Cartilage Damage, Fibrosis, Hip Impingement Syndrome, Hip Osteoarthritis
Conditions
Keywords
Cartilage Microfracture, Losartan, Transforming growth factor beta 1, Hip Arthroscopy
Brief summary
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
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).
Interventions
DRUGLosartan
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.
OTHERPlacebo
Appearance-matched microcrystalline cellulose placebo
Sponsors
United States Department of Defense
Office of Naval Research (ONR)
Steadman Philippon Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Block Randomization
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence 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). | Occurrence of treatment-emergent adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Reported Outcomes Questionnaire - Patient Satisfaction | Baseline, 3 months, 6 months, 12 months and 18 months | Patient Satisfaction * Scale from 1-10. * Higher score represents greater patient satisfaction. |
| Patient Reported Outcomes Questionnaire - Harris Hip Score | Baseline, 3 months, 6 months, 12 months and 18 months | Harris Hip Score (HHS). * Scale from 0-100. * Higher score represents greater hip health. |
| Patient Reported Outcomes Questionnaire - Hip Outcome Score | Baseline, 3 months, 6 months, 12 months and 18 months | Hip Outcome Score (HOS) - Including Sport and Activities of Daily Living (ADL) subscales. * Scale from 0-100. * Higher score represents greater hip health. |
| Patient Reported Outcomes Questionnaire - Western Ontario and McMaster Universities Osteoarthritis Index | Baseline, 3 months, 6 months, 12 months and 18 months | 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. |
| Patient Reported Outcomes Questionnaire | Baseline, 3 months, 6 months, 12 months and 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. |
| Patient Reported Outcomes Questionnaire - Numeric Rating Scale for Pain | Baseline, 3 months, 6 months, 12 months and 18 months | Numeric Rating Scale (NRS) for Pain * Scale from 1-10. * Higher score represents greater pain. |
| Morphological and Quantitative Magnetic Resonance Imaging (MRI) | Baseline and 12 months | 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. |
| Physical Examination of the Hip - Strength | Baseline, 3 months, and 12 months | Standard physical exam assessment of hip strength, measured in Newtons. |
| Physical Examination of the Hip - Range of Motion | Baseline, 3 months, and 12 months | Standard physical exam assessments of hip range of motion (ROM), measured in degrees. |
| Patient Reported Outcomes Questionnaire - Tegner Activity Scale | Baseline, 3 months, 6 months, 12 months and 18 months | Tegner Activity Scale * Scale from 0-10. * Higher score represents greater activity level. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from The Steadman Clinic between March 2, 2020 and August 7, 2020. The first and last participant were enrolled on August 7, 2020.
Pre-assignment details
Of 1 enrolled participant, 1 met inclusion criteria and was randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 1 |
| Placebo Appearance-matched placebo capsules, oral administration, twice daily, taken for 30 consecutive days starting on the evening of the second post-surgery day.
Placebo: Appearance-matched microcrystalline cellulose placebo | 0 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Losartan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 1 participants | — | 1 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 0 |
| other Total, other adverse events | 0 / 1 | 0 / 0 |
| serious Total, serious adverse events | 1 / 1 | 0 / 0 |
Outcome results
Primary
Incidence of Treatment-Emergent Adverse Events
Occurrence of treatment-emergent adverse events
Time frame: 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).
Population: There was 1 subject enrolled into the Losartan arm, but withdrew before any follow-up data was collected. One serious adverse event was reported 3 days post-enrollment. This AE was determined to be unrelated to the research or study drug and is reported in the AE section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Incidence of Treatment-Emergent Adverse Events | 1 participants |
Secondary
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.
Time frame: Baseline and 12 months
Population: Participant was randomized to Losartan arm but withdrew before any follow up data was collected.~Baseline quantitative MRI was not processed due to participant withdrawal and study closure.
Secondary
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.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline SF-12 PCS Score was 48.8 for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Patient Reported Outcomes Questionnaire | 48.8 score on a scale |
Secondary
Patient Reported Outcomes Questionnaire - Harris Hip Score
Harris Hip Score (HHS). * Scale from 0-100. * Higher score represents greater hip health.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline HHS Score was 57 for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Patient Reported Outcomes Questionnaire - Harris Hip Score | 57 score on a scale |
Secondary
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.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline HOS-ADL Score was 68 for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Patient Reported Outcomes Questionnaire - Hip Outcome Score | 68 score on a scale |
Secondary
Patient Reported Outcomes Questionnaire - Numeric Rating Scale for Pain
Numeric Rating Scale (NRS) for Pain * Scale from 1-10. * Higher score represents greater pain.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline NRS Pain Score was 6 for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Patient Reported Outcomes Questionnaire - Numeric Rating Scale for Pain | 6 score on a scale |
Secondary
Patient Reported Outcomes Questionnaire - Patient Satisfaction
Patient Satisfaction * Scale from 1-10. * Higher score represents greater patient satisfaction.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Patient satisfaction is not collected at baseline. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
Secondary
Patient Reported Outcomes Questionnaire - Tegner Activity Scale
Tegner Activity Scale * Scale from 0-10. * Higher score represents greater activity level.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline Tegner Activity Scale was unavailable for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
Secondary
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.
Time frame: Baseline, 3 months, 6 months, 12 months and 18 months
Population: Baseline WOMAC Total Score was 31 for the 1 enrolled participant. Participant was randomized to Losartan arm but withdrew before any follow up data was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losartan | Patient Reported Outcomes Questionnaire - Western Ontario and McMaster Universities Osteoarthritis Index | 31 score on a scale |
Secondary
Physical Examination of the Hip - Range of Motion
Standard physical exam assessments of hip range of motion (ROM), measured in degrees.
Time frame: Baseline, 3 months, and 12 months
Population: Participant was randomized to Losartan arm but withdrew before any follow up data was collected.~Baseline hip range of motion assessment data was not compiled due to participant withdrawal and study closure.
Secondary
Physical Examination of the Hip - Strength
Standard physical exam assessment of hip strength, measured in Newtons.
Time frame: Baseline, 3 months, and 12 months
Population: Participant was randomized to Losartan arm but withdrew before any follow up data was collected.~Baseline hip strength assessment data was not compiled due to participant withdrawal and study closure.