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redesigned trial using another placebo controlled drug
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| Name | Class |
|---|---|
| United States Department of Defense | FED |
| Office of Naval Research (ONR) | FED |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Losartan | Experimental | 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. |
|
| Placebo | Placebo Comparator | Appearance-matched placebo capsules, oral administration, twice daily, taken for 30 consecutive days starting on the evening of the second post-surgery day. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Losartan | Drug | 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. |
| 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). |
| 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).
| Baseline, 3 months, 6 months, 12 months and 18 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marc J Philippon, MD | Steadman Philippon Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Steadman Philippon Research Institute | Vail | Colorado | 81657 | United States |
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Of 1 enrolled participant, 1 met inclusion criteria and was randomized to treatment.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
One (1) participant was enrolled in the study and subsequently randomized to the Losartan arm.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incidence of Treatment-Emergent Adverse Events | Occurrence of treatment-emergent adverse events | 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. | Posted | Number | participants | 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). |
|
1 week
Participant was randomized to Losartan arm but withdrew before any follow up data was collected. Study closed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment | Patient presented with increased from baseline contralateral hip pain secondary to established labral tear during a standard of care post-operative visit for the study hip, which resulted in subsequent contralateral hip surgery. |
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Per opinion of the Principal Investigator, Losartan is now clinically indicated as a standard of care post-operative therapy for patients undergoing hip microfracture surgeries. The study was terminated early, resulting in a singular subject enrolled for data analysis. The subject elected to withdraw from the study prior to the first follow-up data collection timepoint.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Suzanne Liv Page, JD | Steadman Philippon Research Institute | 970-401-8770 | spage@sprivail.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 27, 2019 | Jun 23, 2023 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 15, 2020 | May 21, 2020 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D015207 | Osteoarthritis, Hip |
| D005355 | Fibrosis |
| D003966 | Camurati-Engelmann Syndrome |
| ID | Term |
|---|---|
| D010003 | Osteoarthritis |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| D019808 | Losartan |
| ID | Term |
|---|---|
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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Block Randomization
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|
| Placebo | Other | Appearance-matched microcrystalline cellulose placebo |
|
| Patient Reported Outcomes Questionnaire - Patient Satisfaction | Patient Satisfaction
| Baseline, 3 months, 6 months, 12 months and 18 months |
| Patient Reported Outcomes Questionnaire - Harris Hip Score | Harris Hip Score (HHS).
| 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.
| 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.
| Baseline, 3 months, 6 months, 12 months and 18 months |
| Patient Reported Outcomes Questionnaire - Tegner Activity Scale | Tegner Activity Scale
| 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
| 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 |
| BG001 |
| 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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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 |
|
|
| Secondary | Patient Reported Outcomes Questionnaire | 12-question Short-Form General Health Survey (SF-12) - Including Physical Component Summary (PCS) and Mental Component Summary (MCS).
| 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. | Posted | Number | score on a scale | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
|
| Secondary | Patient Reported Outcomes Questionnaire - Patient Satisfaction | Patient Satisfaction
| Patient satisfaction is not collected at baseline. Participant was randomized to Losartan arm but withdrew before any follow up data was collected. | Posted | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
| Secondary | Patient Reported Outcomes Questionnaire - Harris Hip Score | Harris Hip Score (HHS).
| 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. | Posted | Number | score on a scale | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
|
| Secondary | Patient Reported Outcomes Questionnaire - Hip Outcome Score | Hip Outcome Score (HOS) - Including Sport and Activities of Daily Living (ADL) subscales.
| 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. | Posted | Number | score on a scale | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
|
| 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.
| 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. | Posted | Number | score on a scale | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
|
| Secondary | Patient Reported Outcomes Questionnaire - Tegner Activity Scale | Tegner Activity Scale
| 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. | Posted | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
| Secondary | Patient Reported Outcomes Questionnaire - Numeric Rating Scale for Pain | Numeric Rating Scale (NRS) for Pain
| 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. | Posted | Number | score on a scale | Baseline, 3 months, 6 months, 12 months and 18 months |
|
|
|
| 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. | 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. | Posted | Baseline and 12 months |
|
|
| Secondary | Physical Examination of the Hip - Strength | Standard physical exam assessment of hip strength, measured in Newtons. | 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. | Posted | Baseline, 3 months, and 12 months |
|
|
| Secondary | Physical Examination of the Hip - Range of Motion | Standard physical exam assessments of hip range of motion (ROM), measured in degrees. | 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. | Posted | Baseline, 3 months, and 12 months |
|
|
| 0 |
| 1 |
| 1 |
| 1 |
| 0 |
| 1 |
| EG001 | 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 | 0 | 0 | 0 | 0 | 0 |
|
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| D012216 |
| Rheumatic Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010009 | Osteochondrodysplasias |
| D001848 | Bone Diseases, Developmental |
| D001847 | Bone Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013777 | Tetrazoles |