Losartan to Improve Outcomes After Multi-ligament Knee Injury

NCT ID: NCT06933706

Last Updated: 2026-01-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-01
• Study Completion Date: 2029-09-30

Brief Summary

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.

Detailed Description

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.

Conditions

Multi-ligament Knee Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Losartan

Participants randomized to the Losartan arm will be asked to take 25 mg of losartan per day for 30 days.

Group Type: EXPERIMENTAL

losartan 25 mg

Intervention Type: DRUG

Losartan is an angiotensin-II inhibitor that modulates the renin-angiotensin system by blocking the activation of angiotensin type 1 receptors, thus preventing binding with angiotensin-II and decreasing blood pressure. Losartan has a broader therapeutic potential for muscle healing and treatment for diseases ranging from rheumatoid arthritis, osteoarthritis, chronic kidney disease, Marfan syndrome, and fatty liver. TGF-β plays an active role in fibrosis leading to the formation of adhesions and scar tissue. By limiting the formation of adhesions and scar tissue, losartan may reduce pain, myofibroblast activity, synovitis, fibrosis, and cartilage degeneration.

Placebo

Participants randomized to the Placebo arm will be asked to take one placebo capsule per day for 30 days.

Group Type: PLACEBO_COMPARATOR

Placebo capsule

Intervention Type: OTHER

The placebo capsule will look identical to the active study drug, but will not have any active ingredient and will be filled with corn starch

Interventions

losartan 25 mg

Losartan is an angiotensin-II inhibitor that modulates the renin-angiotensin system by blocking the activation of angiotensin type 1 receptors, thus preventing binding with angiotensin-II and decreasing blood pressure. Losartan has a broader therapeutic potential for muscle healing and treatment for diseases ranging from rheumatoid arthritis, osteoarthritis, chronic kidney disease, Marfan syndrome, and fatty liver. TGF-β plays an active role in fibrosis leading to the formation of adhesions and scar tissue. By limiting the formation of adhesions and scar tissue, losartan may reduce pain, myofibroblast activity, synovitis, fibrosis, and cartilage degeneration.

Intervention Type: DRUG

Placebo capsule

The placebo capsule will look identical to the active study drug, but will not have any active ingredient and will be filled with corn starch

Intervention Type: OTHER

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Kentucky

OTHER

Sponsor Role: collaborator

Walter Reed National Military Medical Center

FED

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Cale Andrew Jacobs, PhD

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Cale Jacobs, PhD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

University of Kentucky

Lexington, Kentucky, United States

Site Status: NOT_YET_RECRUITING

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

Site Status: NOT_YET_RECRUITING

Mass General Brigham

Foxborough, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Cale Jacobs, PhD

Role: CONTACT

cjacobs@bwh.harvard.edu

508-216-1145

Molly Zgoda

Role: CONTACT

mzgoda@mgb.org

508-216-1145

Facility Contacts

Austin Stone, MD, PhD

Role: primary

Xiaoning Yuan, MD, PhD

Role: primary

Cale Jacobs

Role: primary

cjacobs@bwh.harvard.edu

508-216-1145

Other Identifiers

2025P000672

Identifier Type: -

Identifier Source: org_study_id