Losartan to Improve Hip Microfracture

Biologically Regulated Marrow Stimulation by Blocking Fibrosis to Improve Cartilage Repair: A Randomized Double-Blind, Placebo-Controlled Study

Phase I/IIA randomized, double-blind, placebo-controlled clinical trial to assess safety and efficacy of oral losartan for improving cartilage repair following microfracture to treat focal cartilage defects during hip arthroscopy.

This is a prospective, double-blind, placebo-controlled, randomized clinical trial that will be conducted at The Steadman Clinic and Steadman Philippon Research Institute. Articular cartilage defects that extend full thickness to subchondral bone rarely heal without intervention. Some patients may not develop clinically significant problems from acute full-thickness chondral defects, but many eventually suffer from debilitating degenerative changes. Microfracture is the most commonly used first-line treatment technique for chondral lesions in the hip, however, this procedure's effectiveness is limited by the repair tissue being a hybrid of hyaline and fibrocartilage. We hypothesize that administration of a transforming growth factor beta 1 (TGF-β1) blocker, losartan (an approved hypertension drug, angiotensin II receptor antagonist) with microfracture will enhance articular cartilage repair as assessed on quantitative magnetic resonance imaging. We will also measure patient benefit through the recording of patient reported outcomes in the 18 months following surgery. The Division of Pulmonary, Allergy and Rheumatology Products within the Center for Drug Evaluation and Research at the Food and Drug Administration has granted an investigational new drug (IND) exemption to pursue this trial in accordance with 21 CFR 312.2(b).

12.5mg Losartan capsules, oral administration, twice daily (25mg total per day), taken for 30 consecutive days starting on the evening of the second post-surgery day.

Appearance-matched placebo capsules, oral administration, twice daily, taken for 30 consecutive days starting on the evening of the second post-surgery day.

Losartan will be administered to improve the quality of hip cartilage repair following arthroscopic microfracture. Losartan is a known anti-fibrotic agent via blocking of TGF-B1.

Drug related adverse events will be monitored during the medication phase (post-op days 2-31) and orthopaedic-related health and function will be monitored for the entire study duration (18 months).

12-question Short-Form General Health Survey (SF-12) - Including Physical Component Summary (PCS) and Mental Component Summary (MCS). Higher score represents greater health. Scale standardized to a US Population mean of 50 and standard deviation of 10 points.

Hip Outcome Score (HOS) - Including Sport and Activities of Daily Living (ADL) subscales. Scale from 0-100. Higher score represents greater hip health.

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) - Including Pain, Stiffness and Physical Function subscales. Scale from 0-96. Higher score represents worse hip health.

Cartilage quality assessed by blinded radiologist using morphological MRI. Quantitative MRI using T2 mapping images with texture analysis used to assess water content and collagen organization within the cartilage and surrounding tissue.

Inclusion Criteria: Underwent primary hip arthroscopy Underwent baseline quantitative MRI at The Steadman Clinic (TSC) Single, localized, grade 3 or 4 cartilage lesion of the acetabulum or femoral head treated with Bone Marrow Stimulation (BMS; i.e. microfracture) Aged 18-60 at time of surgery Tonnis grade 1 or less Exclusion Criteria: Two or more cartilage lesions of grade 3 or 4 Less than 2 mm of minimal hip joint space Osteoarthritis or diffuse change of cartilage Non-English speaking Prior hip surgery on operative hip Pre-existing bony deformity caused by previous fracture(s) Synovial chondromatosis Pigmented Villonodular Synovitis (PVNS) Dysplasia (center edge angle <20 degrees) History of Avascular Necrosis (AVN), Perthes disease, or slipped capital femoral epiphysis (SCFE) Inflammatory arthritis or other arthritis caused by autoimmune disease Patients allergic to any active or inactive ingredient of losartan Patients taking medication with known losartan interaction, including phenobarbital, rifampin, and fluconazole. Subjects that are currently taking losartan