Clinical trial NCT04212650
Conditions: Hip Osteoarthritis Hip Impingement Syndrome Cartilage Damage Fibrosis
Keywords: Cartilage Microfracture Losartan Transforming growth factor beta 1 Hip Arthroscopy
Sponsor: Steadman Philippon Research Institute
Start date: 2020-08-07; Completion date: 2020-12-04
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: 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. arm 2: Appearance-matched placebo capsules, oral administration, twice daily, taken for 30 consecutive days starting on the evening of the second post-surgery day.
Interventions: intervention 1: Losartan intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: Appearance-matched microcrystalline cellulose placebo

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Sponsor: 
Dr. Marc Philippon, MD 
Steadman Philippon Research Institute 
181 W. Meadow Dr. Suite 1000 
Vail, CO 81657 
 
Grant Support Provided By:  
Office of Naval Research, US Department of Defense 
 
 
 
 
Confidentiality Statement: 
This document contains confidential information and is provided for the sole use of the 
Principal Investigator, Sub-Investigator(s), Staff, Institutional Review Board or Regulatory 
Authorities.  By accepting this document, you agree to maintain the information as 
confidential and to use it only for the purpose of conducting  the study. 
 
Biologically Regulated Marrow Stimulation by 
Blocking Fibrosis to Improve Cartilage Repair: A Randomized
Double Blind, Placebo Controlled Study
Protocol No.: 2019-15
Original Date: – March 27, 2019
Version 001


 
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Table of Contents 
1.0 
Steadman Philippon Research Institute Representatives ........................................4 
2.0 
Protocol Signature Page ..............................................................................................5 
3.0 
Study Synopsis ..............................................................................................................6 
4.0 
Terms and Abbreviations ..........................................................................................11 
5.0 
Introduction ................................................................................................................12 
5.1 
Background and Significance ..........................................................................12 
5.2 
Rationale ..........................................................................................................12 
5.3 
Safety of Administering Losartan to Normotensive Patients ..........................14 
6.0 
Summary of Proposed Placebo Controlled Trial ....................................................16 
6.1 
Blinding............................................................................................................17 
7.0 
Study Medication Treatment ....................................................................................18 
7.1 
Losartan Potassium ..........................................................................................18 
7.2 
Placebo Control ................................................................................................18 
7.3 
PenCol Compounding Pharmacy .....................................................................18 
8.0 
Study Design ...............................................................................................................19 
9.0 
Study Objectives and Endpoints...............................................................................20 
9.1 
Primary Objectives...........................................................................................20 
9.2 
Secondary Objective ........................................................................................20 
9.3 
Study Endpoints ...............................................................................................20 
9.4 
Primary Endpoints: ..........................................................................................20 
9.5 
Secondary Endpoints .......................................................................................20 
10.0 
Study Population ........................................................................................................21 
10.1 
Description .......................................................................................................21 
10.2 
Source of Subjects............................................................................................21 
10.3 
Enrollment Criteria ..........................................................................................21 
10.3.1 Inclusion Criteria .................................................................................21 
10.3.2 Exclusion Criteria ................................................................................21 
11.0 
Study Procedures .......................................................................................................23 
11.1 
Visit 1: Day 1 Post-operative ...........................................................................23 
11.2 
Day 2 Post-operative (No Visit Required) .......................................................24 
11.3 
Day 7-10 Post-operative (No Visit Required) .................................................24 
11.4 
Telephone Contact by Study Team Post-operative day 30- (No Visit Required) 
(approximately one month) ..........................................................................................24 
11.5 
Visit 2: Three Months Post-operative Clinic Visit (+/- 4 weeks) ....................24 
11.6 
6 Months Post-operative -(No Visit Required) (+/- 4 weeks)..........................25 
11.7 
12 Months Post-operative -(No Visit Required) (+/- 8 weeks)........................25 
11.8 
Visit 3: 18 Months Post-operative (+/- 8 weeks) .............................................25 
11.9 
Unscheduled Visits and/or Subject Contact .....................................................25 


 
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12.0 
Study Management of Adverse Events ....................................................................26 
12.1 
Definition .........................................................................................................26 
12.2 
Recording Adverse Events ...............................................................................26 
12.3 
Severity (Intensity) of Adverse Events ............................................................29 
12.4 
Expected and Unexpected Adverse Events ......................................................29 
12.5 
Serious Adverse Events ...................................................................................29 
12.6 
Reporting of Adverse Events ...........................................................................30 
12.6.1 Appointment of a Non-Blinded Medical Monitor and FDA ...............30 
13.0 
Potential Risks to Study Subjects and Risk Mitigation ..........................................31 
13.1 
Risk of Losartan Administration ......................................................................31 
13.2 
Risk of Placebo Administration .......................................................................31 
13.3 
Risks Associated With MRI.............................................................................31 
13.4 
Risks Associated with PRO Questionnaires: ...................................................32 
13.5 
Breach of Confidentiality .................................................................................32 
14.0 
Stopping Rules/Termination of Study Enrollment .................................................33 
14.1 
Termination of Enrollment by the Principal Investigator ................................33 
14.2 
Termination of Enrollment by the Medical Monitor .......................................33 
14.3 
Removal of Subjects from the Study ...............................................................33 
15.0 
Statistical Considerations ..........................................................................................34 
16.0 
Principal Investigator’s Ethical and Regulatory Obligations ................................35 
16.1 
Study Conduct: Ethics and Good Clinical Practice .........................................35 
16.2 
Institutional Review Board ..............................................................................35 
16.3 
Informed Consent.............................................................................................36 
 
Record Keeping and .........................................................................................36 
16.4 
Study Documents .............................................................................................36 
16.4.1 Study Medication Accountability ........................................................37 
16.4.2 Records Retention ................................................................................37 
17.0 
Disclosure and Confidentiality .................................................................................38 
18.0 
Financial Disclosures .................................................................................................39 
19.0 
Interim and Final Study Reports..............................................................................40 
20.0 
Quality Assurance ......................................................................................................41 
20.1 
Subject Completion ..........................................................................................41 
20.2 
Protocol Amendments and Deviations.............................................................41 
21.0 
Declaration of Helsinki ..............................................................................................42 
22.0 
References ...................................................................................................................43 
23.0 
Appendices ..................................................................................................................47 
23.1 
Appendix A: Informed Consent .......................................................................47 
23.2 
Appendix B – Study Schemata ........................................................................58 
 


 
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1.0                  Steadman Philippon Research Institute Representatives 
This Study is an Investigator Sponsored clinical trial to be carried out by The Steadman 
Philippon Research Institute using grant support from the Office of Naval Research, US 
Department of Defense. 
 
 Overall responsibility for the Study will be held by: 
 
Principal Investigator 
Marc Philippon, MD 
Managing Partner, The Steadman Clinic;  
Co-Chairman, Steadman Philippon 
Research Institute 
 
Steadman Philippon Research Institute  
181 W. Meadow Dr. Suite 1000 
Vail, CO 81657 
970-476-1100 
drphilippon@sprivail.org 
 
Independent Medical Monitoring will be provided by an unblinded, appropriately certified 
physician responsible for overseeing the occurrence of adverse events and for providing 
medical advisory assistance to the Study Team.  
 
Medical Monitor 
TBD 
 
 
 
The Study Team 
In addition, there will be a team of Investigators and Research Associates selected by Dr. 
Philippon to whom appropriated duties will be delegated according to their specific 
qualifications.  Collectively Dr Philippon and his designees are referred to as “The Study 
Team” throughout this protocol. 
 
Primary Contact for the Study 
Grant Dornan 
Director of the Center for Outcomes-Based 
Orthopaedic Research (COOR). 
Steadman Philippon Research Institute  
181 W. Meadow Dr. Suite 1000 
Vail, CO 81657 
(970) 479-5868 
gdornan@sprivail.org 
 
 


 
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2.0                Protocol Signature Page 
The signature below constitutes the approval of this protocol entitled, Biologically Regulated 
Marrow Stimulation by Blocking Fibrosis to Improve Cartilage Repair: A Randomized Double 
Blind, Placebo Controlled Study with attachments, and provides the necessary assurances that 
this trial will be conducted in compliance of all stipulations of the protocol, including all 
statements regarding confidentiality, and according to local legal and, regulatory requirements, 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and 
applicable US regulatory requirements. 
 
 
Principal Investigator:  ___________________________________________________ 
Print/Type 
Title:  __________________________________________________________________ 
Signed:  ________________________________________ Date:  _________________ 
 
 
 
 
04/04/2019
Marc J. Philippon, MD
Co-Chairman, Steadman Philippon Research Institute 


 
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3.0                Study Synopsis 
Sponsor: 
Investigator Sponsored Study 
Study Title: 
Biologically Regulated Marrow Stimulation by Blocking Fibrosis 
to Improve Cartilage Repair: A Randomized 
Double Blind, Placebo Controlled Study 
Protocol Number: 
2019-15 
Study Design:  
Randomized, double-blind, placebo controlled 
Study Duration: 
Eighteen (18) months following hip microfracture  
Randomization: 
Subjects are to be assigned to one of two treatment groups using a 
1:1 (losartan/placebo) randomization scheme.   
Study 
Arms/Medication 
Active Treatment: Losartan potassium  12.5mg p.o. BID  
Placebo Control: Appearance matched tablet p.o. BID 
Blinding Procedure: 
Block randomization chart will be securely kept by an Unblinded 
Study Team member, and at the Vail Hospital Pharmacy (point of 
subject distribution)  and with the unblinded Medical Monitor.  All 
study subjects and other Study Team members including the 
Principal Investigator will be blinded to treatment through 18 
months follow-up.  In addition, any individuals engaged by the 
Principal Investigator to provide of radiographic, laboratory testing 
and and/or verification of data will be blinded to treatment.   
Sample Size and 
Study Population: 
A total of 40 male or female subjects ≥ 18 years of age will be 
recruited from up a single clinal site, where the Principal 
Investigator (Investigator Sponsor) conducts patient care. 
All subjects will have agreed to standard of care hip microfracture. 


 
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Objectives:  
Primary Objectives 
To evaluate: 
1. Cartilage quality as assessed by quantitative MRI at 18 
months postoperatively compared between patients treated 
with losartan + microfracture and microfracture + placebo 
alone;  
2. The safety of administering losartan in conjunction with 
microfracture surgery.  
Secondary objectives 
To evaluate: 
1. Patient reported outcomes at 3, 6, 12, and 18 months 
postoperatively compared between patients treated with 
losartan + microfracture and microfracture alone (placebo). 
Endpoints: 
 
 
Primary Endpoints: 
1. T2 mapping values and texture analysis metrics for 
quantitative MRI mapping; 
2. Occurrence of adverse events. 
Secondary Endpoints 
1. Descriptive quantification of  patient reported outcomes in 
each treatment group. 
Inclusion Criteria: 
 
A subject may be included in the study only if he/she meets all of 
the following criteria: 
1. Are aged 18-60 at time of surgery; 
2. Tonnis grade 1 or less; 
3. Present with a single, localized, grade 3 or 4 cartilage lesion 
of the acetabulum or femoral head treated with primary 
BMS (microfracture) performed by Dr. Marc Philippon. 
Exclusion Criteria: 
 
A subject will be excluded for the following reasons: 
General 
1. Non-English speaking; 
2. Diagnosed with inflammatory arthritis or other arthritis 
caused by autoimmune disease; 
3. Taking losartan; 
4. Allergic to any active or inactive ingredient of losartan; 
5. Taking medication with known losartan interaction’ 
6. Are hypotensive as confirmed by the surgical 
anesthesiologist; 
 


 
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Concerning the target hip have on preoperative assessment 
 
7. Prior hip surgery; 
8. Two or more cartilage lesions of grade 3 or 4; 
9. Less than 2 mm of minimal hip joint space; 
10. Osteoarthritis or diffuse change of cartilage; 
11. Pre-existing 
bony 
deformity 
caused 
by 
previous 
fracture(s); 
12. Synovial chondromatosis ; 
13. Pigmented Villanodular Synovitis (PVNS); 
14. Dysplasia (center edge angle <20 degrees); 
15. Coxa profunda; 
16. Protrusia Acetabuli. 
Screening Tools: 
(At preoperative visit) 
Standard of Care Data Collected 
Basic demographic data, medical and surgical history, medication 
review, age, gender, body mass index and chronicity of the injury, 
co-morbidities, smoking status, range of motion, strength and  size 
of the cartilage lesion will be recorded.  Circumduction evaluation 
exercises and range of motion restrictions will be evaluated. Patient 
Reported Outcomes (PRO) tools which will be repeated, at key 
study intervals will be performed and a T2 MRI of the hip will be 
performed as standard of care diagnosis. 
Subject Follow-up: 
All adverse events will be assessed during Study Medication 
administration and for 5 days (+/- 3) days after medication 
completion.  After Study Medication administration only those 
adverse events related to the target hip will be collected. In 
addition, the following data will be collected: 
Visit 1: Post Op Day 1: 
Subject discharge for the hospital is anticipated to occur on POD1.  
At discharge the subject will be provided with a blood pressure cuff 
and be trained on “at home” blood pressure monitoring and 
recording.  They will also be provided with a prescription for Study 
Medication which will be written in a blinded format for either 
losartan or placebo.  Subjects will be instructed to visit the Vail 
Hospital Pharmacy to obtain the correct, blinded Study 
Medication.  Study Medication Logs, and Blood Pressure Logs  
will be provided, with instructions for completion. 
   
Subjects will be instructed to undergo post-operative physical 
therapy, and they will be provided with a document outlining 
recommended content. They will also be provided with a 


 
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prescription for a basic metabolic panel to be drawn by their local 
laboratory within 7-10 days post medication initiation.   
 
POD Day 2 
Subjects begin taking Study Medication 
 
 
POD Day 7-10  (No Visit Required) 
Subjects visit their local laboratory and a Basic Metabolic Panel is 
drawn to include: Glucose, Calcium, Sodium, Potassium, Carbon 
Dioxide (CO2), Chloride; Blood Urea Nitrogen (BUN), and 
Creatinine. 
 
In addition, each subject will be contacted by a Study Team 
member to confirm compliance, and Study Medications are being 
logged. All adverse events and protocol deviations will be 
recorded. 
 
POD Day 35 (+/- 3 days)  Telephone Contact by Study Team 
Post- (No Visit Required)  
Study Medication is expected to be completed at this time. A Study 
Team member will contact each subject to confirm completion. 
Subjects will be asked to send to the Study Team, a copy of the 
Study Medication Log. All adverse events and protocol deviations 
will be recorded. 
 
Visit 2: POD 3 Months (+/- 4 weeks) 
Subjects will be asked to complete the following questionnaires 
either on paper or in electronic format. 
• SF-12 – Short Form General Health Survey; 
• Patient Satisfaction; 
• Harris Hip Score (HHS); 
• Vail Hip Score (VHS); 
• Hip Outcome Score (HOS); 
• Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC); 
• Tegner Activity Scale; and 
• VAS Pain - Visual Analogue Scale for Pain. 
Subjects will receive a focused physical exam, review of all 
medications, strength testing and range of motion (ROM) 
assessment.  Adverse events related to the target hip and protocol 
deviations will be recorded. 
 
POD 6 Months Post-operative -(No Visit Required) (+/- 4 week 


 
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A Study Team member will contact each subject.  Subjects will 
complete electronically each questionnaire as above.  Adverse 
events related to the target hip and protocol deviations will be 
recorded. 
 
POD 12 Months Post-operative -(No Visit Required) (+/- 8 
weeks) 
A Study Team member will contact each subject.  Subjects will 
complete electronically each questionnaire as above.  Adverse 
events related to the target hip and protocol deviations will be 
recorded. 
 
Visit 3: POD 18 Months Post-operative Visit (+/- 8 weeks) 
All procedures performed in POD 3 months will be repeated. In 
addition, subjects will undergo a Morphological and quantitative 
T2 MRI to be performed at Steadman Philippon Research Institute. 
Adverse events related to the target hip and protocol deviations will 
be recorded. 
Statistical Methods 
Intent-to-treat analysis will be performed.  We will compare group 
means, with the hypothesis that greater post-operative PROs and 
higher graft quality as assessed with quantitative imaging will be 
observed in the microfracture plus losartan group compared to 
microfracture alone.  Analysis of Covariance (ANCOVA) or 
Linear mixed-effect models with random intercepts will be used to 
compare groups while adjusting for the baseline measurement of 
each subject. 
 
Sample size for this study was determined via a statistical power 
analysis using published data 
We aim to power this study to detect an effect size between the 
microfracture alone and microfracture plus losartan groups that is 
equal to the observed between-group effect size calculated from 
Apprich, et al (d=1.107). 
 
The significance level will be set at α=0.05. Assuming 2-tailed 
testing and requiring 90% statistical power, 19 patients per group 
are sufficient to detect the effect size of interest.  We aim to enroll 
20 subjects per group.  Power calculations were performed using 
G*Power (version 3.1; Universität Düsseldorf). 
 


 
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4.0                Terms and Abbreviations  
 
Abbreviation 
Term 
BMS 
Bone Marrow Stimulation 
BRBMS 
Biologically Regulated Bone Marrow Stimulation 
COOR 
Center for Outcomes-based Orthopaedic Research 
CRSM 
Center for Regenerative Sports Medicine 
FAI 
Femoro-acetabular Impingement 
MRI 
Magnetic Resonance Imaging 
OA 
Osteo arthritis 
POD 
Post-operative Day (e.g. POD 1, POD 2) 
PRO 
Patient Reported Outcome 
RCT 
Randomized Control Trial 
TGF-β1 
Transforming Growth-Factor Beta 1 
 


 
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5.0                Introduction 
5.1 
Background and Significance 
The Steadman Clinic and the Steadman Philippon Research institute are proposing a 
prospective clinical study to collect safety and efficacy information on the use the drug, 
Losartan, (an FDA approved medication indicated for the treatment of hypertension, diabetic 
neuropathy and hypertension and left ventricular hypertrophy) to test the antifibrotic properties 
of this TGF-β1 blocking agent in reducing the formation of fibrocartilage and increasing 
formation of hyaline cartilage post hip microfracture.  It is proposed that if more durable repair 
tissue (hyaline cartilage) is formed, patients should experience better, long-term clinical 
results. This study is to be used for scientific exploration only. There is no intent to use study 
results to support any change in the labeling of the drug. 
 
This study to be a double blinded, placebo-controlled study of clinically meaningful patient 
reported outcomes including measurements of pain and function. In addition, a T2 MRI will 
be utilized to monitor and characterize the regeneration of fibrocartilage and hyaline cartilage 
in the hip joint at 18 months hip microfracture surgery. All adverse events will be recorded and 
monitored by an unblinded Independent Medical Monitor. 
5.2 
Rationale 
It is well documented that Osteoarthritis (OA) is a leading cause of disability in the United 
States. Hip OA causes pain, decreased hip range of motion, and lower quality of life. (1)  The 
Center for Disease Control and Prevention has reported osteoarthritis affects over 30 million 
adults in the US.(2)  It is estimated that one in four people will develop symptomatic hip 
osteoarthritis in their lifetime.  Untreated, OA leads to advanced cartilage disruption in the 
joint often necessitating a total hip replacement. (3) 
 
The prevalence of total hip replacement was estimated to be at least 2.6 million individuals in 
the United States; the prevalence among adults fifty years of age or older was 2.3 %. (4)  The 
cost of hip replacement continues to increase, with the current cost averaging $30,124 USD 
causing a significant socio-economic burden.(5)  In addition, joint replacement surgeries are 
becoming more prevalent in patients younger than 60 years of age. (6)   With the increasing rate 
of total hip replacement in younger patients, there is a need to develop innovative approaches 
to improve hip cartilage repair in order to prevent or at least postpone the first hip replacement.  
 
Full thickness chondral defects rarely heal without intervention.  Techniques used to treat 
chondral defects and hopefully avoid hip replacement include arthroscopic microfracture (or 
bone marrow stimulation (BMS)), osteochondral autografts, osteochondral allografts, and 
autogenous cell transplantation.(7-9)  Microfracture is the most commonly used first-line 


 
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treatment technique for symptomatic chondral lesions in hip joints.  Microfracture, is easy to 
perform, minimally invasive, and the least expensive treatment for cartilage defects (10-12).  The 
surgical procedure consists of removing the calcified layer and creating small controlled holes 
through the subchondral bone to reach the cancellous bone. (10, 12, 13)  The marrow clot fills the 
chondral defect which is believed to provide bone marrow mesenchymal stem cells that 
subsequently promote cartilage repair. (14, 15) 
 
However, microfracture is cost effective only if results are favorable.  Reports show that 
microfracture has produced good outcomes in patients with grade 3 or 4 cartilage lesions of 
hip joint, however clinical and imaging outcomes vary.  Many scientists and clinicians are 
critical of microfracture because the cartilage repair tissue is a hybrid of hyaline and 
fibrocartilage.  It has been reported that fibrocartilage is the predominant repair tissue 
following the use of the microfracture and bone marrow stimulation techniques. (13, 14, 16) 
Fibrocartilage is not native to the hip joint and is morphologically intended to attach bones and 
limit join mobility.  Hyaline Cartilage is native to all human joints and is morphologically 
intended to provide durable, smooth, lubricated movement.   
 
Given the clear gap in treatment alternatives between microfracture and expensive alternative 
biological therapies, there is a clear need to explore mechanisms by which the outcomes of 
microfracture can be approved.  An enhanced microfracture treatment, or second generation of 
bone marrow stimulation, could be very important in providing an effective,  low cost 
treatment alternative.   
 
The addition of Biologically Regulated Marrow Stimulation (BRMS) through the use of an 
approved pharmaceutical agent (which blocks the production of fibrotic tissue) could lead to 
better outcomes for patients.  We are proposing to explore this possibility  through this 
proposed study where FDA approved losartan will be given for one month after hip  
microfracture.  
 
Losartan, in addition to being an angiotensin receptor blocker, is also a transforming growth 
factor β (TGF-β1) blocking agent.  It is known that (TGF-β) is a central mediator of 
fibrogenesis and that anti-fibrotic agents are reported to enhance articular cartilage repair by 
promoting hyaline cartilage while preventing the fibrosis that typically leads to fibrocartilage. 
Although TGF-β1 is widely believed to be essential for articular cartilage homeostasis, (17, 18) 
it has been recently reported that TGF-β1 is overproduced in osteoarthritic joints. (19)  Recent 
publications have shown a protective effect on hyaline cartilage in TGF-β receptor II 
conditional knock-out mice, and that a higher concentration of TGF-β1 might be one of the 
causes of osteoarthritis.(20, 21)   Further, it was reported that cartilage injury causes activation of 
TGF-β activated kinase-1 (TAK- 1), resulting in inflammation of the joint and degenerative 


 
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changes in the cartilage, (22) and inhibition of TAK-1 can prevent inflammation-related 
cartilage degeneration in an osteoarthritis model.(23)   Furthermore, Price et al reported that 
systemic losartan use inhibited inflammation in the animal arthritis model through suppressing 
tumor necrosis factor alpha in synovial tissues. (24)  Several studies have shown that oral intake 
of losartan can inhibit tissue fibrosis by blocking TGF-β1- pSmad2/3 signaling pathway, in 
musculoskeletal applications.(25-28) 
5.3 
Safety of Administering Losartan to Normotensive Patients 
The proposed protocol requires randomization of individuals to be treated either with  losartan 
12.5mg twice daily or placebo for one month following micro fracture surgery.  Subjects will 
be excluded if they are symptomatically hypotensive, require medication with known 
interactions with losartan (to include all antihypertensive medication) or are currently taking 
losartan for any reason. It is therefore informative to explore the safety of losartan in 
normotensive subjects. 
 
In 1983, Burnier et al (29) reported on their review of the literature in order to define  appropriate 
dosing of antihypertensive medications in circumstances when new medication is being 
developed.  They reported that similar pressor mechanisms are active in hypertensive and 
normotensive subjects.  Doses sufficient to block the pressor effect of Angiotensin I in normal 
volunteers were identical to those needed to treat hypertensive patients.  Although studies 
examined the renin system response of various ACE inhibitors including captopril 5, 20, 25, 
100 and 200mg, enalapril 1.5, 2.5, 10 and 20mg, as well as unspecified doses of pentopril, this 
finding underlines the similarities in pressor response between normal and hypertensive 
individuals.  
 
A number of clinical studies have been performed reporting on the use of antihypertensive 
agents on 138 normotensive subjects. The following is a brief summary of the effects of  
healthy individuals highlighting key data in support of the established safety of administering 
losartan (angiotensin II receptor antagonist) to normotensive individuals.   
 
Upon its introduction into Phase I testing in the 1990s, Burnier et. al. (30) published a further 
review examining the clinical pharmacology of losartan, specifically addressing the effects on 
the renin-angiotensin system, blood pressure and heart rate, renal hemodynamics, renal tubes, 
and uric acid excretion of healthy, normotensive subjects.  This review included studies of a 
total of 126 normotensive individuals and includes the publications by Christen, (31),        
Munifo,(32) Goldberg, (33) Diog,(34) Brunier(35) and Nakashima.(36)  It was found that 
administration of losartan was associated with a dose-dependent increase in plasma renin 
activity and plasma angiotensin II levels, with no significant changes in plasma aldosterone 
obtained with doses smaller than 120mg.  It was also reported that losartan increased uric acid 


 
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excretion (as much as by 30%) and hence decreases serum uric acid levels.  However, there 
was no significant effects on heart rate of healthy, normotensive subjects receiving up to 
120mg of losartan.  Results showed that there was little or no effect on the blood pressure of 
normotensive individuals (unless the subjects are markedly salt-depleted).  
 
This finding confirmed by the dose-ranging study performed by Doig et. al, (34) which included 
5, 10, 25, 50, and 100mg doses of losartan or matched placebo given to 12 normotensive men 
subjected to limited-sodium diets.  More pronounced reductions of blood pressure were seen 
at doses of 50 and 100mg.  Recording of side effects concluded that, at all doses, losartan was 
well tolerated, and side effects were consistent with other angiotensin-converting enzyme 
inhibitors, albeit infrequent.  Lightheadedness was the most commonly reported adverse 
symptom, occurring more prevalently at higher doses of losartan, and was determined to be 
mainly posture-related.  An asymptomatic and rise in transaminase levels in one subject at and 
increase in urea and creatinine in association with nausea in another subject was found.  Both 
adverse events occurred within 24 hrs. of 100mg losartan administration.  
 
Across all studies examined, no significant effects on normotensive subjects were reported at 
the dose proposed in this study (12.5 mg).  In addition, adverse response was seen early in the 
course of losartan administration, and there is no evidence of cumulative response over time. 
However, it should be noted that Azizi et. al (37) studied the additive effects of combined 
angiotensin-converting enzyme inhibitors (in this case, captopril) in 12 healthy individuals 
with the angiotensin II antagonist losartan and found that combined administration had major 
additive effects on plasma renin rise with additional reduction of blood pressure.  This finding 
has informed our decision to exclude from the study, all patients taking medications having 
known interaction with losartan.  


 
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6.0                Summary of Proposed Placebo Controlled Trial 
 
Our objective is to determine in a placebo controlled if the administration of losartan post 
microfracture will result in reduced fibrosis in healing tissue and will improve hyaline cartilage 
repair.  Patients who have undergone microfracture for a focal chondral defect of the femoral 
head or acetabulum will be considered candidates for enrollment. A member of the Study Team 
will review the patients’ record to determine if all inclusion/exclusion criteria are met.  Each 
potential subject will be fully informed regarding all aspects of the proposed study and will be 
required to review and sign a full, IRB approved, informed consent document attached as 
Appendix A.  
 
Forty patients who have consented to participate will be assigned, 1:1 via block randomization, 
one of the two blinded study groups.   
 
1) n=20: standard microfracture + losartan [TGF-β1 blocker]); or  
2) n=20 standard microfracture + placebo. 
 
Losartan and the inactive placebo are collectively referred to as Study Medication. 
 
A  Study Team member will then inform the pharmacist of the patient’s assigned group and 
the patient will pick up study medication prior to leaving the hospital following microfracture. 
This is expected to occur on post-operative day one (POD1).  Subjects will self-medicate for 
one month following surgery either 12.5mg losartan twice daily or placebo twice daily.  A log 
recording medication administration ( Medication Log) will be maintained daily by the subject 
during the administration month. 
 
Subjects will also be given a blood pressure cuff to take home to for twice daily self-monitoring 
and recording of blood pressure while the Study Medication is being administered, after which 
time blood pressure should be measured once weekly until the 3-month visit. 
 
Subjects will be instructed to undergo physical therapy and a document describing the 
recommended content of that therapy will be provided. 
 
At 7-10 days postoperatively subjects will be required to undergo a standard Basic Metabolic 
Panel.  Results will be faxed to the Principal Investigator or designee.  Subjects will also be 
interviewed by telephone by a Study Team member to document possible protocol violations, 
all adverse events, subject blood pressure and compliance with blood draw and study 
medication.  
 


 
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At the conclusion of study medication, subjects will be contacted by the Study Team to confirm 
completion of medication.  The occurrence protocol deviations and of all adverse events will 
be documented. 
 
At three months post operatively, subjects will be seen for a visit The  Steadman Clinic.  A 
copy of the Medication Log will be retained by the Study Team, and subjects will complete  
Patient Reported Outcomes (PROs) either on paper or electronically. These tools are described 
in more detail in Section 13.5 of this protocol.  All medical  history will be updated including 
all medications.  Vital signs will be recorded, and subjects will undergo strength testing and 
range of motion assessment by the Principal Investigator or a designee.  Protocol deviations 
and all adverse events related to the target hip will be collected. 
 
At six and twelve months post operatively, subjects will be required to complete from home 
the assigned PROs electronically.  Subjects will be contacted by phone and protocol 
deviations and all adverse events related to the target hip will be collected. 
 
At eighteen months postoperatively, subjects will be seen at the Steadman Clinic.  PRO 
questionnaires will be completed. Medical  history will be updated including all medications.  
Vital signs will be recorded, and subjects will undergo strength testing and range of motion 
assessment by the Principal Investigator or a designee. In addition, morphological and 
quantitative T2 MRI will be performed to assess the regrowth of new cartilage tissue. protocol 
deviations and all adverse events related to the target hip will be collected. 
 
After all subjects have reached 18 months follow-up, primary and secondary outcomes will be 
analyzed as described in Section 17 of this document.  Unblinding of the Study Team and the 
Subject will occur. 
6.1 
Blinding 
All study subjects and Study Team members responsible for subject evaluation, data 
management and analysis (Including the Principal Investigator) will be blinded to treatment 
through 18 months follow-up.  In addition, any individuals engaged by the Principal 
Investigator to provide of radiographic, laboratory testing and and/or verification of data will 
be blinded to treatment.   
One Study Team Member responsible for group assignment, the pharmacist responsible for 
medication distribution and the Independent Medical Monitor will be unblinded. 


 
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7.0                Study Medication Treatment  
7.1 
Losartan Potassium 
Losartan potassium  is an angiotensin II receptor (type AT1) antagonist.  Losartan potassium, 
a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1­ [p-(o-1H-tetrazol-5-
ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Losartan potassium is a white to 
off-white free-flowing crystalline powder with a molecular weight of 461.01.  It is freely 
soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as 
acetonitrile and methyl ethyl ketone.  Oxidation of the 5-hydroxymethyl group on the 
imidazole ring results in the active metabolite of losartan.  
 
Losartan will be sourced through PenCol Compounding Pharmacy, located in Denver, 
Colorado. provided to subjects in its approved, marketed generic form.  Scored tablets 
containing  25 mg  of active ingredient (losartan) will be split by the pharmacy to provide 
individual dosage of 12.5 mg, to be taken by subjects twice daily (BID).  Directions for Use 
can be found in using the following link. 
https://www.bioportfolio.com/resources/drug/15151/Losartan-Potassium-Sandoz-Inc.html 
. 
7.2 
Placebo Control 
Appearance matched placebo medication will also be compounded at PenCol Compounding 
Pharmacy, located in Denver, Colorado.  
7.3 
PenCol Compounding Pharmacy 
PenCol is accredited by the Pharmacy Compounding Accreditation Board (PCAB).  This 
accreditation confers the most comprehensive compliance assurance in the pharmaceutical 
industry, with standards based on U.S. Pharmacopeial Convention (USP) guidelines.  This 
process includes an extensive on-site survey conducted by an independent expert and annual 
verification ensures compliance with the non-sterile and sterile pharmacy compounding 
process defined by USP <795> and USP <797>.  The address and contact information for  
PenCol is provided below. 
 
1325 South Colorado Boulevard  
Suite B-024  
Denver, CO 80222 
Phone: 303.388.3613 
 
The compounding pharmacy will work directly with the Vail Pharmacy within Vail Health 
Hospital.  All subjects will obtain their medication (or placebo) directly from Vail Pharmacy. 


 
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8.0                 Study Design 
 
This is a prospective, randomized, placebo controlled, double blind study. to be conducted at 
the Steadman Clinic and the Steadman Pilippon Research Institute.  A total of 40 subjects will 
be randomized 1:1  to receive either standard microfracture of the hip + losartan or standard 
microfracture of the hip + placebo. 
 
Subjects will be blinded to medication treatment. To maximize the objectivity of follow-up 
evaluations, all Study Team members involved in study assessments or documentation will be 
blinded through 18 months follow-up. 


 
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9.0                   Study Objectives and Endpoints 
9.1 
Primary Objectives 
To evaluate:  
 
1. Cartilage quality as assessed by quantitative MRI at 18 months postoperatively compared 
between patients treated with losartan + microfracture and microfracture + placebo alone;  
 
2. The safety of administering losartan in conjunction with microfracture surgery.  
9.2 
Secondary Objective 
To evaluate:  
 
1. Patient reported outcomes at 3, 6, 12, and 18 months postoperatively compared between 
patients treated with losartan + microfracture and microfracture alone (placebo).  
9.3 
Study Endpoints 
9.4 
Primary Endpoints: 
1. T2 mapping values and texture analysis metrics for quantitative MRI mapping; 
2. Occurrence of adverse events. 
9.5 
Secondary Endpoints 
1. Descriptive quantification of  patient reported outcomes in each treatment group. 
Investigators and Study Sites 


 
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10.0 
Study Population  
 
Patients who have undergone microfracture for a focal chondral defect of the femoral head or 
acetabulum will be considered candidates for enrollment.  A member of the Study Team will 
review the patients’ standard of care record to determine if all inclusion/exclusion criteria are 
met.  Patients meeting the study's inclusion/exclusion criteria will then be approached by this 
same study member with the opportunity to provide informed consent to enter this study.  This 
meeting will take place during the patient’s first post-operative physical therapy visit in a 
private setting. 
10.1 Description 
Qualified subjects who personally give informed consent will be screened for eligibility.  Only 
subjects who meet all eligibility criteria will be randomized and treated with either losartan or 
placebo.  
10.2 Source of Subjects 
Study subjects will be identified and recruited from the practice of the Principal Investigator. 
No external recruitment or advertising is to be engaged. 
10.3 Enrollment Criteria   
10.3.1 Inclusion Criteria 
Patients who: 
1. Are aged 18-60 at time of surgery; 
2. Tonnis grade 1 or less; 
3. Present with a single, localized, grade 3 or 4 cartilage lesion of the acetabulum or 
femoral head treated with primary BMS (microfracture) performed by Dr. Marc 
Philippon. 
10.3.2 Exclusion Criteria 
Patients who are  
General 
1. Non-English speaking; 
2. Diagnosed with inflammatory arthritis or other arthritis caused by autoimmune disease; 
3. Taking losartan; 
4. Allergic to any active or inactive ingredient of losartan; 
5. Taking medication with known losartan interaction’ 
6. Are hypotensive as confirmed by the surgical anesthesiologist; 
 


 
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Concerning the target hip have on preoperative assessment: 
7. Prior hip surgery; 
8. Two or more cartilage lesions of grade 3 or 4; 
9. Less than 2 mm of minimal hip joint space; 
10. Osteoarthritis or diffuse change of cartilage; 
11. Pre-existing bony deformity caused by previous fracture(s); 
12. Synovial chondromatosis; 
13. Pigmented Villanodular Synovitis (PVNS); 
14. Dysplasia (center edge angle <20 degrees); 
15. Coxa profunda; 
16. Protrusia Acetabuli. 


 
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11.0 
Study Procedures 
 
Patients who present for treatment and in whom operative treatment has been planned, will as 
part of their pre-operative evaluation undergo a standard of care medical review.  Basic 
demographic data will be collected, including age, gender, body mass index, chronicity of the 
injury, and surgical data will be queried. Additional data including medical co-morbidities, 
smoking status, medication use, will be collected. History of hip trauma, range of motion, 
strength, size of the cartilage lesion, circumduction evaluation exercises and range of motion 
restrictions will be evaluated. As standard of care, patients complete several Patient Reported 
Outcomes (PRO) tools which will be repeated, at key study intervals as described in the 
following section of this document, should the patient consent to participate in the study. 
Subjects will also undergo a T2 MRI of the hip as standard of care diagnosis.  
 
These routine baseline measurements will be used to evaluate preliminary eligibility.  If 
eligibility seems likely, a member of the Study Team will briefly describe this study and gauge 
the patient’s interest in participation. 
 
A full Study Schemata is provided in Appendix B. 
11.1 Visit 1: Day 1 Post-operative  
Each potential subject  will be fully informed of  all requirements of participation as well as 
the voluntary nature of participation.  If they are interested in participation, they will be asked 
to sign the Informed Consent Form (ICF) as approved by the reviewing Institutional Review 
Board.  One copy of the completed Informed Consent Form will be given to the subject and 
the original must be retained as a source document.  Subjects will be randomized only after 
informed consent has been obtained.  A unique subject study ID will be assigned upon 
signature of Informed Consent. The subject study ID number will be recorded on all pertinent 
study records, as described in Section 15.5 of this document 
 
Subject discharge for the hospital is anticipated to occur on POD.  At discharge the subject 
will be provided with a blood pressure cuff and be trained on “at home”  blood pressure 
monitoring and recording.  They will be instructed to undergo physical therapy and receive a 
document outlining the recommended content of that therapy.  They will also be provided with 
a prescription for Study Medication which will be written in a blinded format for either losartan 
or placebo.  Subjects will be instructed to visit the Vail Hospital Pharmacy to obtain the correct, 
blinded Study Medication. Study Medication Logs will be provided, with instructions for 
completion.   
 


 
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Subjects will also be provided with a prescription for a basic metabolic panel to be drawn by 
their local laboratory within 7-10 days post medication initiation.   
11.2 Day 2 Post-operative (No Visit Required) 
Subjects begin taking Study Medication 
 
11.3 Day 7-10 Post-operative (No Visit Required) 
Subjects visit their local laboratory and a Basic Metabolic Panel is drawn to include: 
• Glucose; 
• Calcium; 
• Sodium; 
• Potassium; 
• Carbon Dioxide (CO2); 
• Chloride; 
• Blood Urea Nitrogen (BUN); and  
• Creatinine. 
 
In addition, each subject will be contacted by a Study Team member to confirm that the blood 
draw has occurred, and Study Medications are being logged. The occurrence of protocol 
deviations and all adverse events will be recorded. 
11.4 Telephone Contact by Study Team Post-operative day 30- (No Visit Required) 
(approximately one month) 
Study Medication is expected to be completed at this time. A Study Team member will contact 
each subject to confirm that the Study Medication has been completed and logged. Subjects 
will be asked to send to the Study Team, a copy of the Study Medication Log.  The occurrence 
of protocol deviations and all adverse events will be recorded. 
11.5 Visit 2: Three Months Post-operative Clinic Visit (+/- 4 weeks) 
Subjects will be asked to complete the following questionnaires either on paper or in electronic 
format. 
• SF-12 – Short Form General Health Survey; 
• Patient Satisfaction; 
• Harris Hip Score (HHS); 
• Vail Hip Score (VHS); 
• Hip Outcome Score (HOS); 
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); 


 
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• Tegner Activity Scale; and 
• VAS Pain - Visual Analogue Scale for Pain. 
 
Subjects will receive a focused physical exam, review of all medications, strength testing and 
range of motion (ROM) assessment. Protocol deviations and adverse events related to the 
target hip will be recorded. 
11.6 6 Months Post-operative -(No Visit Required) (+/- 4 weeks) 
A Study Team member will contact each subject.  Subjects will complete electronically each 
questionnaire as above.  Adverse events related to the target hip and protocol deviations will 
be recorded. 
11.7 12 Months Post-operative -(No Visit Required) (+/- 8 weeks) 
A Study Team member will contact each subject.  Subjects will complete electronically each 
questionnaire as above.  Adverse events related to the target hip and protocol deviations will 
be recorded. 
11.8 Visit 3: 18 Months Post-operative (+/- 8 weeks) 
All procedures performed in Visit 3 will be repeated. In addition, subjects will undergo a 
Morphological and quantitative T2 MRI to be performed at Steadman Research Institute 
according to a specific and consistent imaging protocol  Adverse events related to the target 
hip and protocol deviations will be recorded. 
11.9 Unscheduled Visits and/or Subject Contact 
In the event that additional visit(s) or subject contact is required other than those described in 
the protocol, the information must be documented in the appropriate study document.  
 


 
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12.0 
Study Management of Adverse Events 
12.1 Definition 
Adverse Event – An adverse event (AE) is any untoward medical occurrence in a subject 
administered a Study Medication and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
whether or not related to the Study Medication (ICH E2A II/A/1, 21 CFR 312.32). 
 
All pre-existing medical conditions will be recorded on the medical history study document. 
Starting with the administration of the Study Medication any new experience that was not 
present at baseline or worsening of an event present at baseline in intensity or frequency, is 
considered an adverse event.   
 
Note: Unchanged, chronic conditions are NOT adverse events and should not be recorded.  
 
It is recognized that subjects will exhibit (throughout follow-up) symptoms of the underlying 
disease process of that fluctuates in severity and duration.   
 
Adverse events will include those occurrences, which when compared to before treatment 
meets any of the following criteria: 
 
• Represent a new event or escalation of an event;  
• Require a new escalation in  treatment; 
• Lasts longer; 
• Experienced more frequently; 
• More intense; 
• Different in character ( e.g. stabbing vs. ache); 
• Experienced in a different part of the body; and/or 
• Brought on by activity that previously did not cause the symptom. 
12.2 Recording Adverse Events 
Adverse events that occur up to 35 days +/- 3 days after the beginning Study Medication 
administration will be recorded.  Terms should be recorded consistently, using acceptable 
medical terms.  When possible, a diagnosis should be identified as the AE (i.e., disease or 
syndrome) rather than the component signs and symptoms, and recorded on the case report 
form (e.g., record congestive heart failure rather than dyspnea, rales and cyanosis).  However, 
signs and symptoms considered unrelated to encountered syndromes or diseases are to be 


 
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recorded as individual AEs (e.g., if congestive heart failure and severe headaches are observed 
at the same time, each experience is to be recorded as an individual AE).  The AE should not 
be recorded as a procedure or clinical measurement (i.e., a laboratory or vital sign) but should 
reflect the reason for the procedure or diagnosis. 
 
Death is considered to be an outcome of an AE.  The cause of death (rather than the term 
“death”) should be recorded on the serious AE and death report case report forms.   
 
Subjects should be encouraged to report AEs spontaneously or in response to general, non-
directed questioning.  At each required visit (or whenever reported) during the study, all AEs 
that have occurred since the previous visit must be recorded on the AE case report form.   
 
All AEs, regardless of seriousness, severity, or presumed relationship to the treatment must be 
recorded using medical terminology  
 
All AEs must be followed until resolution or until a stable clinical endpoint is reached.  All 
measures required for AE management and the ultimate outcome of the AE must be recorded 
in the study  document.  All adverse events that occur in the study population will be tabulated 
and summarized. 
 
Date of Onset and Resolution 
The date of onset is the time at which the subject reports that the incident began.  This may or 
may not be the date on which the Study Team became aware of the event.  The date of 
resolution is the date at which the event was no longer apparent to the subject and/or the Study 
Team.  This may be unknown if at the end of the study the event is not resolved.  In this case, 
the event will be indicated to be unresolved. 
 
Incidence 
An AE may be classified as “intermittent”  or “continuous if has no periods of abatement. 
 
Relationship to Study Medication  
The Principal Investigator is required to assess whether there is a reasonable possibility that 
the Study Medication caused or contributed to an AE. 
 
Many terms and scales are used to describe the degree of causality between a Study Medication 
and an event.  The expression “reasonable causal relationship” is meant to convey in general 
that there are facts (evidence) or arguments to suggest a causal relationship (ICH E2A, III/A/1). 
 


 
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Determination of whether there is a reasonable possibility that a treatment caused or 
contributed to an AE includes assessing temporal relationships, biologic plausibility, 
association (or lack of association) with underlying disease, and presence (or absence) of a 
more likely cause. 
 
As is recommended in FDA draft guidance document, Safety Reporting Requirements for 
INDs and BA/BE Studies (2010), we define four degrees of relatedness: “unrelated”, “probably 
not related”, “suspected adverse drug reaction” (SADR) or “adverse reaction”.  
 
Unrelated (clearly not related to the research) 
The occurrence of the AE is not reasonably related in time, OR the AE is considered unlikely 
to be related to the treatment (biologically implausible). 
 
Probably not related (doubtfully related to the research) 
The administration of the treatment and the AE are not considered reasonably related in time 
AND the AE could also be explained by causes other than the treatment (concurrent 
illness/underlying disease, other drugs or procedures).  
 
Suspected Adverse Drug Reaction (SADR)  
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
treatment caused the AE.  A ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the treatment and the AE.  A SADR reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a treatment.  
The Principal Investigator should consider if exposure to the treatment and the AE are 
reasonably related in time AND the treatment is more likely than other causes to be responsible 
for the AE or is the most likely cause of the AE. 
 
Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions for which there is reason to conclude that the treatment 
caused the event. 
 
If the event is felt by the Principle Investigator to be either a SADR or an adverse reaction, 
every effort will be made to identify the event as related to the Study Medication.  Adverse 
events that are generally felt to be attributable to the Study Medication occur in close temporal 
relationship to the onset of dosing. A discussion of AEs that are common with the Study 
Medication is found in the Section 15.1 of this document  
 


 
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All adverse reactions and SADRs will be followed until resolution or the Investigator judges 
the experience to be chronic or stable. 
12.3 Severity (Intensity) of Adverse Events 
The severity of the adverse events should be assessed based on the following grading scale:  
• Grade 1 ( Mild): Adverse event that is noticeable to the subject and may require 
additional therapy; 
• Grade 2 (Moderate ): Adverse event that interferes with the subject’s activities and 
requires intervention or additional therapies; 
• Grade 3 (Severe): Adverse event that is intolerable, or necessitates additional therapy 
or places the subject at immediate risk of harm; 
• Grade 4: Adverse event that is life‐threatening or disabling  (hospitalization); 
• Grade 5: Adverse event that results in Death. 
12.4 Expected and Unexpected Adverse Events 
“Expected” AEs are those that have been previously reported as associated with the disease 
process.  All others are to be recorded as “Unexpected”.   
12.5 Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Principal Investigator, it results in any of the following outcomes:  
• Death; 
• A life-threatening adverse event. 
An AE or suspected adverse reaction is considered “life-threatening” if, (in the view of the 
Principal Investigator) its occurrence places the patient or subject at immediate risk of death.  
It does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death.   
 
Serious and/or unexpected adverse event(s) may present as either a local or systemic response, 
or both, which may present as an anaphylactic response associated with generalized urticaria, 
shortness of breath, or respiratory or circulatory arrest. 
 
Subjects will be instructed to contact the study site immediately if a systemic reaction occurs 
between scheduled study visits.  Subjects may be assessed initially over the phone and may be 
asked to return to the study site for an additional visit to assess the reaction.  
 


 
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12.6 Reporting of Adverse Events  
12.6.1 Appointment of a Non-Blinded Medical Monitor and FDA 
An Independent Medical Monitor will be selected to oversee study safety..  This individual is 
to be an appropriately certified physician experienced in the management of blood pressure..  
He/she will be unblinded to Study Medication.   
 
The portion of this study which is greater than minimal risk involves administration of losartan 
or placebo for 1 month following enrollment in the study. All adverse events will be monitored 
by the blinded Study Team  during this time period. 
 
The Principal Investigator will be responsible for confirming the severity of all adverse events. 
All serious and unexpected adverse events will be reported to the unblinded Independent 
Medical Monitor within 24 hours of their disclosure to the Principal Investigator.  The Medical 
Monitor will review data or events reported by the Study Team within 72 hours of disclosure 
to the Medical Monitor.  
 
During this time appropriate care will be given to the study subject. If managing adverse events 
requires unblinding to the any member of the Study Team, the appropriate team member will 
disclose the group identity to the necessary medical provider.  
 
The IRB will be notified of unanticipated and serious adverse events within 5 business days of 
identification.  This reporting may come from the Study Team, the Independent Medical 
Monitor, or both.  
 
If a subject experiences a serious and unexpected adverse event while taking losartan, FDA 
will be notified by telephone or facsimile  within 7 days, and in writing within 15 days hours 
(after the Principal Investigator’s initial receipt of the information).   
 
Each written notification may be submitted on FDA Form 3500 or in a narrative format and 
shall bear prominent identification of its contents, i.e., "Med Watch  Safety Report".   
 


 
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13.0 
Potential Risks to Study Subjects and Risk Mitigation 
 
Expected risks to subjects in this study include all those currently associated with osteoarthritis 
and as sequala to microfracture surgery.  Additional risk to subjects which might arise as the 
result of study participation are discussed below. 
13.1 Risk of Losartan Administration 
A full description of expected side effects can be found in Losartan’s directions for use 
https://www.bioportfolio.com/resources/drug/15151/Losartan-Potassium-Sandoz-Inc.html 
Known side effects include dizziness, headache, diarrhea, stomach pain, muscle cramps, leg 
or back pain, insomnia, tiredness and cold or flu symptoms such as stuffy nose, sneezing, sore 
throat, fever and cough.  In addition, there is a chance that administration of losartan will not 
improve the outcomes of microfracture. 
 
Subjects will be fully informed about expected side effects of losartan and will be instructed 
to inform the Primary Investigator should these symptoms become apparent. Informed consent 
will include information revealing that it is unknown if losartan will improve the outcomes of 
microfracture. 
13.2 Risk of Placebo Administration 
If results of this study reveal that administration of losartan improves the results of 
microfracture, subjects randomized to placebo may miss these benefit(s). 
 
Subjects will be fully informed regarding the expected outcomes of standard microfracture 
surgery and will be told that they have only a 50% chance of being randomized to receive 
losartan. In addition, subjects will be told that the advantages of receiving losartan following 
microfracture are unknown. 
13.3 Risks Associated With MRI 
The MRI scan involves exposure to loud noise, and positioning in a small space. Subjects may 
feel claustrophobic, fatigued or nauseated especially if they are uncomfortable with tight 
spaces.  The MRI scan does not involve the use of x-rays or injectable dyes.  There are no 
known reports of increased cancer or birth defects associated with this procedure. The MRI 
scan exposes the subject to high magnetic fields, which can be dangerous for those with 
pacemakers and some metal implants.  
 
All participants will be offered music and/or earplugs to reduce the noise level produced by 
the MRI machine. Participants with a pacemaker, hearing aid, aneurysm clips or artificial heart 
valves, and other forms of loose metal implants will be excluded from the study as assessed by 


 
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a pre-MRI questionnaire administered as part of the eligibility screening prior to enrollment. 
The screening will be conducted again the day of the MRI, to ensure the participant can still 
safely undergo an MRI. It is possible that a participant will become unexpectedly ineligible for 
an MRI between the first and second testing days (e.g. if they receive a pacemaker after the 
first testing day). In this case, the participant will be allowed to continue with motion capture 
and DSX testing but will not have an MRI taken. 
13.4 Risks Associated with PRO Questionnaires:  
Completion of the PRO questionnaires should take each subject approximately 20-30 minutes. 
There is a risk that subjects may find this laborious and experience emotional distress. 
 
To mitigate this experience, subjects will be fully informed and instructed on how to complete 
each questionnaire. Subjects can also elect to taking “breaks” during questionnaire completion. 
Subject will also be offered the option of completing questionnaires electronically at home. 
13.5 Breach of Confidentiality 
There is a possibility that personal information could be accidentally or inappropriately 
breached during this research.  
 
The Steadman Clinic and Steadman Philippon Research Institute use many physical, 
technologic and administrative measures to protect your information.  Deidentifying study 
information, assignment of an alpha-numeric study identifier, locking offices and cabinets, 
password-locked work stations and encryption protect electronic information.  Information 
will be used and analyzed in a manner that does not contain any of identifiable information. 
When results of this research are presented at scientific meetings and in medical journals, all 
information that can possibly identify subjects will be removed. 
 
All electronic  PRO data is encrypted using the AES-256 encryption algorithm, and high-grade 
SHA-256 RSA encryption is used for https connections over TLS. Secure network access is 
enforced by multi-tiered firewalls, custom system configurations and multi-zones networks.  
 
 
 
 
 
 


 
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14.0 
Stopping Rules/Termination of Study Enrollment 
The triggering of stopping rules will result in prompt discontinuation of subject enrollment and 
notification of the Medical Monitor and IRBs.  Although enrollment will cease, all subjects 
enrolled up until that point will continue to be followed according to the protocol for evaluation 
for duration of the clinical trial.  Enrollment will be reconvened only when permission is 
granted by the IRB. 
14.1 Termination of Enrollment by the Principal Investigator 
The Principal Investigator may terminate study enrollment at any time for any of the following 
reasons.  
1. Any unexpected serious or life-threatening AE that cannot be determined to be 
unrelated to Study Medication; 
2. It is determined that the protocol precipitates multiple subject non-compliance issues 
beyond reasonably missed follow-up. 
14.2 Termination of Enrollment by the Medical Monitor 
The Medical Monitor may terminate enrollment due to the emergence of significant safety 
signals. 
14.3 Removal of Subjects from the Study 
Principal Investigators may remove a subject from the study if: 
 
1. Subject demonstrates poor compliance with study protocol; 
2. There is concurrent illness or required medical treatment that interferes with study 
assessments; 
3. The Principal Investigator determines that the subject’s health, safety or welfare is at 
risk. 
 
For subjects taking losartan, symptomatic hypotension, significant electrolyte imbalance, acute 
renal failure, or severe nausea or vomiting precluding medication compliance will result in 
immediate discontinuation of the subject's course of medication. 
 
 


 
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15.0 
Statistical Considerations 
 
Patients will be randomized with a 1:1 allocation ratio into either the microfracture plus 
losartan versus microfracture alone group.  Block randomization will be used with block sized 
of n=8 to ensure that groups are of approximately equal size at study completion, even if some 
patients are lost to follow-up or unenrolled. 
 
Intent-to-treat analysis will be performed.  We will compare group means, with the hypothesis 
that greater post-operative PROs and higher graft quality as assessed with quantitative imaging 
will be observed in the microfracture plus losartan group compared to microfracture alone. 
Analysis of Covariance (ANCOVA) or Linear mixed-effect models with random intercepts 
will be used to compare groups while adjusting for the baseline measurement of each subject. 
 
The effect size of microfracture plus losartan compared to microfracture alone with respect to 
patient reported outcomes is unknown, so a sample size calculation was performed based on 
anticipated quantitative   
 
Anticipated effect sizes for the group difference with respect to MRI-assessed cartilage quality 
were derived from the literature, however a paucity of helpful literature was found in the hip 
literature.  Sample size for this study was determined via a statistical power analysis using 
published data from Apprich, et al (38), who compared patients treated with microfracture of 
the talus versus patients treated with matrix-associated autologous chondrocyte transplantation 
(MACT).  
 
The primary outcome metric reported in Apprich, et al was a semi-quantitative scale of 
diffusion-weighted imaging (DWI) acquired by MRI and the paired differences between DWI 
of the repaired tissue and healthy reference cartilage for each patient was reported for each 
treatment group.  We aim to power this study to detect an effect size between the microfracture 
alone and microfracture plus losartan groups that is equal to the observed between-group effect 
size calculated from Apprich, et al (d=1.107).  
 
The significance level will be set at α=0.05.  Assuming 2-tailed testing and requiring 90% 
statistical power, 19 patients per group are sufficient to detect the effect size of interest. We 
aim to enroll 20 subjects per group. Power calculations were performed using G*Power 
(version 3.1; Universität Düsseldorf). 


 
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16.0 
Principal Investigator’s Ethical and Regulatory Obligations 
 
The Principal Investigator is responsible for ensuring that the trial is conducted according to 
the signed investigator statement, the study protocol and applicable regulations; for protecting 
the rights, safety, and welfare of subjects under the investigator's care; and for the control of 
the Study Medication.  The Principal Investigator shall confirm informed consent for each 
subject to whom losartan or placebo, is administered.  A discussion of the Principal 
Investigator’s minimal responsibilities follows. 
16.1 Study Conduct: Ethics and Good Clinical Practice 
Principal Investigator will administer Study Medication only to subjects under his personal 
supervision or under the supervision of an appropriate Study Team designee responsible to the 
Principal Investigator.   
 
This study must be carried out in compliance with the protocol and in accordance with the 
Good Clinical Practice, ICH Guidelines and the Declaration of Helsinki, concerning medical 
research in humans (Recommendations Guiding Physicians in Biomedical Research Involving 
Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, 
Somerset West 1996).   
 
The Principal Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the applicable regulatory requirements and 
to the principles of Good Clinical Practice to which it conforms. 
16.2 Institutional Review Board 
The Principal Investigator shall assure that an IRB that complies with the requirements set 
forth in ICH and FDA guidelines will be responsible for the initial and continuing review and 
approval of the proposed clinical study.  The Principal Investigator shall also ensure that he or 
she will promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risk to human subjects or others.  Except when the changes constitute 
minor administrative ones or where necessary to eliminate apparent immediate hazards to 
human subjects, the Principal Investigator will not make any changes in the research without 
IRB approval. 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
subject information, must be reviewed and approved by the Institutional Review Board (IRB).  
 
Other Principal Investigator responsibilities relative to the IRB include the following: 
• Submit all protocol amendments to the IRB for review; 


 
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• Report to the IRB any information about serious AEs reported in other studies 
associated with treatment; 
• Provide the IRB with any other information it requests before or during the conduct of 
the study; 
• Report to the IRB all adverse events as required by the approving IRB(s); 
• Maintain a file of IRB/study-related information; 
• Update the IRB on a minimum of a yearly basis; 
• Maintain IRB approval during the duration of the study.  
16.3 Informed Consent 
Principal Investigators must explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail.  Each subject must be informed that participation in the study is 
voluntary and that he or she may withdraw from the study at any time and that withdrawal of 
consent will not affect his or her subsequent medical treatment or relationship with the treating 
physician. 
 
This informed consent should be given by means of a standard written statement, written in 
non-technical language.  The subject should read and consider the statement before signing 
and dating it and should be given a copy of the signed document. 
 
No subject can enter the study before his/her informed consent has been obtained. 
 
The Informed Consent Form must be submitted by the Principal Investigator for IRB approval.   
16.4 Record Keeping and Study Documents 
Study documents used to record demographic, procedural, and follow-up data, as well as any 
adverse clinical events that may occur during the study must be retained by the Principal 
Investigator.   
 
The Principal Investigator must verify personal oversight of the clinical trial and confirm that 
all data recorded is accurate and current.  
 
All data entries must be made only by the Principal Investigator and/or other site trained 
personnel. Training will be documented and logged in the site study binder. 


 
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16.4.1 Study Medication Accountability 
It is the responsibility of the Principal Investigator to ensure that all Study Medication is 
inventoried and accounted for throughout the study and recorded in appropriate documents 
kept in the site study documents.   
16.4.2 Records Retention 
All correspondence related to this clinical study should be kept in appropriate study files at the 
clinical site.  Records of subjects, study documents, product inventory, and IRB and Study 
Team correspondence pertaining to the study must also be kept on file.   
 
 
The Principal Investigator must retain protocols, amendments, IRB/EC approvals, signed and 
dated consent forms, source documents, medical records, case report forms, device 
accountability records, all correspondence and all other documents pertaining to the conduct 
of the study. 
 


 
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17.0 
Disclosure and Confidentiality 
By signing the protocol, the Principal Investigator agree to keep all study documents in strict 
confidentiality and to request similar confidentiality from his/her staff and the Institutional 
Review Board.  study documents (Protocols, and other material) will be stored appropriately 
to ensure their confidentiality.   
 


 
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18.0 
Financial Disclosures 
The Principal Clinical Investigator and other key Study Team members shall provide the IRB 
with sufficient, accurate financial information.  Disclosures shall be promptly updated if any 
relevant changes occur during the course of the Study and for 1 year following the completion 
of the study. 


 
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19.0 
Interim and Final Study Reports 
Principal Investigators shall furnish all progress reports required by the IRB. 
 


 
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20.0 
Quality Assurance 
20.1 Subject Completion 
Any subject who does not return for a scheduled follow-up evaluation will be contacted by 
telephone by the Principal Investigator, or his or her designee, to determine the cause for the 
missed appointment.  Two telephone calls will be made and documented in the study binder, 
in addition to sending a certified letter requesting the subject to contact the office and return 
for his/her evaluation.  If a returned letter receipt or an undeliverable response is received, this 
notice will be retained in the subject’s study binder that will note the subject is lost to follow-
up.  If the study subject wishes to withdraw from the study, the reason(s) for discontinuation 
will be recorded in the subject’s chart and on the appropriate study document. 
20.2 Protocol Amendments and Deviations 
No changes in the study procedures shall be effected without documentation by signed protocol 
amendments.  Documentation must include the date and justification for the change and 
approved by the reviewing IRB prior to implementation of the amendment. 
 
All deviations from the protocol will be recorded from the beginning through the completion 
of Study Medication administration. The Principal Investigator will be required to assess if any 
deviation has resulted in additional subject risk, and/or data integrity. 


 
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21.0 
Declaration of Helsinki 
The study will be conducted according to the guidelines established in the Declaration of 
Helsinki (World Medical Association 1964).  Good Clinical Practices (GCPs) and local ethical 
and legal requirements.  Subjects will be free to withdraw from the study at any stage without 
prejudice to their subsequent treatment.   
 


 
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22.0 
References 
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Dragomir, A. D., Kalsbeek, W. D., Luta, G., and Jordan, J. M. One in four people may 
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11. Steadman, J. R., Hanson, C. M., Briggs, K. K., Matheny, L. M., James, E. W., and Guillet, 
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C. W. Effects of calcified cartilage on healing of chondral defects treated with 
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18. Galera, P., Vivien, D., Pronost, S., Bonaventure, J., Redini, F., Loyau, G., and Pujol, J. 
P. Transforming growth factor-beta 1 (TGF-beta 1) up-regulation of collagen type II in 
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19. Bakker, A. C., van de Loo, F. A., van Beuningen, H. M., Sime, P., van Lent, P. L., van 
der Kraan, P. M., Richards, C. D., and van den Berg, W. B. Overexpression of active 
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osteophyte formation. Osteoarthritis Cartilage 9, 128-136. (2001) 
 
20. Chen, R., Mian, M., Fu, M., Zhao, J. Y., Yang, L., Li, Y., and Xu, L. Attenuation of the 
progression of articular cartilage degeneration by inhibition of TGF-beta1 signaling in a 
mouse model of osteoarthritis. Am J Pathol 185, 2875-2885 (2015). 
 


 
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21. Zhen, G., Wen, C., Jia, X., Li, Y., Crane, J. L., Mears, S. C., Askin, F. B., Frassica, F. J., 
Chang, W., Yao, J., Carrino, J. A., Cosgarea, A., Artemov, D., Chen, Q., Zhao, Z., Zhou, 
X., Riley, L., Sponseller, P., Wan, M., Lu, W. W., and Cao, X. Inhibition of TGF-beta 
signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat 
Med 19, 704-712 (2013). 
 
22. Ismail, H. M., Didangelos, A., Vincent, T. L., and Saklatvala, J. (2017) Rapid Activation 
of Transforming Growth Factor beta-Activated Kinase 1 in Chondrocytes by 
Phosphorylation and K63 - Linked Polyubiquitination Upon Injury to Animal Articular 
Cartilage. Arthritis Rheumatol 69, 565-575 (2017). 
 
23. Cheng, J., Hu, X., Dai, L., Zhang, X., Ren, B., Shi, W., Liu, Z., Duan, X., Zhang, J., Fu, 
X., Chen, W., and Ao, Y. Inhibition of transforming growth factor beta-activated kinase 
1 prevents inflammation-related cartilage degradation in osteoarthritis. Sci Rep 6, 34497 
(2016) 
 
24.  Price, A., Lockhart, J. C., Ferrell, W. R., Gsell, W., McLean, S., and Sturrock, R. D. 
Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: in 
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synovitis. Arthritis Rheum 56, 441- 447 (2007). 
 
25. Bedair, H. S., Karthikeyan, T., Quintero, A., Li, Y., and Huard, J. Angiotensin II receptor 
blockade administered after injury improves muscle regeneration and decreases fibrosis 
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26. Kobayashi, M., Ota, S., Terada, S., Kawakami, Y., Otsuka, T., Fu, F. H., and Huard, J. 
The Combined Use of Losartan and Muscle-Derived Stem Cells Significantly Improves 
the Functional Recovery of Muscle in a Young Mouse Model of Contusion Injuries. Am 
J Sports Med 44, 3252-3261(2016) 
 
27. Kobayashi, T., Uehara, K., Ota, S., Tobita, K., Ambrosio, F., Cummins, J. H., Terada, 
S., Fu, F. H., and Huard, J. The timing of administration of a clinically relevant dose of 
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applied physiology (Bethesda, Md. : 1985) 114, 262-273 (2013). 
 
28. Terada, S., Ota, S., Kobayashi, M., Kobayashi, T., Mifune, Y., Takayama, K., Witt, M., 
Vadala, G., Oyster, N., Otsuka, T., Fu, F. H., and Huard, J. Use of an antifibrotic agent 
improves the effect of platelet-rich plasma on muscle healing after injury. The Journal 
of bone and joint surgery. American volume 95, 980-988 (2013). 
 
29. Brunner, H. R., B. Waeber, and J. Nussberger. “Does Pharmacological Profiling of a 
New Drug in Normotensive Volunteers Provide a Useful Guideline to Antihypertensive 
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30. Burnier, Michel, Bernard Waeber, and Hans R. Brunner. “Clinical Pharmacology of the 
Angiotensin II Receptor Antagonist Losartan Potassium in Healthy Subjects.” Journal of 
Hypertension, 13, Supp 1, s23-s-28, (1995). 
 
31. Christen Y, Waeber B, Nussberger, Porchet M, Borland RM, lee R), et al. Oral 
administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male 
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83, 1333-1342 (1991). 
 
32. Munafo H, Christen Y, Nussberger, Shum l Y, Borland RM, lee R), et al. Drug 
concentration response relationships in normal volunteers after oral administration of 
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33. Goldberg MR, Tanaka W, Barchowsky A, Bradstreet TE, McCrea), lo MW, et al.  Effects 
of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers. 
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34. Doig K, MacFayden R, Sweet CS, lees KR, Reid l.  Dose ranging study of the angiotensin 
type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J 
Cardiovasc Pharmacal, 21 :732-738 (1993). 
 
35. Burnier M, Rutschmann B, Nussberger , Shahinlar S, Versaggi, Waeber B, et al. Salt 
dependent renal effects of an angiotensin II antagonist in healthy subjects. Hypertension, 
22:339-347 (1993). 
 
36. Nakashima M, Uematsu T, Kosuge K, Kanamura M. Pilot study of the uricosuric effect 
of DuP 753, a new angiotensin II receptor antagonist, in healthy subjects. fur J Clin 
Pharmacal, 42:333-335 (1992). 
 
37. Azizi Michel, Chatellier Gilles, Guyene Thanh-Tam, Murieta-Geoffroy Dalia, and 
Ménard Joël. Additive Effects of Combined Angiotensin-Converting Enzyme Inhibition 
and Angiotensin II Antagonism on Blood Pressure and Renin Release in Sodium-
Depleted Normotensives,  Circulation 92, no. 4, 825–34 (1995). 
 
38. Apprich, S., Trattnig, S., Welsch, G. H., Noebauer-Huhmann, I. M., Sokolowski, M., 
Hirschfeld, C.,Stelzeneder, D., and Domayer, S. Assessment of articular cartilage repair 
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23.0 
Appendices 
23.1 Appendix A: Informed Consent 
 
Research Information and Consent for Participation in Biomedical Research 
Biologically Regulated Marrow Stimulation by Blocking Fibrosis to Improve Cartilage Repair: 
A Randomized Double-Blind, Placebo-Controlled Study  
VHH IRB #2019-15 
 
 
I. 
Overview:  You are being asked to take part in a research study.  The information in this 
document should help you to decide whether you want to participate in this study.  The 
sections in this Overview provide the basic information about the study.  More detailed 
information is provided in the remainder of the document. 
 
Study Staff:  This study is being led by Dr. Marc J. Philippon, who is your hip surgeon at 
The Steadman Clinic.  This person is called the Principal Investigator. Other approved 
research staff may act on behalf of the Principal Investigator. In the event of an emergency, 
you may contact Ashley Payne at (970) 306-3171. 
 
Study Details:  This study is being conducted at The Steadman Clinic and Steadman 
Philippon Research Institute and is funded by The United States Department of Defense: 
Office of Naval Research.  The purpose of the study is to test whether the quality of cartilage 
healing after hip microfracture can be improved by taking a low dose of a drug commonly 
prescribed for high blood pressure called losartan. The study procedures include: 
randomization into either the losartan group or the placebo group, a lab test that includes a 
blood draw 1-2 weeks after your surgery, completion of a subjective questionnaire at several 
time points over 18 months following surgery, and returning to The Steadman Clinic for an 
additional MRI 18 months after your surgery.  At the end of the study, the research team will 
compare the losartan and placebo groups in terms of patient-reported outcomes and cartilage 
repair quality. 
 
Participants:  You are being asked to take part because you received hip surgery with Dr. 
Philippon, and a microfracture procedure was used to treat a cartilage injury. You will be 
asked to participate for 18 months following your surgery. 
 
Voluntary Participation:  Your participation in this research is voluntary.  You do not have 
to participate and may stop your participation at any time. Your decision whether or not to 
participate will not affect your current or future dealings with Dr. Philippon, The Steadman 
Clinic, or Steadman Philippon Research Institute. If you decide to participate, you are free 
to withdraw at any time without affecting that relationship. If you decide not to 
participate, your treatment from Dr. Philippon and his team will continue unchanged. 
 
Benefits, Compensation, and Risks:  We do not know if you will receive any benefit from 
your participation. You will receive a $50 Amazon gift card at the completion of the 3-month 
clinic visit and a $150 Amazon gift card at the completion of the 18-month clinic visit and 


 
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MRI. Total compensation for participation is $200 if you complete both on-site the research 
visits.  The most common and most serious risks associated with taking losartan are side-
effects that include dizziness, headache, diarrhea, stomach pain, muscle cramps, leg or back 
pain, insomnia, cold or flu symptoms, and tiredness.  Based on experience with losartan in 
previous patients, the research team believes it may provide benefit to subjects with your 
condition with reasonably limited side-effects.  Your health will be monitored during the 
course of the study, and your medical team will provide guidance about how best to limit 
these potential side-effects, and what to do if they occur.  
 
Confidentiality:  Even if we publish the findings from this study, we will keep your study 
information private and confidential.  Anyone with the authority to look at your records must 
keep them confidential. 
 
 
 
II. 
Conflict of Interest  
 
Your health care provider is an investigator on this research protocol, and as an investigator, is 
interested in both your clinical welfare and in the conduct of this study.  Before entering this study or 
at any time during the research, you may ask for a second opinion about your care from a clinician 
who is not associated with this project.  You are not obligated to participate in any research project 
offered by your clinician.  Your participation in this research study is voluntary and you do not have 
to participate.  The decision to not participate will not affect your clinical care now or in the future. 
Neither Dr. Philippon, nor any members of the research team have any financial relationships with 
any manufacturer or supplier of losartan. 
 
III. 
Why am I being asked to participate in this research? 
 
You have been asked to participate in this research because you underwent hip arthroscopy at The 
Steadman Clinic, and your surgeon, Dr. Philippon, performed a technique called microfracture to treat 
cartilage damage in your hip. 
Approximately 40 subjects may be involved in this research at The Steadman Clinic and 
Steadman Philippon Research Institute.  
Even though you agree to participate in this study and complete the informed consent, it may be 
decided by the study doctor that your participation in this study is not allowed. You must meet the 
following eligibility criteria in order to participate in this study:  
Inclusion Criteria: You are eligible to participate in this study if you meet the following criteria:  
• 
Between 18-60 years of age; 
• 
Underwent microfracture hip surgery for the treatment of grade 3 or 4 cartilage injury.  
Exclusion Criteria: You are not eligible to participate in this study if you: 
• 
Are unable to consent yourself into the research study; 
• 
Have less than 2 millimeters of hip joint space shown on x-ray; 
• 
Have moderate degeneration or arthritis (degeneration of the cartilage tissue) in the 
operative hip joint;  
• 
Had a hip surgery prior to your recent hip surgery;  


 
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• 
Had a previous fracture of the operative hip joint that resulted in bony deformity;  
• 
Have a history of pigmented villonodular synovitis (joint disease characterized by 
inflammation and overgrowth of the joint); 
• 
Have a history of synovial chondromatosis (noncancerous tumor that develops in the 
lining of the hip joint);  
• 
Have a history of hip dysplasia (the hip joint becomes partially or completely 
dislocated);  
• 
Have a history of hip coxa profundal or protrusion acetabuli (deformity of the hip 
socket that causes stability issues);  
• 
Have a history of immune disorders, such as rheumatoid arthritis;  
• 
Have an allergy to any active or inactive ingredient in losartan; 
• 
Have a condition that requires you to take losartan or any other hypertensive 
medication;  
• 
Have a hypotensive condition diagnosed by your primary care physician.  
 
 
IV. 
Study Procedures: What will happen during this study? 
 
This research will be performed at The Steadman Clinic and Steadman Philippon Research Institute, 
including in clinical exam rooms and in the MRI department. 
 
Losartan is a commonly used, FDA approved drug usually prescribed for people with high blood 
pressure or diabetic kidney disease.  The effects and side-effects of the drug are well understood by 
doctors and scientists.  Losartan is not approved for use after hip joint surgery to improve the quality 
of cartilage repair.  The doctors and scientists conducting this study believe that losartan can be 
helpful for patients undergoing the same surgical procedure you have just had. 
 
Randomization and Medication Procedures:  
If you decide to participate, the following procedures will be performed:  
• 
The first step in this research study is to randomly assign you into the losartan group or the 
placebo group.   
• 
You will have a 50% chance of being assigned into each group, and you will not know 
which group you’re in until the completion of the study.  
• 
The second day after hip surgery, you will begin taking your prescribed medication (losartan 
or placebo), which is one tablet, twice per day, for 1 month.   
• 
You will be asked to keep a medication log to document each dose you take during the 
month.   
• 
A list identifying your group assignment will be kept securely within The Steadman Clinic, 
but your medical team will not know which group you are in.  This is called a double-blind, 
placebo-controlled trial. 
 
Research Visits and Procedures:  
• 
At 7-10 days after beginning your medication course, you will visit The Steadman Clinic or a 
laboratory/clinic of your choosing to have a blood test.  The results of this test will be shared 
with the medical staff on the study team to monitor your safety. 


 
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• 
At 7-10 days after beginning your medication course, you will have a phone call with a 
member of the medical staff on the research team where you can report any symptoms or 
side-effects that you may experience. 
• 
You will be given a blood pressure monitoring device for your home use.  With this device 
you will monitor your blood pressure twice per day for two weeks, and then once per week 
until the end of the course of medication (30 days total).  Blood pressure will be maintained 
on a paper log. 
• 
Return to the study site 2 times over the next 18 months.   
• 
The first on-site visit is your standard 3-month follow-up appointment that all of Dr. 
Philippon’s surgical patients attend as part of their regular care.  You will undergo a physical 
exam to assess your hip’s strength and range of motion.  At this appointment you will have an 
opportunity to describe your health status with Dr. Philippon and/or his clinical staff.  The 
study team may use the data collected into your medical record from this visit. 
• 
The second on-site visit occurs 18 months following your surgery and will include a research-
specific MRI of your hip.  At this appointment you will have an opportunity to describe your 
health status with Dr. Philippon and/or his clinical staff.  The study team may use the data 
collected into your medical record from this visit.   
• 
Each on-site visit will take approximately 1 hour.  
• 
You will be asked to complete a subjective questionnaire regarding your hip-related health at 
4 different time points (3, 6, 12 and 18 months). These questionnaires can be completed 
remotely from your home via computer or mobile device. 
• 
Each subjective questionnaire will take approximately 20 minutes to complete.  
 
The study team asks permission to access your medical record to collect the following health 
information for research purposes at the time of your evaluation:  
• 
Gender 
• 
Age  
• 
Height 
• 
Weight  
• 
Smoking status 
• 
Chronic diseases or conditions (not related to your current hip condition) 
• 
Medication use, such as non-steroidal anti-inflammatory drugs 
• 
Physical exam assessment including hip strength and range of motion 
• 
Existing medical imaging (x-ray, MRI or CT). 
 
The study team also asks permission to access your medical record to collect the following injury 
information from your imaging and surgical reports, and to use this for research purposes: 
• 
Pre-existing injury details 
• 
Severity of injury details 
• 
Imaging findings (X-ray or magnetic resonance imaging) 
• 
Injury type 
• 
Previous treatment details (related to your current hip condition)  
 
 
V. 
What are the potential risks and discomforts? 
 


 
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There are possible risks that may be associated with participation in this study.  These risks are listed 
below, but it’s possible that some risks are not yet known. 
 
Side-effects Associated with Losartan (listed in Section I): 
A member of your medical care team will describe the possible side effects of losartan and 
answer any questions you have.  In addition to the risks listed in Section I, some more rare 
risks associate with losartan include renal failure, hypotension, severe vomiting, reactions 
with NSAIDS, and pregnancy risks.  If you experience any unexpected or unpleasant 
symptoms, please contact out to Dr. Philippon’s team as soon as possible.   
 
Risks Associated with Placebo Group Assignment: 
The research team suspects, but is not certain, that losartan can provide a beneficial effect on 
cartilage healing after hip microfracture.  If you are assigned to the placebo group, you may 
miss out on this possible beneficial effect. 
 
Risk of Improper Disclosure of your Personal Information: 
There is a possibility that your personal information will be accidentally or inappropriately 
breached during this research.  The Steadman Clinic and Steadman Philippon Research 
Institute use many physical, technologic and administrative measures to protect your 
information.  Locking offices and cabinets protect information on paper, while password-
locked work stations and encryption protect electronic information.  Whenever possible, 
information will be used and analyzed in a manner that does not contain any of your 
identifiable information.  When results of this research are presented at scientific meetings 
and in medical journals, all information that can possibly identify you will be removed. 
 
Risks or Discomforts Associated with MRI: 
The MRI scan involves loud noises and positioning in a small space. You may feel 
claustrophobic, tired, or nauseated, especially if you are uncomfortable with tight spaces. The 
MRI scan does not involve the use of X-rays or injectable dyes. There are no known reports 
of increased cancer or birth defects associated with this procedure. However, the MRI scan 
exposes you to high magnetic fields, which can be dangerous if you have a pacemaker or 
certain metal implants. 
 
Risks or Discomforts Associated with Questionnaires and Physical Exam:  
There is a potential risk of emotional distress associated with measuring your blood pressure at 
home or completing questionnaires, and a potential risk for pain and/or discomfort associated 
with the physical exam. However, these risks should not exceed that experienced during normal 
activities of daily living.  
 
VI. 
What are the costs for participating in this research? 
 
There are no costs to you for the items and services which are experimental or for research purposes 
only.  
 
 
VII. 
Will I be paid for my participation in this research? 
 


 
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You will receive a $50 Amazon gift card after completion of the 3-month clinic visit, and a $150 
Amazon gift card after completion of the 18-month clinic visit and MRI. If you do not finish the 
study, you will be compensated for the visits you have completed. If you complete the study, you will 
receive a total of $200. You will receive your payment by a member of the study team at the end of 
the research visit.  
 
 
VIII. 
What if I am injured as a result of my participation?  
 
If you get ill or injured from being in the study, Dr. Philippon will help you get medical treatment. 
You should let the study doctor know right away that you are ill or injured. If you believe you have 
become ill or injured from this study, you should contact Dr. Marc Philippon at (970) 476-1100. If 
you believe your illness or injury to be an emergency, contact call 911. 
 
You should let any health care provider who treats you know that you are in a research study. If you 
do seek medical treatment, please take a copy of this document with you because it may help the 
doctors where you seek treatment to treat you. It will also provide the doctors where you seek 
treatment with information they may need if they want to contact the research doctors. 
 
You or your health insurance plan will be billed. No money has been set aside to pay the costs of this 
treatment. Health insurance plans may or may not cover costs of research-related injury or illness. 
You should check with your insurance company before deciding to participate in this research study. 
The study staff will assist you in obtaining pre-authorization from your insurance company. Costs not 
covered by insurance could be substantial.  
 
The Steadman Clinic and Steadman Philippon Research Institute have not set aside any money to pay 
you or to pay for your treatment if you get ill or injured from being in the study. There are no plans 
for The Steadman Clinic and Steadman Philippon Research Institute to provide other forms of 
compensation (such as lost wages or pain and suffering) to you for research related illnesses or 
injuries. The only exception to this policy is if it is proven that your injury or illness is directly caused 
by the negligence of a Steadman Clinic and Steadman Philippon Research Institute employee.  
 
By signing this form, you are not giving up any legal rights to seek compensation of injury. 
 
 
IX. 
Can I withdraw or be removed from the study? 
 
If you decide to participate, you are free to withdraw your consent and discontinue participation at 
any time without affecting your future care at The Steadman Clinic.  You will still receive standard of 
care treatment for your condition if you choose to withdraw. 
 
You have the right to leave a study at any time without penalty.  If leaving could affect your safety, 
the investigator will provide information about recommended steps for leaving the study.   
 
The researchers also have the right to stop your participation in this study without your consent if they 
believe it is in your best interest. 
 
X. 
Future use of identifiable private information or identifiable biospecimen 


 
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Your personal identifiers might be removed from your identifiable private records. After removal of 
information that could identify you, your information could be used and/or distributed to another 
investigator for future research studies without additional consent from you. 
 
 
XI. 
What about your privacy and confidentiality? 
 
The people who will know that you are a research subject are members of the research team, and if 
appropriate, your physicians and nurses.  No information about you, or provided by you, during the 
research, will be disclosed to others without your written permission, except if necessary to protect 
your rights or welfare (for example, if you are injured and need emergency care) or if required by 
law.  
 
Study information which identifies you and the consent form signed by you will be looked at and/or 
copied for examining the research by: 
• 
Food and Drug Administration (FDA) – to ensure the research is done properly. 
• 
Department of Defense – study sponsor. 
• 
Office for Human Research Protections (OHRP) – to ensure the research is done 
properly. 
• 
Vail Health Institutional Review Board – to ensure the research is done properly. 
 
A possible risk of the research is that your participation in the research or information about you and 
your health might become known to individuals outside the research.  Your original signed consent 
document will be kept in an unlabeled paper envelope and stored in a locked cabinet within The 
Steadman Clinic.  Other personal information that will be collected for this study will be stored 
separately from the research data on a password protected excel spreadsheet within the clinic. Only 
authorized personnel from The Steadman Clinic will have access to your personal information. Some 
of the information used for this research is standardly collected for all hip surgery patients and this 
information will remain in your medical record for use by your clinical care team.  The information 
collected for research only will be maintained for up to two years following completion of the study.  
De-identified data may be kept indefinitely. 
When the results of the research are published or discussed in conferences, no information will be 
included that would reveal your identity.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. law. This web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
 
XII. 
What happens if new information becomes available about the study? 
 
During the course of this study, we may find more information that could be important to you.  
This includes information that, once learned, might cause you to change your mind about being 
in this study. We will notify you as soon as possible if such information becomes available. 
As part of being in this study, you will undergo an additional MRI.  If the study team identifies 
anything important to your health or relevant to your optimal treatment course, the information 
will be provided to you.  This could include abnormal findings on your MRI that may require 


 
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further testing.  If this occurs, the results will not be placed in your medical record at The 
Steadman Clinic and you may need to meet with professionals with expertise to help you learn 
more about your research results.  The study team/study will not cover the costs of any follow-up 
consultations or actions.   
 
XIII. 
Who should I contact if I have questions about the research? 
 
Contact the researchers Dr. Marc Philippon, Dr. Ashley Payne or Dr. Johnny Huard at 970-476-1100: 
• 
if you have any questions about this study or your part in it,   
• 
if you feel you have had a research-related injury (or a bad reaction to the study treatment), 
and/or 
• 
if you have questions, concerns or complaints about the research. 
 
 
XIV. 
Who should I contact if I have questions about my rights as a research subject? 
 
If you have questions about your rights as a research subject or concerns, complaints, or to offer input 
you may call Mary Crumbaker, Chief Ethics and Compliance Officer at Vail Health at 970-477-5197. 
 
 
XV. 
Authorization to use and disclose Protected Health Information 
 
The purpose of this section is to give your permission to the research team to obtain and use your 
patient information. Your patient information will be used to do the research named above. 
 
State and federal privacy laws protect your patient information. These laws say that, in most cases, 
your health care provider can release your identifiable patient information to the research team only if 
you give permission by signing this form. 
You do not have to sign this permission form. If you do not sign it, you will not be allowed to join the 
research study. Your decision to not sign this permission will not affect any of your treatment, any 
other treatment, healthcare, enrollment in health plans or eligibility for benefits. 
 
What information will be obtained and used? 
“Patient information” means the health information in your medical or other healthcare records. It 
also includes information in your records that can identify you. For example, it can include your 
name, address, phone number, birthdate, and medical record number. 
By signing this form you are giving permission to the following organization(s) to disclose your 
patient information for use in this research. 
• 
Vail Health (includes Shaw Cancer Center, Howard Head and all Diversified Services clinic 
locations) 
• 
Vail Valley Surgical Center 
• 
The Steadman Clinic 
 
What information will be released for research use? 
If you give your permission and sign the last page of this form, you are allowing the health care 
providers indicated above to release the following medical records containing your Personal Health 


 
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Information to the researchers for use in this project. Your Personal Health Information includes health 
information in your medical records, financial records and other information that can identify you. 
 
The specific information that will be released and used for this research is described below: 
• 
Medical history / treatment 
• 
Consultation 
• 
Diagnostic imaging report 
• 
Radiology films (like X-rays or CT scans or MRI’s) 
• 
Laboratory / diagnostic tests 
• 
Operative reports (about an operation) 
• 
Patient-reported outcomes from questionnaires 
• 
Clinical exam information (like hip strength or range of motion) 
• 
Basic demographic information:  
 
Gender 
 
Age  
 
Height 
 
Weight  
 
Body mass index (BMI) 
 
Smoking status 
 
Medical comorbidities (presence of two chronic diseases or conditions)  
 
How will my patient information be used? 
The following groups of people may also be able to see your health information and may use that 
information to conduct this research: 
• 
The research team for the research described in the Consent Form; 
• 
Vail Health Institutional Review Board (VH IRB); 
• 
US Department of Defense (DoD); 
• 
The independent medical monitor for this study; 
• 
Others who are required by law to review the quality and safety of the research, 
including U. S. government agencies such as The U.S. Food and Drug 
Administration (FDA) or the Office of Human Research Protections; 
 
Your patient information will be used and/or given to others for the following reasons: 
• 
To monitor safety 
• 
To do the research 
• 
To study the results, and  
• 
To see if the research was done right 
 
If the results of this study are made public, information that identifies you will not be used.  
The researcher will use your patient information only in the ways that are described in the research 
consent form that you sign and as described in this HIPAA Authorization.   
You can ask questions about what the research team will do with your information and how they will 
protect it. The privacy laws do not always require the receiver of your information to keep your 
information confidential.  After your information is given to an organization that is not subjected to 
the privacy laws, e.g. a research organization, there is a risk that it could be shared without your 
permission. 


 
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How long will this authorization be valid? 
 
This permission for the researchers to obtain your patient information:    
• 
Ends when the research is complete and any required monitoring of the study is finished. 
 
Cancelling your permission: 
 
You may change your mind at any time.   To take back your permission, you must send your written 
request to: 
Kate Wilmouth 
Steadman Philippon Research Institute  
181 W. Meadow Dr. Suite 1000 
Vail, CO 81657 
 
If you take back your permission, the research team may still keep and use any patient information 
about you that they already have. But they can’t obtain more health information about you for this 
research unless it is required by a federal agency that is monitoring the research. 
 
If you take back your permission, you will need to leave the research study.  Changing your mind will 
not affect any other treatment, payment, health care, enrollment in health plans, or eligibility for 
benefits. 
 
 
Consent to take Part in Research and Authorization for the Collection, Use, and Disclosure of 
Health Information 
 
 
 
Signature of Subject 
 
I have read (or someone has read to me) the above information.  I have been given an opportunity to 
ask questions and my questions have been answered to my satisfaction.  I agree to participate in this 
research and authorize the use of my health information as outlined above.  I will be given a copy of 
this signed and dated form. 
 
 
 
Signature of Subject 
 
 
Date 
 
 
Print Name of Subject 
 
 
 
 
 
 
 
 


 
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Statement of Person Obtaining Informed Consent and Research Authorization 
 
I have carefully explained to the person taking part in the study what he or she can expect 
from their participation.  I confirm that this research subject speaks the language that was 
used to explain this research and is receiving an informed consent form in their primary 
language.  This research subject has provided legally effective informed consent. 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date (must be same as subject’s) 
 
 
Printed Name of Person Obtaining Consent 
 
 
 
 


 
 
 
 
 
 
 
Page 58 of 58 
 
23.2 Appendix B – Study Schemata 
 
Standard of Care Used for 
Screening 
Visit 1 
POD 1 
 
Telephone 
Contact 
Telephone 
Contact 
Day 35 
Visit 2 
3 months 
Telephone 
Contact 
Telephone 
Contact 
Visit 3 
18 Months 
Window 
 
(or upon 
discharge) 
7-10 days post 
discharge 
+/- 
3 days 
+/- 
4 weeks 
6 months 
+/- 
4 weeks 
12 months 
+/- 
8 Weeks 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
Vitals, H&P  
X 
 
 
 
X 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
Demographic Info 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
X 
 
 
 
Trauma Chronology  
X 
 
 
 
 
 
 
 
Circumduction eval 
X 
 
 
 
X 
 
 
 
ROM  
X 
 
 
 
X 
 
 
 
T2 MRI 
X 
 
 
 
 
 
 
X 
Strength Testing 
X 
 
 
 
X 
 
 
 
SF-12 
X 
 
 
 
X 
X 
X 
X 
Patient Satisfaction 
X 
 
 
 
X 
X 
X 
X 
 HHS 
X 
 
 
 
X 
X 
X 
X 
 VHS 
X 
 
 
 
X 
X 
X 
X 
 HOS 
X 
 
 
 
X 
X 
X 
X 
 WOMAC 
X 
 
 
 
X 
X 
X 
X 
Tegner Activity Scale 
X 
 
 
 
X 
X 
X 
X 
VAS 
X 
 
 
 
X 
X 
X 
X 
Informed Consent  
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Medication Pick -up 
 
X 
 
 
 
 
 
 
Blood Pressure Cuff, 
Medication and BP 
Logs. PT instructions 
 
X 
 
 
 
 
 
 
Compliance Check 
 
 
X 
X 
 
 
 
 
Protocol Deviations 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X* 
X* 
X* 
X* 
Basic Metabolic 
Panel 
 
 
X 
 
 
 
 
 
*As related to the target hip only 
 

ICF_000.pdf: 
 
 
Study Title: Biologically Regulated Marrow Stimulation 
by Blocking Fibrosis to Improve Cartilage Repair: A 
Randomized Double-Blind, Placebo-Controlled Study 
 
NCT number: NCT04212650 
 
Version date: May 13, 2020 
 
IRB-Approved date: May 15, 2020 
 
Combined Informed Consent and HIPAA Form 
 
 


 
 
 
 
 
 
 
Losartan for Hip Microfracture Clinical Trial 
 
v11, submitted 05/13/2020  
Page 1 of 14 
 
IRB Form #002 Jan 2019 
 
Research Information and Consent for Participation in Biomedical Research 
 
Biologically Regulated Marrow Stimulation by Blocking Fibrosis to Improve Cartilage Repair: A 
Randomized Double-Blind, Placebo-Controlled Study  
VHH IRB #2019-15 
 
 
I. 
Overview:  You are being asked to take part in a research study.  The information in this 
document should help you to decide whether you want to participate in this study.  The sections 
in this Overview provide the basic information about the study.  More detailed information is 
provided in the remainder of the document. 
 
Study Staff:  This study is being led by Dr. Marc J. Philippon, who is your hip surgeon at The 
Steadman Clinic.  This person is called the Principal Investigator. Other approved research staff may 
act on behalf of the Principal Investigator. In the event of an emergency, you may contact Dr. Ashley 
Payne at (775) 229-3801 or Dr. David A. Kuppersmith at (970) 476-1100. 
 
Study Details:  This study is being conducted at The Steadman Clinic and Steadman Philippon 
Research Institute and is funded by The United States Department of Defense: Office of Naval 
Research.  The purpose of the study is to test whether the quality of cartilage healing after hip 
microfracture can be improved by taking a low dose of a drug commonly prescribed for high blood 
pressure called losartan. The study procedures include: randomization into either the losartan 
group or the placebo group, a lab test that includes a blood draw 1-2 weeks after your surgery, 
completion of a subjective questionnaire at several time points over 18 months following surgery, 
and returning to The Steadman Clinic for an additional MRI 12 months after your surgery.  At the 
end of the study, the research team will compare the losartan and placebo groups in terms of 
patient-reported outcomes and cartilage repair quality. 
 
Participants:  You are being asked to take part because you received hip surgery with Dr. Philippon, 
and a microfracture procedure was used to treat a cartilage injury. You will be asked to participate 
for 18 months following your surgery. 
 
Voluntary Participation:  Your participation in this research is voluntary.  You do not have to 
participate and may stop your participation at any time. Your decision whether or not to participate 
will not affect your current or future dealings with Dr. Philippon, The Steadman Clinic, or Steadman 
Philippon Research Institute. If you decide to participate, you are free to withdraw at any time 
without affecting that relationship. If you decide not to participate, your treatment from Dr. 
Philippon and his team will continue unchanged. 


 
 
 
 
 
 
 
Losartan for Hip Microfracture Clinical Trial 
 
v11, submitted 05/13/2020  
Page 2 of 14 
 
IRB Form #002 Jan 2019 
 
Benefits, Compensation, and Risks:  We do not know if you will receive any benefit from your 
participation. You will receive a $50 Amazon gift card at the completion of the 3-month clinic visit 
and a $150 Amazon gift card at the completion of the 12-month clinic visit and MRI. Total 
compensation for participation is $200 if you complete both on-site the research visits.  The most 
common and most serious risks associated with taking losartan are side-effects that include 
dizziness, headache, renal failure, diarrhea, stomach pain, muscle cramps, leg or back pain, 
insomnia, cold or flu symptoms, and tiredness.  Based on experience with losartan in previous 
patients, the research team believes it may provide benefit to subjects with your condition with 
reasonably limited side-effects.  Your health will be monitored during the course of the study, and 
your medical team will provide guidance about how best to limit these potential side-effects, and 
what to do if they occur.  
 
Confidentiality:  Even if we publish the findings from this study, we will keep your study information 
private and confidential.  Anyone with the authority to look at your records must keep them 
confidential. 
 
 
II. 
Conflict of Interest  
 
Your health care provider is an investigator on this research protocol, and as an investigator, is interested 
in both your clinical welfare and in the conduct of this study.  Before entering this study or at any time 
during the research, you may ask for a second opinion about your care from a clinician who is not associated 
with this project.  You are not obligated to participate in any research project offered by your clinician.  Your 
participation in this research study is voluntary and you do not have to participate.  The decision to not 
participate will not affect your clinical care now or in the future. 
Neither Dr. Philippon, nor any members of the research team have any financial relationships with any 
manufacturer or supplier of losartan. 
 
III. 
Why am I being asked to participate in this research? 
 
You have been asked to participate in this research because you underwent hip arthroscopy at The 
Steadman Clinic, and your surgeon, Dr. Philippon, performed a technique called microfracture to treat 
cartilage damage in your hip. 
Approximately 60 subjects may be involved in this research at The Steadman Clinic and Steadman Philippon 
Research Institute.  


 
 
 
 
 
 
 
Losartan for Hip Microfracture Clinical Trial 
 
v11, submitted 05/13/2020  
Page 3 of 14 
 
IRB Form #002 Jan 2019 
Even though you agree to participate in this study and complete the informed consent, it may be decided 
by the study doctor that your participation in this study is not allowed. You must meet the following 
eligibility criteria in order to participate in this study:  
Inclusion Criteria: You are eligible to participate in this study if you meet the following criteria:  
• Between 18-60 years of age; 
• Underwent microfracture hip surgery for the treatment of grade 3 or 4 cartilage injury; 
• Underwent standard baseline MRI at The Steadman Clinic. 
Exclusion Criteria: You are not eligible to participate in this study if you: 
• Are unable to consent yourself into the research study; 
• Have less than 2 millimeters of hip joint space shown on x-ray; 
• Have moderate degeneration or arthritis (degeneration of the cartilage tissue) in the operative hip 
joint;  
• Had a hip surgery prior to your recent hip surgery;  
• Had a previous fracture of the operative hip joint that resulted in bony deformity;  
• Have a history of pigmented villonodular synovitis (joint disease characterized by inflammation and 
overgrowth of the joint); 
• Have a history of synovial chondromatosis (noncancerous tumor that develops in the lining of the 
hip joint);  
• Have a history of hip dysplasia (the hip joint becomes partially or completely dislocated);  
• History of Avascular Necrosis (AVN), Perthes disease, or slipped capital femoral epiphysis (SCFE); 
• Have a history of immune disorders, such as rheumatoid arthritis;  
• Taking losartan or a medication with known losartan interaction, including phenobarbital, rifambin, 
or fluconazole; 
• Have an allergy to any active or inactive ingredient in losartan; 
• Have a condition that requires you to take losartan or any other hypertensive medication;  
• Have a hypotensive condition diagnosed by your primary care physician.  
 
IV. 
Study Procedures: What will happen during this study? 
 
This research will be performed at The Steadman Clinic and Steadman Philippon Research Institute, 
including in clinical exam rooms and in the MRI department. 
 
Losartan is a commonly used, FDA approved drug usually prescribed for people with high blood pressure 
or diabetic kidney disease.  The effects and side-effects of the drug are well understood by doctors and 
scientists.  Losartan is not approved for use after hip joint surgery to improve the quality of cartilage repair.  


 
 
 
 
 
 
 
Losartan for Hip Microfracture Clinical Trial 
 
v11, submitted 05/13/2020  
Page 4 of 14 
 
IRB Form #002 Jan 2019 
The doctors and scientists conducting this study believe that losartan can be helpful for patients undergoing 
the same surgical procedure you have just had. 
 
Randomization and Medication Procedures:  
If you decide to participate, the following procedures will be performed:  
• The first step in this research study is to randomly assign you into the losartan group or the placebo 
group.  A member of the study team on Dr. Philippon’s clinical team will write the prescription, and 
you (or your caregiver) will pick up the study medication at Vail Valley Pharmacy in Edwards on 
either the first or second day after your surgery, Colorado which is 14 miles west of the Vail 
Hospital. 
• You will have a 50% chance of being assigned into each group, and you will not know which group 
you’re in until the completion of the study.  
• The second day after hip surgery, in the evening, you will begin taking your prescribed medication 
(losartan or placebo), which is one tablet, twice per day, for 1 month.   
• Your doses should occur as closely as possible to 8:00 AM and 8:00 PM each day. 
• You will be asked to keep a medication log to document each dose you take during the month.  You 
will also use this form to document any symptoms or side-effects that you may experience that are 
potentially related to the study medication. 
• If you miss a dose, you should not double your next dose.  Instead, you should resume the planned 
dosage at the next scheduled dosing time point. 
• At your first clinic visit to TSC following completion of your medication, you will be asked to return 
the remaining capsules in the original prescription bottle. Your prescription will contain several 
more capsules than needed for 1 month of daily intake in case of capsule loss. 
• A list identifying your group assignment will be kept securely within The Steadman Clinic, but your 
medical team will not know which group you are in.  This is called a double-blind, placebo-
controlled trial.  Only one member of the study team, Vail Valley Pharmacy, and an independent 
medical monitor will know your group identity. 
• You will be provided with a medication card that will indicate your study participation information 
about the possibility that you are taking Losartan, and instructions on how to obtain further 
information.  This medication card can be provided to other health care providers during the course 
of this study. 
 
 
Research Visits and Procedures:  
At 7-10 days after beginning your medication course. 
• Phone call with a member of the medical staff on the research team where you can report any 
symptoms or side-effects that you may experience.  The most common signs or symptoms 
associated with losartan include chest pain, shortness of breath and heart palpitations. 
• Staff will ask you to scan or fax a copy of your medication log to The Steadman Clinic.  This can 
include taking a photograph and emailing to Dr. Philippon’s team, if preferred. 


 
 
 
 
 
 
 
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• The study team will arrange a visit to The Steadman Clinic or a laboratory/clinic of your choosing to 
have a blood test.  The results of this test will be shared with the medical staff on the study team to 
monitor your safety. 
• Study funds will cover the cost of this lab work.  If you or your insurance are billed any fees by 
accident, please contact Ashley Payne at apayne@thesteadmanclinic.com, and the study team 
correct this as quickly as possible. 
 
At 18-24 days after beginning your medication course. 
• Phone call with a member of the medical staff on the research team where you can report any 
symptoms or side-effects that you may experience. 
• Staff will ask you about how your physical therapy is going. 
 
At 32-38 days after beginning your medication course. 
• Phone call with a member of the medical staff on the research team where you can report any 
symptoms or side-effects that you may experience. 
• Staff will ask you about how your physical therapy is going. 
 
TSC Clinic Visit 3 Months following surgery 
• Dr. Philippon’s surgical patients attend this as part of their regular care.  You will undergo a physical 
exam to assess your hip’s strength and range of motion.   
• At this appointment you will have an opportunity to describe your health status with Dr. Philippon 
and/or his clinical staff.   
• The study team may use the data collected into your medical record from this visit. 
• You will be required to bring your medication log, and your medication bottle with any unused study 
medication to this visit. 
• Either at home prior to the appointment, or using a tablet device in the clinic on the day of your 
appointment, you will complete a questionnaire regarding the health and function of your hip. 
• The clinic visit will require approximately 1 hour to complete. 
 
Hip Questionnaire Completion from Home at 6 and 18 Months following surgery. 
• You complete a subjective questionnaire regarding your hip-related health. These questionnaires 
can be completed remotely from your home via computer or mobile device.  You will receive the 
questionnaire link by email, and a member of the study team may call to remind you to complete 
this questionnaire. 
• Each subjective questionnaire will take approximately 20 minutes to complete.  
 
TSC Clinic Visit 12 Months following surgery 
• The second on-site visit occurs 18 months following your surgery and will include a research-specific 
MRI of your hip.   


 
 
 
 
 
 
 
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• At this appointment you will have an opportunity to describe your health status with Dr. Philippon 
and/or his clinical staff, and you will undergo a standard hip physical exam.  The study team may 
use the data collected into your medical record from this visit.   
• Either at home prior to the appointment, or using a tablet device in the clinic on the day of your 
appointment, you will complete a questionnaire regarding the health and function of your hip. 
• The clinic visit will require approximately 1 hour to complete. 
 
The study team asks permission to access your medical record to collect the following health information 
for research purposes at the time of your evaluation:  
• Gender 
• Age  
• Height 
• Weight  
• Smoking status 
• Chronic diseases or conditions (not related to your current hip condition) 
• Medication use, such as non-steroidal anti-inflammatory drugs 
• Physical exam assessment including hip strength and range of motion 
• Existing medical imaging (x-ray, MRI or CT). 
 
The study team also asks permission to access your medical record to collect the following injury 
information from your imaging and surgical reports, and to use this for research purposes: 
• Pre-existing injury details 
• Severity of injury details 
• Imaging findings (X-ray or magnetic resonance imaging) 
• Injury type 
• Previous treatment details (related to your current hip condition)  
 
 
V. 
What are the potential risks and discomforts? 
 
There are possible risks that may be associated with participation in this study.  These risks are listed below, 
but it’s possible that some risks are not yet known. 
 
Side-effects Associated with Losartan: 
A member of your medical care team will describe the possible side effects of losartan and answer 
any questions you have.  The most common and most serious risks associated with taking losartan 
are side-effects that include dizziness, headache, diarrhea, stomach pain, muscle cramps, leg or back 
pain, insomnia, cold or flu symptoms, and tiredness.  Some more rare risks associate with losartan 
include electrolyte abnormalities, renal failure, hypotension, severe vomiting, reactions with 


 
 
 
 
 
 
 
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NSAIDS, and pregnancy risks.  If you experience any unexpected or unpleasant symptoms, please 
contact out to Dr. Philippon’s team as soon as possible.   
 
Risks Associated with Placebo Group Assignment: 
The research team suspects, but is not certain, that losartan can provide a beneficial effect on 
cartilage healing after hip microfracture.  If you are assigned to the placebo group, you may miss 
out on this possible beneficial effect. 
 
Risk of Improper Disclosure of your Personal Information: 
There is a possibility that your personal information will be accidentally or inappropriately breached 
during this research.  The Steadman Clinic and Steadman Philippon Research Institute use many 
physical, technologic and administrative measures to protect your information.  Locking offices and 
cabinets protect information on paper, while password-locked work stations and encryption protect 
electronic information.  Whenever possible, information will be used and analyzed in a manner that 
does not contain any of your identifiable information.  When results of this research are presented 
at scientific meetings and in medical journals, all information that can possibly identify you will be 
removed. 
 
Risks or Discomforts Associated with MRI: 
The MRI scan involves loud noises and positioning in a small space. You may feel claustrophobic, 
tired, or nauseated, especially if you are uncomfortable with tight spaces. The MRI scan does not 
involve the use of X-rays or injectable dyes. There are no known reports of increased cancer or birth 
defects associated with this procedure. However, the MRI scan exposes you to high magnetic fields, 
which can be dangerous if you have a pacemaker or certain metal implants. 
 
Risks or Discomforts Associated with Questionnaires and Physical Exam:  
There is a potential risk of emotional distress associated with completing questionnaires, and a 
potential risk for pain and/or discomfort associated with the physical exam. However, these risks 
should not exceed that experienced during normal activities of daily living.  
 
VI. 
Are there reproductive risks to participation in this study? 
 
If you are a woman: Participating in this research may involve risks to pregnant women and/or an unborn 
baby. To protect against possible side effects of the study drug, losartan, you may not take part in this study 
if you are pregnant or nursing a child. If you are a woman of childbearing ability, the study doctor 
recommends that you at least two method of birth control or to be abstinent (i.e., not have sex) throughout 
the study. Acceptable methods of birth control include: oral contraceptive and condom, intra-uterine 
device (IUD) and condom, diaphragm with spermicide and condom. If you think that you have become 
pregnant during the study, you must tell the doctor immediately. 
 


 
 
 
 
 
 
 
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If you become pregnant while you are taking losartan, stop taking losartan and call your doctor 
immediately. Losartan may cause death or serious injury to the fetus when taken in the last 6 months 
of pregnancy. 
 
VII. 
What are the costs for participating in this research? 
 
There are no costs to you for the items and services which are experimental or for research purposes only.  
 
 
VIII. 
Will I be paid for my participation in this research? 
 
You will receive a $50 Amazon gift card after completion of the 3-month clinic visit, and a $150 Amazon gift 
card after completion of the 12-month clinic visit and MRI. If you do not finish the study, you will be 
compensated for the visits you have completed. If you complete the study, you will receive a total of $200. 
You will receive your payment by a member of the study team at the end of the research visit.  
 
 
IX. 
What if I am injured as a result of my participation?  
 
If you get ill or injured from being in the study, Dr. Philippon will help you get medical treatment. You should 
let the study doctor know right away that you are ill or injured. If you believe you have become ill or injured 
from this study, you should contact Dr. David A. Kuppersmith or Dr. Marc Philippon at (970) 476-1100. If 
you believe your illness or injury to be an emergency, contact call 911. 
 
If you are injured, you should let any health care provider who treats you know that you are in a research 
study. If you do seek medical treatment, please take a copy of this document with you because it may help 
the doctors where you seek treatment to treat you. It will also provide the doctors where you seek 
treatment with information they may need if they want to contact the research doctors. 
 
You or your health insurance plan will be billed. No money has been set aside to pay the costs of this 
treatment. Health insurance plans may or may not cover costs of research-related injury or illness. You 
should check with your insurance company before deciding to participate in this research study. The study 
staff will assist you in obtaining pre-authorization from your insurance company. Costs not covered by 
insurance could be substantial.  
 
The Steadman Clinic and Steadman Philippon Research Institute have not set aside any money to pay you 
or to pay for your treatment if you get ill or injured from being in the study. There are no plans for The 
Steadman Clinic and Steadman Philippon Research Institute to provide other forms of compensation (such 
as lost wages or pain and suffering) to you for research related illnesses or injuries. The only exception to 


 
 
 
 
 
 
 
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this policy is if it is proven that your injury or illness is directly caused by the negligence of a Steadman Clinic 
and Steadman Philippon Research Institute employee.  
 
By signing this form, you are not giving up any legal rights to seek compensation of injury. 
 
 
X. 
Can I withdraw or be removed from the study? 
 
If you decide to participate, you are free to withdraw your consent and discontinue participation at any 
time without affecting your future care at The Steadman Clinic.  You will still receive standard of care 
treatment for your condition if you choose to withdraw. 
 
You have the right to leave a study at any time without penalty.  If leaving could affect your safety, the 
investigator will provide information about recommended steps for leaving the study.   
 
The researchers also have the right to stop your participation in this study without your consent if they 
believe it is in your best interest. 
 
XI. 
Future use of identifiable private information or identifiable biospecimen 
 
Your personal identifiers might be removed from your identifiable private records. After removal of 
information that could identify you, your information could be used and/or distributed to another 
investigator for future research studies without additional consent from you. 
 
XII. 
What about your privacy and confidentiality? 
 
The people who will know that you are a research subject are members of the research team, and if 
appropriate, your physicians and nurses.  No information about you, or provided by you, during the 
research, will be disclosed to others without your written permission, except if necessary to protect your 
rights or welfare (for example, if you are injured and need emergency care) or if required by law.  
 
Study information which identifies you and the consent form signed by you will be looked at and/or copied 
for examining the research by: 
• Food and Drug Administration (FDA) – to ensure the research is done properly. 
• Department of Defense – study sponsor. 
• Office for Human Research Protections (OHRP) – to ensure the research is done properly. 
• Vail Health Institutional Review Board – to ensure the research is done properly. 
 
A possible risk of the research is that your participation in the research or information about you and your 
health might become known to individuals outside the research.  Your original signed consent document 


 
 
 
 
 
 
 
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will be kept in an unlabeled paper envelope and stored in a locked cabinet within The Steadman Clinic.  
Other personal information that will be collected for this study will be stored separately from the research 
data on a password protected excel spreadsheet within the clinic. Only authorized personnel from The 
Steadman Clinic will have access to your personal information. Some of the information used for this 
research is standardly collected for all hip surgery patients and this information will remain in your medical 
record for use by your clinical care team.  The information collected for research only will be maintained 
for up to two years following completion of the study.  De-identified data may be kept indefinitely. 
When the results of the research are published or discussed in conferences, no information will be included 
that would reveal your identity.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. 
This web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.  
 
 
XIII. 
What happens if new information becomes available about the study? 
 
During the course of this study, we may find more information that could be important to you.  This includes 
information that, once learned, might cause you to change your mind about being in this study. We will 
notify you as soon as possible if such information becomes available. 
As part of being in this study, you will undergo an additional MRI.  If the study team identifies anything 
important to your health or relevant to your optimal treatment course, the information will be provided to 
you.  This could include abnormal findings on your MRI that may require further testing.  If this occurs, the 
results will not be placed in your medical record at The Steadman Clinic and you may need to meet with 
professionals with expertise to help you learn more about your research results.  The study team/study will 
not cover the costs of any follow-up consultations or actions.   
 
XIV. 
Who should I contact if I have questions about the research? 
 
Contact the researchers Dr. Marc Philippon, Dr. Ashley Payne or Dr. Johnny Huard at 970-476-1100: 
• if you have any questions about this study or your part in it,   
• if you feel you have had a research-related injury (or a bad reaction to the study treatment), and/or 
• if you have questions, concerns or complaints about the research. 
 
 
XV. 
Who should I contact if I have questions about my rights as a research subject? 
 


 
 
 
 
 
 
 
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If you have questions about your rights as a research subject or concerns, complaints, or to offer input you 
may call Mary Crumbaker, Chief Ethics and Compliance Officer at Vail Health at 970-477-5197. 
 
 
XVI. 
Authorization to use and disclose Protected Health Information 
 
The purpose of this section is to give your permission to the research team to obtain and use your patient 
information. Your patient information will be used to do the research named above. 
 
State and federal privacy laws protect your patient information. These laws say that, in most cases, your 
health care provider can release your identifiable patient information to the research team only if you give 
permission by signing this form. 
You do not have to sign this permission form. If you do not sign it, you will not be allowed to join the 
research study. Your decision to not sign this permission will not affect any of your treatment, any other 
treatment, healthcare, enrollment in health plans or eligibility for benefits. 
 
What information will be obtained and used? 
“Patient information” means the health information in your medical or other healthcare records. It also 
includes information in your records that can identify you. For example, it can include your name, address, 
phone number, birthdate, and medical record number. 
By signing this form you are giving permission to the following organization(s) to disclose your patient 
information for use in this research. 
• Vail Health (includes Shaw Cancer Center, Howard Head and all Diversified Services clinic locations) 
• Vail Valley Surgical Center 
• The Steadman Clinic 
 
What information will be released for research use? 
If you give your permission and sign the last page of this form, you are allowing the health care providers 
indicated above to release the following medical records containing your Personal Health Information to the 
researchers for use in this project. Your Personal Health Information includes health information in your 
medical records, financial records and other information that can identify you. 
 
The specific information that will be released and used for this research is described below: 
• Medical history / treatment 
• Consultation 
• Diagnostic imaging report 


 
 
 
 
 
 
 
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• Radiology films (like X-rays or CT scans or MRI’s) 
• Laboratory / diagnostic tests 
• Operative reports (about an operation) 
• Patient-reported outcomes from questionnaires 
• Clinical exam information (like hip strength or range of motion) 
• Basic demographic information:  
 Gender 
 Age  
 Height 
 Weight  
 Body mass index (BMI) 
 Smoking status 
 Medical comorbidities (presence of two chronic diseases or conditions) 
 
 
How will my patient information be used? 
The following groups of people may also be able to see your health information and may use that 
information to conduct this research: 
• The research team for the research described in the Consent Form; 
• Vail Health Institutional Review Board (VH IRB); 
• US Department of Defense (DoD); 
• The independent medical monitor for this study; 
• Others who are required by law to review the quality and safety of the research, including 
U. S. government agencies such as The U.S. Food and Drug Administration (FDA) or the Office 
of Human Research Protections; 
 
Your patient information will be used and/or given to others for the following reasons: 
• To monitor safety 
• To do the research 
• To study the results, and  
• To see if the research was done right 
 
If the results of this study are made public, information that identifies you will not be used.  
The researcher will use your patient information only in the ways that are described in the research consent 
form that you sign and as described in this HIPAA Authorization.   
You can ask questions about what the research team will do with your information and how they will 
protect it. The privacy laws do not always require the receiver of your information to keep your information 


 
 
 
 
 
 
 
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confidential.  After your information is given to an organization that is not subjected to the privacy laws, 
e.g. a research organization, there is a risk that it could be shared without your permission. 
How long will this authorization be valid? 
 
This permission for the researchers to obtain your patient information:    
• Ends when the research is complete and any required monitoring of the study is finished. 
 
Cancelling your permission: 
 
You may change your mind at any time.   To take back your permission, you must send your written request 
to: 
Kate Wilmouth 
Steadman Philippon Research Institute  
181 W. Meadow Dr. Suite 1000 
Vail, CO 81657 
 
If you take back your permission, the research team may still keep and use any patient information about 
you that they already have. But they can’t obtain more health information about you for this research 
unless it is required by a federal agency that is monitoring the research. 
 
If you take back your permission, you will need to leave the research study.  Changing your mind will not 
affect any other treatment, payment, health care, enrollment in health plans, or eligibility for benefits. 
 
 
 
 


 
 
 
 
 
 
 
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Consent to take Part in Research and Authorization for the Collection, Use, and Disclosure 
of Health Information 
 
Signature of Subject 
I have read (or someone has read to me) the above information.  I have been given an opportunity to ask 
questions and my questions have been answered to my satisfaction.  I agree to participate in this research 
and authorize the use of my health information as outlined above.  I will be given a copy of this signed and 
dated form. 
 
 
 
Signature of Subject 
 
 
Date and Time 
 
 
Print Name of Subject 
 
 
 
 
Statement of Person Obtaining Informed Consent and Research Authorization 
 
I have carefully explained to the person taking part in the study what he or she can expect from their 
participation.  I confirm that this research subject speaks the language that was used to explain this research 
and is receiving an informed consent form in their primary language.  This research subject has provided 
legally effective informed consent. 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date (must be same as subject’s) 
 
 
Printed Name of Person Obtaining Consent