Losartan to Improve Hip Microfracture

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Hip Osteoarthritis, Hip Impingement Syndrome, Cartilage Damage, Fibrosis

Intervention / Treatment
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* Drug: Losartan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Block Randomization
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan<br>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. | Drug: Losartan<br>* 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.<br>* Other names: Losartan Potassium;|
| Placebo Comparator: Placebo<br>Appearance-matched placebo capsules, oral administration, twice daily, taken for 30 consecutive days starting on the evening of the second post-surgery day. | Other: Placebo<br>* Appearance-matched microcrystalline cellulose placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Occurrence of treatment-emergent adverse events | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Reported Outcomes Questionnaire | 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. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Patient Satisfaction | Patient Satisfaction Scale from 1-10. Higher score represents greater patient satisfaction. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Harris Hip Score | Harris Hip Score (HHS). Scale from 0-100. Higher score represents greater hip health. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Hip Outcome Score | Hip Outcome Score (HOS) - Including Sport and Activities of Daily Living (ADL) subscales. Scale from 0-100. Higher score represents greater hip health. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Western Ontario and McMaster Universities Osteoarthritis Index | 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. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Tegner Activity Scale | Tegner Activity Scale Scale from 0-10. Higher score represents greater activity level. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Patient Reported Outcomes Questionnaire - Numeric Rating Scale for Pain | Numeric Rating Scale (NRS) for Pain Scale from 1-10. Higher score represents greater pain. | Baseline, 3 months, 6 months, 12 months and 18 months | 
| Morphological and Quantitative Magnetic Resonance Imaging (MRI) | 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. | Baseline and 12 months | 
| Physical Examination of the Hip - Strength | Standard physical exam assessment of hip strength, measured in Newtons. | Baseline, 3 months, and 12 months | 
| Physical Examination of the Hip - Range of Motion | Standard physical exam assessments of hip range of motion (ROM), measured in degrees. | Baseline, 3 months, and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cartilage Microfracture, Losartan, Transforming growth factor beta 1, Hip Arthroscopy