Ability of Oral Steroid (Oxandrolone) to Halt Fatty Infiltration and Aid Rotator Cuff Healing: A Double-Blind, Randomized Clinical Trial
Phase: NA
Conditions: Rotator Cuff Tear
Sponsor: University of Southern California

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
1 
 
Title:  Ability of Oral Steroid (Oxandrolone) to Halt Fatty Infiltration and Aid Rotator Cuff Healing: A 
Double-Blind, Randomized Clinical Trial 
 
Principal Investigator(s): George F. Hatch III 
 
Co-Investigators(s): Todd Schroeder, Alexander E. Weber, Anthony Essilfie, Keemia Soraya Heidari, 
Alexis Rounds, Erik Mayer, Santano Rosario, Alan Gurler, C. Thomas Vangsness Jr., Seth Gamradt, 
James Tibone, Reza Omid, Lori Michener 
 
Participants/Locations: Keck School of Medicine of USC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
2 
 
 
 
TABLE OF CONTENTS 
 
 
Section  
 
 
 
 
 
 
 
 
 
 
 
1.0   
Background  
 
 
 
 
 
 
 
 
  
   
 
2.0   
Objectives and Purpose 
 
3.0   
Study Design 
 
4.0   
Drug Information 
 
5.0   
Selection and Withdrawal of Subjects 
 
6.0   
Study Agent Administration and Safety 
 
7.0   
Clinical and Laboratory Evaluations 
 
8.0   
Criteria for Evaluation and Endpoint Definitions 
 
9.0   
Data Collection and Monitoring 
 
10.0 
Statistical Consideration 
 
11.0 
Registration Guidelines 
 
12.0 
Biohazard Containment 
 
13.0 
Ethical and Regulatory Considerations 
 
14.0 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
3 
 
1.0   
Background 
 
Rotator cuff tears are currently one of the most common causes of musculoskeletal pain and 
disability, and affect between 30% and 50% of the adult population over the age of 50 years.16,17 A torn 
rotator cuff can cause progressive loss of shoulder function and significant pain.4,5 The ramifications of 
rotator cuff tears are realized at both the individual and societal level where the direct costs of diagnosis 
and treatment and the indirect costs of loss of income, missed workdays, and disability payments continue 
to rise at exponential rates.17,18 The rate at which arthroscopic rotator cuff repair is being performed has 
increased by greater than 500% over the last 15 years.18,19 Given these high personal and societal costs, it 
is paramount to improve rotator cuff healing rates and decrease retearing and the need for reoperation. 
Significant advancements in arthroscopic surgical techniques have led to a more stable 
mechanical environment to promote rotator cuff healing following repair.20 Despite these major technical 
advances, there has been relatively slow progress consistently improving the biologic environment of 
healing tissues. This is especially true for rotator cuff repair where incomplete healing and retears remain 
a common postoperative complication. Studies suggest retear rates of up to 40% following small and 
medium tear repairs, and as high as 94% following for large and chronic tear repairs.21,22 Failure to heal 
the rotator cuff and rotator cuff retearing have clinical ramifications aside from the aforementioned 
societal and financial implications. Longitudinal clinical studies have demonstrated decreased functional 
improvement, diminished clinical outcomes, and lower patient satisfaction in those that have failure of 
healing or retears following rotator cuff repair.4,5  
There are many predisposing factors that may prompt rotator cuff healing failure or retear. These 
factors can be divided into patient-specific factors (patient age, gender, body-mass index (BMI), smoking 
status, and comorbidities) and tear-specific factors (tear pattern, tear size, and tear chronicity).23,24 The 
major biologic sequelae of a constellation of both patient- and tear-specific factors are the changes to the 
muscle-tendon unit.7,25 The hallmarks of these changes are muscle atrophy, fatty infiltration, and 
intercellular fibrosis of the torn rotator cuff muscle-tendon unit.7,25 These changes begin at the time of the 
tear and currently go largely unaddressed at the time of repair. 
Researchers have pursued biologic augmentation at the time of arthroscopic rotator cuff repair; 
however, time-zero modifications to the healing interface with growth factors, platelet-rich plasma, and 
stem cells have failed to address the hallmarks of the biologic problem (muscle atrophy, fatty infiltration, 
and intercellular fibrosis).26 Therefore, these modalities in both preclinical and clinical models have failed 
to consistently demonstrate improvements in healing rates, retear rates, functional results, or patient 
satisfaction.27-29 Recently, researchers have attempted to address the biologic hallmarks of rotator cuff 
tearing with a series of animal studies examining the effects of anabolic steroids on rotator cuff 
healing.25,30,31 This line of preclinical studies demonstrated that anabolic steroids, when administered as an 
adjuvant to rotator cuff repair, can halt the progression of fatty infiltration, decrease muscle atrophy, and 
promote rotator cuff healing. 
Despite the wide range of doses in controlled clinical trials, our proposed dose has not been 
studied.  The drug manufacturer, Gemini Labs LLC, is providing the drug in 6mg doses for the study and 
the proposed oxandrolone dose in men is 24mg/day.  Currently, the FDA-approved dose in adults is up to 
20mg/day, usually in two to four divided doses.  Most controlled studies use doses of 5–20mg/day.3,36  In 
patients with moderate to severe alcoholic hepatitis, however, doses have been given up to 80mg/day.37  
Adverse events are typically dose-dependent and correlate to the duration of use.36  Serious hepatic 
toxicity has not been shown with short term (≤3 months) treatment of oxandrolone, even with up to 
80mg/day.36,37 
The objective of this research proposal is to perform a clinical trial, translating this previous line 
of preclinical research into the clinical arena. The purpose of this double-blind, randomized study is to 
compare the outcomes of rotator cuff repair augmented with 12 weeks of an oral, FDA-approved anabolic 
steroid to the outcomes of rotator cuff repair augmented with 12 weeks of placebo medication. The long-
term implications of this study has the potential to provide direct and immediate clinical impact and 
healthcare savings by aiding rotator cuff healing. 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
4 
 
 
 
2.0   
Objectives and Purpose 
 
Specific Aim #1. Determine if oral Oxandrolone administration will improve rotator cuff healing 
following rotator cuff repair. 
Oxandrolone is an orally administered synthetic derivative of testosterone that is approved by the Federal 
Drug Administration (FDA) in patients who have lost weight resulting from extensive surgery, severe 
trauma, chronic infection, or as an adjunctive therapy to promote weight gain. It is also approved for bone 
pain associated with osteoporosis, and to attenuate protein catabolism associated with the prolonged use 
of corticosteroids. Oral administration of Oxandrolone has demonstrated increases in lean mass, protein 
synthesis, and wound healing with no long-term adverse events in trauma patients as well as healthy male 
controls.1-3 The aforementioned safety and efficacy profile of oral Oxandrolone makes it an appealing 
adjuvant treatment to counteract the major biologic consequences of a chronically torn rotator cuff 
(muscle atrophy, fatty infiltration, and intercellular fibrosis), which are known to lead to poor healing and 
diminished clinical outcomes.4,5 The primary aim of this double-blind, randomized study is to compare 
the rotator cuff healing rates between an experimental group receiving 12 weeks of daily, orally 
administered Oxandrolone following rotator cuff repair to a control group undergoing the same rotator 
cuff repair and receiving 12 weeks of a daily, orally administered placebo medication. The healing 
spectrum from complete healing to retear will be defined based on a previously validated diagnostic 
imaging metric. The primary outcome measure is rotator cuff muscle-tendon structural healing as 
measured by the Sugaya classification on magnetic resonance imaging (MRI) at the primary end-point of 
6 months.6 We will continue to follow for one year. We hypothesize that those in the experimental group 
(Oxandrolone group) will have greater rotator cuff tendon structural healing as compared to the control 
(Placebo group) at the primary end-point of 6 months post-operative.  
The secondary measure of healing will be the degree of fatty infiltration of the muscle-tendon unit on 
MRI using the Goutallier grading classification.7  We hypothesize that those in the experimental group 
(Oxandrolone group) will have less fatty infiltrate as compared to the control (Placebo group) at primary 
end-point of 1 year.  
 
Specific Aim #2. To determine if oral Oxandrolone administration will improve shoulder functional 
outcomes following rotator cuff repair. 
Multiple rotator cuff repair studies have demonstrated that patients with MRI evidence of rotator cuff 
muscle-tendon healing following repair have improved function in the form of postoperative range of 
motion and strength.8,9 The secondary aim of this double-blind, randomized study is to compare the 
functional outcomes between the experimental group (rotator cuff repair and 12 weeks of Oxandrolone) 
and the control group (rotator cuff repair and 12 weeks of placebo). Functional outcome will be defined 
based on the literature standards of postoperative shoulder active range of motion and isometric 
strength.10,11  We hypothesize that those in the experimental group will have improved shoulder 
functional outcomes following rotator cuff repair compared to the placebo group at 1 year. .  
 
Specific Aim #3: To determine if Oxandrolone administration will improve patient-reported 
outcomes (PROs) and patient satisfaction following rotator cuff repair. 
Rotator cuff muscle-tendon healing following repair is also associated with improved patient-reported 
outcomes (PROs) and patient satisfaction.8,9 The third aim of this double-blind, randomized study is to 
compare the PROs and satisfaction level between the experimental group (rotator cuff repair and 12 
weeks of Oxandrolone) and the control group (rotator cuff repair and 12 weeks of placebo). Patient-
reported outcome will be defined based on the validated American Shoulder and Elbow Surgeons 
Shoulder Assessment (ASES) and a Visual Analog Pain Scale (VAS).11-13 Patient satisfaction will be 
assessed with the literature standard, single-stem patient acceptable symptom state (PASS) 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
5 
 
questionnaire.11,14,15  We hypothesize that the experimental group will have improved patient-reported 
outcomes and satisfaction compared to the placebo group at 1 year.  
 
 
3.0   
Study Design 
 
Trial Design 
This is a single-center, prospective 1:1 double blind randomized control trial. The trial will be conducted 
at the University of Southern California (USC), Keck School of Medicine in Los Angeles, California. 
Patients will be recruited from the Department of Orthopaedics. Men and women, 40–75 years of age, 
with MRI proven rotator cuff tears, indicated and scheduled for repair will be eligible for inclusion. Men 
and women with acute tears and those with significant comorbid liver, lung, cardiac, and kidney 
conditions will be excluded. Women who are pregnant or nursing will also be excluded. Women of child-
bearing potential will be required to take a monthly urine pregnancy test and be on an agreed upon 
contraceptive. Participants will be randomized into one of two groups, a control group (receiving placebo 
medication) and an experimental group (receiving oral Oxandrolone,12 mg twice daily for men and 6 mg 
twice daily for women for 12 weeks). Dosing will begin at the time of surgery and continue for 12 weeks, 
with medication dispensed by the USC Pharmacy. The study will be double-blinded: neither the treating 
surgeon nor the patient will know to which group the patient is enrolled.  
 
Surgical Procedure 
Arthroscopic inspection of the shoulder will be performed to verify the presence of a rotator cuff tear and 
to measure the size of the tear. In all cases a standard arthroscopic double-row technique will be used to 
repair the rotator cuff tendon.19,20 Treatment of the biceps tendon, need for subacromial decompression, 
and/or acromioclavicular joint resection will be at each surgeon’s discretion. Intraoperative measurements 
of rotator cuff tear type and size as well as the details of the surgical procedure will be recorded. 
 
Postoperative Rehabilitation 
All participants in the study will undergo a standardized rehabilitation protocol for rotator cuff repair as 
agreed upon by the surgeons involved. Rehabilitation will be supervised by a licensed physical therapist. 
Adherence to the rehabilitation protocol will be assessed by review of patient treatment logs. If there are 
alterations to the standard postoperative rehabilitation course, the treating surgeon will be notified and 
will determine if the alteration in course warrants removal from the study. Patients who do not meet 80% 
adherence to the standardized protocol will be considered non-compliant and controlled for in the data 
analysis. 
 
Feasibility  
The study team has the experience, knowledge, and capability to conduct this study. The surgeons 
involved perform approximately 400 rotator cuff repairs per year. The study team assembled has 
conducted similar prospective studies in the past on rotator cuff healing. In addition, the study team has 
experience with clinical trials involving anabolic steroids. 
 
The collaborative nature of the study is exemplified in the sharing of responsibilities. The majority of the 
clinical care proposed in this study (demographic data, medical history, physical examinations, vital 
signs, preoperative MRI without contrast) is standard-of-care treatment for rotator cuff tears all surgeons 
involved and will be overseen as such. The outcome measures collection will be monitored by a research 
coordinator through the Department of Orthopaedic Surgery. The research coordinator will be responsible 
for arranging follow-up care and confirming that postoperative MRI, functional tests, and patient-reported 
outcome measure are completed. The safety profile including laboratory tests and body composition will 
be performed under the guidance and monitoring of Dr. Schroeder based on his extensive knowledge of 
the anabolic steroid field. The body composition measurements will be made in Dr. Schroeder’s 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
6 
 
laboratory. Postoperative rotator cuff repair rehabilitation and patient-reported outcome data will be 
overseen by Dr. Michener, given her career-long expertise in shoulder-specific rehabilitation and shoulder 
pathology patient-reported outcome measures. In addition, patient recruitment will not be an issue as the 
study-eligible population significantly overlaps with the patient population most frequently affected by 
symptomatic, chronic rotator cuff tears. 
 
Key Personnel 
George F. “Rick” Hatch III, MD is an assistant professor in the Department of Orthopaedic Surgery at 
the Keck School of Medicine of USC and the director of the USC Orthopaedic Surgery Sports Medicine 
Fellowship. He specializes in sports medicine, with a focus on disorders and injuries affecting the 
shoulder, elbow, and knee. His research interests focus on shoulder instability, stability of the reverse 
total shoulder prosthesis, treatment of infected shoulder prosthesis, outcomes following multi-ligament 
knee injuries and testosterone supplementation in orthopaedic post-operative rehabilitation. Dr. Hatch is a 
member of multiple orthopaedic societies including: The American Association of Orthopaedic Surgeons, 
The American Orthopaedic Society of Sports Medicine, The Western Orthopaedic Association, and The 
Arthroscopic Association of North America. In addition, Dr. Hatch is an elected member of the American 
Shoulder and Elbow Surgeons, the most exclusive and prestigious specialty society in the United States 
for shoulder and elbow surgeons. 
 
Alexander Weber, MD is a specialist in the field of orthopaedic surgery and sports medicine at USC. Dr. 
Weber’s practice has an emphasis on arthroscopic surgery of the shoulder, elbow, hip, and knee. He also 
has specialized training in all types of shoulder replacement. He has research and clinical interests in the 
treatment of the athlete’s hip and biologic solutions to cartilage restoration. He has lectured nationally and 
internationally on hip arthroscopy for the treatment of FAI and cartilage preservation/restoration of the 
knee and has authored scientific articles and book chapters that advance the clinical practice of 
Orthopaedics and sports medicine.  
 
E. Todd Schroeder, PhD is the director of the Clinical Exercise Research Center at the University of 
Southern California, Division of Biokinesiology and Physical Therapy and has conducted numerous 
clinical investigations with androgens including oxandrolone. 
 
Anthony Essilfie, MD is a 3rd year orthopaedic surgery resident at LAC+USC medical center. He has 
particular interest in arthroscopy of the shoulder. He will be assisting with coordination of the study and 
cooperation with the IRB. 
 
K. Soraya Heidari, BA is a fourth year medical interested in pursuing a career in orthopaedic surgery. 
She will be assisting with coordination of the study.  
 
Alexis Rounds, BS is a medical student research fellow for the Department of Orthopaedic Surgery at the 
Keck School of Medicine of USC. She will be assisting with coordination of the study and is the main 
IRB contact person.  
 
Erik Mayer, BS is a medical student research fellow for the Department of Orthopaedic Surgery at the 
Keck School of Medicine of USC. He will be assisting with coordination of the study.  
 
Santano Rosario, BS is a medical student research fellow for the Department of Orthopaedic Surgery at 
the Keck School of Medicine of USC. He will be assisting with coordination of the study.  
 
Alan Gurler, MS completed his Master of Science in Biokinesiology at the University of Southern 
California and has an Adjunct Faculty position in the Division of Biokinesiology & Physical Therapy.  

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
7 
 
His main research interests are to better understand physiologic changes after the cessation of anabolic 
androgenic steroid use, and subsequently to restore normal function. 
 
C. Thomas Vangsness Jr., MD is a professor in the Department of Orthopaedic Surgery at the Keck 
School of Medicine of USC. He specializes in the treatment and prevention of orthopaedic and sports-
related injuries, including ACL reconstruction, meniscus surgery, cartilage repair and restoration, rotator 
cuff surgery and shoulder instability/dislocations. Dr. Vangsness is internationally recognized for his 
expertise in shoulder and knee surgery and has conducted and published extensive research with a focus 
on such topics as shoulder and ligament biomechanics, stem cell biology, allograft transplantation, and 
meniscal cartilage. Dr. Vangsness has been on the editorial board of several orthopaedic journals. He is a 
member of several organizations including the American Orthopaedic Society for Sports Medicine, 
American Shoulder and Elbow Surgeons, The Arthroscopy Association of North America, and the 
International Society of Orthopaedic Surgery and Traumatology (SICOT).  
 
Seth Gamradt, MD is an Associate Professor of Clinical Orthopaedic Surgery at the Keck School of 
Medicine of USC and is a director of Orthopaedic Athletic Medicine for USC Athletics. Dr. Gamradt is 
on the editorial board of the journal Techniques in Shoulder and Elbow Surgery, and he is a Reviewer for 
the American Journal of Sports Medicine and the Journal of Shoulder and Elbow Surgery and is a 
member of many professional organizations, including: The American Shoulder and Elbow Surgeons 
(ASES), the Association of Clinical Elbow and Shoulder Surgeons (ACESS), American Orthopaedic 
Society for Sports Medicine, Arthroscopy Association of North America, and the American Academy of 
Orthopaedic Surgeons. 
 
James Tibone, MD holds the Moss Foundation Professorship in Sports Medicine in the Department of 
Orthopaedic Surgery at the Keck School of Medicine of USC and he is the medical director for USC’s 
Athletic Department. Dr. Tibone is an internationally recognized expert in sports injuries of the shoulder, 
knee and elbow and total and reverse shoulder replacement surgeries and was the North American editor 
for the Journal of Shoulder and Elbow Surgery. He has served on numerous national professional 
committees, and is a past president of the American Shoulder and Elbow Surgeons. 
 
Reza Omid, MD is an Associate Professor in the Department of Orthopaedic Surgery at the Keck School 
of Medicine of USC. He specializes in complex reconstruction of all shoulder and elbow conditions.  He 
also has extensive experience in arthroscopic procedures and has pioneered several novel minimally 
invasive arthroscopic techniques for shoulder reconstruction. Dr. Omid leads the Shoulder & Elbow 
Trauma Service at LAC+USC Medical Center, one of the busiest Level 1 trauma centers in the nation. He 
is actively involved in research and has authored numerous articles. Dr. Omid is also involved in 
numerous national organizations including the prestigious American Shoulder & Elbow Surgeons (ASES) 
Society, the American Academy of Orthopaedic Surgeons (AAOS), and Arthroscopy Association of 
North America (AANA). 
 
Lori Michener, PhD is a Professor of Clinical Physical Therapy and the Director of the COOR (Clinical 
biomechanics and Orthopedic Outcomes Research) Laboratory. As the Director of Clinical Outcomes and 
Research, she directs the development, collection, and analysis of patient-rated outcomes and the process 
of care in the USC Physical Therapy Associates Clinics, and serves as a resource for clinical research. Dr. 
Michener's research characterizes the biomechanics of musculoskeletal shoulder pain, diagnosis and 
treatment of shoulder and cervical pain, clinical trials investigating optimal treatment strategies for 
shoulder and cervical disorders, and the use of patient-rated outcomes measurement tools to assess health 
related quality of life. 
 
 
4.0   
Drug Information 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
8 
 
 
Oxandrolone is an orally administered synthetic derivative of the hormone testosterone, and is classified 
as an anabolic steroid.  In males, testosterone has many vital functions such as the development and 
support of reproductive organs, increased skeletal muscle mass, bone mineral density, and growth of 
facial and body hair. 
 
Oxandrolone is approved by the Federal Drug Administration (FDA) in patients who have lost weight 
resulting from extensive surgery, severe trauma, chronic infection, or as an adjunctive therapy to promote 
weight gain. It is also approved for bone pain associated with osteoporosis, and to attenuate protein 
catabolism associated with the prolonged use of corticosteroids. Oral administration of Oxandrolone has 
demonstrated increases in lean mass, protein synthesis, and wound healing with no long-term adverse 
events in trauma patients as well as healthy male controls.1-3 Elevated liver transaminase levels have been 
noted but have been transient and asymptomatic.1-3 The aforementioned safety and efficacy profile of oral 
Oxandrolone makes it an appealing adjuvant treatment to counteract the major biologic consequences of a 
chronically torn rotator cuff (muscle atrophy, fatty infiltration, and intercellular fibrosis), which are 
known to lead to poor healing and diminished clinical outcomes.4,5 
 
Oxandrolone has been associated with the following side effects: 
 
• 
Central Nervous System: Habituation, excitation, insomnia, depression, and changes in libido. 
• 
Larynx: Deepening of the voice in females. 
• 
Cardiovascular: Edema 
• 
Breast: Gynecomastia. 
• 
Hepatic: Cholestatic jaundice with, rarely, hepatic necrosis and death. Hepatocellular neoplasms 
and peliosis hepatis with long-term therapy (see US Boxed Warning below). Reversible changes 
in liver function tests also occur including increased bromsulfophthalein (BSP) retention, changes 
in alkaline phosphatase and increases in serum bilirubin, aspartate aminotransferase (AST, 
SGOT) and alanine aminotransferase (ALT, SGPT).  
• 
Genitourinary: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, 
chronic priapism, epididymitis, and bladder irritability.  
• 
Hematologic: Bleeding in patients on concomitant oral anticoagulant therapy. 
• 
Metabolic/Endocrine: Decreased glucose tolerance, increased creatinine excretion, increased 
serum levels of creatinine phosphokinase (CPK). Inhibition of gonadotropin secretion.  
• 
Fluid and Electrolytes: Retention of serum electrolytes (sodium chloride, potassium, phosphate, 
calcium).  
• 
Musculoskeletal: Premature closure of epiphyses (in children). 
• 
Dermatologic: Acne (especially in females and prepubertal males), hirsutism and male pattern 
baldness in females. 
• 
Patients with moderate to severe COPD or COPD patients who are unresponsive to 
bronchodilators should be monitored closely for COPD exacerbation and fluid retention. 
 
Contraindications: nephrosis, carcinoma of breast or prostate, hypercalcemia, pregnancy 
US Boxed Warning:  
Peliosis hepatitis: A condition in which liver, and sometimes, splenic tissue is replaced with blood-filled 
cysts which has occurred in patients receiving androgenic anabolic steroids. These cysts may be 
associated with hepatic dysfunction and even liver failure. This condition is usually completely reversible 
with cessation of drug.  

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
9 
 
Liver cell tumors: Most often benign and androgen-dependent, however, fatal malignant tumors have 
occurred. Withdrawal of the drug often results in regression or cessation of tumor progression. Hepatic 
tumors associated with androgens and anabolic steroids are much more vascular than other hepatic tumors 
and may be silent until life-threatening, intra-abdominal hemorrhage develops.  
Blood Lipid Changes: Changes associated with increased risk of atherosclerosis are seen in patients 
treated with androgens or anabolic steroids, including decreased high-density lipoprotein (HDL) and 
increased low-density lipoprotein (LDL).   
 
Pregnancy: Oxandrolone is classified as Category X in pregnancy due to teratogenic effects including 
embryotoxicity, fetotoxicity, infertility, and possible masculinization of the fetus. 
 
Breast Feeding: It is unknown whether Oxandrolone is excreted in human milk. Because of the potential 
of serious adverse reactions in nursing infants from Oxandrolone, women who are nursing and do not 
wish to stop may not take part in the study.  
 
 
 
5.0   
Selection and Randomization of Subjects 
 
Participants 
Men and women, aged 40-75 years, presenting to an orthopaedic surgeon with a full thickness rotator cuff 
tear will be eligible for study screening. The inclusion and exclusion criteria are listed below.  
 
All eligible patients will receive information about the trial verbally and in writing. After signing written 
informed consent, they will be randomly allocated to undergo rotator cuff repair followed by standard of 
care structured rehabilitation with Oxandrolone administration or standard of care structured 
rehabilitation with placebo. Allocation will be performed using computer software and will occur at the 
pharmacy to ensure that all investigators are blinded. The USC Pharmacy will prepare sequentially 
numbered, opaque, sealed envelope containing the assigned interventions to ensure randomness is 
preserved. The surgeon, PI, study team, and physical therapist will not know to which study arm the 
patient was randomized. The protocol for rehabilitation will remain the same for all patients. The USC 
Pharmacy will provide the investigators with a list of all participants and group assigned at the end of the 
study.  Investigators will not have access to the study group assignment for any participant during data 
collection, to ensure adequate double-blinding of both the investigators and participants.  
 
Inclusion criteria 
• 
Men and women age 40-75 years old who have failed nonoperative management of chronic, full 
thickness rotator cuff tears confirmed by MRI without contrast 
 
Exclusion criteria 
• 
Patients with prior shoulder surgery or prior rotator cuff repair 
• 
Tears larger than 5cm 
• 
Significant glenohumeral arthritis (Hamada Grade 2 or higher) 
• 
Untreated diabetes mellitus 
• 
Pituitary tumor 
• 
Rheumatoid Arthritis  
• 
Uncontrolled hypertension 
• 
Congestive Heart Failure 
• 
Myocardial Infarction within the past 6 months 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
10 
 
• 
End-stage renal disease 
• 
Liver enzymes two times the normal value 
• 
DVT within the past 6 months  
• 
Disorder of the coagulation system 
• 
Currently taking anticoagulation 
• 
Claustrophobia 
• 
Prior or current use of anabolic steroids 
• 
Chromosomal disorders 
• 
Prostate cancer 
• 
Breast cancer 
• 
Hypercalcemia 
• 
Medications that interfere with testosterone production or function, including but not limited to 
5α-reductase inhibitors 
• 
Pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the Screening visit through 6 weeks after the last dose of study 
treatment. 
• 
Any other condition or treatment interfering with completion of the trial 
 
 
6.0   
Study Agent Administration and Safety 
   
Oxandrolone Administration 
Oxandrolone will be given to experimental  men (12 mg BID) and women (6 mg BID) for 12 weeks 
starting the day of surgery. Previous clinical studies where oxandrolone was given for greater than 6 
months have shown no androgenic effects, behavioral changes, sepsis, hirsutism, or acne in the patient 
population. Elevated liver transaminase levels have been noted but have been transient and 
asymptomatic.1-3 
 
Patient Safety and Compliance 
Patients will have liver transaminase levels measured when preoperative labs are obtained. Additionally, 
liver enzymes will be assessed at 2, 6, 12, and 24 weeks after rotator cuff repair. Testosterone levels and a 
quantitative assay for oxandrolone will also be drawn prior to supplementation, at the 2 week post-
operative visit and at the 6 month post-operative visit to assess for compliance. Any adverse medication 
reaction will be met with cessation of medication, but will continue to be followed for outcome data 
collection.  
 
 
7.0   
Clinical and Laboratory Evaluations 
 
Program Time Line 
Study participants will be tested on multiple occasions. Information will be collected prior to surgery, 
followed by measurements on the day of procedure, and 2, 6, 12, 24, 52, and 104 weeks after surgery. 
Surgery will be performed on an arranged date with the orthopaedic surgeon. Physical therapy will follow 
a pre-defined protocol with a physical therapist. 
 
Testing Visits 
Outcome measures and safety measures will be collected at routine postoperative visits with the operating 
surgeon. Dates and involved events are described in Table 1 below. 
 
 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
11 
 
Schedule of Events 
Event 
Pre-Procedure  Procedure 
Day 
Post-Operative Week 
2 
6 
12 24 52 104 
Informed Consent 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
 
 
Medical History 
x 
x 
 
 
 
 
 
 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
Blood draw: Testosterone level and 
Oxandrolone level 
x 
 
x 
 
 
x 
 
 
Blood draw: Liver Enzymes 
x 
 
x 
 
 
x 
 x 
x 
Outcomes: 
 
 
 
 
 
 
 
 
MRI: rotator cuff healing; Sugaya 
classification (primary outcome) 
x 
 
 
 
x 
 
x 
x 
MRI: Fatty infiltrate (secondary outcome) 
x 
 
 
 
x 
 
x 
x 
MRI: Muscle volume (secondary outcome) 
x 
 
 
 
x 
 
x 
x 
Body Composition – lean mass & body fat 
(secondary outcome) 
x 
 
x 
x 
x 
x 
x 
x 
Questionnaires: 
ASES, VAS, PASS  (secondary outcome) 
x 
x 
x 
x 
x 
x 
x 
x 
Shoulder Range of Motion (secondary 
outcome) 
x 
x 
x 
x 
x 
x 
x 
x 
Shoulder Strength (secondary outcome) 
x 
x 
x 
x 
x 
x 
x 
x 
Table 1. Outline of pre- and postoperative timing of events and schedule of data collection. 
 
Demographics.  
Demographics of age, height, weight, race, arm dominance, and tear size and location will be recorded. 
 
Inclusion and Exclusion Criteria.   
The inclusion and exclusion criteria will be confirmed prior to enrolled, as described above in section 5.0. 
 
Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive 
months, ie, who have had menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation) 
must have a negative serum or urine pregnancy test with a sensitivity of ≤25 mIU/mL within 48 hours 
prior to study entry. 
 
Females of reproductive potential must agree not to participate in the conception process (ie, active 
attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to 
pregnancy, must use at least one reliable form of contraceptive. Female subjects must use contraceptives 
while receiving study treatment and for 6 weeks after stopping study treatment. 
 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
12 
 
Acceptable forms of contraceptives include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormonal contraceptive 
 
NOTE: Written self-reported or partner reported sterility or lack of reproductive potential will be 
acceptable in place of contraceptive use.  
 
Medical History.   
A standard medical history questionnaire will be completed by the participant of past medical history of 
their shoulder pain, co-morbidities, and medical history of all other conditions. 
 
Vital Signs.   
Vital signs of temperature, blood pressure, respiration rate, and heart rate will be recorded.  
 
Blood Draws 
As described above, blood will be collected to monitor any adverse effects on the participant’s health and 
to assess for medication compliance.  
 
 
Outcomes: 
 
MRI rotator cuff healing; Sugaya classification (Primary outcome).  All participants will have a 
standardized MRI T2-weighted images without contrast, and used to classify rotator cuff integrity using 5 
categories of the Sugaya classification.  The 5 categories are:  type I= rotator cuff sufficient thickness 
with homogeneously low intensity on each image; type II= rotator cuff sufficient thickness, partial high-
intensity area; type III= insufficient rotator cuff thickness with less than half the thickness as compared to 
normal cuff, but without discontinuity; type IV= minor rotator cuff discontinuity with only 1 – 2  slices on 
imaging that suggest a small full-thickness tear; and type V= major discontinuity observed in more than 2 
slices on imaging, suggesting a medium or large full-thickness tear.33 
 
MRI: Fatty infiltrate (Secondary outcome).  All participants will have a standardized MRI T2-weighted 
images without contrast. The  Goutallier grading classification7 will be used to assess fatty infiltration on 
5 categories of grade 0=  no fatty infiltration; grade 1= some fatty streaks; grade 2= less fat than muscle; 
grade 3= as much fat as muscle; and grade 4= more fat than muscle. 
 
MRI – muscle volume (Secondary outcome).  All participants will have a standardized MRI T2-weighted 
images without contrast, using the scapular plane of the sagittal-oblique image to measure supraspinatus 
muscle volume.  Muscle volume will be measured by tracing the outer borders of the muscle, expressing 
the volume in mm2.34 
 
Body Composition (Secondary outcome), 
Study participants’ lean mass and body fat percentage will be measured by bioelectrical impedance using 
Biospace InBody. The participant will have measurements at their preoperative visit and all postoperative 
visits.  
 
Questionnaires (Secondary outcomes). 
The participant will be asked to complete 3 questionnaires.  Two questionnaires will be used to assess 
shoulder pain and function; American Shoulder and Elbow Surgeons Shoulder Assessment (ASES) to 
assess the patient-rated shoulder function on a scale of 0 -100 (0= no shoulder function/ disability), and a 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
13 
 
Visual Analog Pain Scale (VAS) to assess the level of pain on a scale of 0 -10 (0 = no pain).11-13 Patient 
satisfaction will be assessed with a single item question labeled the patient acceptable symptom state 
(PASS) questionnaire.11,14,15  The PASS is a 2-item question asking the patient their option of their current 
state of their shoulder, and if it is satisfactory for them.  ASES, VAS, and PASS questionnaires at each 
visit to assess clinical outcomes.  
 
Shoulder Range of Motion and Strength (Secondary outcomes). 
Shoulder range of motion of flexion, abduction, external and internal rotation will be measured. During 
active range of motion, patients will be asked to move the shoulder as much as they can in the direction 
indicated by the investigator. Once participants reach their maximum range of motion, the measure will 
be recorded with a goniometer in degrees of motion.  Two measures will be taken for each direction, and 
averaged for data analysis.   
     Shoulder strength will be measured using a hand-held device of: shoulder flexion, elevation on the 
scapular plane (scaption), external rotation, and internal rotation. The hand-held device (Hoggan Health 
Industries Inc., West Jordan, UT) is small device that contains a force transducer, measuring strength in 
kg of force. It is also commonly use in clinical settings, as it allows for accurate, and reliable measure. 
The arm of the patient will be positioned in a similar set of positions. The device will then be placed in 
contact with the distal segment. Participants will be asked to push against the device as hard as they can. 
Two measures for each movement will be collected. One-minute rest will be provided between measures. 
 
Treatment 
 
Orthopaedic Surgery 
Rotator cuff repair will be performed by fellowship trained orthopaedic surgeons listed above.   
 
Physical Therapy 
Rehabilitation will follow a standard guideline under the supervision of a licensed physical therapist and 
the participant’s physician.  
 
8.0   
Criteria for Evaluation and Endpoint Definitions 
 
Outcome Measures 
The primary outcome measure will be rotator cuff healing as measured by the MRI Sugaya 
classification.6,7 Measures will be performed at 12 weeks (the conclusion of Oxandrolone vs. placebo 
treatment), 6 months, 1 year and 2 years follow-up.  The primary end-point will be 6 months. 
 
Secondary outcome measures will include: 
1) MRI evidence of rotator cuff fatty infiltration and muscle volume. 
2) Patient-reported outcomes will be assessed with the ASES, a VAS, and PASS questionnaire. 
3) Functional outcome will be assessed with shoulder range of motion with goniometer and 
isometric shoulder strength measures using a handheld dynamometer 
4) Lean body mass and fat will be assessed with bioelectric impedance. 
 
 
9.0   
Data Collection and Monitoring 
 
The research coordinator, employed by the Department of Orthopaedic Surgery, will be responsible for 
patient enrollment and data collection. Source documents will be stored in an office in a locked cabinet 
within the Department of Orthopaedic Surgery. Data will also be collected and stored using CTSI 
RedCap.  
 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
14 
 
 
10.0 
Statistical Considerations 
 
Statistical Methods 
Descriptive statistics will be performed for participant demographics, historical information, 
intraoperative variables, as well as baseline testosterone, MRI measures of rotator cuff integrity, rotator 
cuff fatty infiltrate, rotator cuff muscle volume, shoulder strength, shoulder range of motion, patient-rated 
outcomes and body composition. Comparison for the primary outcome measure of rotator cuff integrity 
between groups from baseline to 1 year (primary endpoint) will be performed using a repeated measures 
analysis of Generalized Estimating Equation (GEE), appropriate for ordinal data.  The GEE will also be 
used to compare between groups over time for the secondary outcome of fatty infiltrate (ordinal data). For 
all other secondary outcome variables, we will also use GEE for linear regression (ordinal data) or mixed 
model (continuous data) with repeatedly measured outcomes. Significance level will be established as p < 
0.05. Analyses will be performed using STATA 13 software (College Station, TX) or SPSS and in 
consultation with the Statistics Department at USC. 
 
Power Analysis and Sample Size 
A power analysis for a sample size estimation was performed to detect a difference of 1 Sugaya grade (1- 
5 grades) classification (primary outcome) between the experimental and control group using 3 repeated 
measurements (baseline, 12 week, and 6 months).14  The power analysis was based with 2-sided alpha = 
0.05 and power of 80%, and assuming a correlation among the repeated measures of 0.7 and overall SD 
of 2, giving a minimum sample size of 104 participants (n=52 participants in each group). This 
corresponds to an ANOVA effect size of 0.28 (28% of variance in primary outcome explained by 
treatment effect), or alternatively a moderate Cohen’s D effect size (group mean difference divided by 
SD) of 0.5. Oversampling by 10% to account for possible attrition yields a total of 116 participants with 
58 per group.  
 
 
11.0 
  
Registration Guidelines  
 
At time of registration, two copies of a signed and dated participant’s Informed Consent form with Bill of 
Rights must be available (an original for patient’s medical chart; one copy for the patient, one copy for 
the research records) 
 
12.0 
  
Biohazard Containment 
 
Biohazard materials will be disposed of properly in the clinic. Blood will be stored safely and securely 
until analysis.  
 
 
13.0 
  
Ethical and Regulatory Considerations 
 
All institutional and Federal regulations concerning the Informed Consent will be fulfilled. The study will 
be conducted in adherence to ICH Good Clinical Practice. 
 
 
14.0 
  
References 
 
1. Wolf SE, Thomas SJ, Dasu MR, Ferrando AA, Chinkes DL, Wolfe RR, Herndon DN. Improved net 
protein balance, lean mass, and gene expression changes with oxandrolone treatment in the severely 
burned. Ann Surg. 2003;237(6):801-10; discussion 10-1. 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
15 
 
2. Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone 
on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. 
Ann Surg. 2007;246(3):351-60; discussion 60-2. 
3. Schroeder ET, Vallejo AF, Zheng L, Stewart Y, Flores C, Nakao S, Martinez C, Sattler FR. Six-week 
improvements in muscle mass and strength during androgen therapy in older men. J Gerontol A Biol 
Sci Med Sci. 2005;60(12):1586-92. 
4. Gerber C, Fuchs B, Hodler J. The results of repair of massive tears of the rotator cuff. J Bone Joint 
Surg Am. 2000;82(4):505-15. 
5. Meyer DC, Wieser K, Farshad M, Gerber C. Retraction of supraspinatus muscle and tendon as 
predictors of success of rotator cuff repair. Am J Sports Med. 2012;40(10):2242-7. 
6. Sugaya H, Maeda K, Matsuki K, Moriishi J. Repair integrity and functional outcome after 
arthroscopic double-row rotator cuff repair. A prospective outcome study. J Bone Joint Surg Am. 
2007;89(5):953-60. 
7. Goutallier D, Postel JM, Bernageau J, Lavau L, Voisin MC. Fatty muscle degeneration in cuff 
ruptures. Pre- and postoperative evaluation by CT scan. Clin Orthop Relat Res. 1994;(304):78-83. 
8. Le BT, Wu XL, Lam PH, Murrell GA. Factors predicting rotator cuff retears: an analysis of 1000 
consecutive rotator cuff repairs. Am J Sports Med. 2014;42(5):1134-42. 
9. Kim HM, Caldwell JM, Buza JA, Fink LA, Ahmad CS, Bigliani LU, Levine WN. Factors affecting 
satisfaction and shoulder function in patients with a recurrent rotator cuff tear. J Bone Joint Surg Am. 
2014;96(2):106-12. 
10. Kelly BT, Kadrmas WR, Speer KP. The manual muscle examination for rotator cuff strength. An 
electromyographic investigation. Am J Sports Med. 1996;24(5):581-8. 
11. Makhni EC, Steinhaus ME, Morrow ZS, Jobin CM, Verma NN, Cole BJ, Bach BR, Jr. Outcomes 
assessment in rotator cuff pathology: what are we measuring? J Shoulder Elbow Surg. 
2015;24(12):2008-15. 
12. Richards RR, An KN, Bigliani LU, Friedman RJ, Gartsman GM, Gristina AG, Iannotti JP, Mow VC, 
Sidles JA, Zuckerman JD. A standardized method for the assessment of shoulder function. J Shoulder 
Elbow Surg. 1994;3(6):347-52. 
13. Michener LA, Snyder AR, Leggin BG. Responsiveness of the numeric pain rating scale in patients 
with shoulder pain and the effect of surgical status. J Sport Rehabil. 2011;20(1):115-28. 
14. Michener LA. Patient- and clinician-rated outcome measures for clinical decision making in 
rehabilitation. J Sport Rehabil. 2011;20(1):37-45. 
15. Mintken PE, McDevitt AW, Cleland JA, Boyles RE, Beardslee AR, Burns SA, Haberl MD, Hinrichs 
LA, Michener LA. Cervicothoracic Manual Therapy Plus Exercise Therapy Versus Exercise Therapy 
Alone in the Management of Individuals With Shoulder Pain: A Multicenter Randomized Controlled 
Trial. J Orthop Sports Phys Ther. 2016;46(8):617-28. 
16. Yamaguchi K, Ditsios K, Middleton WD, Hildebolt CF, Galatz LM, Teefey SA. The demographic 
and morphological features of rotator cuff disease. A comparison of asymptomatic and symptomatic 
shoulders. J Bone Joint Surg Am. 2006;88(8):1699-704. 
17. Vitale MA, Vitale MG, Zivin JG, Braman JP, Bigliani LU, Flatow EL. Rotator cuff repair: an 
analysis of utility scores and cost-effectiveness. J Shoulder Elbow Surg. 2007;16(2):181-7. 
18. Ensor KL, Kwon YW, Dibeneditto MR, Zuckerman JD, Rokito AS. The rising incidence of rotator 
cuff repairs. J Shoulder Elbow Surg. 2013;22(12):1628-32. 
19. Colvin AC, Egorova N, Harrison AK, Moskowitz A, Flatow EL. National trends in rotator cuff repair. 
J Bone Joint Surg Am. 2012;94(3):227-33. 
20. Lee TQ. Current biomechanical concepts for rotator cuff repair. Clin Orthop Surg. 2013;5(2):89-97. 
21. Boileau P, Brassart N, Watkinson DJ, Carles M, Hatzidakis AM, Krishnan SG. Arthroscopic repair of 
full-thickness tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am. 
2005;87(6):1229-40. 

Protocol Number: APP-17-01020 
Version Date: 9/1/2017 
16 
 
22. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of 
completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 
2004;86-A(2):219-24. 
23. Bjornsson HC, Norlin R, Johansson K, Adolfsson LE. The influence of age, delay of repair, and 
tendon involvement in acute rotator cuff tears: structural and clinical outcomes after repair of 42 
shoulders. Acta Orthop. 2011;82(2):187-92. 
24. Moraiti C, Valle P, Maqdes A, Boughebri O, Dib C, Giakas G, Kany J, Elkholti K, Garret J, Katz D, 
Leclere FM, Valenti P. Comparison of functional gains after arthroscopic rotator cuff repair in 
patients over 70 years of age versus patients under 50 years of age: a prospective multicenter study. 
Arthroscopy. 2015;31(2):184-90. 
25. Gerber C, Meyer DC, Schneeberger AG, Hoppeler H, von Rechenberg B. Effect of tendon release 
and delayed repair on the structure of the muscles of the rotator cuff: an experimental study in sheep. 
J Bone Joint Surg Am. 2004;86-A(9):1973-82. 
26. Patel S, Gualtieri AP, Lu HH, Levine WN. Advances in biologic augmentation for rotator cuff repair. 
Ann N Y Acad Sci. 2016;1383(1):97-114. 
27. Ruiz-Moneo P, Molano-Munoz J, Prieto E, Algorta J. Plasma rich in growth factors in arthroscopic 
rotator cuff repair: a randomized, double-blind, controlled clinical trial. Arthroscopy. 2013;29(1):2-9. 
28. Rodeo SA, Delos D, Williams RJ, Adler RS, Pearle A, Warren RF. The effect of platelet-rich fibrin 
matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med. 
2012;40(6):1234-41. 
29. Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA. Application of bone 
marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med. 
2009;37(11):2126-33. 
30. Gerber C, Meyer DC, Nuss KM, Farshad M. Anabolic steroids reduce muscle damage caused by 
rotator cuff tendon release in an experimental study in rabbits. J Bone Joint Surg Am. 
2011;93(23):2189-95. 
31. Gerber C, Meyer DC, Fluck M, Benn MC, von Rechenberg B, Wieser K. Anabolic Steroids Reduce 
Muscle Degeneration Associated With Rotator Cuff Tendon Release in Sheep. Am J Sports Med. 
2015;43(10):2393-400. 
32. Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs Health. 
2008;31(2):180-91. 
33. Sugaya H, Maeda K, Matsuki K, Moriishi J. Functional and structural outcome after arthroscopic full- 
thickness rotator cuff repair: single-row versus dual-row fixation. Arthroscopy. 2005;21(11):1307-16. 
34. Jo CH, Shin JS. Changes in appearance of fatty infiltration and muscle atrophy of rotator cuff muscles 
on magnetic resonance imaging after rotator cuff repair: establishing new time-zero traits. 
Arthroscopy. 2013;29(3):449-58. 
35. Kim JH, Hong IT, Ryu KJ, Bong ST, Lee YS, Kim JH. Retear rate in the late postoperative period 
after arthroscopic rotator cuff repair. Am J Sports Med. 2014;42(11):2606-13.  
36. Orr R, Singh MF. The anabolic androgenic steroid oxandrolone in the treatment of wasting and 
catabolic disorders: review of efficacy and safety. Drugs. 2004;64(7):725-750. 
37. Mendenhall CL, Moritz TE, Roselle GA, et al. A study of oral nutritional support with oxandrolone in 
malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs 
cooperative study. Hepatology 1993; 17 (4): 564-76.