats for co-authorship will be required as a precondition for receiving data.