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.

Study Overview

• Status: Terminated
• Conditions: Fibrosis; Hip Osteoarthritis; Cartilage Damage; Hip Impingement Syndrome
• Intervention / Treatment: Drug: Losartan; Other: Placebo

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Vail, Colorado, United States, 81657
      • Steadman Philippon Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan; 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; 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.; Other Names: Losartan Potassium
Placebo Comparator: Placebo; 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; Appearance-matched microcrystalline cellulose placebo

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Steadman Philippon Research Institute
• Collaborators: United States Department of Defense; Office of Naval Research (ONR)
• Investigators: Principal Investigator: Marc J Philippon, MD, Steadman Philippon Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2020
• Primary Completion (Actual): December 4, 2020
• Study Completion (Actual): December 4, 2020

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 24, 2019
• First Posted (Actual): December 27, 2019

Study Record Updates

• Last Update Posted (Actual): October 30, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Hip Arthroscopy; Losartan; Cartilage Microfracture; Transforming growth factor beta 1
• Additional Relevant MeSH Terms: Pathologic Processes; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Fibrosis; Osteoarthritis, Hip; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 2019-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No