Clinical trial NCT02938923
Conditions: Hip Fracture Frailty Sarcopenia
Sponsor: Washington University School of Medicine
Start date: 2019-03-05; Completion date: 2023-11-06
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomized controlled double-blinded multi-center clinical trial enrolling female hip fracture patients who are 65 and older. It will compare the effects of six months of supervised exercise training combined with daily topical testosterone gel, to six months of supervised exercise and inactive gel, and to Enhanced Usual Care. The randomization protocol is that for every nine participants randomized, 4 will be assigned to the topical testosterone gel and supervised exercise training group; 4 will be assigned to topical inactive gel and supervised exercise training group; and 1 will be assigned to the enhanced usual care group. All participants will receive nutritional counseling, and calcium and vitamin D supplements.

Detailed description:
Hip fractures are common among older women and can have a devastating impact on their ability to remain independent. A clinically important functional decline and failure to recover following a hip fracture has been documented as late as a year after the fracture, even among women who were functioning at high levels before the event. Age-associated androgen deficiency in women contributes to deficits in muscle mass, strength and power that are common in this patient population before the fracture, and are exacerbated afterward. A pilot study of testosterone (T) supplementation in elderly female hip fracture patients has demonstrated the feasibility of T treatment in this population, and showed gains in lean body mass (LBM) and muscle strength with active drug, compared to placebo. The benefits of exercise in restoring muscle strength and physical function after a hip fracture have been documented. However, it remains unclear whether T treatment can augment the effects of exercise on mobility and patient-reported function after hip fracture.

The STEP-HI study is a 3-group, multi-center, randomized, placebo-controlled, double-blinded, parallel group clinical trial in older female hip fracture patients. Between 120 and 168 female hip fracture patients, age 65 years and older, will be randomized from multiple clinical sites in the USA, using objective screening criteria for T deficiency (serum total testosterone level \< 60 ng/dL) and physical frailty (Modified Physical Performance Test (PPT) Score of 12-28). The primary study aim is to compare supervised exercise training (EX) with inactive (placebo) gel (EX+P) and EX combined with T therapy (EX+T), to ascertain the incremental impact of adding T to EX in older adult women with a recent hip fracture. The study team will carefully monitor testosterone levels, adverse events, biochemical parameters, and factors related to adherence to the interventions.

Information from this study has the potential to alter treatment of hip fracture in older women, a problem that contributes to significant morbidity and mortality, and has a large public health impact. The STEP-HI study is highly aligned with NIA's mission of identifying interventions that target common geriatric conditions and improve treatment options for older adults with multiple morbidities or risk factors.

Arms: arm 1: Supervised exercise training 2 times per week and topical testosterone 1% gel (12.5 mg per pump depression) daily, both for six months duration. arm 2: Supervised exercise training 2 times per week and placebo gel daily, both for six months duration. arm 3: Home exercise program 3 times per week and monthly health education modules, both for six months duration.
Interventions: intervention 1: Testosterone intervention 2: Placebo gel intervention 3: Supervised exercise training intervention 4: Home exercise program intervention 5: Health Education Modules
Intervention descriptions: intervention 1: Topical testosterone gel 1% intervention 2: Inactive skin gel intervention 3: Multicomponent exercise program focused primarily on progressive resistance exercise training intervention 4: Flexibility exercises performed at home 3 times per week and reviewed by study staff once a month. intervention 5: 30-40 minute presentations conducted by study staff for participants focused on health concerns unrelated to exercise.

Protocol documents:
ICF_002.pdf: 
Version 12.2 
STEP-HI ICF 
10 Nov 2020 
 
 Combining Testosterone Therapy 
and Exercise to Improve Function 
Post Hip Fracture 
STEP-HI Project 
Starting a Testosterone and Exercise Program after Hip Injury 
 
IND - 066697 
IRB - 201609077 
Clinical Trials.gov – NCT02938923 
 
 
Most Recent Informed Consent 12.2 
Version Date: November 10, 2020 
IRB Approved: June 13, 2023 
 
 
 
Contact PI Ellen F. Binder, MD 
Washington University School of Medicine 
 


 
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RELEASED DATE: 06/15/23 
EXPIRATION DATE: 06/11/24 
 
Version 12.2 
 
10 Nov 2020 
INFORMED CONSENT DOCUMENT 
 
Project Title:  STEP-HI Study: Combining Testosterone Therapy and Exercise to Improve 
Function Post Hip Fracture  
 
Principal Investigator:    Ellen Binder, MD 
 
Research Team Contact:  Amy Young, 314-273-0338, amyyoung@wustl.edu 
 
This consent form describes the research study and helps you decide if you want to 
participate. It provides important information about what you will be asked to do 
during the study, about the risks and benefits of the study, and about your rights and 
responsibilities as a research participant. By signing this form, you are agreeing to 
participate in this study. 
• You should read and understand the information in this document including 
the procedures, risks, and potential benefits.  
• If you have questions about anything in this form, you should ask the 
research team for more information before you agree to participate. 
• You may also wish to talk to your family or friends about your participation 
in this study. 
• Do not agree to participate in this study unless the research team has 
answered your questions and you decide that you want to be part of this 
study.  
 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study. We invite you to participate in this research study because you 
are female, 65 years old or older, and you recently had surgery to repair a hip fracture. 
 
Decreased muscle strength, muscle mass (amount of muscle), and bone are common in 
women over the age of 65 years following a hip fracture. Low testosterone (“male” 
hormone) levels occur with aging in both men and women, and are associated with a 
decline in muscle strength. 
 
The purpose of this research study is to see if 6 months of testosterone gel therapy 
combined with resistance (weight) training exercise improves physical function after a 
hip fracture more effectively than resistance training alone, or an independent home 
exercise program. 
 
Testosterone gel is approved by the U.S. Food and Drug Administration to increase 


 
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           10 Nov 2020 
testosterone levels in men who do not produce enough of the hormone naturally. 
However, the use of testosterone gel is considered investigational in this research 
study. Testosterone gel is being compared to a placebo, which is an inactive substance 
containing no active study drug. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
The study staff will review all the requirements and restrictions of the study with you 
to determine if you qualify for the study and to answer your questions. You may be 
able to complete a portion of the activities with research staff from your home, either 
over the phone or through video call.  However, some parts of the screening, baseline, 
month 3, and month 6 visit must be completed at the research center.  Transportation 
will be provided to you for all study-related visits to the research center. 
 
SCREENING VISIT (Expected to last about 2.5 hours)  
You must complete the screening visits prior to study entry to determine whether you 
are eligible to continue in the study.  The screening visit may take up to two sessions, 
depending on staff availability and your preference. Transportation will be provided 
for any visits occurring at the research center. 
• We will ask you questions about your medical history, any current illnesses, and 
any medications you are taking. During your participation, you should tell the 
study team before you take any new medication, even if it is prescribed by 
another doctor for a different medical problem or something purchased over the 
counter.  
• We will collect information about your primary care physician, orthopedic 
surgeon, and oncologist (if applicable) so we can notify them of your interest in 
the study and confirm that participation is safe for you. 
• You will be asked to complete questionnaires about your mood and about angina 
(chest pain). We will also ask questions to check your memory and thinking 
abilities. You do not have to answer any question you do not want to answer. 
• Your heart rate, blood pressure, and weight will be measured. 
• You will have a physical examination performed by a study physician or 
Advanced Practice provider. The physical exam will include a neurological and 
musculoskeletal evaluation. 
• A blood sample will be collected for some laboratory tests to make sure it is safe 
for you to participate in the study. About 3 teaspoons (13.5 ml) of blood will be 
collected into about 4 small tubes. It may also be necessary to re-draw a portion 
of the blood sample. 
• An electrocardiogram (ECG) will be done. An ECG painlessly measures the 


 
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           10 Nov 2020 
electrical action of your heart and helps evaluate the health of your heart. It 
involves placing electrodes (sticky patches) on your chest, arms, and legs. It 
takes less than 10 minutes to complete. 
• If you are found to be at higher risk of having heart complications from exercise 
training, you will be referred to your primary care doctor for clearance to be part 
of this study. Your doctor may order a stress test or other tests that are part of 
the standard of care for people with heart conditions or cardiac risk. 
• You will complete a Modified Physical Performance Test (mPPT) to measure 
your strength, walking speed, and balance. You will only be required to perform 
activities that you are capable of doing on your own. The mPPT is made up of 9 
tasks. Some of the tasks will be timed. 
o Book lift 
o Putting on a lab coat 
o Picking up a penny from the floor 
o Standing balance 
o Standing up 5 times from a chair 
o 50 foot walk, including a turn 
o Climb 10 stairs 
o 360 degree turn 
o Climbing 2 flights of stairs.  
 
BASELINE VISIT (Expected to last about 6 hours) 
If you fulfill all screening criteria and choose to participate in the study, you will be 
asked to complete more procedures and tests that may be scheduled on several days in 
a 2 week period.  When coming to the research center, transportation will be provided 
to you. The following activities will be completed during the baseline visits: 
• Your walking endurance will be measured using a 6-Minute Walk Test 
(6MWD). You will be asked to walk for 6 minutes along a marked path. The 
goal is to walk as far as possible. You may set your own pace and rest as 
needed. The distance you cover will be measured. 
• You will complete the same Modified Physical Performance Test (mPPT) to 
measure your strength, walking speed, and balance that you completed at the 
Screening visit. 
• You will complete a 4 meter timed walk at your usual pace and at a fast pace.  


 
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           10 Nov 2020 
• You will perform a 1-Repetition Max (1-RM) test to measure the muscle 
strength of your legs. 1-RM is the maximal amount of weight that you can lift 
one time.  For the test, you will perform a leg press exercise on a weight 
machine that has been chosen specifically to accommodate patients who have 
undergone hip fracture repair. 
• You will be asked to grip a tool called a dynamometer to measure the strength of 
your hand and forearm. 
• You will be asked to complete questionnaires that include questions about your 
ability to perform activities of daily living (ADLs), your perceptions of your 
health, pain symptoms, your mood, and your physical activities. You do not 
have to answer any questions you do not want to answer. 
• You will have a physical exam performed by a study physician or Advanced 
Practice provider to update any changes since the screening physical exam and 
check for hair growth patterns to compare with later changes that might occur as 
a result of taking testosterone. 
• You will have blood drawn for laboratory testing so the study team knows 
where your levels are at the beginning of the study. A total of about 2 teaspoons 
(10.5 ml) of blood will be collected - usually 2 tubes.  In order to get an accurate 
reading, a portion of the blood sample may have to be re-drawn. 
• You will have a Dual X-ray Absorptiometry (DXA) Scan: DXA is a type of x-
ray that measures bone density and total body mass (muscle and fat). This test 
will take approximately 30 minutes to perform, and will require that you lie on a 
table for about 15 minutes.  There is a small chance you will be asked to repeat 
the scan to obtain the best possible image. 
• You will have a mammogram if you haven’t had one in the past 6 months. A 
mammogram is an x-ray of the breast. The breast is briefly compressed while 
the x-ray images are taken. The total examination takes 10-15 minutes. If you 
have had a mammogram in the past 6 months, you will need to provide the 
report or give your permission for the study to get the report. If you have not had 
a mammogram in the past 6 months you will be required to have one. 
• A dietician will meet with you to assess your nutrition. The dietician may make 
recommendations to improve your diet. 
• A physical therapist will complete an evaluation with you to find any physical 
limitations or impairments that may limit your ability to perform specific 
exercises or require modifications. 


 
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           10 Nov 2020 
RANDOMIZATION (Expected to last about 1 hour) 
If you are eligible for the study, you will be randomly assigned to one of three groups 
after completion of the baseline visits. By “random”, we mean that neither you nor any 
of the study research members can select the group you will be in. Using a procedure, 
like rolling dice, a computer program assigns you to one of the three study groups: 
 
1. Enhanced Usual Care 
2. Supervised Exercise Program with Inactive Gel (Placebo) 
3. Supervised Exercise Program with Active Gel (Testosterone) 
 
Even though the assignment is random, you do not have an equal chance of being 
assigned to each group.  Only 1 out of 9 participants will be assigned to the Enhanced 
Usual Care group.  4 of the 9 will be assigned to the Supervised Exercise Training 
Program with Inactive Gel (Placebo) and the remaining 4 will be assigned to the 
Supervised Exercise Training Program with Active Gel (Testosterone). 
 
INTERVENTIONS 
1-Enhanced Usual Care 
You will receive a home exercise program that consists of a set of 9 exercises focused 
on joint range of motion and flexibility. Each month an exercise trainer will review the 
exercises with you. All exercises are similar to standard care (regular care you would 
receive if you chose not to participate in this study) you would receive after being 
discharged from physical therapy after a hip fracture repair. You will be given an 
illustrated guide to the exercises and written instructions. You are encouraged to 
perform the exercises 3 times per week over the 6 month period. You will maintain a 
log of your exercise sessions on a form. The study forms will be turned in to the study 
team on a monthly basis. The study team will also check in with you by phone or email 
to ask if you have questions and offer encouragement. 
 
You will participate in a monthly follow-up visit where study staff will review any 
symptoms you are having, review the assigned exercises, collect your exercise log, and 
provide a health education session. The monthly sessions will typically last about 60 
minutes. The month 3 and 6 visits will be longer for follow-up assessments. 
Transportation will be provided to all visits at the research center. 
 
Study procedure 
M1 
M2 
M3 
M4 
M5 
M6 
Home based exercise program 
x 
x 
x 
x 
x 
x 
Health Education session 
x 
x 
x 
x 
x 
x 
Calcium & Vitamin D 
x 
x 
x 
x 
x 
x 
Dietary Assessment 
 
 
x 
 
 
 


 
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           10 Nov 2020 
2-Supervised Exercise Program and Inactive Gel (Placebo) 
3-Supervised Exercise Program and Active Gel (Testosterone) 
Exercise Intervention: 
The supervised exercise program will be led by a physical therapist, exercise 
physiologist, certified personal trainer, or a qualified exercise professional directly 
supervised by a physical therapist.  Exercise sessions will be conducted at an 
outpatient exercise or rehabilitation facility. You will be expected to attend an average 
of two exercise sessions per week for 6 months. Each session will last about 1 hour. 
Transportation will be provided to all the exercise sessions. Your first exercise session 
will take place within one week of your randomization visit. 
 
The exercise program will be advanced gradually and conducted in two phases. Phase 
1 is light resistance, flexibility, and balance training. This phase is meant to improve 
balance, range-of-motion, muscular endurance, and to prepare you for Phase 2 of the 
program. Phase 1 will last about one month. Phase 2 consists of progressive resistance 
training. You will exercise using weight machines and free-weights. Phase 2 will last 
about five months. 
 
In the event of increased COVID restrictions, a remotely supervised exercise program 
will be provided. If possible, exercise sessions will be conducted by the exercise 
trainer remotely through a secure video call using a tablet or laptop with a camera.  
You will be able to borrow a tablet and stand from the study, if you do not have one. 
 
You will also be encouraged to walk for about 20 minutes and perform a standardized 
set of exercises at home about 3 other days of the week. You will be provided with a 
form to track your home exercise activities. Upon completion of the 6 months of 
training, you will be given a set of exercises to continue exercising safely on you own. 
 
Topical Gel Intervention: 
You will receive a topical gel that must be placed on the skin daily. The study gel is in 
a pump bottle to make it easy for you to use.  The gel will be either testosterone or 
placebo. You will not know which gel is prescribed for you. The gel containers will 
look identical.  
 
At randomization, you will receive a bottle of testosterone gel or placebo gel and 
detailed instructions on how to use it properly. A study staff member will observe 
while you apply the first dose of gel. You are expected to apply the gel on your own, 
as directed during the 6-month intervention period (Randomization to Month 6). You 
will receive a log that you will use to record the amount of gel applied each day, the 
location on the skin, and the time of day. During the first month, you will receive a 
weekly phone call to discuss any questions you have about applying the gel. 


 
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           10 Nov 2020 
It is important that no one else be exposed to the gel. To prevent this you should 
always: 
1. Wash your hands immediately with soap and water after applying the gel. 
2. Allow the gel to fully dry. 
3. Cover the part of your skin where gel was applied if coming in direct contact 
with others (for example, holding children) within 2 hours of application. 
4. Wash the part of the skin where gel was applied well with soap and water before 
there is skin-to-skin contact with another person. 
Each month, the study staff will ensure you have enough gel for the next month. The 
study staff member will review your gel use logs and review any symptoms you have 
experienced. 
 
To make sure that the topical gel is at the target dose, the study team will draw a tube 
of blood (1 teaspoon or 6 ml) 2 weeks after you start applying the gel to test the 
hormone levels. The study team will let you know if you need to use more or less of 
the topical gel. This change will be made for both women who are using the 
testosterone and the placebo. The blood tests to check your hormone levels will be 
repeated monthly.  Each month, you will apply the gel and have your blood drawn 2 
hours after the gel application to make sure it is done consistently each time.  There is 
a small chance the blood sample will need to be re-drawn after a visit. 
 
Study procedure 
M1 
M2 
M3 
M4 
M5 
M6 
Center based exercise program 
2 times 
a week 
2 times 
a week 
2 times 
a week 
2 times 
a week 
2 times 
a week 
2 times 
a week 
Home maintenance exercises 
x 
x 
x 
x 
x 
x 
Apply Gel 
x 
x 
x 
x 
x 
x 
Calcium & Vitamin D 
x 
x 
x 
x 
x 
x 
Dietary Assessment 
 
 
x 
 
 
 
 
All Study Participants: 
All study participants will be provided with a daily vitamin D supplement, which is 
2000 units per day in one capsule. You will also be given a daily 500 mg calcium 
supplement that would be taken twice a day, unless it is determined that you should not 
take calcium. The tablets will be provided to you by the study team. 
 
In addition, you will receive a nutrition assessment to ensure sufficient nutrient intake 
during the study. You will visit with the study dietician at baseline and again at Month 
3 to receive feedback on your nutrition. Also, if you lose more than 5% of your body 
weight in a month, the dietician will follow up with you. 
 


 
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FOLLOW-UP VISITS 
(Expected to last about 1-2 hours for months 1, 2, 4, & 5 and about 3-5 hours at 
months 3 & 6) 
Each month during the intervention period (Randomization to Month 6), you will have 
a study follow-up visit. After the 6 month intervention period, you will have your final 
study visit. You may receive a telephone call 9 months after randomization to answer a 
brief questionnaire about how you have been since the intervention period ended. The 
table below lists the schedule of the assessments for follow-up. 
 
Schedule of Study Assessments for Follow-up        
W=Week and M=Month 
Follow-up visits 
W2 M1 M2 M3 M4 M5 M6 M9 
Physical and Questionnaire Measures 
  
  
  
  
  
  
  
  
Height, Weight, Vital signs 
  
x 
x 
x 
x 
x 
x 
  
Physical exam 
  
  
  
x 
  
  
x 
  
Questionnaires 
  
  
  
x 
  
  
x 
x 
Adverse Event Assessment 
  
x 
x 
x 
x 
x 
x 
  
Physical Performance Measures 
  
  
  
  
  
  
  
  
Modified Physical Performance Test (mPPT) 
  
  
  
x 
  
  
x 
  
Six Minute Walk Distance (6MWD) 
  
  
  
x 
  
  
x 
  
1-RM 
  
  
  
x 
  
  
x 
  
4 Meter Walk 
  
  
  
x 
  
  
x 
  
Hand Grip Strength 
  
  
  
x 
  
  
x 
  
Procedures 
  
  
  
  
  
  
  
  
DXA Scan 
  
  
  
  
  
  
x 
  
Mammogram 
(Exercise Group only) 
  
  
  
  
  
  
x 
  
Transvaginal Ultrasound  
(Exercise Group only if uterus present) 
  
  
  
  
  
  
x 
  
Laboratory Blood Draw 
  
  
  
  
  
  
  
  
Testosterone Level (Exercise Group) 1 tsp 
x 
x 
x 
x 
x 
x 
x 
  
Testosterone Level (Usual Care Group) 1 tsp 
  
  
  
x 
  
  
x 
  
Safety Labs (1 – 2.5 teaspoons) 
  
  
  
x 
  
  
x 
  
 


 
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           10 Nov 2020 
Transvaginal ultrasound. This procedure will only be done once at the end of month 6 
ONLY if you participated in the supervised exercise training groups and have a uterus. 
The purpose of this test is to measure the thickness of the lining of your uterus (called 
the endometrium). 
• An instrument, which is smaller than a speculum (normally used to look at the 
cervix), is inserted into the vagina that causes sound waves to bounce off organs 
inside the pelvis. These sound waves create echoes that are sent to a computer, 
which creates a picture called a sonogram. 
• If the ultrasound measurement of the lining of the uterus is greater than 4 
millimeters thick, you will be referred to your gynecologist or PCP to evaluate the 
cause of the thickened tissue.   
 
WILL YOU SAVE MY BLOOD SAMPLES OR RESEARCH DATA TO USE IN 
FUTURE RESEARCH STUDIES? 
As part of this study, we are obtaining blood samples from you. We would like to use 
this blood for studies going on right now as well as studies that are conducted in the 
future.  These studies may provide additional information that will be helpful in 
understanding hip fracture recovery, or other diseases or conditions, including research 
to develop investigational tests, treatments, drugs or devices that are not yet approved 
by the U.S. Food and Drug Administration.  It is unlikely that what we learn from 
these studies will have a direct benefit to you.  There are no plans to provide financial 
compensation to you should this occur.  By allowing us to use your blood you give up 
any property rights you may have in the blood. 
 
We might remove identifiers from your blood sample and then use the biospecimens 
for future research studies or share them with other researchers for their future 
research. If this occurs we will not ask you for additional consent for these uses of your 
information and blood. 
 
We will share your blood and data with other researchers. They may be doing research 
in areas similar to this research or in other unrelated areas.  These researchers may be 
at Washington University, other sites participating in the STEP-HI study, other 
research centers and institutions, or industry sponsors of research.  We may also share 
your research data with large data repositories (a repository is a database of 
information) for broad sharing with the research community.  If your individual 
research data is placed in one of these repositories only qualified researchers, who 
have received prior approval from individuals that monitor the use of the data, will be 
able to look at your information.   
If you change your mind and do not want us to store and use your blood for future 


 
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research you should contact the research team member identified at the top of this 
document.  The blood will no longer be used for research purposes. However, if some 
research with your blood has already been completed, the information from that 
research may still be used. Also, if the blood has been shared with other researchers it 
might not be possible to withdraw the blood to the extent it has been shared. 
 
Please place your initials in the blank next to Yes or No for each of the questions 
below: 
 
My blood & data may be stored and used for future research as described above. 
 
_____ Yes          _____ No 
Initials               Initials 
 
My blood & data may be shared with other researchers and used by these 
researchers for the future research as described above. 
 
_____ Yes          _____ No 
Initials              Initials 
 
VIDEO RECORDING 
One aspect of this study involves making video recordings of you during your center-
based exercise program. For a selection of participants, videos will be taken to make 
sure that all of the exercise professionals are completing the exercises in the same way. 
Only the exercise professionals at the site and physical therapy supervisors working 
with the study have access to the videos. The videos will be uploaded to a secure 
location for viewing and will be destroyed at the end of the study.  You can choose not 
to be video recorded and still participate in the study. 
 
I give you permission to make video recordings of me during this study.  
 
_____ Yes  _____ No 
Initials 
Initials 
  


 
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HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 30 people will take part in this study conducted by investigators at 
Washington University. A total of approximately 200 people are expected to 
participate across the United States. 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for about 10 months. 
There will be visits for screening and baseline. You will have monthly research visits 
for about 6 months after randomization. The timing of study visits may be modified to 
accommodate you and the schedule of the study team. You may also receive a brief 
telephone follow-up 9 months after randomization.  
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. 
In addition to these, there may be other unknown risks, or risks that we did not 
anticipate, associated with being in this study.  
 
Some risks described in this consent document, if severe, may cause death.  
 
You should report any injuries or illnesses you experience while you are in the study, 
even if you do not think they are related.  
 
Medications: 
Testosterone gel 
Less Likely / Less Common (Occurring in less than 5% of women) 
• Mild swelling of the ankles from fluid retention  
• Hair growth  
Rare (Occurring in less than 1% of women) 
• Facial acne 
• Scalp hair loss 
• Enlarged clitoris 
• The effects of testosterone on blood lipids (triglycerides and cholesterol) have 
been both positive and negative. High levels of these can cause heart disease and 
stroke. 
• For women with a uterus, there is a possibility that testosterone therapy could 
cause a buildup of the lining of the uterus, and rarely, cause vaginal bleeding. If 
you develop vaginal bleeding during the study, it will be necessary to evaluate 
your uterus with a vaginal ultrasound at that time (as discussed in the section 
about the vaginal ultrasound). 
 


 
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During the intervention, the study team will be monitoring you for these symptoms.  
These symptoms are typically reversible with prompt discontinuation of the drug. Very 
rarely, some of these side effects may not be reversible. Occasionally, people have 
allergic reactions to medications which may require medical treatment. A severe 
allergic reaction could be life-threatening. Examples of an allergic reaction include: a 
rash; shortness of breath; wheezing; difficulty breathing; sudden drop in blood 
pressure; swelling around the mouth, throat, or eye; fast pulse; and sweating. You 
should get immediate medical help and contact the study doctor if you have any of 
these or any other side effects during the study. 
 
Women with a history of breast or gynecological cancers may experience disease 
recurrence or occurrence of a new primary malignancy. If you have experienced these 
types of cancers, we encourage you to discuss this study with your primary care 
physician and/or oncologist and consider whether you should have any additional 
follow-up with your physicians during or after study participation. 
 
Calcium supplements 
Less Likely/Less Common 
• Mild constipation  
 
Vitamin D supplements 
Vitamin D toxicity has not been observed with doses below 10,000 units per day, 
which is much higher than the dose of 2000 units per day that will be administered in 
this study. Although we do not anticipate toxicity from the vitamin D supplement, the 
following are rare side effects: 
Rare 
• Elevated calcium level in the blood 
• Kidney stones 
• Frequent urination 
• Irregular heart beat 
 
Strength testing, physical assessments, and exercise sessions: 
Likely/Common 
• Strength testing may cause minor and temporary muscle soreness or joint 
stiffness. The soreness typically begins 1-3 days after exercise begins, does not 
last more than 2-3 days and does not damage the muscle. You may also 
experience minor fatigue following exercise sessions or visits. 


 
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           10 Nov 2020 
• Mild to moderate physical activity may cause sore or pulled muscles, heart 
problems, physical discomfort, and/or accidental injuries such as falling. You 
may also experience some physical discomfort such as increased heart rate, 
chest pain, shortness of breath, headache, nausea, and/or fatigue.  
Less Likely/Less Common 
• You may fall during one of the intervention sessions or clinical assessment 
visits. This risk is minimal and is no different than the risk that is normally 
present during walking. A study staff member will be beside you during all 
activities, which will reduce the risk of falling.  
Rare 
• You may fall and fracture a bone during the tests of your walking and balance. 
This risk will be minimized through the use of a safety belt during testing 
procedures. 
• With any exercise, there is always a risk something abnormal could occur with 
the heart. 
• You may fall during performance of the home exercises. In order to reduce this 
risk, you will be instructed in proper technique. 
 
Safety Assessments: 
Mammogram and transvaginal ultrasound 
Likely/Common 
• You may experience some discomfort from the mammogram and/or 
transvaginal ultrasound. 
Less Likely/Less Common 
• The transvaginal ultrasound (for women with a uterus) may be uncomfortable 
due to abdominal pressure and/or positioning of the legs. These tests will be 
done in a modified fashion for comfort and to maintain any hip restrictions that 
you may have. 
 
Blood draws 
Likely/Common 
• Bleeding, bruising, or discomfort at the blood draw site 
Less Likely/Less Common 
• Pain at the blood draw site 
• Dizziness or feeling faint 
Rare 
• Infection 
 


 
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           10 Nov 2020 
ECG 
Less Likely/Less Common 
• Patches used during the ECG may cause a skin reaction such as redness or 
itching  
• Patches may also cause skin discomfort and/or hair loss 
 
Radiation 
This study will expose you to radiation from DXA scans and mammograms. The 
amount of radiation from this, when averaged over your entire body, is 4% of the 
amount of radiation exposure all people in St. Louis receive each year from naturally 
occurring radiation sources. The risk from the radiation exposure in this study is too 
small to be measured. It is not a big risk when compared with other risks you take 
every day. If you want to know more about radiation exposure, please see the 
“Radiation Fact Sheet” located at https://hrpo.wustl.edu/participants/radiation-fact-
sheet or ask the study staff for a copy. 
 
Interviews 
Less Likely/Less Common 
• Fatigue, embarrassment, and possibly nervousness 
Fatigue will be kept to a minimum by keeping the interview sessions brief and taking 
frequent breaks. You do not have to answer any question you do not want to answer. 
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may 
be accidentally disclosed. We will use our best efforts to keep the information about 
you secure. Please see the section in this consent form titled “How will you keep my 
information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You may or may not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study 
because this study may identify effective interventions for recovery of function in 
people after they have broken a hip. By knowing this information, we may be able to 
help people get back to their prior level of function after a hip fracture.  
 


 
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           10 Nov 2020 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, you can consult your doctor about 
the other options that are available to you. Instead of being in this study, you could 
choose not to participate in this study. You could obtain health screening evaluations 
and health education from your own healthcare provider. You could also choose to 
increase your activity level without enrolling in this study. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any additional costs for being in this research study. 
 
WILL I BE PAID FOR PARTICIPATING? 
You will not be paid for being in this research study. 
 
WHO IS FUNDING THIS STUDY? 
The National Institute on Aging (NIA) is funding this research study. This means that 
Washington University is receiving payments from NIA to support the activities that 
are required to conduct the study. No one on the research team will receive a direct 
payment or increase in salary from NIA for conducting this study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any 
complications from this research. If you feel you are injured because of the study, 
please contact the investigator at 314-286-2707 and/or the Human Research Protection 
Office at 1-800-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your 
participation in research will be made by Washington University. If you need to seek 
medical care for a research-related injury, please notify the investigator as soon as 
possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
Other people such as those indicated below may become aware of your participation in 
this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
• Government representatives, (including the Office for Human Research 
Protections) to complete federal or state responsibilities 
• The U.S. Food and Drug Administration (FDA) 
• The National Institute on Aging (NIA)  
• The sponsor (NIA) may also inspect any part of your medical record for the 


 
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           10 Nov 2020 
purposes of auditing the conduct of the study 
• Your primary care physician if a medical condition that needs urgent attention is 
discovered 
• Hospital or University representatives, to complete Hospital or University 
responsibilities 
• Information about your participation in this study may be documented in your 
health care records and will be available to anyone with access to your health 
care record, including your health insurance company.  This information may 
also be released as part of a release of information request  
• The last four digits of your social security number may be used in hospital or 
University systems to track billing information for research procedures 
• Washington University’s Institutional Review Board (a committee that oversees 
the conduct of research involving human participants) and the Human Research 
Protection Office. The Institutional Review Board has reviewed and approved 
this study. 
• Staff at the University of Colorado in order to review the exercise intervention 
videos and DXA scans for quality control. 
• A data safety monitoring board 
• Any report or article that we write will not include information that can directly 
identify you.  The journals that publish these reports or articles require that we 
share your information that was collected for this study with others to make sure 
the results of this study are correct and help develop new ideas for research. 
Your information will be shared in a way that cannot directly identify you. 
 
To help protect your confidentiality, completed questionnaires and study forms will be 
kept in participant binders and stored in locked offices. No unauthorized person will be 
allowed to see the binders or forms. You will be identified only by a unique 
identification number on data collection forms. Names will only be used to make sure 
that the recorded information is for the person to whom it refers. All electronic data 
and computer files will be kept secure with multiple levels of password protection. 
Blood samples, video recordings, and DXA scans will be labeled with your study 
identification number.  


 
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           10 Nov 2020 
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. 
 
We will disclose to the proper authorities information shared with us or activities we 
observe concerning abuse, neglect or harm to others or yourself. 
 
To further protect your privacy, this research is covered by a Certificate of 
Confidentiality from the federal government. This means that the researchers can 
refuse to disclose information that may identify you in any legal or court proceeding or 
to anyone who is not connected with the research except if:  
• there is a law that requires disclosure, such as to report child abuse and neglect, 
or harm to self or others;  
• you give permission to disclose your information, including as described in this 
consent form; or 
• it is used for other scientific research allowed by federal law. 
You have the right to share your information or involvement in this study with anyone 
at any time. You may also give the research team permission to disclose your 
information to a third party or any other person not connected with the research.  
 
If information about you or your involvement in this research is placed in your medical 
record the information may no longer be protected under the Certificate. However, 
information in your medical records is protected in other ways.    
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is 
protected by federal law under HIPAA (the Health Insurance Portability and 
Accountability Act). To take part in this research, you must give the research team 
permission to use and disclose (share) your PHI for the study as explained in this 
consent form. The research team will follow state and federal laws and may share your 
health information with the agencies and people listed under the previous section titled, 
“How will you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it 
may no longer be protected by HIPAA. 
 
The research team will only use and share your information as talked about in this 
form or as permitted or required by law. When possible, the research team will make 


 
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           10 Nov 2020 
sure information cannot be linked to you (de-identified). Once information is de-
identified, it may be used and shared for other purposes not discussed in this consent 
form. If you have questions or concerns about your privacy and the use of your PHI, 
please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given 
access to your health care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
• Your treatment or the care given by your health provider. 
• Your insurance payment or enrollment in any health plans. 
• Any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research. 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your 
information (you may revoke your authorization).  
• To revoke your authorization, complete the withdrawal letter, found in the 
Participant section of the Human Research Protection Office website at 
http://hrpo.wustl.edu/participants//withdrawing-from-a-study/ or you may 
request that the investigator send you a copy of the letter. 
• If you revoke your authorization: 
 The research team may only use and share information 
already collected for the study. 
 Your information may still be used and shared as necessary 
to maintain the integrity of the research, for example, to 
account for a participant’s withdrawal from the research 
study or for safety reasons. 
 You will not be allowed to continue to participate in the 
study. 
 


 
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           10 Nov 2020 
Can we contact you by email? 
We would like to contact you by email for the purposes listed below. Some of these 
emails may contain health information that identifies you. 
• Appointment scheduling and reminders 
• Answer questions you may have 
 
Only the research team will have access to your email communications. We will only 
communicate by email to send you the information listed above. If you have any 
questions or need to contact us for an urgent or emergent situation, please contact the 
research team member identified at the top of this document. 
 
You should be aware that there are risks associated with sending your health 
information via email. 
• There is always a risk that the message could be intercepted or sent to the 
wrong email address. To avoid sending messages to the wrong email 
address, the first email we send you will be a test message to ensure we 
have the correct email address. 
• When using any computer you should be careful to protect your username 
and password. Make sure you log-out before getting up from the 
computer. 
• If you share a home computer with other family members, and do not 
want them to know you are participating in this study make sure you 
provide an email address that only you can access.  
• Your employer will have access to any email communications sent or 
received on any electronic devices used for work or through a work 
server. 
 
Do you agree to allow us to send your health information via email?   
 
_____ Yes  _____ No 
Initials 
Initials 
 


 
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           10 Nov 2020 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary. You may choose not to take 
part at all. If you decide to be in this study, you may stop participating at any time. 
Any data that was collected as part of your participation in the study will remain a part 
of the study records and cannot be removed. 
 
If you decide not to be in this study, or if you stop participating at any time, you won’t 
be penalized or lose any benefits for which you otherwise qualify. 
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in 
participating in the study or you may send in a withdrawal letter. A sample withdrawal 
letter can be found at http://hrpo.wustl.edu/participants/ under Withdrawing from a 
Research Study. 
 
If you decide to leave the study early, we will ask you to return for one study visit to 
provide 6-month data. If you decline the 6-month visit, we will request that you 
complete an early discontinuation visit. This visit would be shorter and include less 
tests than the 6-month assessment. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness 
to continue participating in the study, we’ll promptly provide you with that 
information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the investigator or the study sponsor might decide to end 
your participation in this research study earlier than planned. This might happen for no 
reason or because in our judgment it would not be safe for you to continue, because 
your condition has become worse, or because the sponsor has decided to stop the 
research. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions. If you have any questions about the research study 
itself, please contact: Dr. Ellen Binder at 314-286-2707. If you experience a research-
related injury, please contact: Dr. Ellen Binder at 314-286-2707.  
 


 
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           10 Nov 2020 
If you have questions, concerns, or complaints about your rights as a research 
participant, please contact the Human Research Protection Office at 660 South Euclid 
Avenue, Campus Box 8089, St. Louis, MO  63110, 1-800-438-0445, or email 
hrpo@wustl.edu.  General information about being a research participant can be found 
on the Human Research Protection Office web site, http://hrpo.wustl.edu. To offer 
input about your experiences as a research participant or to speak to someone other 
than the research staff, call the Human Research Protection Office at the number 
above. 
 
This consent form is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by 
agreeing to participate in this study. As a participant, you have rights and 
responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential 
benefits and decide if you want to participate without any pressure from the 
research team or others. 
• To understand all of the information included in the document, have your 
questions answered, and receive an explanation of anything you do not 
understand. 
• To follow the procedures described in this document and the instructions of the 
research team to the best of your ability unless you choose to stop your 
participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your 
participation, or if you are unable to continue and wish to stop participating in 
the research study. 
Your signature indicates that this research study has been explained to you, that your 
questions have been answered, and that you agree to take part in this study. You will 
receive a signed and dated copy of this form. 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 06/11/24. 
 
__________________________________________ 
______________________ 
(Signature of Participant)  
 
 
 
 
(Date) 
 
____________________________________________ 
(Participant's name – printed) 
 


 
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           10 Nov 2020 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where 
appropriate, with the participant’s legally authorized representative. The participant 
has indicated that they understand the risks, benefits, and procedures involved with 
participation in this research study. 
 
 
__________________________________________          ______________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed) 

Prot_SAP_000.pdf: 
 
 
 
 
 
Combining Testosterone Therapy 
and Exercise to Improve Function 
Post Hip Fracture 
 
STEP-HI Project 
Starting a Testosterone and Exercise Program after Hip Injury 
 
IND - 066697 
IRB - 201609077 
Clinical Trials.gov – NCT02938923 
 
 
 
 
Study Protocol 
Version 12.5 
November 15, 2022 
 
 
 
 
Contact PI 
Ellen F. Binder, MD 
Washington University School of Medicine 
 
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
2 
Table of Contents 
Acronyms Dictionary ................................................................................ 9 
Section 1: 
Executive Summary.......................................................... 11 
Section 2: 
Study PIs and Participating Clinical Sites ...................... 13 
 
STEP-HI PIs ...............................................................................................................13 
 
Participating Clinical Sites .......................................................................................13 
Section 3: 
Study Organization & Administration ............................. 16 
 
Study Chair ................................................................................................................17 
 
National Institute on Aging (NIA) .............................................................................17 
 
Data and Safety Monitoring Board (DSMB) .............................................................17 
 
Executive Committee (EC) .......................................................................................18 
 
Steering Committee (SC) ..........................................................................................18 
 
Clinical Coordinating Center (CCC) .........................................................................19 
 
CCC Oversight and Monitoring Responsibilities ...................................................19 
 
CCC Intervention Training and Fidelity Monitoring ...............................................20 
 
Ancillary Studies Committee ................................................................................20 
 
Data Coordinating Center (DCC) ..............................................................................20 
 
Publications Committee .......................................................................................21 
 
Single Institutional Review Board (sIRB) ................................................................21 
 
Central Pharmacy Services ......................................................................................21 
 
Centralization of Laboratory Testing .......................................................................21 
 
Central DXA Imaging Center ....................................................................................21 
 
Clinical Sites .............................................................................................................21 
Section 4: 
Study Objectives .............................................................. 23 
 
Primary Objective .....................................................................................................23 
 
Secondary Objectives ..............................................................................................23 
 
Exploratory Objectives .............................................................................................23 
Section 5: 
Background ...................................................................... 24 
 
Consequences of Hip Fracture ................................................................................24 
 
Rehabilitation and Exercise Strategies after Hip Fracture .....................................24 
 
Decrements in Muscle Mass and Strength after Hip Fracture ...............................25 
 
Testosterone Deficiency in the Elderly and in Hip Fracture Patients ....................25 
 
Rationale for the Interventions ................................................................................26 
 
Androgen Replacement .......................................................................................26 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
3 
 
Rationale for targeting female hip fracture patients ..............................................28 
 
Rationale for a 3-Group Design............................................................................28 
 
Rationale for a 6-month intervention period .........................................................28 
 
Preliminary Data/Efficacy and Safety of Testosterone Replacement after Hip 
Fracture 28 
 
Safety Measures in Pilot Study ............................................................................29 
 
Addressing Safety Concerns ................................................................................29 
Section 6: 
Study Design..................................................................... 31 
 
Overview of Study Design ........................................................................................31 
 
Screening ..................................................................................................................32 
 
Randomization ..........................................................................................................32 
 
Interventions .............................................................................................................32 
 
Source Documentation .............................................................................................33 
 
Efficacy and Safety Measures ..................................................................................33 
 
Blinding of Study Staff .............................................................................................33 
Section 7: 
Eligibility ........................................................................... 35 
 
Inclusion Criteria.......................................................................................................35 
 
Exclusion Criteria .....................................................................................................35 
 
Concomitant Medications ........................................................................................36 
 
Prohibited medications .........................................................................................36 
 
Pharmacologic Agents for Osteoporosis ..............................................................37 
Section 8: 
Recruitment and Retention .............................................. 38 
 
Identification of Hip Fracture Patients .....................................................................38 
 
Participant Recruitment and Pre-Screening ...........................................................38 
 
Informed Consent .....................................................................................................39 
 
Enrollment .................................................................................................................39 
 
Screening ..................................................................................................................40 
 
Retention Promotion Efforts ....................................................................................40 
 
Drop-out Prevention Efforts .....................................................................................41 
 
Premature Withdrawal from the Study ....................................................................41 
 
Replacement of Subjects .........................................................................................42 
 
Monitoring Recruitment and Retention ...................................................................42 
 
Monitoring and Quality Control of Recruitment and Retention ..............................42 
Section 9: 
Study Measures ................................................................ 43 
 
Physical and Questionnaire Measures ....................................................................43 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
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Demographics ......................................................................................................43 
 
Medical History ....................................................................................................43 
 
Medications or Medication Updates .....................................................................43 
 
Height, Weight, and Vital Signs ............................................................................43 
 
Physical Examination ...........................................................................................43 
 
Short Blessed Test (SBT) ....................................................................................43 
 
Activities of Daily Living (ADLs) ...........................................................................44 
 
Geriatric Depression Scale – Short Form (GDS-SF) ............................................44 
 
Seattle Angina Questionniare-7 (SAQ-7) .............................................................44 
 
Hip Rating Questionnaire (HRQ) ..........................................................................44 
 
PROMIS® Global Health ......................................................................................44 
 
Brief Resilience Scale (BRS) ...............................................................................45 
 
Ferriman-Gallwey Scale .......................................................................................45 
 
Physical Performance Measures .............................................................................45 
 
Six Minute Walking Distance (Primary Outcome Measure) ..................................45 
 
Leg Press 1-Repetition Max Test .........................................................................45 
 
Modified Physical Performance Test (mPPT) .......................................................46 
 
Short Physical Performance Battery (SPPB) ........................................................46 
 
Hand Grip Strength ..............................................................................................46 
 
Other Procedures ......................................................................................................46 
 
Laboratory Blood Tests ........................................................................................46 
 
Electrocardiogram (ECG) .....................................................................................46 
 
Dual Energy X-Ray Absorptiometry (DXA) ...........................................................47 
 
Mammogram........................................................................................................47 
 
Transvaginal Ultrasound ......................................................................................47 
Section 10: Assessment Schedule ...................................................... 48 
Table 2: Schedule of Assessments ....................................................................................48 
 
Screening Assessments ...........................................................................................49 
 
Baseline Assessments .............................................................................................49 
 
Follow-up Assessments ...........................................................................................50 
 
Order of Study Procedures ......................................................................................51 
Section 11: Standard Care Procedures for All Participants .............. 52 
 
Dietary Assessments ................................................................................................52 
 
Vitamin D3 and Calcium Supplementation ..............................................................52 
 
Physical Therapy Evaluation....................................................................................53 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
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Section 12: Randomization .................................................................. 54 
Section 13: Enhanced Usual Care (EUC) Group Activities ................ 55 
 
Home Exercise Program ...........................................................................................55 
 
Home Exercise Adherence ..................................................................................55 
 
Health Education Sessions ......................................................................................55 
Section 14: Supervised Exercise Training Group Interventions ....... 56 
 
Physical Therapy Exercises (Phase 1) ....................................................................57 
 
Progressive Resistance Training (Phase 2) ............................................................57 
 
Remote Supervised Exercise Sessions ..................................................................58 
 
Home Maintenance Exercise Prescription ..............................................................58 
 
Scheduling Exercise Intervention Visits .................................................................58 
 
Missed Exercise Sessions ...................................................................................58 
 
Adherence Measurements .......................................................................................59 
 
Fidelity Plan for Exercise Interventions ..................................................................59 
 
Initial Training and Certification for Procedural Reliability .....................................59 
 
Ensuring Ongoing Competency ...........................................................................60 
Section 15: Testosterone/Placebo Intervention ................................. 61 
 
Drug Distribution ......................................................................................................61 
 
Dosing and Schedule ...............................................................................................61 
 
Dose Adjustments ....................................................................................................62 
 
Adverse Events and Symptom Monitoring ...........................................................62 
 
Medication Adherence .........................................................................................62 
 
Fidelity Plan for Study Drug Procedures ..............................................................63 
Section 16: Safety Considerations ...................................................... 64 
 
Pre-Intervention Safety Screening ...........................................................................64 
 
Safety Considerations for Study Assessments ......................................................64 
 
Safety Considerations for Testosterone Therapy ...................................................64 
 
Evaluation of Hirsutism (Ferriman-Gallwey scale) ................................................64 
 
Adverse Event Assessment .................................................................................64 
 
Laboratory Testing ...............................................................................................64 
 
Transvaginal Ultrasound ......................................................................................65 
 
Mammogram........................................................................................................65 
 
Safety Considerations for Supervised Resistance Training Program ..................65 
 
Safety Considerations for Remote Exercise Program ............................................66 
 
Safety Considerations for Home Exercise Program ...............................................66 


STEP-HI Protocol 
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Participant Education about Potential Risks ..........................................................66 
Section 17: Adverse Event Reporting ................................................. 67 
 
Definitions .................................................................................................................67 
 
Categorizing an Adverse Event ...............................................................................69 
 
Expectedness ......................................................................................................69 
 
Relatedness .........................................................................................................71 
 
Severity ................................................................................................................71 
 
Adverse Event Recording ........................................................................................71 
 
Adverse Event Reporting .........................................................................................72 
 
Emergency Unblinding .............................................................................................72 
 
Adverse Event Monitoring ........................................................................................72 
 
CCC Monitoring ...................................................................................................72 
 
Internal Safety Monitor (ISM) ...............................................................................72 
 
Independent Data and Safety Monitoring Board (DSMB) .....................................73 
Section 18: Discontinuation ................................................................ 74 
 
Study Drug Discontinuation .....................................................................................75 
 
Study Exercise Intervention Discontinuation .........................................................75 
 
Early Withdrawal Visit ..............................................................................................75 
Section 19: Sample Size and Statistical Power .................................. 76 
Section 20: Statistical Analysis ........................................................... 78 
 
Specific Aim 1 ...........................................................................................................78 
 
Specific Aim 2 ...........................................................................................................78 
 
Specific Aim 3 ...........................................................................................................79 
Section 21: Clinical Coordinating Center (CCC) Activities ................ 80 
 
Study Protocol, Manual of Procedures, and Informed Consent ............................80 
 
Study Protocol .....................................................................................................80 
 
Manual of Procedures ..........................................................................................80 
 
Informed Consent ................................................................................................80 
 
Clinical Site Coordination ........................................................................................80 
 
Budgets ...............................................................................................................80 
 
Regulatory ...........................................................................................................80 
 
Clinical Site Visits .....................................................................................................80 
 
Site Initiation ........................................................................................................80 
 
Site Monitoring .....................................................................................................81 
 
Communication with Clinical Sites ..........................................................................81 


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Reportable Adverse Event (RAE) Reporting ...........................................................81 
 
Meetings and Training Sessions .............................................................................81 
 
Investigator Meeting.............................................................................................81 
 
Steering Committee and DSMB Calls ..................................................................81 
 
Training Sessions ................................................................................................82 
 
Clinical Site Conference Calls ..............................................................................82 
 
Study Equipment and Website .................................................................................82 
 
Collaboration with the Data Coordinating Center ...................................................82 
 
Central Lab, Pharmacy, and DXA Coordination ......................................................82 
Section 22: Data Coordinating Center (DCC) Activities ..................... 83 
 
DCC Responsibilities during the Study Start-Up Period ........................................83 
 
Forms Design ......................................................................................................83 
 
Training and Certifying Personnel ........................................................................83 
 
Data Management .....................................................................................................84 
 
The REDCap System ...........................................................................................84 
 
Testing the Data Management System at the DCC ..............................................84 
 
Data Security and Confidentiality .........................................................................85 
 
The SAS Data Codebook .....................................................................................85 
 
Data/Resource Sharing Plan ................................................................................85 
 
Quality Control ..........................................................................................................86 
 
Ensuring Data Accuracy and Completeness ........................................................86 
 
Data Queries........................................................................................................87 
 
Data Audits ..........................................................................................................87 
 
Quality Control of Forms and the Data Entry System ...........................................87 
 
Summary Reports ................................................................................................88 
 
Site Visits .............................................................................................................88 
 
WUSTL Box ...............................................................................................................88 
 
Randomization ..........................................................................................................88 
Section 23: Participant Rights and Confidentiality ............................ 89 
 
Institutional Review Board (IRB) ..............................................................................89 
 
Informed Consent Forms (ICF) ................................................................................89 
 
Disposition of Informed Consent Forms ...............................................................90 
 
HIPAA Authorization ............................................................................................90 
 
Participant Confidentiality ........................................................................................90 
Section 24: Research Publication Policy ............................................ 92 


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Section 25: Ancillary Studies Policies ................................................ 93 
 
Concurrent Studies ...................................................................................................93 
Section 26: Skeletal Muscle Mass using Creatine Dilution Method .. 94 
 
General Information ..................................................................................................94 
 
Background and Significance ..................................................................................94 
 
Study Objectives .......................................................................................................95 
 
Specific Aim 1 ......................................................................................................95 
 
Specific Aim 2 ......................................................................................................95 
 
Specific Aim 3 ......................................................................................................95 
 
Specific Aim 4 ......................................................................................................95 
 
Participants ...............................................................................................................95 
 
Inclusion Criteria ..................................................................................................95 
26.2.2 
Exclusion Criteria .................................................................................................95 
 
Study Design .............................................................................................................96 
 
Recruitment and Retention ......................................................................................96 
 
Informed Consent ................................................................................................96 
 
Enrollment ...........................................................................................................97 
 
Study Withdrawal .................................................................................................97 
 
Study Discontinuation ..........................................................................................97 
 
Replacement of Subjects .....................................................................................97 
 
Study Measures – University of California-Berkeley ..............................................97 
 
Safety .........................................................................................................................97 
 
Risks ....................................................................................................................97 
 
Adverse Event Reporting .....................................................................................98 
 
Site Monitoring .....................................................................................................98 
 
Statistical Analysis ...................................................................................................98 
 
Approach for Specific Aim 1 .................................................................................98 
 
Approach for Specific Aim 2 .................................................................................98 
 
Approach for Specific Aim 3 .................................................................................98 
 
Approach for Specific Aim 4 .................................................................................98 
Section 27: References ...................................................................... 100 
 
 
 


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Acronyms Dictionary 
1-RM  
One Repetition Maximum 
6MWD  
Six Minute Walk Distance 
ADLs  
Activities of Daily Living 
AE 
 
Adverse Event 
aLBM  
Appendicular Lean Body Mass 
ASC 
 
Ancillary Studies Committee 
BMD  
Bone Mineral Density 
BRS 
 
Brief Resilience Scale 
CCC 
 
Clinical Coordinating Center 
cPI 
 
Contact Principal Investigator 
CRF 
 
Case Report Form 
CSA 
 
Cross-Sectional Area 
DCC 
 
Data Coordinating Center 
DSMB  
Data and Safety Monitoring Board 
DXA 
 
Dual-energy X-ray Absorptiometry 
E 
 
Estrogen 
EC 
 
Executive Committee 
ECG 
 
Electrocardiogram 
EP 
 
Exercise Physiologist 
ES 
 
Endocrine Society 
EUC 
 
Enhanced Usual Care Group 
EX 
 
Exercise intervention treatment group with placebo gel 
EX+T  
Exercise intervention treatment group with testosterone gel 
FDA 
 
US Food and Drug Administration 
FFM 
 
Fat-Free Mass 
FSQ 
 
Functional Status Questionnaire 
GDS-SF 
Geriatric Depression Scale – Short Form 
HRPO  
Human Research Protection Office 
HRQ  
Hip Rating Questionnaire 
HRT 
 
Hormone Replacement Therapy 
HSL 
 
Hebrew SeniorLife 
IADLs  
Instrumental Activities of Daily Living 
IDS 
 
Investigational Drug Service 
ICF 
 
Informed Consent Form 
IM 
 
Intervention Monitor 
IMAGE 
Investigations in Metabolism, Aging, Gender and Exercise (University of CO) 
ISM 
 
Internal Safety Monitor 
LBM 
 
Lean Body Mass 
MOP  
Manual of Procedures 
mPPT  
modified Physical Performance Test 
NIA 
 
National Institute on Aging 
OARS  
Older Americans Resources and Services Questionnaire 
OHRP  
Office for Human Research Protections 
PC 
 
Publications Committee 
PCP 
 
Primary Care Provider 
PD 
 
Program Director 


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PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
Pitt 
 
University of Pittsburgh Medical Center 
PK 
 
Pharmacokinetic 
PRT 
 
Progressive Resistance Training 
PT 
 
Physical Therapist 
QC 
 
Quality Control 
QOL 
 
Quality of Life 
RAE 
 
Reportable Adverse Event 
RCT 
 
Randomized Controlled Trial 
ROM  
Range of Motion 
SAE 
 
Serious Adverse Event 
SAQ-7  
Seattle Angina Quesitonnaire-7 
SC 
 
Steering Committee 
sIRB 
 
Single Institutional Review Board 
SPPB  
Short Physical Performance Battery 
STEP-HI 
Starting a Testosterone and Exercise Program after Hip Injury 
T 
 
Testosterone 
UCD 
 
University of Colorado - Denver 
UConn  
University of Connecticut Health 
UMJH  
University of Maryland/Johns Hopkins 
UofU  
University of Utah 
UP 
 
Unanticipated Problem 
UTMB  
University of Texas Medical Branch at Galveston 
WU 
 
Washington University in St. Louis 
 
 


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Section 1: Executive Summary 
Hip fractures are common in older women and can have a devastating impact on their ability to 
remain independent.  A significant functional decline following a hip fracture has been 
documented even among individuals who were functioning at high levels before the event.  
Such individuals may require continued supportive services and are at high risk for recurrent 
falls and institutionalization.  High-risk patients include those with deficits in skeletal muscle 
strength during the post-fracture period.  Age-associated androgen deficiency contributes to 
deficits in muscle mass, strength and power that are common in older women before a hip 
fracture, and are exacerbated thereafter.  A pilot study of testosterone (T) therapy in elderly 
female hip fracture patients demonstrated the feasibility of T therapy in this population, and 
showed gains in lean body mass and muscle strength in response to the active drug, compared 
to placebo.  It is unclear whether these improvements can translate into sustained 
improvements in physical function, or whether combining T therapy with exercise can augment 
the effects of both treatments.  There is also very little information available about the effects of 
testosterone therapy in older women with sarcopenia.   
Study Title 
Combining Testosterone Therapy and Exercise to Improve Function Post Hip Fracture 
Study Acronym - STEP-HI Project 
Starting a Testosterone and Exercise Program after Hip Injury 
 
Objectives 
The primary goal of this study is to establish that improvements from baseline to post-
intervention (6-month) on the Six Minute Walking Distance (6MWD) are significantly greater for 
the combination of testosterone therapy and exercise training relative to a control condition or 
exercise training alone.  In addition, a number of secondary outcomes will be evaluated, 
including 1-RM strength, body composition and bone mineral density of the non-fractured hip, 
objective physical performance tests, and self-reported performance of activities of daily living 
and quality of life.    
Design and Outcomes 
A randomized, double-blind, placebo controlled, parallel group study in older adult female hip 
fracture patients will be conducted at multiple clinical sites.  All participants will complete a 6-
month treatment period.  Participants will be randomly assigned to one of three study groups: 
1. Enhanced Usual Care (Home exercise + Health Education) (EUC) 
2. Exercise (Placebo gel + Supervised Exercise Training) (EX) 
3. Combined (Testosterone gel + Supervised Exercise training) (EX+T) 
 
Females age 65 and older with a recent hip fracture at the clinical sites will be evaluated for 
eligibility between 6-24 weeks following surgery.  After consent to participate, eligible 
participants will undergo a comprehensive screening assessment.  Those who complete the 
screening assessment and meet all eligibility criteria will be randomized to one of the three 
study groups after completing the baseline assessments. Randomization of between 120 and 
168 participants with recent surgical repair of a hip fracture will take place within 24 weeks 
following surgery.   
 


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Primary and secondary study outcomes will be measured at baseline, 3 months and 6 months 
post-randomization.  Safety measures and adherence measures will be collected monthly and a 
brief questionnaire may be administered at 9 months post randomization.   
 
 
 


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Section 2: Study PIs and Participating Clinical Sites 
 STEP-HI PIs 
Contact PI, Program Director (cPI/PD)  
Steering Committee Chair and Clinical Coordinating Center Director  
Ellen Binder, MD 
Washington University in St. Louis 
660 South Euclid, Campus Box 8303 
St. Louis, MO 63110 
Phone:  (314) 286-2707 
Fax:       (314) 286-2701 
ebinder@wustl.edu 
 
Study PI and Data Coordinating Center Director 
Ken Schechtman, PhD 
Washington University in St. Louis 
660 South Euclid, Campus Box 8067 
St. Louis, MO 63110 
Phone: (314) 362-3606 
kschechtman@wustl.edu 
 
Study PI 
Jay S. Magaziner, PhD, MSHyg 
University of Maryland 
660 West Redwood St., Suite, 200 Howard Hall 
Baltimore, MD 21201 
Phone: (410) 706-3553 
Fax: (401) 706-4433 
jmagazin@epi.umaryland.edu 
  Participating Clinical Sites 
Boston (1) 
Hebrew SeniorLife (HSL)/Beth Israel (BI)/Harvard Medical School 
Douglas P. Kiel, MD, MPH 
 
 
Sarah Berry, MD, MPH 
Clinical Site PI 
 
 
 
Clinical Site Co-Investigator 
1200 Centre Street 
 
 
 
1200 Centre Street 
Boston, MA 02131 
 
 
 
Boston, MA 02131 
Phone:  (617) 971-5373 
 
 
Phone:  (617) 971-5383 
Fax:      (617) 971-5339 
kiel@hsl.harvard.edu  
 
 
Sarahberry@hsl.harvard.edu 
 
 


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St. Louis (2) 
Washington University in St. Louis (WU) 
Ellen Binder, MD 
Clinical Site PI 
660 South Euclid, Campus Box 8303 
St. Louis, MO 63110 
Phone:  (314) 286-2707 
Fax:       (314) 286-2701 
ebinder@wustl.edu 
 
Denver (3) 
University of Colorado (UCD) 
Kerry Hildreth, MD 
 
 
Clinical Site PI 
 
 
 
 
Campus Box: B-179  
 
 
 
12631 East 17th Ave.  
 
 
 
Aurora, CO 80045 
 
 
 
 
Phone: (303) 724-1919 
 
 
 
Fax: (303) 724-1918  
 
 
 
Kerry.Hildreth@ucdenver.edu 
 
Connecticut (4) 
University of Connecticut (UConn Health) 
George Kuchel, MD, CM, FRCP, AGSF 
Richard Fortinsky, PhD 
Clinical Site PI 
 
 
 
Clinical Site Co-Investigator 
263 Farmington Avenue 
 
 
263 Farmington Avenue 
Farmington, CT 06030 
 
 
Farmington, CT 06030 
Phone:  (860) 679-6796                                 Phone: (860) 679-8069 
 
Fax: (860) 679-1307    
 
 
Fax: (860) 679-1307 
kuchel@uchc.edu 
 
 
 
fortinsky@uchc.edu 
 
Baltimore (5) (UMJH) 
University of Maryland Baltimore  
 
Johns Hopkins University  
Denise Orwig, PhD 
 
 
 
Adrian Dobs, MD, MHS 
Clinical Site PI 
 
 
 
Clinical Site Co-Investigator 
660 West Redwood Street, Suite 200 
1830 Monument Street, Suite 328 
Baltimore, MD 21201  
 
 
Baltimore, MD 21287 
Phone:  (410) 706-2406 
 
 
Phone:  (443) 287-4000   
Fax:       (410) 706-4433 
 
 
Fax:    (410) 955-8172   
dorwig@som.umaryland.edu  
 
adobs@jhu.edu 
 
Galveston (6) 
University of Texas Medical Branch at Galveston (UTMB) 
Elena Volpi, MD, PhD 
Clinical Site PI 
301 University Blvd 
Rebecca Sealy Hospital - 6.610 
Galveston, TX 77555 
Phone: (409) 772-1977 
Fax: (409) 772-8931 
evolpi@UTMB.EDU 
 
 
 


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Salt Lake City (8) 
University of Utah Health (UofU) 
Robin Marcus, PT, PhD 
Clinical Site PI 
Department of Physical Therapy and Athletic Training 
520 Wakara Way, Rm 125 
Salt Lake City, UT 84108 
Phone: (801) 581-4813 
Fax: (801) 585-5629 
robin.marcus@hsc.utah.edu 
 
Pittsburgh (9) 
University of Pittsburgh (Pitt)/ University of Pittsburgh Medical Center (UPMC)  
Christine McDonough, PT, PhD 
Clinical Site PI Bridgeside Point 1 
100 Technology Dr. 
Pittsburgh, PA 15219 
Phone: (412) 383-4603 
cmm295@pitt.edu 
 


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Section 3: Study Organization & Administration 
This study is a multi-site, randomized, double-blinded, placebo controlled, parallel group study 
with a Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC) at Washington 
University in St. Louis (WU), which will lead the clinical sites.  In addition to these units, the 
project will have a Steering Committee (SC) that will provide the expertise needed to conduct 
this trial.  A project Organization Chart is provided below.  Each clinical site will be affiliated with 
a university and will be recruiting females aged 65 and older who have experienced a recent hip 
fracture repair. Most of the key personnel have collaborated on the design of this study; several 
will have multiple roles in its execution, based on individual areas of expertise.  
  
 
 


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  Study Chair 
Dr. Ellen Binder, contact principal investigator (cPI) and Project Director (PD) of the grant 
awarded by the National Institute on Aging (NIA) will serve as the study chair.  Responsibilities 
of the study chair will include: 
• 
Providing overall organization and scientific direction of the trial 
• 
Serving as chair of the SC 
• 
Administering logistics for the Data and Safety Monitoring Board (DSMB) in consultation 
with the NIA program official 
• 
Working with investigators and staff in the CCC, DCC, and clinical sites to maximize 
collaboration 
• 
Providing updates on progress to the NIA 
• 
Participating or supervising site visits to clinical sites to assess quality and assist with 
problems 
• 
Defining analyses of study data 
• 
Overseeing manuscript preparation 
 
In the unlikely event the Study Chair becomes unable to serve, another Study PI will serve as 
the Study Chair.   
  National Institute on Aging (NIA) 
This is an investigator-initiated project and funding is provided by an R01 grant.  The funding 
agency is the NIA.  The NIA will appoint members of the DSMB, who will review study data and 
safety presented by the study team and report to the NIA program official.  The NIA program 
official will then report the outcome of the DSMB review to the NIA director following established 
internal procedures.  The PI will also report study progress to the NIA on an annual basis unless 
asked to report at a different interval.  According to PA-10-067, a Non-Competing Continuation 
Grant Progress Report (PHS 2590) will be completed by the PI annually and financial 
statements will be provided as required in the NIH Grants Policy Statement.  A final progress 
report, invention statement, and Financial Status Report will be submitted by the study chair 
when the award is relinquished or when it is terminated. 
  Data and Safety Monitoring Board (DSMB) 
Members of the DSMB will be appointed by and report to the NIA. They will monitor accruing 
data in order to confirm that the participants in the trial are being cared for safely.  
Responsibilities of the DSMB will include: 
• 
Review of the research protocol, informed consent documents and plans for data and 
safety monitoring 
• 
Advise the NIA on the readiness of the study investigators and staff to initiate 
recruitment 
• 
Evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that can affect study outcome 
• 
Consider factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety of 
the participants or the ethics of the trial 


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• 
Review, approve, and monitor ancillary studies 
• 
Review study performance, make recommendations and assist in the resolution of 
problems reported by the PI 
• 
Protect the safety of the study participants 
• 
Report to the NIA on the safety and progress of the trial  
• 
Make recommendations to the NIA and the cPI concerning continuation, termination or 
other modifications of the trial based on the observed beneficial or adverse effects of the 
treatment under study 
• 
If appropriate, review the results of interim analyses in accordance with stopping 
guidelines, which are clearly defined in advance of data analysis and have the approval 
of the DSMB 
• 
Ensure the confidentiality of the study data and the results of monitoring  
• 
Assist the NIA by commenting on any problems with study conduct, enrollment, sample 
size and/or data collection 
 
The DSMB will discharge itself from its duties when the study is complete. Study completion will 
be considered in consultation with the study chair and NIA after no further outcome data are 
being collected in the main study and the main paper reporting on the primary outcome has 
been published. 
  Executive Committee (EC) 
The EC consists of the three study PIs (Contact PI, DCC Director, and Study Co-Investigator).  
Responsibilities will include: 
• 
Supervising the overall conduct of the trial 
• 
Serving as primary liaison body to the NIA, regulatory agencies, and the study DSMB 
• 
Chairing Steering Committee Meetings   
 
The Study Chair will chair Steering Committee Meetings.  When the Study Chair is unavailable 
one of the other two Study PIs will chair the meeting. 
  Steering Committee (SC) 
The SC will be charged with the overall governance of the study.  Responsibilities will include:  
 
• 
Approving the final protocol and Manual of Procedures 
• 
Generating and approving study policies 
• 
Considering modifications of the protocol and study operations 
• 
Providing oversight of the CCC and DCC 
• 
Problem-solving issues brought forward by the CCC, DCC, Site PIs, and coordinators 
• 
Reviewing issues related to protocol deviations and making final determinations 
regarding continued participation 
• 
Monitoring study performance 
• 
Appointing and chairing sub-committees 
• 
Implementing recommendations from the DSMB 
 
Voting members of the SC will include the Contact PI, one member from each clinical site 
(Clinical Site PI or designee), and the other 2 Study PIs.  If the contact PI also serves as the 


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Site PI then only one vote will be allowed; the 2 Study Co-Investigators will be allowed one 
combined vote (to ensure an uneven number of voting members).  All major scientific decisions 
will be determined by a simple majority of SC voting members.  The SC will meet at least 
monthly throughout the study.   
  Clinical Coordinating Center (CCC) 
The CCC will be primarily responsible for managing study operations and ensuring adherence 
to the study protocol.  Responsibilities will include: 
• 
Finalizing the study protocol, Manual of Procedures (MOP) and any subsequent 
amendments 
• 
Submitting study protocol, consent form, and any subsequent amendments to the WU 
Single Institutional Review Board (sIRB) 
• 
Tracking protocol amendments and ensuring their implementation 
• 
Procuring standardized equipment and materials for the clinical sites 
• 
Providing standardized study materials to clinical sites 
• 
Tracking protocol deviations and developing Corrective Action Plans 
• 
Tracking the implementation of the Corrective Action Plans 
• 
Staffing of an unblinded physician to monitor participant testosterone and CBC levels 
and recommend adjustments as necessary 
• 
Organizing and providing staff support for meetings of committees 
• 
Recording minutes from Steering Committee meetings, and sub-committee meetings, as 
indicated 
• 
Organizing training sessions of site coordinators, evaluators, dieticians, and 
PTs/exercise interventionists 
• 
Providing training related to clinical operation of study 
• 
Producing documents and forms in collaboration with the DCC 
• 
Reviewing reportable adverse events (RAEs) and submitting RAEs and Serious Adverse 
Events (SAEs) to the sIRB, DSMB, FDA, and NIA as per the protocol 
• 
Developing monitoring and quality assurance plans 
• 
Performance of monitoring and quality assurance visits to the clinical sites 
• 
Monitor sites for human subjects training and certification records, including CITI training 
and GCP certification 
• 
Interfacing with the Investigational Drug Service (IDS) to ensure proper distribution of 
study drug and placebo to each clinical site 
• 
Interfacing with the Central Lab to ensure proper distribution of lab kits and facilitating 
the reporting of results to the appropriate individuals 
• 
Interfacing with the Central DXA Imaging Center at UCD to ensure timely review of DXA 
scans and transfer of data to the DCC 
 CCC Oversight and Monitoring Responsibilities  
The CCC will refine and optimize procedures and strategies for recruitment and retention of 
study participants and for maintaining adherence to the protocol.  The CCC will oversee 
recruitment progress at all sites, intervene in cases of under-recruitment, and report recruitment 
progress to the SC. The CCC will oversee retention efforts and investigate and intervene when 
a site is having retention problems.  The CCC will utilize reports from the study database which 
will allow monitoring of recruitment, retention, and data collection by clinical site.  Another 


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responsibility of the CCC is ensuring that protocols are followed for data collection procedures 
and that each clinical site establishes standard operating procedures and maintains a current 
version throughout the study.  The CCC will also monitor data collection for the STEP-HI study 
and approved ancillary studies.  
 CCC Intervention Training and Fidelity Monitoring 
The CCC will finalize and refine the study Manual of Procedures (MOP) and work closely with 
the clinical sites to implement related training to provide the intervention while following Quality 
Control (QC) procedures.  The CCC will be responsible for the procedures for training, and 
certifying all PTs and exercise interventionists involved in the intervention protocols, 
documenting any changes to procedures in the MOP, and distributing updates to the clinical 
sites.   
 Ancillary Studies Committee 
The Ancillary Studies Committee (ASC) will review proposals for ancillary studies and provide a 
recommendation for/against approval to the SC.  Members of the ASC will be appointed by the 
Study Chair. The ASC Chair will be responsible for distributing proposals and related materials 
to committee members, organizing meetings and recording minutes, and providing reports to 
the SC. See Section 25 for Ancillary Studies Policies.   
  Data Coordinating Center (DCC) 
The DCC’s primary responsibility will be to manage data operations, monitor adherence to the 
study protocol and implement the data analysis plan. Responsibilities will include:  
• 
Developing, implementing, and monitoring the data management and randomization 
plans, and, in collaboration with the CCC, the data safety and monitoring plan. 
• 
Overseeing training of clinical site staff with regard to data entry, data correction, and 
randomization procedures 
• 
Assisting CCC on development of data collection form templates and overseeing the 
implementation of paper-based and web-based forms  
• 
Monitoring completion and timeliness of case report form submissions and query 
responses 
• 
Developing and implementing data edit specifications 
• 
Monitoring distribution of data queries to clinical sites 
• 
Monitoring sites’ responsiveness to queries 
• 
Participating in quality assurance visits to the clinical sites 
• 
In collaboration with the CCC, preparing reports on study progress and study results for 
the DSMB (twice per year and upon request), the NIA (annually and upon request), sIRB 
(annually and upon request), and the SC (upon request) 
• 
Preparing data files to be shared with any ancillary studies that are approved by the SC 
• 
Developing and maintaining a file share site in WUSTL Box to ensure up-to-date study 
documents (e.g., data collection forms, manuals, protocol, study personnel contact 
information) 
• 
In collaboration with the Publications Committee, Steering Committee, and CCC, 
preparing final data files and performing data analyses for publications and 
presentations 


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 Publications Committee 
The Publications Committee (PC) will review proposals for abstracts and manuscripts and 
provide a recommendation for/against approval to the Steering Committee.  Members of the PC 
will be appointed by the Study Chair.  The DCC Director will chair the PC, and will be 
responsible for distributing proposals and related materials to PC committee members, 
organizing meetings and recording minutes, and providing reports to the SC.    
  Single Institutional Review Board (sIRB) 
A sIRB will provide oversight of this study as related to the protection of human subjects and 
compliance with related federal regulations.  The Washington University Human Research 
Protection Office (HRPO) will serve as the sIRB.  For more information see Section 23. 
  Central Pharmacy Services  
The University of Iowa Pharmaceuticals will be responsible for the purchase, relabeling, and 
distribution of the active investigational drug. The University of Iowa Pharmaceuticals or a 
similar pharmacy contracted by the CCC will be responsible for packaging, labeling, and 
distributing the placebo gel to the clinical sites.  Each clinical site will be responsible for 
maintaining thorough records on the STEP-HI Investigational drug accountability log showing 
receipt, distribution, and  destruction (in the case of expired drug) for investigational drug at their 
site, through an Investigational Pharmacy or Drug Service as directed by the standard operating 
procedures at their institution.   
 
Centralization of Laboratory Testing 
Washington University Core Laboratory will provide centralized laboratory services for all clinical 
sites.  The Central Lab will provide pre-assembled kits for blood draws based on assessment 
time point and supply shipping kits for return to the appropriate processing lab.  The Central Lab 
will provide training and a MOP for all procedures related to laboratory testing.  The central lab 
will provide results in a timely fashion to the DCC, individual site PIs, or Unblinded CCC 
physician as indicated. 
 
Central DXA Imaging Center 
The University of Colorado Denver Investigations in Metabolism, Aging, Gender and Exercise 
(IMAGE) center will be responsible for managing the dual energy X-ray absorptiometry (DXA) 
imaging component of the STEP-HI Project. They will be responsible for the DXA Acquisition 
Manual which will be included in the Manual of Procedures, oversee certification of DXA 
technicians, perform image review, analysis of DXA scans obtained using Hologic machines 
and software, and assist CCC staff with quality control for all STEP-HI clinical sites. 
 
Clinical Sites 
The study has collaborating clinical sites each with a clinical site PI and coordinator. The clinical 
sites are Washington University in St. Louis (WU), Baltimore-University of Maryland/Johns 
Hopkins (UMJH), University of Connecticut Health Center (UConn), Hebrew SeniorLife (HSL), 
University of Colorado - Denver (UCD), and University of Texas Medical Branch at Galveston 
(UTMB), University of Utah Health (UofU), and University of Pittsburg Medical Center (UPMC). 
 
Responsibilities of the clinical site PI (with assistance from the coordinator) will include:  


STEP-HI Protocol 
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• 
Maintaining cooperation of study hospitals and ensuring that medical staff involved with 
the care of hip fracture patients are well informed about the trial 
• 
Recruiting study participants according to the study protocol 
• 
Ensuring retention and adherence of study participants 
• 
Performing all study-related assessments (including complete tracking of outcomes 
during follow-up) 
• 
Overseeing completion of data collection forms, enrolling participants using the 
automated randomization system, and entering data and processing data edit queries  
• 
Training (in collaboration with the CCC) and supervising staff at the clinical site; 
assigning tasks to data collectors, PTs, and dieticians; and providing day-to-day 
supervision of their work 
• 
Protecting participant safety and verifying that informed consent procedures are followed 
according to Good Clinical Practice guidelines 
• 
Providing oversight to safety monitoring at their individual clinical site 
• 
Properly maintaining all clinical site study materials and records 
• 
Reporting all Reportable Adverse Events (RAEs) and protocol deviations 
• 
Participating in the study sub-committees and manuscript preparation 
 
 
 
 


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Section 4: Study Objectives 
  Primary Objective 
Primary Aim 
Specific Aim 1:  To determine whether improvements in functional status, as measured by the 
Six Minute Walk Distance (6MWD) from baseline to post-intervention (month 6), are significantly 
greater for EX+T relative to EX alone, and relative to EUC. 
Hypothesis 1: Compared to EX and EUC, the EX+T group will have significantly greater 
improvements in 6MWD. 
  Secondary Objectives 
Specific Aim 2:  To determine whether improvements from baseline to post-intervention (month 
6), are significantly greater for EX+T relative to EX alone, and relative to EUC, for the following 
outcome measures: 
a) Whole body and appendicular lean body mass (LBM), measured using dual-energy x-ray 
absorptiometry (DXA); 
b) Leg press strength measured by the 1-repetition maximum test (1-RM); 
c) Functional performance measured by objective physical performance tests (modified 
Physical Performance Test Score (mPPT), Short Physical Performance Battery (SPPB); 
performance of Activities of Daily Living (ADLs) measured by self-report; 
d) Quality of life measured by self-report (Hip Rating Questionnaire, PROMIS® - Global 
Health); 
e) Bone mineral density (BMD) of the non-fractured proximal femur, measured by DXA. 
Hypothesis 2 : Compared to EX and EUC, the EX+T group will have greater improvements in 
LBM, 1-RM strength, objective physical performance measures, self-reported ADLs, self-
reported quality of life, and BMD of the non-fractured proximal femur.    
  Exploratory Objectives 
Specific Aim 3:  To obtain preliminary data regarding the sustainability of the effects of the 
EX+T and the EX interventions at 3 months after discontinuation of the active interventions (i.e. 
month 9 after randomization) on self-reported measures of ADL function and quality of life.  
 
 


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Section 5: Background 
Hip fractures represent a major public health problem of increasing magnitude. Annual 
incidence in the United States is approximately 98 fractures per 100,000 population, and an 
estimated 300,000 Americans aged 65 years and over sustain a hip fracture each year(1, 2). The 
incidence of hip fractures increases exponentially with age, so that 90% of such fractures occur 
after age 70(3) years. The majority of hip fractures occur in females over 60 years of age, and 
white females aged 85 years and older are the population at highest risk(4). As this is one of the 
fastest growing segments of our population, the burden of care for hip fracture patients is 
anticipated to rise dramatically. 
  Consequences of Hip Fracture 
Although advances in surgical techniques have reduced mortality after hip fracture repair, many 
patients remain unable to achieve full functional recovery. Studies have documented that 
between 22% and 76% of hip fracture patients do not recover to their pre-fracture ambulatory or 
functional status within 6 to 12 months of the fracture event(5-8). It is notable that although poor 
pre-fracture functional status increases the risk of poor recovery, many previously high 
functioning patients have significant mobility and ADL deficits after a hip fracture. Up to 60% of 
previously high functioning patients required assistance in ADLs, and 83% required the use of 
an assistive device at 6 months post-fracture(9). Magaziner et al. found that 25-40%(8, 10) of 
patients show a decline in walking ability, and 20% demonstrate a decline in instrumental 
activities of daily living (IADLs=shopping, laundry, etc.) between 6 and 12 months post-fracture. 
Patients who experienced such declines are more likely to experience re-hospitalization or a fall. 
Thus, despite standard rehabilitation techniques, many previously independent older patients 
require ongoing assistance with ADLs and IADLs between 6 and 12 months post-fracture. 
Interventions designed to reduce physical impairments post-fracture may thus be beneficial for 
long-term recovery, functional independence, and as a pathway to reduce health care costs.  
  Rehabilitation and Exercise Strategies after Hip Fracture  
Information about the relationship between functional outcomes and the amount or intensity of 
rehabilitation services is limited, despite a growing body of literature in this area. A Cochrane 
Review of multidisciplinary rehabilitation for older people with hip fracture included 13 trials and 
could only conclude that multidisciplinary team management is not harmful and may improve 
functional recovery(11). It did not address questions related to the intensity or duration of therapy 
services. A second Cochrane Review of interventions for improving mobility after hip fracture 
included 19 trials of “mobilization strategies”(12). Twelve trials evaluated interventions soon after 
surgical repair, and found conflicting results regarding the efficacy of weight-bearing, 
strengthening, or intensive PT interventions on mobility. Of seven trials of interventions started 
after hospital discharge, including one by Binder, et al. (13), three included intensive PT or 
strengthening programs, and showed improvements in mobility outcomes. The authors 
concluded that there is still insufficient evidence to establish the best strategies to enhance 
mobility after hip fracture. There was a suggestion that intensive strengthening programs started 
after hospital discharge improve short- and long-term mobility outcomes, but more evidence is 
needed to support this conclusion. The exercise intervention described in this proposal is based 
on previous work by Binder, et al. (13), showing that intensive multi-component exercise is safe 
and effective for hip fracture patients with physical frailty and impaired mobility. A recently 
published trial of a home-based intervention(14) that was considerably less intensive, 


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demonstrated very modest improvements in physical function that were comparable to the 
improvements observed in the Control group in Binder’s trial.  
  Decrements in Muscle Mass and Strength after Hip Fracture 
Factors associated with poor post-fracture outcomes also may contribute to the etiology of the 
fracture itself and place the patient at very high risk for recurrent falls and fractures. Decrements 
in neuromuscular function contribute to the risk of hip fracture. Two studies have documented 
an association between reduced muscle strength and increased fracture risk(15, 16). Fox, et al. (17) 
documented a 6% decline in lean body mass at 12 months post-fracture in a sample of elderly 
female hip fracture patients. Older hip fracture patients are at greater risk for decrements in 
muscle strength pre- and post-fracture because of age-associated changes in skeletal muscle. 
Decrements in muscle mass and muscle power are associated with functional impairments(18-21) 
and disability(22-24) in the elderly.  
 
In a previous RCT of intensive exercise in frail hip fracture patients by Binder et al., clinically 
significant improvements in measures of physical performance, including muscle strength, were 
observed. However, significant group differences in the changes in fat-free mass (FFM) over the 
6-month treatment period were not observed(13). This raises a question as to whether anabolic 
therapies aimed at increasing FFM and muscle strength, when combined with intensive 
exercise, can enhance the anabolic effects of exercise and achieve greater improvements in 
physical function and health outcomes than exercise alone. This study aims to address this 
question.  
  Testosterone Deficiency in the Elderly and in Hip Fracture Patients  
The major biologically active circulating androgen in males and females is testosterone (T). 
Evidence from a number of studies in men strongly suggests that total, free, and bioavailable T 
levels in serum decrease with advancing age (25-28). T deficiency is associated with decreases in 
lean body mass(29) and bone mass(30)  in young, hypogonadal men. In aging men, a decline in 
testosterone and an increase in pro-inflammatory markers such as IL-6 and TNFα are 
associated with decreased muscle and bone mass(31), and may contribute to physical frailty(32). 
There is a paucity of information regarding the clinical significance of low testosterone T levels 
in elderly women(33). After menopause, ovarian production of androgens (including T) persists, 
but declines(34). Plasma T levels have been documented to decrease by approximately 50% 
following ovariectomy (35). Results from cross-sectional studies of age-related changes in T 
levels in women are variable. The majority of studies suggest a gradual decline in T levels 
between age ~20 years and menopause, with levels in post-menopausal and elderly women 
30% to 50% below that of pre-menopausal women(34, 36-40).  
 
In women, low serum T levels have been associated with lower BMD (41, 42) and hip fracture (43-
45). In the Rancho Bernardo Study, bioavailable T levels in women were positively correlated 
with loss of vertebral height over 16 years (46). In another cross-sectional study of men and 
women (aged 20-90 years), Khosla et al.(37) found that bioavailable T and estrogen (E) levels 
correlated with BMD of the spine and femur, though multivariate analysis showed that E was the 
only independent predictor of BMD. However, in both men and postmenopausal women E is 
produced in large part by conversion of T. Therefore, low T levels may contribute indirectly to 
the effects of low E levels on BMD. Dubin, et al. (47) found that women with hip fractures had 
lower total T levels at the time of fracture than healthy controls, though the difference did not 


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reach statistical significance. Women with a trochanteric fracture also had a significant decline 
in T, but not E or other androgen levels, over the 12 months following the fracture.  
 
Age-associated decrements in skeletal muscle mass are well documented in women, although 
the underlying mechanisms are not well understood. Women lose fat-free mass with the onset 
of menopause(48, 49). In 43-73 year old women, Hakkinen and Pakarinen (50) found associations 
between serum total and bioavailable T level, and muscle cross-sectional area (CSA) (r=0.46, 
p<0.05), and maximal muscle force production (r=0.62, p<0.01). Gower et al.(51) also found a 
significant correlation between free T levels, and total lean mass (r=0.24, P<0.5) and leg lean 
mass (r=0.31, p<0.01) in postmenopausal women (n=70). In 59-78 year old women using HRT 
for 2 years, Iannuzzi-Sucich et al.(52) found that total T, but not E level, was an independent 
predictor of DXA-derived appendicular skeletal muscle mass.  
 
These studies suggest that low bioavailable T levels in women may: 1) be a risk factor for hip 
fracture; 2) contribute to age-associated declines in skeletal muscle mass and strength, and 
bone mass and; 3) contribute to declines in lean body and bone mass during the year following 
a hip fracture. However, data regarding the relationship between serum T-levels and age-
associated declines in muscle mass and strength are very limited in women, and there is a need 
for more clinical studies to address this issue(31, 53). 
  Rationale for the Interventions 
There have been very few studies of anabolic steroids in women focused on skeletal muscle 
strength and physical function, and most have been conducted with younger, healthier women. 
Hip fracture patients have a high prevalence of sarcopenia, which is an important risk factor for 
persistent mobility and ADL impairment. Treatment of elderly female hip fracture patients with 
short-term T therapy represents a novel treatment modality. In light of the modest effects of 
standard care exercise observed in hip fracture patients, the addition of an anabolic agent to 
intensive exercise has great potential to yield significant improvements in post-fracture 
functioning. Combining short-term T therapy and exercise, if demonstrated to be safe and 
efficacious, could lead to a major change in clinical practice for female hip fracture patients, and 
could have a huge impact on the approach to clinical care for this patient population, and other 
female patient populations after periods of hospitalization and immobility.  
 Androgen Replacement   
Studies of the effects of androgen therapy have been performed primarily in hypogonadal and 
healthy elderly men; patients with chronic diseases associated with muscle wasting, such as 
AIDS, COPD, chronic renal failure; surgical wounds; and in women with postmenopausal 
osteoporosis. Several studies have demonstrated that T replacement increases fat-free mass 
and decreases fat mass in young eugonadal(54) and hypogonadal men(55-57), elderly hypogonadal 
men(58), and in middle-aged and elderly men with low T levels(27, 59, 60). T replacement in 
hypogonadal men also increases maximum voluntary muscle strength (27, 59). Studies in elderly 
men with low T levels are inconsistent with respect to effects on muscle strength(61, 62). Studies 
that did not show positive effects on muscle strength enrolled men that were not uniformly 
hypogonadal, were healthier, and/or were more physically fit(27) or used dynamometry to assess 
muscle strength(58). In a placebo-controlled study, Bakhshi et al.(63) observed improvements in 
grip strength and measures of ADL function in response to T therapy in frail elderly men 
admitted to a VA Geriatric Evaluation unit (GEM) for rehabilitation. Another small, placebo-


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controlled trial of T therapy prior to elective knee replacement in older men showed significant 
improvements in transfer ability, and trends for decreased hospital LOS and improved mobility, 
in the T treatment group(64). Oxandrolone, a synthetic analog of testosterone, has been shown 
to increase muscle protein synthesis rate in young men(65, 66) and has also been shown to 
increase body weight and lean body mass (LBM) in young men with HIV(67), surgical patients 
with non-healing wounds(68), elderly men and women with severe burns(69), and male and female 
COPD patients with weight loss(70). Two recent RCTs of T therapy in older men with physical 
frailty(71, 72) showed significant increases in LBM, muscle strength and physical function, although 
a study by Basaria et al.(72) reported a higher incidence of adverse cardiac and respiratory 
events in the T group than placebo, raising some concerns about the safety of T therapy in 
frailer populations.  
 
Studies of the effects of androgen therapy on LBM in women are both limited and 
inconsistent(31, 33). Lovejoy(73) conducted a 9-month RCT comparing nandrolone, spironolactone, 
and placebo in 30 healthy, obese, postmenopausal women; they observed significant group 
differences in the changes in serum T levels, with ~2 kg increase in LBM in the nandrolone-
treated group.  Davis(74) conducted a 2-year RCT of 50 mg of estradiol (E) vs. or  E+T implants 
(50mg), finding an increase total T levels to the upper range of normal for premenopausal 
women (Total T=2.3 nM/L). The E+T group also had increased fat-free mass (FFM) (~3 kg, vs. a 
decline in the E group) over 2 yrs. Dobs(75) conducted a 16-wk RCT of oral E (1.25 mg) vs. E+T 
(2.5 mg methyl-testosterone) in post-menopausal women, observing significant increases in 
FFM and lower extremity strength only in the E+T group.  Recently Huang(76) conducted a 6-
month RCT in 71 healthy women (mean age ~54 yrs.) with low serum T levels after 
hysterectomy +/- oophorectomy who received E+placebo vs. one of 5 doses of intramuscular T. 
Dose-dependent improvements were observed in FFM, chest-press power and loaded stair-
climb power in the T-treated subjects.  Women receiving the higher T doses achieved 
supraphysiologic serum T levels which were well tolerated during the 6-month study.  
 
Miller(77) conducted a 12-week, RCT of 2 transdermal T doses in  54 women with AIDS wasting 
and low T levels. They found that while women on the physiologic T dose (total T levels ~100 
ng/dl) had increased body weight, only those on the supraphysiologic dose (total T ~155 ng/dL) 
had increased FFM (+0.5 kg).  Both T doses were well tolerated, with no differences in adverse 
events. Dolan(78) conducted a RCT of physiologic T replacement in 57 HIV-infected women with 
weight loss and low T levels. T therapy was well tolerated and resulted in significant increases 
in muscle mass, measured by urinary creatinine excretion, and several measures of muscle 
strength. Choi(79) conducted a RCT of physiologic T replacement in 52 HIV-infected women with 
weight loss, and observed no significant changes in FFM, leg strength or power, or quality of 
life. 
 
            
Androgen or T therapy in younger women and HIV+ women can increase serum T levels and, in 
some studies, is associated with improvements in body composition and muscle strength.  In 
these short-term studies, even supraphysiologic dose of T have been well tolerated.  There are 
little or no data on changes in function, in older women or women post-hip fracture.  This study 
will address these knowledge gaps. 


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 Rationale for targeting female hip fracture patients   
This study will focus on female hip fracture patients for several reasons.  First, females 
comprise ~75% of elderly hip fracture patients, and therefore study findings will impact a large 
proportion of this patient population. Second, in our experience conducting a pilot study of 
testosterone therapy in older men with physical frailty, we found that a high proportion of male 
hip fracture patients had contraindications to testosterone therapy due to prostate disease or 
other medical issues. Third, because of concerns about potential sex differences in the 
response to testosterone therapy, it would be necessary to enroll a sufficient number of men to 
perform sub-group analyses, which would require a very large sample.  Lastly, there are already 
more data available about testosterone therapy in older men with sarcopenia and mobility 
impairments. 
 Rationale for a 3-Group Design   
We considered a 2x2 factorial design, which would allow us to investigate the effects of each 
intervention alone in comparison to placebo. The required sample size was ~400+ subjects, 
which would require more clinical sites and be more costly.  Because hip fracture patients who 
undergo surgical repair all receive some form of exercise as part of their rehabilitation, we do 
not think that a testosterone alone arm has much “real world” applicability, and therefore 
planned a design that will allow us to evaluate the benefits of adding testosterone to an exercise 
program that has demonstrated benefits in the target population. 
 Rationale for a 6-month intervention period 
Although a shorter intervention period has the advantages of lower costs and attrition rates, our 
previous studies of testosterone, and those of other anabolic agents conducted in older adults, 
suggest that a treatment duration of 6 months may be necessary to translate into clinically 
meaningful improvements in muscle mass, strength, and function. 
 Preliminary Data/Efficacy and Safety of Testosterone Replacement 
after Hip Fracture  
Dr. Binder conducted a pilot study entitled Testosterone therapy after hip fracture in elderly 
female hip fracture patients (R21 AG023716 PI Binder). The study aims were to: 1) document 
the feasibility of recruiting frail elderly female hip fracture patients to participate in a 6-month RCT 
of topical testosterone therapy; 2) obtain preliminary information about the tolerability and safety of 
a supra-physiologic dosage of topical testosterone (T) therapy; 3) obtain preliminary information 
regarding the effects of 6 months of  T therapy on a number of outcomes, including  lean mass, 
muscle strength, physical functional capacity, and quality of life.  Participants met inclusion criteria 
similar to those for this clinical trial. Women were randomly assigned to placebo or T therapy for 6 
months, using a topical gel, at a supra-physiologic dose (target serum T level range 110-160 
ng/dL). All women were prescribed a low-intensity flexibility home exercise program that was not 
intended to increase muscle strength, similar to standard of care upon discharge from a post hip 
fracture PT program. Adherence to therapy, based on monthly weights of the gel bottle, was 
79% (83% placebo; 77% T gel). Only two women (1 T-gel, 1 placebo) dropped out; both 
determined to be unrelated to the study or medication.  
Table 1. Baseline and Change in Outcomes after 6 months of Testosterone therapy 
Variable 
Time point 
Placebo 
Group (n=5) 
Testosterone 
Group (n=9) 
p-value 


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Testosterone Level 
(ng/dL) 
Baseline 
20.2 ± 9.1 
19.7 ± 11.3 
 
Change 
16.2 ± 10.3 
145.2 ± 88.2 
0.007 
Lean Body Mass (kg) 
Baseline 
38.6 ± 2.2 
38.0 ± 6.3 
 
Change 
-0.01 ± 0.9 
1.6 ± 1.8 
0.03 
Knee Extension 1-RM 
(lbs.) 
Baseline 
63.1 ± 16.3 
61.4 ± 22.0 
 
Change 
6.3 ± 9.2 
12.8 ± 8.6 
0.20 
Hip Rating 
Questionnaire (HRQ) 
Score 
Baseline 
79 ± 13 
77 ± 12 
 
Change 
0.8 ± 13 
6 ±10 
0.45 
 
As shown in the table above, the target T level in the T-gel group was achieved. We observed a 
significant group difference in the changes in lean body mass, and trends toward greater 
improvements in leg strength and quality of life (HRQ score) in response to T therapy.  
 Safety Measures in Pilot Study  
Despite careful monitoring for signs of hirsutism, endometrial hyperplasia, changes in 
hematocrit, serum LFTs and lipids, no differences were observed for any of the safety 
parameters or the frequency of reported symptoms. There was one report of increased arm hair 
growth (T-gel group) that resolved several months after discontinuation of the medication. 
Although the sample size was very small and insufficient to draw definitive conclusions about 
the safety of testosterone therapy in this population, it did provide valuable preliminary data on 
patient recruitment, effect size for outcome measures, and information that the proposed dose 
of topical T therapy is well tolerated.     
 Addressing Safety Concerns 
The pilot study conducted at WU demonstrated the feasibility of administering topical 
testosterone gel to frail women with hip fractures, who tolerated the medication at the proposed 
dose well and demonstrated improvements in key outcome measures that will be used in the 
larger trial. These preliminary data were used to design this multicenter trial with a larger sample 
size.    
 
In designing this larger study we have carefully considered safety concerns given recent studies 
that have raised questions about the safety of testosterone replacement in men(72), and the 
2014 Endocrine Society (ES) Clinical Practice Guideline for Androgen Therapy in Women(80).  A 
systematic review and meta-analysis of testosterone(81) and DHEA therapy in women performed 
for this guideline found a higher rate of androgenic events associated with testosterone, mainly 
increased non-scalp hair growth, and a neutral or slightly increased risk of breast cancer.  Trials 
to date have been either of insufficient size to either determine or exclude a causal relationship 
for cancer risk. The ES guideline for women prescribed T-therapy recommended: 1) use of non-
oral preparations; 2) monitoring T levels 3-6 weeks and 6 months after initiation of therapy; 3) 
cessation of therapy for women who have not responded by 6 months; and 4) clinical trials that 
will measure multiple safety and clinical endpoints. Recent systematic reviews of the efficacy 
and safety of transdermal testosterone in post-menopausal women have shown small increases 
in rates of acne and hair growth, but no differences from placebo in other androgenic effects, 
including alopecia and voice deepening, and no differences from placebo in total adverse 
events and serious adverse events.(82, 83)   
 


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The protocol proposed for this trial is consistent with the recent ES guideline and will provide 
very important and useful information about clinically meaningful outcomes and the safety of 
short-term testosterone replacement therapy prescribed for this target patient population. 
Alternative anabolic agents, such as oxandrolone and oral T have greater safety risks; SARMs 
and myostatin inhibitors are not clinically available and it will be several years before any are 
approved for use in the U.S.   
   
 
 
 


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Section 6: Study Design 
  Overview of Study Design 
A randomized, double-blind, placebo controlled, parallel group study in elderly female hip 
fracture patients will be carried out at multiple clinical sites.  All participants will complete an 
approximate 6-month treatment period and study follow-up visits.  Participants will be randomly 
assigned to one of three study groups: 
1. Enhanced Usual Care (Home exercise + Health Education) (EUC) 
2. Exercise (Placebo gel + Supervised Exercise Training) (EX) 
3. Combined (Testosterone gel + Supervised Exercise Training) (EX+T) 
 
Randomization of 120-168 participants with recent surgical repair of a hip fracture will take place 
within 6-24 weeks of surgery. Female hip fracture patients age 65 and older at the clinical sites 
will be evaluated for eligibility.  Following consent to participate, eligible participants will undergo 
a comprehensive screening assessment.  Participants who complete the screening assessment 
and meet all eligibility criteria will be scheduled for baseline visits and randomized to one of the 
three study groups at the conclusion of the baseline measurements.  Figure 1 shows the 
sequence of participant contacts and study measurements from the time of surgery until the 
final assessment approximately 9 months post-randomization.  Transportation to all study visits 
and exercise sessions will be offered and provided if desired by the study participant. 
Figure 1.  Timeline for recruitment, randomization, and follow-up. 
 


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All participants will receive counseling by a dietician to facilitate adequate nutrient intake 
inclusive of a healthy diet. At the randomization visit, the EX and EX+T participants will receive 
their first monthly supply of study drug or placebo.  For the EX and EX+T participants, initiation 
of the exercise interventions with an exercise interventionist, who is supervised by a physical 
therapist (PT), should take place as soon as possible, up to seven days following 
randomization. The EUC group will be given a home exercise program, contacted weekly 
(phone or email) by the study staff, and have monthly follow-up visits that will include a health 
education module. 
  Screening  
Potential participants will undergo screening 6 to 22 weeks after hip fracture repair surgery. 
Participants who are beyond 22 weeks past their hip fracture repair surgery may be approached 
and screened with the approval of the CCC.  Subject eligibility will be determined by the 
following procedures: 
• 
Evaluation of medical history, concurrent illnesses, concomitant medications, and 
completion of the Angina Questionnaire (SAQ-7); 
• 
Screening for cognitive status and depression using the Short Blessed Test (SBT) and 
Geriatric Depression Scale (GDS-SF); 
• 
Resting 12-lead electrocardiogram (ECG); 
• 
Physical exam by a site physician or Advanced Practice provider; 
• 
Assessment of physical function using the mPPT; and 
• 
Laboratory Tests: Complete metabolic panel, Complete blood count, TSH, HbgA1c, and 
Testosterone level.   
  Randomization  
Randomization will occur between 6 to 24 weeks after the participant’s hip fracture surgery.  
Only women that qualify for the study based on the screening process will be scheduled for 
baseline assessments and randomization. The study coordinator will assure that all eligibility 
criteria are documented in REDCap prior to randomization. For more information see Section 
12.  
  Interventions 
Participants in all intervention groups will receive nutritional counseling to promote adequate 
nutrient intake.  Participants in all intervention groups will receive 2,000 IU vitamin D3 and 1,000 
mg of calcium daily for the duration of the 6-month intervention period. 
 
The enhanced usual care group (EUC) will complete a home-based, low-intensity exercise 
program independently 3 times per week. They will also receive weekly contact by phone or 
email from the study staff to encourage adherence, answer questions, and keep contact. In 
addition, the EUC group will attend a health education session once a month.  Whenever 
possible, the health education sessions will be combined with monthly study visits when 
transportation is provided. The EUC group will not use the testosterone or placebo gel. 
 


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Over an approximate 6-month intervention period, participants in the EX and EX+T study 
groups will complete a supervised multimodal exercise program that includes progressive 
resistance training sessions. Visits with exercise interventionists will take place at the study 
center or dedicated exercise facility.   
 
Participants in the EX and EX+T study groups will also receive treatment with either placebo or 
testosterone gel, respectively. Testosterone and placebo gels will be administered in identical 
bottles to participants who will be blinded to medication group assignment.  All participants will 
be instructed in proper application of the gels by the study staff.  
  Source Documentation 
Source documents include original records of clinical observations, laboratory reports, DXA 
images, radiology reports, ultrasound reports, and medical records including: progress notes, 
clinic notes, hospital charts, and other records or reports of procedures performed during the 
study period. The clinical sites are required to retain all source documentation in the 
participant’s research binder.  When applicable, data entered into REDCap must be verifiable in 
the source documents maintained by the clinical sites. 
  Efficacy and Safety Measures 
Primary and secondary outcome measures will be assessed at baseline, month 3, and month 6.  
Primary efficacy measure: Six Minute Walking Distance (6MWD)(83-85) 
Secondary efficacy measures: Total and Appendicular Lean Body Mass (LBM, aLBM) as 
measured by Dual Energy X-ray Absorptiometry (DXA), Total Body and Total Femoral Bone 
Mineral Density (BMD) of the unfractured limb as measured by DXA, 1-RM strength for leg 
press, Modified Physical Performance Test Score (mPPT)(86), Short Physical Performance 
Battery (SPPB)(87, 88), 50 ft. and 8 ft. Gait Speed (each performed as part of mPPT and SBBP, 
respectively), Functional Status Questionnaire (FSQ)(89), Older Americans Resources and 
Services (OARS)(90) questionnaire for Activities of Daily Living (ADL), Hip Rating Questionnaire 
(HRQ)(91), PROMIS® Global Health(92), and Brief Resilience Scale (BRS)(93). 
To address Aim 3, which is exploratory, a limited number of secondary outcome measures will 
be obtained by telephone interview at month 9: 1) Functional Status Questionnaire (FSQ), Older 
Americans Resources and Services (OARS) questionnaire for Activities of Daily Living (ADL); 2) 
Hip Rating Questionnaire (HRQ); and 3) PROMIS® Global Health. 
Safety measures: Participants will be carefully monitored for the development of side effects 
and potential health problems related to the interventions.  Adverse Event (AE) assessments, 
physical examinations, and laboratory testing will be performed at prescribed intervals to 
monitor for exercise and medication side effects and will be reviewed by the clinical site 
physician.  Following the intervention period, a mammogram and transvaginal ultrasound will 
also be performed to monitor for medication side effects. 
  Blinding of Study Staff 
All study staff will be blinded to investigational drug treatment assignment. Because of the 
structure of the exercise programs and the importance of making the interventions accessible to 
the target population, it will not be feasible to blind study participants and all staff to the exercise 


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interventions. The staff responsible for administering the interventions will be blinded to 
participants’ study outcomes. Clinical site PIs and clinical site coordinators who are responsible 
for assigning work and/or assessing for treatment fidelity of exercise interventionists in both 
groups will be unblinded to exercise intervention assignments, but not involved in assessments 
of study outcomes.   
 
To the extent possible, the research staff administering the outcome assessments will be 
blinded to exercise intervention group.  Blinded study staff performing follow-up assessments 
will be instructed not to ask about treatment (exercise) assignment when in contact with 
participants. Participants will be instructed not to discuss their treatment experience (including 
the identity of the exercise interventionist) during study visits and telephone calls conducted by 
blinded staff.  
 
Only designated members of the DCC staff and members of the DSMB will see group-specific 
study results. In the event of inadvertent unblinding of study staff, a protocol deviation will be 
reported and a notation will be made in the participant binder specifying the circumstances of 
the unblinding event and a list of all persons unblinded.  
 
 


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Section 7: Eligibility 
Following initial identification of participants by referral and/or chart review, participants will be 
evaluated for eligibility at two time points:  a pre-screen and a study screening visit.  Participants 
will be followed between pre-screen and screening to allow for additional assessment of 
eligibility prior to formal screening.  Pre-screening will assess eligibility of the potential 
participant on a selection of the medical history inclusion and exclusion criteria. Pre-screening 
questions will be collected using a standardized interview that can be administered over the 
telephone or in-person. Other criteria will be reviewed from the participant’s medical record.  If 
the participant appears to meet the pre-screening criteria, a more detailed screening visit will 
involve assessment for medical, safety, and feasibility criteria.  The pre-screening and screening 
visit should be completed within 22 weeks of surgical hip repair.  Participants who are beyond 
22 weeks past their hip fracture repair surgery may be approached and screened with the 
approval of the CCC.  
  Inclusion Criteria 
1. Female 65 years and older. 
2. Surgical repair of a non-pathologic fracture of the proximal femur (Including: femoral 
neck or intracapsular, intertrochanteric, and subtrochanteric fractures), with a surgical 
repair date that is within 24 weeks at randomization.  If a revision of such a fracture is 
performed due to failure of the repair, that surgery revision date may be used to 
calculate the time frame for the screening and randomization dates. 
3. Functional impairment at the time of screening, defined as a modified Physical 
Performance Score (mPPT) of 12-28.  
4. Serum total testosterone level <60 ng/dL. 
5. Community-dwelling or in assisted living prior to the hip fracture event.  
  Exclusion Criteria 
1. Use of progestin or androgen containing compound within the previous 6 months. 
2. Cognitive impairment or dementia of severity sufficient to interfere with ability to fully 
participate in the study or provide one’s own informed consent, or a score of ≥11  on the 
Short Blessed Test of Orientation, Memory and Concentration(94, 95).  
3. Visual or hearing impairments that interfere with following directions for research 
procedures. 
4. Active or unstable cardiopulmonary disease (recent MI, unstable angina, class III or IV 
CHF) within prior 6 months, which would limit full participation in this study. 
5. Uncontrolled hypertension, defined as a systolic BP > 160 mm Hg or diastolic BP > 95 
mmHg, on at least two occasions. 
6. Respiratory disease requiring chronic continuous oxygen therapy, or oxygen therapy 
during walking or exercise, which would limit full participation in this study. 
7. History of: a) Breast, ovarian, endometrial or cervical cancer with diagnosis within the 
previous 10 years; b) Breast, ovarian, endometrial or cervical cancer of Stage 2 or higher. 
8. Elevated liver transaminase or alkaline phosphatase levels ≥ 2.5 times above normal 
range. 
9. Erythrocytosis defined as hematocrit ≥ 51% at all sites but UCD and UofU, or ≥ 52% at 
the UCD and UofU sites. 
10. Severe anemia defined as Hgb < 7 gm/dL. 
11. History of HIV or active viral hepatitis. 


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12. Uncontrolled diabetes defined as HgbA1C>10%. 
13. GDS-SF score ≥ 12 at the screening assessment. 
14. Recent history of alcohol or substance abuse, or current alcohol intake of ≥ 10 
drinks/week. 
15. Untreated or unstable thyroid disease, with serum TSH level ≥ 10 mIU/L or TSH level ≤ 
0.4 mlU/L. Levels outside of the given range require site physician documentation 
addressing treatment or absence of thyroid disease and approval by the CCC. 
16. Current use of aldactone, flutamide or leflunomide. 
17. Treatment with systemic corticosteroids (daily dose > 5 mg prednisone or equivalent) for 
at least 90 days within the previous 12 months. 
18. Musculoskeletal or neurological conditions that limit full participation in this study, could 
be made worse by exercise training, or not expected to improve with exercise. 
19. End Stage Renal Disease on dialysis or GFR<15 ml/min. 
20. History of idiopathic deep venous thrombosis or pulmonary embolus (i.e., not related to 
period or immobilization or surgery), any pulmonary embolus less than 12 weeks prior to 
the first screening visit, recurrent or multiple venous thrombi; history of a hypercoagulable 
state such as Factor V Leiden thrombophilia.  
21. Lower extremity amputation other than toes. 
22. Planned joint surgery during the intervention period. 
23. Severe lower extremity pain or ulceration that could limit full participation in this study. 
24. Allergy to gel components. 
25. Residence too far from research center (specific distance to be determined by each site), 
or planned travel greater than 2 weeks within the next 9 months. 
26. Anticipated to be permanently living in a nursing home at the time of randomization.   
27. Site investigator’s judgment that the participant would not be able to complete research 
procedures or interventions.   
28. Participation in another research study that in the site investigator’s judgment could 
interfere or conflict with STEP-HI research assessments or interventions.   
  Concomitant Medications 
The name of any prescription and over-the-counter medication that the participant is taking at 
the time of enrollment as well as any additional prescription and over the counter medication 
used during the study will be documented in the participant’s study record.  Medications will be 
reviewed with participants monthly at each study follow up visit. 
 Prohibited medications 
 Treatment with the following concomitant medications is prohibited during study: 
• 
Androgen, progestin, or any other anabolic agent 
• 
Aldactone 
• 
Flutamide 
• 
Leflunamide  
• 
Treatment with systemic corticosteroids at a daily dose of >5 mg prednisone or 
equivalent for a duration of 90 days or longer within the previous 12 months 
 
If a patient takes a prohibited medication during the study, the site must notify the CCC. The 
decision to discontinue or to keep the patient in the study will be made after consultation 


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between the site PI and the Study Chair. The dose and duration of the prohibited medication 
used will be a factor in the decision. 
 Pharmacologic Agents for Osteoporosis   
Based on previous hip fracture studies, we anticipate that 30-50% of the patients enrolled will be 
taking bisphosphonates for osteoporosis, and some will be started on them during the 
intervention period.  We will record medication use at baseline and monthly during the 6 month 
intervention period. The information will be used to interpret results.  Since these medications 
should be distributed equally among the three study groups, we do not anticipate that they will 
affect the intention-to-treat analyses.   
 
 


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Section 8: Recruitment and Retention 
 Identification of Hip Fracture Patients 
Potential participants will be identified from local site acute care hospitals (orthopedic and 
rehabilitation units), skilled nursing facilities, home care programs, and the community-at-large.  
The target sample size is between 120 and 168 randomized participants. In order to achieve 
this target, it will be necessary to identify more than 4000 hip fracture patients across all sites.  
This estimate is based on previous experience conducting clinical trials with the proposed 
interventions in hip fracture patients, with similar eligibility criteria to the current study.  
 
 Participant Recruitment and Pre-Screening 
Each site PI and/or coordinators must ensure a systematic method to identify potential 
participants at their center. Specific strategies will include discussion of the study with the local 
orthopedic surgical team, screening at affiliated rehab centers, and gaining access to a hospital 
database by engaging a bioinformatics or information technology group to locate patient’s status 
post hip surgery based on ICD 10 or CPT code all subject to IRB approval. Recruitment fliers 
will also be given to inpatients referred by hospital or rehab staff, physicians, or surgeons. 
 
Those volunteers who may be eligible for participation in the study will be administered a brief 
pre-screening interview either by telephone or in person.  Those who meet eligibility criteria after 
the pre-screening interview will be invited to undergo a more detailed screening evaluation near 
the end of her course of standard physical therapy. 
 
Once a potential subject is identified, the investigator and/or coordinator will screen the medical 
history including medications and laboratory studies to confirm that the patient may be eligible. If 
the patient’s physician or a research team member believes that the patient is cognitively 
impaired or otherwise unable to provide informed consent, the patient should not be invited to 
participate. All subjects should be able to understand the nature of the research and their 
participation, and show the ability to consider the alternatives including the option of non–
participation. Patients who agree to consider participation should provide their contact 
information.  Potential participants will then be contacted periodically through their course of 
standard rehabilitation to build rapport and determine when they are ready to be screened for 
the study.   
 
To guide recruitment efforts and methods, participants who refuse to complete the pre-
screening interview or refuse consent following the pre-screening interview will be asked 
reasons for refusal.     
 
If the participant refuses participation, but agrees to be contacted further, the CCC will follow-up 
with a qualitative interview to gather more information about reasons for refusal. The information 
collected will be kept in an anonymous fashion and will not have any identifiers or patient data 
associated with it. 
  
Recruitment will last for approximately 45 months, with a goal for each clinical site to randomize 
1-2 participants per month. 


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 Informed Consent  
Written informed consent and appropriate HIPAA authorizations and/or waivers will be obtained 
in compliance with procedures reviewed and approved by the site IRBs and the sIRB at 
Washington University. Each of the clinical sites’ IRBs will review and agree to rely on 
Washington University’s sIRB prior to any data collection.  Study staff will follow the Good 
Clinical Practice guidelines for informed consent. A copy of the informed consent form (ICF) will 
always be provided (either in person or by mail) to potential participants to allow for adequate 
review of the information and to allow review with family members. Prior to obtaining informed 
consent, time will be given to the potential participant to review the consent form and ask 
questions.  Study staff will summarize all components of the ICF and remind potential 
participants that participation in the study is voluntary and that she has the right to withdraw at 
any time. It will also be explained that signing the consent form allows the study to confirm final 
eligibility before randomization to a treatment group. The consent process will be performed 
without the use of any coercive language or behavior, and with respect for the person's 
autonomy.  
The goal of the informed consent process is to increase potential participants’ understanding of 
the objectives and expectations of the study in order to better enable them to decide whether or 
not to enroll.  Therefore, every effort will be made to help potential participants fully understand 
the research project.  During the informed consent process, study staff will provide participants 
with adequate information concerning the study procedures, respond to questions and 
concerns, and ensure that each individual understands all the information provided.   
Potential participants who choose to enroll will be asked questions about the main parts of the 
study to assess their understanding of the expectations, risks, and benefits. The researchers will 
ensure the potential participant has decisional capacity by asking the participant to reply to the 
following questions after the consent has been explained: 1) Why is this study being done?, 2) 
What are the risks of participating in this study?, 3) What are the potential benefits of 
participating in this study?, 4) Is the study voluntary?.  Based on the responses to these 
questions, the person conducting the informed consent will determine whether the potential 
participant has decisional capacity. Any questions/concerns about a participant’s ability to 
provide consent will be discussed with the site PI.  Individuals who do not understand the study 
purpose, risks, and benefits are not able to provide their own informed consent and will not be 
eligible for participation. The informed consent process will be documented on the 
Documentation of Informed Consent Form. The form confirms that the study was explained, 
ample time was given to read and discuss the ICF, questions (if any) were answered, subject 
agreed to participate and signed the ICF and HIPAA Authorization (if separate), and a copy of 
the signed ICF was given to the participant. If necessary, a copy of the ICF can be left in the 
chart of the facility based on site policy.  For women who provide informed consent, the original 
signed ICF will be maintained at the clinical site and a copy of the signed ICF will be given to the 
participant. The clinical site PI and/or designee will ensure the accuracy, completeness, 
legibility, and timeliness of the informed consent process conducted by the study staff before 
any screening data are collected. 
 Enrollment 
Date of enrollment in this trial is defined as the date of informed consent. 


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 Screening  
After signing the informed consent form, screening assessments will be conducted with each 
participant.  The purpose of the screening assessments is to identify any contraindications to 
exercise training or testosterone therapy and other exclusion criteria.  Screening assessments 
may occur any time after informed consent is obtained and prior to randomization, but these 
tests should be performed as early in the visit window as possible. Re-screening will be allowed 
if the reason for screen failure can be realistically corrected within 22 weeks of the hip surgery. 
 
Screening is performed in stages so that an individual with a contraindication to study 
participation does not undergo unnecessary tests. Screening assessments will include a review 
of all disqualifying medical conditions, assessment of cognitive status with the Short Blessed 
Test (SBT), and assessment of mood with the Geriatric Depression Scale Short-form (GDS-SF).  
Activities of Daily Living (ADLs) prior to the hip fracture will also be assessed.  Blood will be 
collected at screening and the following tests performed: complete metabolic panel, complete 
blood count, TSH, hemoglobin A1c, and serum testosterone.  An ECG and full physical exam 
will be performed.  The study coordinator will notify the participant’s primary care physician and 
orthopedic surgeon of her interest in the study, obtain answers to questions about the 
participant’s medical history, and answer questions that the patient’s physicians may have about 
the study.  
 
The screening visit may be completed in up to two separate sessions with the first session 
occurring in the participant’s home, remotely, or over the phone at the discretion of the clinical 
site coordinator.  See section 10.1 for the list of measures and acceptable collection locations.  
An abbreviated mPPT may be completed in the participant’s home if she appears too frail to 
meet eligibility criteria.  If an abbreviated mPPT is completed, the full 9 item mPPT assessment 
must still be completed at the clinical center.   
 
If the physician determines that performance of the mPPT or intensive exercise poses a cardiac 
risk for the participant, then she will be referred to her PCP for further testing (i.e. exercise 
stress test) and clearance. Participants may also be excluded if, in the investigator’s opinion, 
there is evidence of cognitive impairment or dementia which is sufficient to interfere with 
informed consent or adherence to the study protocol. The clinical site physician must review all 
study eligibility documents and sign off on final eligibility for all potential participants prior to 
collection of baseline data. Section 10.1 Screening Assessments contains a detailed inventory 
of screening assessments that will be completed.   
  Retention Promotion Efforts 
At the time of randomization, participants will receive written instructions in a study folder about 
the schedule of follow-up assessments, exercise or health education visits, dietary assessment, 
and phone contact numbers for site study staff.  To maintain rapport, the same staff member for 
a given study role (coordinator, exercise interventionist, etc.) will, whenever possible, contact 
the participant throughout the study. Minimizing waiting time, providing transportation at no 
charge, streamlining visit activities, and providing comfortable waiting room facilities makes the 
visits more pleasant, thereby enhancing participant retention at follow-up assessments. 
Participants in the EUC group will be contacted weekly by telephone in an effort to maintain 
rapport and provide some increased social contact. Regular phone contact also aids retention. 


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Participants will receive reminders prior to each follow-up assessment.   
Clinical sites will keep detailed records of rescheduled and missed study assessment visits as 
well as missed intervention visits. Participant retention will be monitored, and efforts will be 
made to provide support and encouragement to participants who are at risk of being lost to 
follow-up. 
  Drop-out Prevention Efforts 
The following procedures will be implemented to minimize and monitor missed follow-up 
assessments and intervention visits: 
• 
Providing pre-visit reminders (e.g., letters and phone calls) for upcoming assessment 
visits.   
• 
Calling participants the day before a follow-up assessment to remind them of the visit 
and the time for transportation pick-up, if appropriate. 
• 
Providing transportation to assessment and intervention visits. 
• 
Monitoring participation and attendance within each clinical site by the DCC, so that staff 
will be alerted to a missed intervention or assessment visit. 
• 
Rescheduling the visit within the visit window, if possible. 
• 
Monitoring exercise attendance weekly and contacting participants who miss sessions to 
discuss reasons and help them problem-solve barriers to adherence that are identified. 
• 
Monitoring gel application adherence monthly (bottle weights), observing application 
technique monthly, and discussing any problems or barriers to adherence that are 
identified.  
 
Some randomized participants may not actively participate in the study, either by declining the 
intervention visits and/or by not attending follow-up assessments. These participants will be 
followed until the end of the study unless they explicitly request not to be contacted. Also, 
considerable effort will be expended to collect data on the primary outcome at each of the 
follow-up assessments. 
  Premature Withdrawal from the Study 
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion.  
 
Any participant who is randomized, should be encouraged to continue in the study for safety 
monitoring and outcome assessments at the specified time points in the protocol.  If a 
participant does not wish to complete the remaining outcome assessments, it will be proposed 
to only complete the 6 month assessment or return to the research center for an early 
withdrawal visit. An early withdrawal visit would be scheduled as soon as possible and include 
prioritized outcome measures that allow the participant to stop at any point or skip any 
measures. 
 
The site PI has the right to discontinue an intervention or a participant from the study in the 
event of an intercurrent illness, serious adverse event (SAE), protocol violation, or other 
reasons. See Section 18: Discontinuation for more information. An excessive rate of 


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withdrawals and discontinuations would render the study uninterpretable; therefore, 
unnecessary discontinuation of participants should be avoided.  
  Replacement of Subjects 
Subjects who withdraw from the study or are prematurely discontinued from the study will not be 
replaced. 
 
Monitoring Recruitment and Retention 
The DCC, in collaboration with the CCC, will monitor recruitment and retention. The DCC will 
track screening and recruitment yields against the number expected per site. The DCC will work 
closely with clinical site PIs and the CCC to identify and reduce barriers to recruitment within 
either clinical sites or the study hospitals. The number of patients screened relative to the 
number of participants recruited in each facility will be reviewed quarterly. 
 Monitoring and Quality Control of Recruitment and Retention 
The DCC will collect data to monitor recruitment and retention activities, the number of potential 
participants screened at each site, the yield at the various screening phases, the percent who 
are eligible, and the percent who are randomized. This monitoring will allow early detection of 
site recruitment and retention issues. Reports from the database can also be generated 
according to individual study staff member to identify possible areas for retraining. Retention will 
be monitored through completion rates of follow-up assessment visits and intervention visits. 
Regular reports will be available to clinical sites and the CCC.  The CCC coordinator will 
maintain regular phone contact with clinic staff to: 
1. Review recruitment goals and yields for clinical sites, 
2. Review the recruitment plan and progress in achieving the objectives outlined in 
the plan, 
3. Share successful and unsuccessful recruitment methods, and  
4. Review retention. 
 
If clinical sites encounter difficulties in recruitment or retention, the CCC (or a subgroup it 
designates) will provide a graduated set of assistance responses that are based on the degree 
of recruitment or retention shortfall. Solutions will be developed that are based on site-specific 
issues. 


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Section 9:  Study Measures 
  Physical and Questionnaire Measures 
Detailed instructions on administration and documentation forms can be found in the Manual of 
Procedures. These evaluations will be conducted during an in-person, or when feasible by 
remote video call, or phone interview and are not presented in order of administration. 
 Demographics 
Basic demographic information will be collected from the participant by a study staff member 
and entered into the Demographics study form. 
 Medical History 
A study staff member will record the participant’s medical history through a series of yes or no 
questions about previous diagnosis and past or current health issues. The answers will be 
recorded on the Medical History Form. Input from the site physician can also be obtained to 
complete the questionnaire. Information will also be collected on the type of hip surgery for the 
Hip Fracture History Form. If questions arise, permission will be requested to obtain medical 
records from the participant to complete the information. 
 Medications or Medication Updates 
Study staff will collect all medications (prescribed and regularly used over-the-counter) that the 
participants are currently taking and those in the recent past that may interfere with the active 
medication for the current study. Medications will be reviewed with the participant monthly so 
records can be updated.  
 Height, Weight, and Vital Signs 
Study staff will record the height and weight of the participant to track for changes. Weight will 
be measured monthly in kilograms by scale. Height will be measured in centimeters at the 
baseline, month 3, and month 6 visits. Blood pressure and pulse will be measured at each 
monthly visit, as well as before and after center-based exercise sessions. 
 Physical Examination  
A physical examination by the clinical site PI, a designated physician, or an Advanced Practice 
provider will be conducted at the study center for screening and follow-up purposes. The 
examination should be considered a routine physical examination but will include a detailed 
neurological and musculoskeletal evaluation. A manual breast examination is required at 
screening if the participant has had a mammogram within the past 6 months and therefore is not 
required to undergo a mammogram during baseline assessments (per Section 9.3.4).   
 Short Blessed Test (SBT)  
All participants will have their cognitive function evaluated at screening using the Short Blessed 
test of Orientation, Concentration, and Memory (SBT).  Those participants with a score of 11 or 
greater on the test will be excluded from the study.  In the event that the consenting party has 
concerns about a participant’s ability to consent, the SBT will be administered to measure 
cognitive function before proceeding with other screening measures. 


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 Activities of Daily Living (ADLs) 
Information about performance of activities of daily living (ADLs) will be collected using two 
scales that have been well validated for use with older adults in a variety of outpatient settings, 
and with which we have extensive experience in the hip fracture population: the Duke Older 
Americans Resources and Services (OARS) scales, and the Functional Status Questionnaire 
(FSQ). The two scales provide complementary information about ADL performance. An 
Assistive Devices Checklist (ADC) has also been developed to be administered with the ADL 
measures. A modified OARS instrument will be administered at screening to assess abilities 
prior to the hip fracture. The ADL questionnaires will be administered at baseline, 3 months, and 
6 months to look for changes in ADLs.  Based on clinical site resources and participant 
availability, the ADL questionnaire will be administered via a telephone call at 9 months. 
9.1.7.1 
Older Americans Resources and Services (OARS) 
The OARS queries about requirement for assistance (human or assistive device) during daily 
activities. 
9.1.7.2 
Functional Status Questionnaire (FSQ) 
The FSQ queries about amount of difficulty experienced during daily task performance during 
the past 4 weeks. Since the tasks are the same listed in the OARS the questionnaires have 
been combined to assess if a task was completed with assistance and how difficult it was to 
complete the task. 
 Geriatric Depression Scale – Short Form (GDS-SF) 
Participants will be screened for depression using the Geriatric Depression Scale – Short Form 
(GDS-SF).  Participants will be excluded and referred to their PCP if their GDS-SF score is ≥ 12 
at screening (on or off treatment). The GDS-SF will also be administered at baseline, month 3, 
and month 6. 
 Seattle Angina Questionniare-7 (SAQ-7) 
The SAQ-7 asks about limited activities and the amount of chest pain or tightness participants 
have had over the previous 4 weeks. This questionnaire will be administered at screening to 
assess if participants are at higher cardiac risk during exercise training. 
 Hip Rating Questionnaire (HRQ) 
Participants will be administered the Hip Rating Questionnaire (HRQ) at baseline, month 3, 
month 6, and month 9.  The HRQ is a 14 item inventory of patient reported pain level, mobility, 
and activities of daily living directly related to the hip fracture event. 
 PROMIS® Global Health   
The 10-item PROMIS® Global Health instrument has Global Physical Health and Global Mental 
Health components to measure overall quality of life. Patient-Reported Outcomes Measurement 
Information System (PROMIS®) was recently developed and validated to be psychometrically 
accurate to be used with the general population, as well as individuals with chronic conditions. 
The measure will be administered at baseline, month 3, month 6, and month 9.  


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 Brief Resilience Scale (BRS) 
The Brief Resilience Scale (BRS) measures self-perceived psychological resilience, defined as 
the ability to bounce back after a stressful event. The BRS includes 6 statements related to the 
construct of bouncing back after a stressful event, and the 5 response options for each 
statement range from “strongly agree” to “strongly disagree”(91).  
The role of psychological resilience among older women following hip fracture has received little 
scientific attention. We hypothesize that level of psychological resilience will have an 
independent effect on primary and secondary outcomes in the STEP-HI study. Administering 
the BRS at study baseline and month 6 will allow us to observe the degree to which resilience 
might change over time in relation to treatment group membership in the STEP-HI study. To our 
knowledge, the degree to which participation in a supervised exercise program and use of 
testosterone might improve level of psychological resilience in older women after hip fracture 
has not been studied.  
 Ferriman-Gallwey Scale 
The Ferriman-Gallwey Scale will be utilized to look for hair growth that may result from 
testosterone gel usage. A limited physical exam will be done by the site physician or Advanced 
Practice provider to complete the scale at the baseline, 3 month, and 6 month assessments. 
 Physical Performance Measures 
Detailed instructions on administration of measures are in the study Manual of Procedures.  
These measures will be administered by certified study staff that are blinded to the extent 
possible to exercise group assignment.  
 Six Minute Walking Distance (Primary Outcome Measure) 
Walking endurance will be measured using a 6-Minute Walk Distance at baseline, month 3, and 
month 6.  Participants will be asked to walk back and forth on a measured path marked clearly 
at both ends for turning purposes, while being told when each minute has passed, and receiving 
verbal encouragement (“you’re doing well” or “keep up the good work”) every 60 seconds.  
 Leg Press 1-Repetition Max Test 
Muscle strength will be measured as the maximal amount of weight that the participant is able to 
lift for one repetition (1-RM).  1-RM will be obtained for leg press of the fractured and 
unfractured limb simultaneously, using identical weight-lifting equipment across clinical sites that 
will be purchased and distributed by the CCC. 1-RM assessments will be performed at baseline, 
month 3, and month 6.  
 
Subjects will be asked to move against progressively heavier resistance loads until a repetition 
failure is achieved.  A rest period will separate each repetition. A repetition failure will be defined 
as 1) the inability to move against the resistance to the required range of motion, or 2) not using 
proper technique, or 3) the subject not feeling safe in trying a heavier resistance. The 1-RM is 
defined as the greatest resistance that could be overcome through a defined range of motion 
using proper techniques. 


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 Modified Physical Performance Test (mPPT)  
A modified version of the Physical Performance Test (mPPT) will be used to measure physical 
function at screening. The modification substitutes a chair-rise task (See SPPB) and a balance 
task (See SPPB) for writing and eating tasks, in order to emphasize lower extremity function. 
The modified PPT includes nine standardized tasks.  Seven tasks are timed:  book lift, putting 
on a lab coat, picking up a penny from the floor, standing balance (progressive Romberg), 
standing up five times from a 16-inch chair, 50 foot walk including a turn, and timed stair climb 
for 10 steps. Two tasks are not timed: 360 degree turn and climbing 2 additional flights of steps. 
The score for each item ranges from 0 to 4, with 36 representing a perfect score. Test-retest 
reliability for the modified PPT score is 0.96(96, 97).  Because there is some overlap between the 
mPPT and SPPB items, we have integrated the two scales so that participant burden is 
minimized but it is still possible to obtain scores on each of the scales.  Participants with a score 
of 12-28 are in the acceptable range to be included in the study; others will be excluded. The 
mPPT will also be completed at baseline, 3 months and 6 months. 
 Short Physical Performance Battery (SPPB)  
The Short Physical Performance Battery (SPPB) is another well validated objective physical 
performance measure that has been used in a number of epidemiological and intervention trials 
in older adults to identify risk for disability(87, 88).  The SPPB will be completed at baseline, month 
3, and month 6. It consists of three items, two of which are performed as part of the mPPT:  a 
chair rise task and a progressive Romberg balance test.  Gait speed for 4 meters is performed 
as a separate item from the mPPT tasks (see below).  
9.2.4.1 
Four Meter Walk (Gait Speed) 
Gait speed will be measured over a 4 meter distance on a standard walkway at baseline, month 
3, and month 6.  Participants are timed on the speed at which they walk the 4 meter distance, 
both at their preferred or normal speed and for a “fast walk.” Use of walking aids is allowed.   
 Hand Grip Strength 
A hand grip dynamometer will be used to measure the maximum isometric strength of the hand 
and forearm muscles at baseline, month 3, and month 6. Sites may use equipment available at 
their site, though a Jamar device is preferred. 
  Other Procedures 
 Laboratory Blood Tests 
Blood will be drawn to check total blood count (CBC), blood chemistry (CMP), liver enzymes, 
thyroid hormone level (TSH), glucose (HgbA1c), Cholesterol (Total, LDL, and HDL), estradiol 
level, sex hormone binding globulin (SHBG) level, Vitamin D levels (serum 25-OH), and 
Testosterone (total and free) levels. Not all labs will be drawn at each time point. Labs will not 
be identical across all randomized groups; the EUC group will not have monthly testosterone 
draws. Only the testosterone level of the EX and EX+T group will be drawn at week 2. For 
further details, see Table 2: Assessment Schedule.  
 Electrocardiogram (ECG)  
A standard 12-lead electrocardiogram (ECG) will be performed and evaluated locally at each 
clinical site at screening.  The ECG will be performed at the study center.  The ECG will allow 


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the investigator to assess patients for any abnormalities that, in the investigator’s opinion, could 
increase the patient’s risk of participating.  ECGs will be interpreted by the clinical site PI or a 
qualified designee, who will document their review.  ECG reports should be retained with source 
documentation. 
 Dual Energy X-Ray Absorptiometry (DXA) 
Appendicular and total LBM and bone mineral density of the proximal femur of the unfractured 
limb will be determined by Dual Energy X-Ray Absorptiometry (DXA) scanning. Whole body 
measurements will be taken at baseline and month 6.  Baseline scans should be completed 
prior to dispensing of study drug to participants.  DXA scans should always be performed before 
exercise or 1-RM measurements.   
All DXA imaging scans obtained will be transferred to the IMAGE center at UCD for quality 
control. DXA scans will be reviewed for proper positioning and artifacts within one week of 
image acquisition. Sites will be immediately notified about significant problems and a repeat 
scan will be scheduled. DXA imaging scans obtained using Hologic scanners will be analyzed 
by the IMAGE center. 
 Mammogram 
A Mammogram will be completed at baseline if the participant hasn’t had one in the past 6 
months or if documentation of a mammogram in the past 6 months is not available. The 
mammogram will be repeated at month 6 as a safety assessment for the supervised exercise 
groups (EX and EX+T) only. 
 Transvaginal Ultrasound 
For women who participated in the EX or EX+T group and have a uterus, a transvaginal 
ultrasound will be completed at the month 6 assessment.  The ultrasound will measure the lining 
of the uterus.  In cases where the measurement exceeds 4 mm, participants will be referred to 
their gynecologist for possible further assessment and treatment. 
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
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Section 10: 
Assessment Schedule 
Table 2: Schedule of Assessments 
Study procedure 
Screening Baseline W2 
M1 
M2 
M3 
M4 
M5 
M6 
M9 
Physical and Questionnaire Measures 
  
  
  
  
  
  
  
  
  
  
Demographics 
x 
  
  
  
  
  
  
  
  
  
Medical History 
x 
  
  
  
  
  
  
  
  
  
Angina Questionnaire (SAQ-7) 
x 
  
  
  
  
  
  
  
  
  
Medications or medication updates 
x 
x 
  
x 
x 
x 
x 
x 
x 
  
Height 
  
x 
  
  
  
x 
  
  
x 
  
Weight, Pulse, Blood pressure 
x 
x 
  
x 
x 
x 
x 
x 
x 
  
Physical exam 
x 
 x 
  
  
  
x 
  
  
x 
  
Short Blessed Test (SBT) 
x 
  
  
  
  
  
  
  
  
  
Hip Rating Questionnaire (HRQ) 
  
x 
  
  
  
x 
  
  
x 
x 
Brief Resilience Scale (BRS) 
  
x 
  
  
  
  
  
  
x 
  
Geriatric Depression Scale (GDS-SF) 
x 
x 
  
  
  
x 
  
  
x 
  
Pre-fracture Activities of Daily Living (ADLs) 
x 
  
  
  
  
  
  
  
  
  
Older Americans Resources & Services (OARS) 
  
x 
  
  
  
x 
  
  
x 
x 
Functional Status Questionnaire (FSQ) 
  
x 
  
  
  
x 
  
  
x 
x 
Assistive Device (ADC) 
x 
x 
  
  
  
x 
  
  
x 
x 
PROMIS - Global Health 
  
x 
  
  
  
x 
  
  
x 
x 
Dietary Assessment 
  
x 
  
  
  
x 
  
  
  
  
Ferriman-Gallwey Scale 
  
x 
  
  
  
x 
  
  
x 
  
Adverse Event (AE) Assessment 
  
x 
  
x 
x 
x 
x 
x 
x 
  
Fall Log 
  
x 
  
x 
x 
x 
x 
x 
x 
  
Exercise Log 
  
x 
  
x 
x 
x 
x 
x 
x 
  
Functional Measures 
  
  
  
  
  
  
  
  
  
  
Physical Therapy Exam 
  
x 
  
  
  
  
  
  
  
  
Modified Physical Performance Test (mPPT) 
x 
x 
  
  
  
x 
  
  
x 
  
Six Minute Walk Distance (6MWD) 
  
x 
  
  
  
x 
  
  
x 
  
Leg Press 1-RM 
  
x 
  
  
  
x 
  
  
x 
  
4 Meter Walk (SPPB-Gait speed) 
  
x 
  
  
  
x 
  
  
x 
  
Hand Grip Strength 
  
x 
  
  
  
 x 
  
  
x 
  
Procedures 
  
  
  
  
  
  
  
  
  
  
ECG 
x 
  
  
  
  
  
  
  
  
  
DXA Scan 
  
x 
  
  
  
  
  
  
x 
  
Mammogram 
(**only for EX & EX+T at M6) 
  
x 
  
  
  
  
  
  
x** 
  
Transvaginal Ultrasound  
(only for EX & EX+T AND if uterus present) 
  
  
  
  
  
  
  
  
x 
  
Laboratory 
  
  
  
  
  
  
  
  
  
  
Testosterone Total & Free Levels (EX & EX+T) 
x 
x 
x 
x 
x 
x 
x 
x 
  
Testosterone Total & Free Levels (EUC) 
x 
  
  
  
x 
  
  
x 
  
Complete Metabolic Panel (CMP) 
x 
  
  
  
x 
  
  
x 
  
Complete Blood Count (CBC) 
x 
  
  
  
x 
  
  
x 
  
TSH 
x 
  
  
  
  
  
  
  
  
  
HgbA1c 
x 
  
  
  
  
  
  
  
  
  
Estradiol Level 
  
x 
  
  
  
  
  
  
x 
  
SHBG Level 
  
x 
  
  
  
  
  
  
x 
  
Cholesterol (Total, LDL, and HDL) 
  
x 
  
  
  
  
  
  
x 
  
25-OH Vitamin D Level 
  
x 
  
  
  
  
  
  
x 
  
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
49 
 
Screening Assessments 
The screening assessments are performed no earlier than six weeks and no later than 22 
weeks after the hip fracture repair.  Participants who are beyond 22 weeks past their hip fracture 
repair surgery may be approached and screened with the approval of the CCC.  The screening 
visit can be divided into two visits and completed at the clinical site center or as noted below, 
some of the assessments may be able to be completed by phone, via remote video call, or in 
the participant’s home depending on site resources and availability. The following items will be 
completed at screening (See Table 2: Assessment Schedule):  
• 
Demographics (In home, by phone or video call, or onsite) 
• 
Medical History (In home, by phone or video call, or onsite) 
• 
Medications (In home, by phone or video call, or onsite) 
• 
Weight & Vital Signs (Onsite) 
• 
Complete Physical Exam (In home or onsite) 
• 
Short Blessed Test (SBT) (In home, by phone or video call, or onsite) 
• 
Pre-Fracture Older Americans Resources and Services (PFOARS) Questionnaire (In 
home, by phone or video call, or onsite) 
• 
Geriatric Depression Scale (GDS-SF) (In home, by phone or video call, or onsite) 
• 
Angina Questionnaire (SAQ-7) (In home, by phone or video call, or onsite) 
• 
Modified Physical Performance Test (mPPT) (Onsite) 
• 
ECG (Onsite) 
• 
Blood Draw (In home or onsite) for the following labs: 
o CMP 
o CBC  
o TSH  
o HgbA1c 
o Serum Testosterone Level (Free and Total) 
 
Baseline Assessments 
The baseline assessments may be performed between 6 and 24 weeks after the surgical repair 
of the hip fracture, but must allow for randomization to occur within 24 weeks of the surgical 
repair. All baseline assessments must be completed within 3 weeks of the completion of the 
screening assessments. The CCC may approve a short extension (roughly 1 week) in cases 
where mammogram, DXA, blood results, or other tests need follow-up.  Multiple visits will be 
allowed to complete the baseline assessments, but ideally all baseline components will be 
completed in 3 or fewer visits. As noted below, some of the assessments may be able to be 
completed by phone, via remote video call, or in the participant’s home depending on site 
resources and availability. Randomization can occur when all baseline assessments are 
completed and eligibility is verified. Once a participant is randomized, that date becomes the 
anchor (day 0). The following measures will be assessed at the baseline visit(s) (see Table 2: 
Assessment Schedule):  
• 
Medication updates (In home, by phone or video call, or onsite) 
• 
Height, Weight and Vital Signs (Onsite) 
• 
Six Minute Walk Distance (Onsite) 
• 
DXA (Onsite) 
• 
1-Repetition Maximum (Onsite) 
• 
Modified Physical Performance Test (mPPT) (Onsite) 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
50 
• 
4 Meter Walk (SPPB - Gait Speed) (Onsite) 
• 
Hand Grip Strength (Onsite) 
• 
Hip Rating Questionnaire (HRQ) (Onsite, if possible) 
• 
PROMIS® Global Health Questionnaire (Onsite, if possible) 
• 
Brief Resilience Scale (BRS) (Onsite, if possible) 
• 
Older Americans Resources and Services (OARS) Questionnaire (Onsite, if possible) 
• 
Functional Status Questionnaire (FSQ) (Onsite, if possible) 
• 
Geriatric Depression Scale Short form (GDS-SF) (Onsite, if possible) 
• 
Dietary assessment and consultation (In home, by phone or video call, or onsite) 
• 
Mammogram (if not completed in the past 6 months) (Onsite) 
• 
Physical exam and completion of Ferriman-Gallwey Scale (In home or onsite) 
• 
Physical Therapy Exam (In home or onsite) 
• 
Blood draw (In home or onsite) for the following lab tests: 
o 25-OH Vitamin D 
o Serum Estradiol 
o Serum SHBG 
o Serum Lipids 
 
Follow-up Assessments 
The following measurements will be collected as part of the follow-up visits. Follow-up visits will 
begin at 2 weeks (target 14 days) for the EX and EX+T participants and then at month 1 (target 
28 days) through month 6 (target 168 days). The monthly visits are targeted for every 4 weeks 
or 28 days, but allow windows for scheduling.  Participant and facility schedules will be taken 
into account when scheduling assessment visits and are not expected to be conducted on the 
exact date suggested by the visit title.  As noted below, some of the assessments may be able 
to be completed by phone, via remote video call, or in the participant’s home depending on site 
resources and availability. EUC participants will not have a 2 week visit, but will begin at month 
1. The Month 6 assessment will begin after the exercise sessions are completed and will be 
scheduled as close to 25 weeks after randomization as possible.  Not all of these assessments 
are performed at each visit (See Table 2: Assessment Schedule): 
• 
Height, Weight, and Vital Signs (In home, by phone or video call, or onsite) 
• 
Six Minute Walk Distance (Onsite) 
• 
DXA (Onsite) 
• 
1-Repetition Maximum (Onsite) 
• 
Modified Physical Performance Test (mPPT) (Onsite) 
• 
4 Meter Walk (SPPB - Gait Speed) (Onsite) 
• 
Hand Grip Strength (Onsite) 
• 
Hip Rating Questionnaire (HRQ) (Onsite, if possible) 
• 
PROMIS® Global Health Questionnaire (Onsite, if possible) 
• 
Brief Resilience Scale (BRS) (Onsite, if possible) 
• 
Older Americans Resources and Services (OARS) Questionnaire (Onsite, if possible) 
• 
Functional Status Questionnaire (FSQ) (Onsite, if possible) 
• 
Geriatric Depression Scale Short Form (GDS-SF) (Onsite, if possible) 
• 
Adverse Event Assessment (In home, by phone or video call, or onsite) 
• 
Dietary assessment and consultation (In home, by phone or video call, or onsite) 
• 
Physical Exam and completion of Ferriman-Gallwey Scale (In home or onsite) 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
51 
• 
Mammogram (only women in the EX and EX+T groups) (Onsite) 
• 
Transvaginal Ultrasound (only women in the EX and EX+T groups with a uterus) 
(Onsite) 
• 
Blood draw (In home or onsite) for the following lab tests: 
o 25-OH Vitamin D 
o Serum Testosterone  
o Serum Estradiol  
o Serum SHBG  
o Complete Metabolic Panel 
o Complete Blood Count 
o Serum Lipids 
 
Order of Study Procedures  
Detailed information regarding ordering of study procedures is described in the Manual of 
Procedures. 
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
52 
Section 11: 
Standard Care Procedures for All Participants 
 
Dietary Assessments 
All subjects will undergo a nutritional assessment at baseline by a dietician to: 1) document the 
subject’s caloric intake, primarily focusing on the macronutrient composition of the diet and; 2) 
evaluate for any recent weight loss. The dietitian will perform a 24-hour diet recall and enter the 
information into a web-based food record. 
 
The dietician will use the information obtained from the food record, measurements of height 
and weight to make dietary recommendations consistent with standard of care after hip fracture 
repair (98).  A specific diet will not be prescribed, but rather, participants will be counseled on 
ways to enhance their protein and caloric intake, as indicated.  We will encourage a diet that 
contains 1.2 gm/kg per day of protein(99). Caloric needs will be estimated using the Mifflin-St. 
Jeor equation (100) and adding an activity correction factor of 1.4.  
For any participant requiring supplementation of calories and/or protein intake, the dietary 
counseling will aim to optimize the participant’s ability to implement this on her own.  
 
 
Participants will be weighed monthly. The dietitian will administer the web-based food record 
again at month 3 and review the results with the participant. The dietician will work with 
participants on an individualized basis to adjust dietary intake, as indicated based on measures 
of body weight and macronutrient intake, as measured by the food diary. The study coordinator 
will notify the site PI and the dietician regarding any participant who loses greater than 3% of 
body weight over a month. Loss of 5% body weight between visits will trigger a referral to the 
dietician for follow-up. 
 
Vitamin D3 and Calcium Supplementation 
Because of the high prevalence of Vitamin D deficiency in this population(101), and to minimize 
the potentially confounding effect of vitamin D myopathy(102), we will provide vitamin D 
supplementation to all participants enrolled in the study. In the WU hip fracture studies, the 25-
OH vitamin D level at baseline was 16±9 ng/mL and in the BHS studies it was 12 ng/mL. 25-OH 
Vitamin D levels will be measured at baseline and Month 6. At randomization all participants will 
be provided with Vitamin D3 2,000 IU to be taken daily.  Based on data from Gallagher(103), this 
should be sufficient to increase vitamin D levels into the normal range quickly and maintain 
them during the study.  Participants will also be given calcium carbonate at 1,000 mg/daily in 
divided doses. Calcium and/or Vitamin D will not be given to those participants with 
contraindications identified by the site physician at screening. 
 
At monthly assessment points, each site will provide randomized participants a monthly supply 
of the following: 
• 
2,000 IU Vitamin D3, one tablet daily  
• 
500 mg Calcium, 1 tablet twice daily 
 
Each site will prepare a label and directions for the use of all study supplements that complies 
with federal and state requirements. Each clinical site will be responsible for maintaining the 
STEP-HI drug accountability log for the Calcium and Vitamin D3. 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
53 
 
Physical Therapy Evaluation 
All participants will undergo a clinical evaluation at baseline by a site Supervising Physical 
Therapist. The purpose of this evaluation is to identify the patient’s physical 
limitations/impairments (e.g., ROM limitations, hip precautions, pain, assistive devices, etc.) that 
may limit their ability to perform specific exercises and/or require modifications. Information 
obtained from this evaluation will be used by the Supervising PT to provide guidance to exercise 
interventionists conducting the exercise programs. 
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
54 
Section 12: 
Randomization 
The DCC will create an online password protected randomization system that will be used to 
facilitate the random assignment of subjects to the three study arms.  Site pharmacists will be 
assigned a unique, nontransferable user ID that will be required to obtain random treatment 
allocations. The system will be created using the built-in randomization module of the REDCap 
system.  The DCC will randomize participants in REDCap if all eligibility criteria are satisfied.  
Then the pharmacists will login to obtain the assignment to dispense the appropriate gel bottle if 
participants are randomized to the EX group.     
At the outset of the study, participants were randomized equally into each study group.  
Following the presentation to the DSMB on April 22, 2020, the sample size was reduced from 
300 to 120-168 participants.  The numbers in each group will be adjusted as follows: 
Randomized 
Participants 
Participants in EX+T 
Participants in EX+P 
Participants in EUC 
300 
100 
100 
100 
168 
70 
70 
28 
120 
50 
50 
20 
 
The randomization structure was altered to assure that each group would be fulfilled with 
roughly 1 in 9 participants being assigned to EUC and the other 8 being assigned to an EX 
group (equally divided between EX and EX+T).  To avoid temporal bias, randomization will be 
blocked within clinical sites using random block sizes in order to preclude the possibility that 
investigators might know in advance the assignment of the last subject in a particular block. 
To ensure that those performing evaluations remain blinded to treatment assignment, 
randomization assignments will only be viewed by appropriate unblinded site investigational 
pharmacists who have received training and certification on STEP-HI randomization 
procedures.  
The date of randomization will mark the start of follow-up for each participant; a computer record 
is maintained for each attempt to randomize a participant. The clinical site coordinator will 
inform participants of their exercise group assignment. The coordinator will also provide the 
name of the exercise interventionist who will be contacting them. The coordinator will then alert 
the assigned exercise interventionist, who will contact the participant to schedule the first 
intervention visit. 
Participants will be assigned to one of three treatment groups for 6 months:   
 
1. Enhanced Usual Care (Home exercise + Health Education)(EUC) 
2. Exercise (Placebo gel + Supervised Exercise Training)(EX) 
3. Combined (Testosterone gel + Supervised Exercise training)(EX+T) 
 
Subjects in the EX and EX+T groups will be blinded to medication group assignment with 
testosterone and placebo administered identically.  Participants in the two Supervised Exercise 
Training groups (EX and EX+T) will receive supervised exercise training. The Enhanced Usual 
Care group (EUC) will receive a low intensity home-based exercise program and monthly health 
education sessions, but will not apply gel.   


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
55 
Section 13: 
Enhanced Usual Care (EUC) Group Activities 
 
Home Exercise Program 
Participants assigned to the EUC group will be prescribed an approximate 6-month low intensity 
home-based exercise program that mimics standard clinical care at the time of discharge from 
physical therapy after a hip fracture repair.  The instructional sessions will be conducted at the 
clinical site, in your home, or over video call by an exercise interventionist, which is defined as a 
physical therapist, exercise physiologist, certified personal trainer, or an individual with an 
appropriate level of experience, as approved by the CCC.  EUC participants will be prescribed a 
standard set of 9 exercises.  The participants will be shown how to do the exercises and given 
written instructions with diagrams illustrating the exercises. Participants will be instructed to 
perform the exercises 3 times per week, performing each exercise for 10 repetitions.  
Participants will not be discouraged to perform the exercises more often.  The exercise 
interventionist will meet with the participant monthly to review the exercises, observe their 
performance, and provide guidance for correct performance and standardized instructions for 
progressing some of the exercises.  
 Home Exercise Adherence 
All participants will maintain a log of their exercise sessions on a log form.  The forms will be 
turned in to the study coordinator on a monthly basis. Adherence will be measured as the 
percentage of exercise sessions completed out of a possible 72 sessions. 
 
Health Education Sessions 
Participants in the EUC group will attend a monthly health education session to address health 
issues unrelated to exercise(104, 105). Health education sessions will be led by the study 
coordinator or other appropriately trained study staff, and will cover topics on healthy aging with 
use of publicly accessible content.  The health education sessions will be presented using 
materials prepared with PowerPoint software. Education sessions will last approximately 30-40 
minutes and will ideally be scheduled to coincide with the participant’s monthly follow-up visit.  
The educational sessions may take place in the participants’ home, via remote video call, or 
over the telephone. 
 
 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
56 
Section 14: 
Supervised Exercise Training Group Interventions 
The Supervised Exercise program is whole body, multi-modal program that is conducted in two 
phases: a light resistance, flexibility, and balance training program (Phase 1, approximately one 
month), followed by progressive resistance training (Phase 2, approximately five months).  
Participants will be asked to complete exercise training sessions 2 times per week for 6 months. 
Each session will last approximately 60 minutes, including rest periods. Priority will be given to 
onsite training sessions conducted at an exercise training facility and/or outpatient rehabilitation 
center specified at each of the clinical sites.  If after starting the intervention, the participant 
refuses to attend onsite training sessions due to fear of COVID-19 or in the event the gym is 
closed due to COVID-19 restrictions, remotely supervised training sessions will be offered.  The 
training sessions will be conducted by an exercise interventionist. Exercise interventionists will 
be supervised by a site PT and will also be monitored by the lead CCC PT.  A clinical site 
physician will provide medical supervision. 
 
This program will be modified as necessary to accommodate subjects with physical impairments 
that would make a given exercise difficult, inappropriate, or unsafe. Any modifications will be 
discussed with the Supervising PT and/or site PI.  If possible, the remote supervised exercise 
sessions will be conducted using secure video calling to be able to demonstrate proper form 
and visualize the participant completing the exercises.  As long as the participant has home 
wireless internet, additional equipment (such as tablet with camera and stand) can be loaned to 
assure technology is not a barrier. 
 
Some equipment, such as weight training machines, may vary between clinical sites, and will be 
approved in advance by the CCC.  Equipment used for remote sessions (such as blood 
pressure cuff, leg weights, or TheraBands) will be provided, if needed. 
 
Because the first consideration in designing the individualized weight-training programs is 
participant safety and well-being, exercise prescriptions will be individualized and ongoing 
monitoring during each session will be performed using the modified Borg scale, with the 
parameters outlined in the Manual of Procedures. In addition, as a safety precaution, blood 
pressure and heart rate will be measured before and after each intervention session. All 
exercise interventionists will be familiar with the site institutional policies to provide or activate 
immediate care when faced with medical emergencies. 
 
During the onsite sessions, the participants will perform all free-weight and machine-based 
resistance exercises at a target goal of 80% of a 1-repetition maximum. There is no need to 
perform an actual 1-RM to progress exercise using these criteria. A participant is exercising at 
80% of a 1-RM when she can lift a weight 8 times against a given resistance, but is unable to 
complete the 9th repetition.  During remote supervised exercise sessions, participants will be 
encouraged to complete as many repetitions as possible, since the weights and equipment 
available may not allow the onsite target of 80% of a 1-RM.  The number of repetitions the 
participant is able to do will help calculate the dose received. 
 
During the first exercise intervention visit, participants will be oriented to the exercise staff, the 
facility and some of the exercise equipment.  The appropriate exercise intensity will be 
measured after participants have become familiar with the equipment.  Each session must start 
with an active warm up activity (walking, arm circles) and end with an active cool down. The 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
57 
preferred order of intervention is flexibility exercises, resistance training exercises, and function-
based activities. 
 
Physical Therapy Exercises (Phase 1) 
The purpose of the Phase 1 exercise program is to promote improvements in balance, range of 
motion, muscular endurance, speed of movement, and coordination, and to prepare participants 
for the machine-based weight-training portion of the intervention. The Phase 1 exercises 
become progressively more difficult and advanced over the training period. 
 
For a portion of the session, participants may perform individualized exercises designed to 
correct specific impairments that are detected during the baseline evaluation by the Physical 
Therapist (such as poor flexibility in a joint not included in the standard protocol that could 
impact function).   
 
During Phase 1, onsite strengthening exercises will be performed at an 8-RM intensity. A 
participant is exercising at an 8-RM when she can lift a weight 8 times against a given 
resistance, but is unable to complete the 9th repetition appropriately. During remote sessions, 
participants will be encouraged to perform the exercise until they demonstrate failure.  If the 
participant is able to lift the weight more than 8 times, weights will be increased if safe and 
feasible to do so.  Failure is defined as the inability to complete final repetition through full, 
available range of motion without significant compensation. Signs of compensation are as 
follows: sudden increases in speed to overcome resistance, improper form, and/or increase in 
the level of assistance needed. 
 
Progressive Resistance Training (Phase 2) 
Phase 2 consists of five months of progressive resistance training (PRT).  This is an essential 
component of this intervention because high-intensity weight-training programs have 
demonstrated the greatest effects on increasing muscle strength in older adults.  PRT will be 
performed using weight-lifting machines and free-weights when onsite or free weights, 
TheraBands, and found objects during remote sessions. 
 
Like Phase 1, Phase 2 onsite strengthening exercises will be performed at an 8-RM intensity. A 
participant is exercising at an 8-RM when she can lift a weight 8 times against a given 
resistance, but is unable to complete the 9th repetition appropriately. During remotely supervised 
exercise sessions, participants will be encouraged to perform the exercise until they 
demonstrate failure.  If the participant is able to lift the weight more than 8 times, weights will be 
increased if safe and feasible to do so.  Failure is defined as the inability to complete final 
repetition through full, available range of motion without significant compensation. Signs of 
compensation are as follows: sudden increases in speed to overcome resistance, improper 
form, and/or increase in the level of assistance needed.  Functional resistance exercises should 
be progressed by increasing difficulty of the task. 
 
Equipment for onsite weight training sessions includes free weight sets (barbells and dumbbells) 
and weight-lifting machines.  Remote training sessions require ankle weights, Therabands, or 
other objects found around the home to offer appropriate resistance.  Equipment is not needed 
for the functional resistance exercises.  


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
58 
 
Remote Supervised Exercise Sessions 
Participants who are unable to present to the center due to COVID restrictions, will be asked to 
perform the supervised exercise sessions remotely through secure video calls with the exercise 
interventionist.  Tablets with cameras and stands will be provided to participants who do not 
have the equipment necessary to participate in a video call.  The stands will ensure the exercise 
interventionist can view the participant performing the exercises.  Prior to the session, the study 
staff will review the procedures to log on to the video call with the participant.  When the video 
call starts, the exercise interventionist will verify the participant’s name and location to dispatch 
emergency personnel, if needed.  The exercise interventionist will assess the environment 
visible on camera for safety concerns and conduct a symptom check and vital sign 
measurements with an electronic blood pressure cuff. 
During the session, the exercise protocol will be delivered, which closely follows the Phase 1 
and Phase 2 onsite exercise sessions, only excluding exercises that are unsafe without 
assistance or deemed inappropriate for the individual.  Participants will be encouraged to 
perform the exercise until they demonstrate failure.  If the participant is able to lift the weight 
more than 8 times, weights will be increased if safe and feasible to do so.  The sessions are 
recorded by the exercise interventionist on the exercise logs. 
 
Home Maintenance Exercise Prescription 
Participants in the Supervised EX groups will also be given a set of a few functional-based 
exercises to complete on their own at home about 3 days per week on non-supervised exercise 
days and encouraged to perform a progressive walking program (for a goal of 10-20 minutes 
total a day).  Participants will record home exercise sessions on a daily log sheet. 
 
Scheduling Exercise Intervention Visits 
General requirements for scheduling of exercise intervention visits:  
1. The first exercise intervention visit should occur within 7 days of randomization, but 
preferably within 3 days.    
2. Exercise intervention should occur two times per week, and onsite sessions should 
never occur on two consecutive days, even when moving from one week to the next. 
3. Within the 6-month intervention period, unexpected missed visits can be made up as 
long as there is at least a day of rest scheduled between each exercise session.  If the 
participant or research staff anticipate missed sessions due to 3-month testing or any 
other reason, visits can be made up the week prior as well. 
4. During weeks with a study follow-up visit, exercise intervention visits may occur on the 
same day if the follow-up visit does not include any physical performance measures and 
provided that follow-up activities are completed first.   
5. If a participant misses 2 consecutive exercise sessions or more than 2 visits in any 
month that are not made up, the site coordinator will be notified. 
 Missed Exercise Sessions 
Participants who miss an exercise session (or anticipate missing one) will be allowed to make it 
up, preferably within the same (Monday-Friday) week, but could also be allowed to add a 
session any time prior to the 6 month assessment.  As with scheduling exercise intervention 
visits in general, a make-up session may not be scheduled on a day preceding or following a 
scheduled onsite exercise session. The site coordinator must be notified of any participant who 


STEP-HI Protocol 
Ver 12.5 (15 Nov 2022) 
59 
misses 2 consecutive sessions or more than two sessions in a month, to consider what can be 
done to reduce missed sessions. 
 
Adherence Measurements 
Adherence to the supervised exercise program will be measured as the percentage of exercise 
sessions successfully completed out of a possible 48 sessions.  We define a successfully 
completed exercise session as one in which 70% or more of the exercises are performed at the 
target number of repetitions. Exercise interventionists will complete a checklist and exercise log 
each visit documenting the number of sets, repetitions, weight used or other specifications of 
the exercise. If the participant was able to complete at least 5 repetitions, the set will be 
considered complete. Adherence to the home maintenance exercises will be measured with log 
forms similar to the EUC group. 
 
Fidelity Plan for Exercise Interventions 
Treatment fidelity(106, 107) for the interventions will be evaluated with regard to: (1) design, which 
focuses on whether the interventions are consistent with underlying theories, and whether the 
study is free of contamination such as treatment crossover or unintended motivational 
interventions; (2) training, which addresses skill acquisition and maintenance for PT/exercise 
interventionists; (3) delivery, or the assessment that the interventions were implemented as 
intended by study coordinators, dieticians, and physical therapists/exercise interventionists; (4) 
receipt, which focuses on whether or not the participant understood and received the 
interventions as intended.  Overall, treatment fidelity data will provide information on the 
adherence of the exercise interventionists to the interventions, and the adherence of the 
participants to the prescribed activities.  Monitoring treatment fidelity also will provide an 
opportunity to address potential study problems, such as drift from the intervention protocols 
that could threaten the study’s ability to detect treatment differences.  The Clinical Coordinating 
Center (CCC) will be responsible for oversight of treatment fidelity procedures.  
 Initial Training and Certification for Procedural Reliability 
The Clinical Coordinating Center (CCC) Lead Physical Therapist and staff will serve as 
Intervention Monitors (IMs) and will train all clinical site staff in the onsite supervised exercise, 
remote supervised exercise, and home exercise intervention procedures. Knowledge of 
procedures will be tested by written examination. Following the written examination, the clinical 
site Supervising Physical Therapist will observe site exercise interventionists conducting at least 
one Phase 1 onsite session and at least one Phase 2 onsite supervised exercise session with a 
volunteer (mock) participant using standardized checklists.  The sessions will also be video 
recorded.  The structured checklist assesses data completeness, physical performance, 
qualitative observations, and verbal and non-verbal communication. The checklist will also 
document whether the participant completed the warm up exercises, necessary repetitions at 
the appropriate intensity and cool down exercises. If the exercise interventionist scores 90% or 
higher, the video file will be sent to the CCC PT/IM for review.  If the score is less than 90%, the 
Supervising PT will proceed with retraining and remediation until the exercise interventionist 
scores 90% or higher on the fidelity checklist.   
 
The CCC PT/IMs will review the Phase 1 and Phase 2 exercise session videos using the fidelity 
checklists.  If the score is 90% or higher, the exercise interventionist is considered “STEP-HI 
certified” and the CCC will issue a certificate of completion.  When a new staff member joins the 


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project, training will include viewing of a required training video and the procedures described 
above. 
 Ensuring Ongoing Competency 
We will use a multi-faceted approach to ensure ongoing treatment fidelity.  The approaches 
include direct observations by the site Supervising PT and CCC Lead PT, periodic review of 
exercise logs, mandatory monthly conference calls lead by the CCC Physical Therapist with site 
Supervising PTs and exercise interventionists, and face-to-face meetings with the intervention 
team when indicated for remediation that cannot be managed by other means.  
14.7.2.1 
Direct Observation of Exercise Procedures 
The Supervising PT will directly observe exercise interventionists during onsite exercise training 
sessions or remote sessions, and document their observations using standardized checklists.  
Each exercise interventionist will be directly observed by the Supervising PT during the training 
of the first two or three participants; at least two sessions during Phase 1 and two sessions 
during Phase 2.  The Supervising PT will use the checklist and their observations to provide 
specific feedback to the exercise interventionists about their implementation of the exercise 
protocol, any specified modifications, and other issues such as verbal and non-verbal 
communication with participants. 
Site Supervising PTs will be responsible for observing exercise interventionists on a monthly 
basis, using the standardized checklists.  Approximately every six months, a video recording of 
one Phase 1  exercise session or one Phase 2 session will also be sent to the CCC Lead PT  to 
ensure appropriate ongoing fidelity to the exercise protocol. The CCC Lead PT will review video 
recordings using the standardized checklists. If the score on the checklist is less than 90%, the 
clinical site PI and site Supervising PT will be notified. A remediation plan will be proposed that 
will offer refresher training to ensure accurate understanding of the protocol, follow-up 
observation visits, and possible dismissal if warranted.    
14.7.2.2 
Review of Intervention Logs 
The clinical site exercise interventionists will review participant home exercise logs monthly, 
either on site or electronically in REDCap. The clinical site study coordinator, in collaboration 
with the DCC, will monitor whether the supervised exercise intervention logs are complete for all 
sessions, whether exercises are recorded as complete, and whether any modifications to the 
intervention protocol are appropriately documented.  The progression of the supervised exercise 
program will also be monitored by the site Supervising PT, and by the CCC Lead PT. This 
information will be available to the CCC PT for discussion with clinical site staff directly, and/or 
during monthly conference calls.  Additional follow-up will be mandated if problems with 
administration of the interventions are identified. A remediation plan will developed and 
monitored if there is ongoing lack of progress.  
14.7.2.3 
Mandatory Conference Calls with PTs and Exercise Interventionists 
The CCC IM/Lead PT will conduct monthly telephone calls with PTs and exercise 
interventionists.  Minutes of the telephone meetings will be recorded. During these calls, the 
CCC PT will ask questions to identify problems with delivering the intervention, provide 
guidance, and assist with problem solving. If problems are identified, the CCC Lead PT may 
schedule an individual site telephone call and review of exercise logs.  


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Section 15: 
 Testosterone/Placebo Intervention  
 
Drug Distribution 
Testosterone therapy will be provided in the form of a topical gel (generic 1.0% testosterone, 
like those manufactured by Perrigo or Activas/Teva).  Topical T gel will be used because it is 
documented to provide continuous transdermal delivery of T for 24 hrs.(108-110).  The advantage 
of topical therapy over oral or intramuscular preparations is that it is easier to achieve and 
maintain stable physiologic levels of T, particularly in women, and is safer. The potential 
advantages of topical gel over a transdermal patch include ease of delivery and dose titration, 
better skin tolerability, and invisibility after application(33).   
 
Placebo will be provided as an identical but inactive gel (hand sanitizer Purell™ or an equivalent 
generic) in identical bottles. 
 
The CCC will arrange for both the active and inactive gels to be shipped to the Clinical Site 
Investigational Pharmacies. The investigational pharmacy at each clinical site will be 
responsible for receiving, storing, and distributing the testosterone and placebo bottles. Detailed 
logs showing the receipt, distribution, and destruction of the investigation drug will be kept.  All 
pump bottles will be weighed by the local Clinical Site Investigational Pharmacist at the time that 
the bottle is dispensed. This information will be recorded and maintained by the Clinical Site 
Investigational Pharmacist. An Investigational Drug Accountability Log entry will be completed 
by the Clinical Site Investigational Pharmacist each time a gel bottle is received, dispensed, or 
destroyed. All expired, unused, or empty containers at the clinical centers can be disposed of 
per the institution’s standard drug destruction procedure. Written documentation of what bottles 
were discarded, and the date is mandatory. The gel bottles must be stored at 20 to 25°C (68 to 
77°F).  Excursions between 15°C and 30°C (59°F and 86°F) that are experienced in 
pharmacies, hospitals, and warehouses, and during shipping are allowed.  Provided the mean 
kinetic temperature does not exceed 25°C, transient spikes up to 40°C are permitted as long as 
they do not exceed 24 hours. 
 
Dosing and Schedule 
Women assigned to the active treatment group (EX+T) will be prescribed a dose of T gel that is 
anticipated to achieve a supra-physiologic serum T level (target T level 110 -160 ng/dl; 
reference range 12 - 78 ng/dl). The initial dosage of T gel will be 12.5 mg (1 pump depression 
per day of 1% testosterone gel) to achieve total testosterone levels in the target range.  T-levels 
will be measured at 2 weeks, 1 month, and then monthly. Women with serum testosterone 
levels below the target range will have their dose increased by 12.5 mg (1 pump depression) 
increments, to a maximum of 37.5 mg (3 pump depressions).  Women with levels above the 
target range will have their dose reduced to 12.5 mg (1 pump depression) every other day.  
Subsequent dose adjustments will be individualized by the CCC unblinded physician. 
 
Dispensing of the first month’s supply of study drug or placebo will occur on the day of 
randomization.  Subsequent refills will occur at study follow-up visits or before, if needed. 
 
Participants will meet with the study coordinator at the randomization visit to receive detailed 
oral and written instructions regarding the proper application of the gel. The study coordinator 
will observe the patient self-apply the first dose of gel.  Participants will also be educated about 


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the precautions that should be taken to prevent other individuals from being exposed to the gel. 
These include washing hands with soap and water immediately after applying the gel and 
covering the application site with clothing after the gel has dried. Additionally, the application 
site should be washed thoroughly with soap and water prior to skin-to-skin contact with another 
person, which should be several hours after gel application.  
 
Dose Adjustments 
Peak serum total testosterone levels will be measured at 2 weeks post randomization and at the 
monthly visits. Doses will be adjusted by an un-blinded study physician in the CCC who is not 
involved in screening, baseline or follow-up testing.  On the day of the follow-up visit, the 
participant will be instructed not to apply the gel until their appointment at the clinical research 
facility. The participant will apply the gel under the direct supervision of the study coordinator.  A 
blood sample for peak testosterone levels will be obtained 2 hours after gel application.  
Testosterone levels will be reported only to the unblinded CCC physician. To maintain blinding, 
the unblinded CCC physician will direct dose adjustments and a member of the CCC or DCC 
will communicate changes in prescriptions to the clinical site coordinator.  The CCC physician 
will direct a subject in the placebo (EX) group to be treated similarly to an active treatment 
(EX+T group) subject (e.g., have the gel dosage increased or decreased by one pump 
depression).  Individuals with mild symptoms or signs of virilization who wish to continue in the 
study will have the dosage reduced.  For the active T-gel participants we will aim to maintain the 
level within the bounds of the target range (110-160 ng/dl), but if this is not tolerated the dosage 
will be adjusted to the highest tolerable dosage.  
 Adverse Events and Symptom Monitoring 
Adverse events (AEs) will be solicited on a monthly basis and documented if a participant 
volunteers an event to a study staff member.  The study coordinator will review adverse events 
with the participants if additional information is needed and document the AE. Study staff will 
notify the site physician of any concerning symptoms as soon as possible.  Women assigned to 
either the EX+P or EX+T groups who experience an adverse event due to an acute 
cardiovascular event such as a TIA, CVA, or cardiac ischemia will have their assigned gel 
treatment discontinued, but can continue other study interventions and procedures unless 
instructed not to by their health care providers. 
 Medication Adherence 
Participants will maintain a daily log in which they will record the location on the skin and the 
time of day the gel was applied each day. The study coordinator will telephone the subject 
weekly during the first month to discuss any questions that arise in relation to gel application.   
 
At monthly follow-up visits the pump bottle dispensed previously will be returned to the 
investigational pharmacy, documented, and weighed. For women prescribed a dose of less than 
one pump depression per month, the bottle may be returned after two months. The study 
coordinator will document the prescribed dosage/amount (number of pumps) and frequency that 
the subject is administering the gel.  The investigational pharmacist will be responsible for 
weighing the returned pump bottle and completing any required regulatory documentation. 
 
Adherence to the medication will be measured using bottle weights, serum testosterone levels, 
and monthly log reviews.  Based on the prescribed dosage, adherence will be measured as the 


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percentage of the expected gel bottle weight.  Adherence will also be measured as the 
percentage of testosterone levels within the target range over the 24 week treatment period, 
and the percentage of reported vs. expected gel applications.   
 Fidelity Plan for Study Drug Procedures 
Fidelity to the testosterone and placebo procedures will be monitored through blinded reporting 
of bottle weight and testosterone level by clinical site.  If bottle weights indicate consistent 
adherence of < 90% or sub-therapeutic testosterone levels in the active treatment group then 
the IM will conduct a site visit to review procedures with the site study coordinator.  The DCC 
will generate these monthly reports for the CCC.  
 
 


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Section 16: 
Safety Considerations 
 
Pre-Intervention Safety Screening 
Potential participants will be excluded during screening if they have cardiovascular diseases or 
other conditions that would make it unsafe for them to participate in one or both of the study 
interventions. Information about these conditions will be obtained through chart review, 
interviews, and consultation with a medical professional familiar with the potential participant 
(e.g., primary care provider, orthopedic surgeon). The clinical site physician and PI will be 
responsible for giving permission for potential participants to be randomized, based on thorough 
review of all eligibility information.  
 
Safety Considerations for Study Assessments 
All study assessments will be done by certified staff, trained to perform the tests safely.  If, 
during any physical testing or evaluations, a participant reports chest pain, tightness or 
pressure, significant shortness of breath or difficulty breathing, or feeling faint, lightheaded, or 
dizzy, the test will be stopped. All research staff who administer 1-RM testing or exercise 
procedures will be familiar with the site policies to provide or activate immediate care when 
faced with medical emergencies.  
 
Safety Considerations for Testosterone Therapy 
Participants will be rigorously monitored for the development of side effects and potential health 
problems.  Participants will be monitored for signs of hirsutism, endometrial hyperplasia, 
changes in hematocrit, serum liver function tests and lipids, and cardiovascular outcomes.  
 Evaluation of Hirsutism (Ferriman-Gallwey scale) 
The clinical site PI, a designated physician, or an Advanced Practice provider will complete a 
physical exam to assess for hirsutism using the Ferriman-Gallwey scale at baseline, month 3, 
and month 6.    
 Adverse Event Assessment 
At baseline and at each monthly follow-up visit, study staff will ask participants about and 
document any new or worsening symptoms.  Study staff will review symptoms with the clinical 
site PI and report all symptoms that are considered AEs as directed in Section 17. 
 Laboratory Testing 
Screening laboratory testing will include a complete metabolic panel (CMP), liver function (with 
complete metabolic panel), complete blood count (CBC), TSH, HgbA1c, and testosterone levels 
(serum free and total). Baseline laboratory testing will include other hormone levels (serum 
estradiol and SHBG), Serum 25-OH vitamin D level, and cholesterol levels (Total, LDL and 
HDL). All of these laboratory tests (with the exception of TSH and HgbA1c) will be repeated on 
all participants at month 6. In the interim, all participants will have a CMP, CBC, and total 
testosterone level measured at the month 3 visit. Testosterone levels will be measured in the 
EX and EX+T groups at week 2, 2 weeks later (month 1), and then monthly.  LFT results will be 
reviewed by the Site Physician or a designee within 3 days, but preferably sooner, of the date 
that the test is reported. Following screening, testosterone levels and CBC results will be 
reviewed by the unblinded CCC physician within 3 days, but preferably sooner, of the date that 


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the test result is reported. The unblinded CCC physician will instruct each clinical site 
coordinator to make dose adjustments as necessary.   
 Transvaginal Ultrasound 
Women in the EX and EX+T groups with a uterus will undergo a transvaginal ultrasound after 
completion of the interventions at 6 months. Women who develop abnormal or unexpected 
vaginal bleeding over the course of the intervention will also be asked to undergo a vaginal 
ultrasound.  Ultrasounds will be read locally by a designated physician.  The clinical site PI will 
review the results and document this in the participant record. Women who have significant 
endometrial hypertrophy, defined as an endometrial wall thickness > 4 mm will be referred to 
their gynecologist or primary care physician for follow-up. 
 Mammogram  
Mammograms will be performed on all participants at baseline (if they haven’t had one within 
the past 6 months) Women in the EX and EX+T groups will undergo an additional mammogram 
at the end of the 6-month intervention period.  Mammograms will be read locally by a 
designated physician.  The clinical site PI will review the results and document this in the 
participant record. Abnormal test results will be discussed with the participant’s primary care 
physician. 
 
Safety Considerations for Supervised Resistance Training Program 
There is no expectation that the EX Program will evoke serious cardiovascular responses; 
however, participants will be warned of a possible risk. Cardiac events are rare, with estimates 
of one event per 60,000 participant-hours in aerobic exercise programs(111). No significant 
cardiac events were reported after performing 1-RM testing for over 6600 healthy subjects(112). 
The American Heart Association’s guidelines for resistance training for adults with and without 
cardiovascular disease reports the safety of high intensity resistance training and testing in 
persons with coronary disease which found an absence of anginal symptoms, ischemic ST-
segment depression, abnormal hemodynamics, complex ventricular dysrhythmias, and 
cardiovascular complications(113, 114). Less serious risks may include chest pain, fainting, 
hypotension, or muscle strain. We have minimized risk to participants by following the 
guidelines suggested by Gill et al.(115)  Blood pressure and heart rate will be monitored using a 
standard blood pressure cuff and palpation of peripheral pulse. 
 
Another concern is the presence of osteoporosis and the risk of inducing a compression fracture 
or a lower extremity fracture. The exercises have been designed to minimize this risk. The risk 
of inducing a compression fracture will be minimized because the exercises are performed in 
supine, sitting, and upright standing positions with minimal to no trunk flexion(116). The PT will 
also remind the participant to minimize flexion to the spine during all standing exercises. 
Delayed onset muscle soreness is a common occurrence after the initiation of an exercise 
program. The soreness occurs in the muscle belly 1-3 days after the initiation of exercise and 
lasts 2-3 days. There is no effective way to eliminate the risk of delayed onset muscle soreness, 
but it is hoped that the orientation process and gradual increase in intensity will reduce the risk. 
The participants will be informed about the condition, what it feels like, how long it lasts, and 
suggested ways of decreasing the pain including the use of superficial heat or ice. If a 
participant reports continued discomfort, the site physician will discuss this with the participant 
and contact their primary care provider (PCP) as necessary.  


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Safety Considerations for Remote Exercise Program 
The remotely supervised exercise sessions will utilize precautions similar to the onsite 
supervised program.  Participants will monitor their blood pressure and heart rate before and 
after each exercise session.  Exercise interventionists will monitor the participant for proper form 
during the sessions and will instruct participants in the proper use of equipment.  If an adverse 
event occurs during the session, the exercise interventionist will report back to the coordinator 
or PI and in severe circumstances, will call on emergency services.  
 
Safety Considerations for Home Exercise Program 
The exercises in the EUC program are similar to those prescribed by physical therapists at the 
end of standard treatment for a hip fracture and therefore are similar to “usual care” for 
community-dwelling hip fracture patients, except that subjects enrolled in the study are 
monitored on a monthly basis in person and will receive weekly contact for 
encouragement.  Participants will be instructed in the proper execution of all assigned exercises 
by certified staff.   
 
Participant Education about Potential Risks 
Potential risks associated with study-related activities and interventions will be explained to 
each participant by trained study personnel during the informed consent process and during 
study orientation. Each participant will be instructed to report the occurrence of a new symptom, 
medication, or health event to appropriate study staff at scheduled data collection times, to PTs 
or exercise interventionists administering the intervention, or spontaneously at any other time. 
Participants also will be encouraged to report concerns about the safety of participating in the 
study.  


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Section 17: 
 Adverse Event Reporting 
Each site PI has primary responsibility for the safety of participants at his/her clinical site. An 
Internal Safety Monitor (ISM) will review decisions made by site PIs and the categorization of 
events. In addition, an Independent Data and Safety Monitoring Board (DSMB) will monitor the 
study safety and any potential treatment-related adverse events (AEs), serious adverse events 
(SAEs), and reportable adverse events (RAEs) to protect the safety of study participants.  
 
Many definitions used in this section are published in the January 2007 OHRP Guidance on 
Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events, OHRP Guidance and can be found at: 
http://www.hhs.gov/ohrp/policy/advevntguid.html. 
 
Definitions 
Adverse Events (AEs) 
An adverse event (AE) is any unfavorable or untoward medical occurrence in a human study 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s involvement in the research, 
whether or not considered related to participation in the research.  
An AE includes any abnormal sign such as abnormal findings from routine exam or laboratory 
tests, or any disease condition that is present during the participant’s involvement in the 
research. Some examples of adverse events include: 
• 
Any new and pre-existing  symptoms or conditions that have become worse either in 
frequency or severity or both, even if the event was not caused by the study treatment or 
procedure. 
• 
Any recurrence of previously resolved condition whether or not it is related to the study 
treatment or procedure. 
• 
Any clinically significant findings from the study-related or non-study related procedures 
such as ECG findings, laboratory findings, vital sign measurements, physical exams and 
any other procedures. 
 
Serious Adverse Events (SAEs) 
An AE is considered “serious” if it results in any of the following outcomes: 
• 
Death 
• 
Is life threatening, or places the participant at immediate risk of death (e.g., MI, 
stroke/TIA) 
• 
Requires or prolongs hospitalization 
• 
Causes significant disability or incapacity (e.g., torn muscle or ligament) 
• 
Requires medical or surgical intervention to prevent significant disability (e.g., hip 
fracture) 
 
Unanticipated Problems (UPs) 
Unanticipated problems include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected, in terms of nature, severity, or frequency, given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the study population;  


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2. Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. (Note per OHRO guidelines, any AE that is serious (i.e. a 
SAE), unexpected, and related or possibly related to participation in the research 
automatically meets this third criterion. 
Reportable Adverse Events (RAEs) 
RAEs are events that have potential implications for participant safety and require individual 
reporting to the CCC.  If the event falls into at least one of the following categories it will be 
considered an RAE: 
• 
Serious Adverse Events (SAEs) 
• 
Unanticipated Problems (UPs) 
 
Adverse Event Reporting Period 
Prior to randomization, only adverse events that are a direct result of study procedures or occur 
while the participant is under study staff supervision will be documented.  From randomization 
until 30 days after the participant’s final assessment visit, all AEs (regardless of relatedness) will 
be documented. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition, even if it occurs intermittently.  At the final study visit, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be documented. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the site PI until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the participant should be instructed to report any subsequent event(s) that the 
participant, or the participant’s physician, believe might be reasonably related to participation in 
the study. Sites should document any death or adverse event occurring at any time after a 
participant has discontinued or withdrawn from study participation that may reasonably be 
related to the study. 
 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
A clinical laboratory abnormality or abnormal objective test finding should be reported as an AE 
if any one of the following conditions is met: 
• 
The test result is associated with accompanying symptoms; 
• 
The test result requires additional diagnostic testing or medical surgical intervention; OR 
• 
The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE.  Any abnormal test result that is determined to be an error does not require reporting as 
an AE.  


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Surgery, Hospitalization, or Prolonged Hospitalization 
Any adverse event that results in surgery, hospitalization, or prolonged hospitalization should be 
documented and reported as a serious adverse event unless: 
• 
The hospitalization or prolonged hospitalization is for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome of 
an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
• 
The hospitalization is for respite care 
• 
The hospitalization is planned or for routine maintenance of a device in place before 
informed consent and the outcome was uneventful. 
 
Categorizing an Adverse Event 
 Expectedness 
Each AE should be evaluated as to whether it is expected or unexpected. 
Expected Adverse Events 
An AE can be deemed as expected if it can be: 
• 
Anticipated on the basis of prior experience with the intervention under investigation; 
• 
Attributed to the underlying condition of the participant being studied; OR 
• 
Attributed to the patient population being studied. 
The following are expected adverse events that will be listed in the ICF: 
 
MEDICATIONS 
Testosterone Gel:   
o 
mild edema in legs 
o 
facial acne 
o 
hair growth 
o 
scalp hair loss 
o 
enlarged clitoris 
o 
change in blood lipids 
o 
uterus lining thickening 
o 
vaginal bleeding 
o 
allergic reaction characterized by: 
o rash 
o shortness of breath 
o wheezing 
o difficulty breathing 
o sudden drop in blood pressure 
o swelling around the mouth, throat, or eye 
o fast pulse 
o sweating 
 
Calcium Supplements: 
o 
constipation 
 
Vitamin D Supplements: 
o 
elevated calcium level in blood 


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o 
kidney stones 
o 
frequent urination 
o 
irregular heart beat 
 
STRENGTH TESTING, PHYSICAL ASSESSMENTS, and EXERCISE SESSIONS: 
o 
muscle soreness 
o 
joint stiffness 
o 
foot, knee, hip, or back pain 
o 
fatigue 
o 
pulled muscles 
o 
heart problems (following exercise) 
o 
fall (with or without injury) 
o 
increased heart rate 
o 
chest pain 
o 
shortness of breath 
o 
headache 
o 
nausea 
 
SAFETY ASSESSMENTS 
Blood Draws: 
o bleeding 
o bruising 
o pain 
o dizziness 
o fainting 
o infection 
 
ECG: 
o skin redness at patch site 
o skin itching at patch site 
o skin discomfort at patch site 
o hair loss with patch removal 
 
Mammogram: 
o 
discomfort 
 
Transvaginal Ultrasound: 
o 
discomfort 
 
Unexpected Adverse Events 
An AE is considered unexpected if the event: 
• 
Is not anticipated on the basis of information associated with resistance training in the 
elderly, the investigational drug package insert, or the current IRB approved consent.  
• 
Cannot be attributed to the underlying disease, disorder, or condition of the participant 
being studied or to the patient population; OR  
• 
Exceeds the frequency or severity anticipated. 


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 Relatedness 
The potential relationship of the event to the study intervention and/or participation is assessed 
by the site PI and/or study clinician and reviewed by the ISM. The categories are: 
• 
Definitely Related:  The adverse event is clearly related to the investigational 
agent/procedure – i.e., an event that: 
o follows a reasonable temporal sequence from administration of the study 
intervention,  
o follows a known or expected response pattern to the suspected intervention,  
o is confirmed by improvement on stopping and reappearance of the event on 
repeated exposure and  
o could not be reasonably explained by the known characteristics of the subject’s 
clinical state. 
• 
Possibly Related:  An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of 
other factors.  
 
• 
Not Related:  An adverse event clearly unrelated to the investigational agent/procedure - 
i.e., another cause of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study intervention; and/or a 
causal relationship is considered biologically implausible.  
 
 Severity 
The following guidelines will be used to rate the severity of RAEs: 
• 
Mild: Participant is aware of signs or symptoms that are transient in nature, easily 
tolerated; do not require therapy or medical evaluation and are only minor irritants that 
cause no loss of time from normal activities. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant 
and may interfere with daily activities. Symptoms may require minimal, local, or 
noninvasive medical intervention only. 
• 
Severe:  Events interrupt the participant’s normal daily activities and are usually 
incapacitating. Significant symptoms may require hospitalization or invasive medical 
intervention.  
• 
Life threatening: Events that may involve acute, life-threatening metabolic or 
cardiovascular complications (such as circulatory failure, hemorrhage, sepsis) or life-
threatening physiological consequences. Intensive care or emergent invasive procedure 
is required to prevent death or disability. 
• 
Fatal: Events result in death. 
Severity is not synonymous with seriousness. A severe headache may not necessarily have a 
severity rating of “severe”.  However, mild chest pain may result in a day’s hospitalization and 
be classified with a rating of “severe”. 
 
Adverse Event Recording 
At each monthly visit, study staff will seek information on adverse events by specific questioning 
and, as needed, by examination.  If, at an intervention visit or during a phone conversation, 
participants volunteer that an event occurred, adverse events will be recorded by study staff. All 
adverse events should be reported on the case report form (CRF) and the appropriate source 


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documentation should be filed in the participant’s binder.  All clearly related signs, symptoms, 
and abnormal diagnostic procedure results should be recorded, but should be grouped under 
one diagnosis. 
All adverse events occurring during the adverse event reporting period must be recorded.  The 
clinical course of each event should be followed until resolution. Serious adverse events that are 
still ongoing at the end of the adverse event reporting period must be followed up to determine 
the final outcome.  Any serious adverse event that occurs after the adverse event reporting 
period and is considered to be possibly related to study participation should be recorded and 
reported immediately. 
 
Adverse Event Reporting 
Clinical site PIs will be responsible for reviewing AEs and assuring accurate and timely reporting 
of RAEs. Clinical sites will be responsible for reporting RAEs to their respective IRBs and risk 
management offices according to local requirements. The clinical site physician or designee will 
be available for consultation and participant evaluation (if needed) during time periods when 
participants are engaged in interventions or clinical assessments.  The clinical site PI will also 
review RAEs recorded at the site.  The CCC will report AEs to the appropriate groups and 
agencies within the required timeframe as defined in the Manual of Procedures.  The CCC will 
also communicate information back to the sites and make changes to the ICF as requested by 
the monitoring groups and agencies. 
 
Emergency Unblinding 
The unblinding of treatment assignment for a subject may be necessary due to a medical 
emergency or any other significant medical event. Subject safety must always be the first 
consideration in making such a decision. The site PI should make every effort to contact the 
Study Chair prior to unblinding to determine whether it is necessary. If unblinding is deemed 
crucial, the site PI will contact the site investigational pharmacist or the unblinded CCC 
physician for the treatment group assignment. The site PI will detail the reason for the decision 
and include appropriate source documents. The investigator will inform the CCC coordinator 
that the subject has been unblinded. If an investigator is unblinded, the participant may remain 
in the study after obtaining approval from the Study Chair. 
 
Adverse Event Monitoring 
 CCC Monitoring 
The CCC, with the help of DCC reports, will monitor site recording and reporting procedures and 
unresolved AEs at site visits and remotely as described in Section 21.5: Reportable Adverse 
Event (RAE) Reporting. 
 Internal Safety Monitor (ISM) 
CCC physicians who are not affiliated with conducting the study will serve as ISMs to review the 
final status of RAEs reported to the CCC on a rotating basis.  After a RAE is finalized by a 
clinical site and reported to the CCC, it will then be forwarded to the on-call ISM.  The ISM will 
be responsible for: 
• 
Confirming or refuting the final classification of an event as an RAE; 
• 
Confirming or refuting the classification of expectedness of the RAE; 


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• 
Confirming or refuting the classification of relatedness to the study intervention 
and/or participation of the RAE; 
• 
Confirming or refuting the classification of severity of the RAE; and 
• 
Recommending changes to the protocol or consent form, if he/she believes changes 
are warranted. 
 Independent Data and Safety Monitoring Board (DSMB) 
The DSMB will receive safety reports and meet roughly every 6 months to monitor study safety 
and progress.  They will make recommendations regarding study initiation, continuation, and 
protocol changes.  The DSMB may meet at any time needed to review the study relevant 
information, such as occurrence of RAEs, scientific or therapeutic developments that may have 
an impact on the safety of the participants or the ethics of the trial. The DSMB will make 
recommendations to the NIA and the cPI, concerning continuation, termination, or other 
modifications to the study based on the observed beneficial or adverse effects of the treatment 
under study. Because the DSMB may be required to review unblinded analyses, their names 
and contact information are not included in this document and will not be made available to the 
study staff members.  
 


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Section 18: 
Discontinuation 
Discontinuation as used herein refers to (1) the discontinuation of the treatment in particular 
individuals because of adverse events; (2) the discontinuation of the study because of adverse 
events, demonstrated efficacy, or futility; and (3) the discontinuation of a single arm of the study 
because of adverse events, or demonstrated futility associated with the particular study arm. 
 
Certain RAEs may result in a temporary interruption or early discontinuation of trial 
assessments and interventions or components of these assessments and interventions in an 
individual participant. After such RAEs occur, a participant may resume the trial intervention 
when the clinical site physician and the primary care provider (if participant has one) agree that 
it is appropriate. Women assigned to either the EX+P or EX+T groups who experience an 
adverse event due to an acute cardiovascular event such as a TIA, CVA, or cardiac ischemia 
will have their assigned gel treatment discontinued, but can continue other study interventions 
and procedures unless instructed not to by their health care providers.  For mild problems that 
require temporary cessation of intervention, the clinical site PI, in consultation with the clinical 
site physician and participant, will confirm that the participant can resume the study intervention.  
 
At any time, the DSMB may recommend discontinuation of any component or intervention group 
of the study for any of the following reasons: 
1)  Adverse events: Compelling evidence from this or any other study of an 
adverse effect of the study intervention(s) that is sufficient to override any 
potential benefit of the interventions to the target population. 
2)  Demonstrated efficacy: Compelling evidence from this or any other study of a 
significant beneficial effect of the study intervention(s), such that its continued 
denial to other study group(s) would be unethical. The possibility of an interim 
futility analysis will be discussed with the DSMB. 
3)  Demonstrated futility: A very low probability of addressing the study goals 
within a feasible time frame. 
 
The site PI may recommend discontinuation of all components of the intervention in a given 
participant for the following reasons: 
1)  Participant becomes lost to follow-up. 
2)  To protect a patient from excessive risk, as per the safety alert and action tables 
(See MOP). 
3)  To maintain study integrity if the participant is found to be untruthful. 
4)  Participant has a change in cognitive status causing safety concern. 
 
Procedures for assessment of excessive risk or change in cognitive status are discussed in 
more detail in the MOP. 
  
The participant may also withdraw voluntarily from participation in the study at any time and for 
any reason. If the participant decides to withdraw from intervention participation, she will be 
encouraged to continue in the study for safety monitoring and outcome assessments at the 
specified time points in the protocol. If she declines, we will request that she return to the 
research center for a final early withdrawal visit. Prioritized outcome measures will be performed 
at this study withdrawal visit allowing the participant to stop at any point. 
 


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Participants who choose to withdraw early or are discontinued by the study will not be replaced. 
 
Study Drug Discontinuation 
Subjects who permanently discontinue study medication and who do not withdraw from the 
study will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Particular emphasis will be placed on encouraging participants who discontinue study 
medication to return for the final study visit. 
 
Study Exercise Intervention Discontinuation 
Participants who permanently discontinue the weekly exercise interventions and do not 
withdraw from the study will be asked to continue use of the gel and to return to the clinic for all 
remaining study visits per the visit schedule. 
Participants who discontinue any part of the home exercise program or no longer wish to attend 
the monthly health education classes, will no longer be contacted weekly. They will still be 
asked to participate in the assessment time points if they are willing. 
 
Early Withdrawal Visit 
Participants who are not willing to continue with the assessment schedule will be asked to 
complete the 6 month visit at 6 months post randomization. If the participant is unwilling to wait 
until the 6 month time, an abbreviated withdrawal visit will be requested as detailed in the MOP, 
no matter what assessment time point is due or is coming due.  The participant is able to refuse 
any assessment she doesn’t want to complete. 
 
 


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Section 19: 
Sample Size and Statistical Power 
The primary goal of this study, as reflected in the specific aims, is to compare the change from 
baseline to six months in six minute walk distance (6MWD) in the exercise (EX) group with the 
corresponding change in the exercise plus testosterone (EX+T) group.  Prior data from a 
previous pilot study led us to base those computations  on projected changes in 6MWD of 42.7 
+ 69.2 meters in the EX group and 82.2 + 92.5 meters in the EX+T group. 
Our original power computations assumed a 20% dropout rate during the 6-month intervention 
period.  However, results to date from current STEP-HI participants are far better than that.  As 
of the end of February, 2020, only two of the 25 women randomized to the EX groups chose not 
to use the gel (after randomization) and are participating in the study in all other respects; a third 
subject cannot participate fully in the exercise program due to an ankle fracture.  She also 
continues to participate in all other aspects of the protocol and will provide follow-up data, as 
able.  Impressively, STEP-HI has not had any study participants withdraw to date among the 38 
randomized participants, 13 of whom have completed the 6-month intervention period, with 22 
having been in the study for four months or more.  Based on this experience we perform revised 
power computations using assumed dropout rates of 5% and 10%. 
Because the primary goal of the study involves comparisons between the EX and the EX+T 
groups, we have constructed a revised protocol that changes the randomization ratio 
such that starting with this version of the protocol, more subjects would be randomized 
into the EX groups than into the Enhanced Usual Care (EUC) group.  Specifically, we have 
constructed a revised randomization scheme whose purpose would be to complete 
randomization with 70 subjects in the EX group, 70 in the EX+T group, and 28 in the EUC group 
(total N = 168).  If the total N turns out to be 120, the randomization scheme will yield 50 
subjects in each EX group and 20 in the EUC group. 
Using the projected 6MWD changes (42.7 + 69.2 meters in the EX group and 82.2 + 92.5 
meters in the EX+T group), assuming two-sided tests at the 0.05 level of significance, and 
assuming that the number of non-dropouts will be either 66 / 47 per group (5% dropout rate with 
the two sample sizes reflecting a total N of 168 or 120) or 63 / 45 (10% dropout rate), we get the 
following results:  For a total N of 168, the power is 0.79 for a 5% dropout rate and 0.77 for a 
10% dropout rate.  If N=120, the power is 0.64 for a 5% dropout rate and 0.62 if the dropout rate 
is 10%.  These results are summarized in Table 1. 
Table 1:  Power computations comparing the baseline to six month change in 6MWD in the EX 
group with the corresponding change in the EX+T group.  Results are based on two sided tests 
at the 0.05 level of significance.   
Total 
sample 
size 
Number randomized 
to each intervention 
group 
Dropout 
rate 
5% 
10% 
168 
70 
0.79 0.77 
120 
50 
0.64 0.62 
 


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While these power values are less than ideal, we emphasize that they are only marginally below 
the initially planned 0.8 when the sample size is 168.  The reasons for this relatively high power 
despite a reduction in sample size from the originally proposed n=300 is the imbalanced 
randomization we are proposing and the very positive results we have experienced thus far with 
respect to dropout rates.   
We note also that if the number of randomized subjects were to turn out to be only 120, the 
power is reduced to 0.64 and 0.62, depending on the presumed dropout rate.  While this is 
clearly lower than we would like, we emphasize that power values in this range leave a 
reasonable chance of achieving significance if our effect size projections are accurate.  
Moreover, when interim analyses are performed in group sequential trials that permit stopping 
early due to futility, it is standard to stop early when the conditional power is less than 0.2 or 0.3.  
We are aware of no study where a conditional power as high as 0.62 or 0.64 led to early 
stopping for reasons of futility. 
 
 


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Section 20: 
Statistical Analysis 
The analysis of data will be based on the Intention-to-Treat principle under which all patients 
randomized in each group will be analyzed as a part of that group regardless of subsequent 
events.   
 
Specific Aim 1  
Addresses the question of whether T therapy combined with supervised exercise (EX+T) will 
induce greater improvements in the 6MWD relative to the EUC and EX conditions alone. The 
primary goal of this study are to determine if there are between-group differences in the change 
over time in 6MWD.  Analytic strategies are based on the fact that all outcomes, including 
secondary outcomes, are continuous variables scheduled to be measured on at least three 
occasions. Initial analyses will include chi square tests and t-tests to compare baseline values of 
key demographic, clinical, and physiologic parameters. Because we expect the primary 
outcomes to be normally distributed or transformable to normality, between group comparisons 
of 6MWD will be performed using mixed model repeated measures analysis of variance. All 
mixed model analyses will be implemented using PROC MIXED in SAS and will be preceded by 
an evaluation of the data, intended to determine what covariance structure should be used.  
Since past experience suggests that correlation coefficients between time points will be greater 
for time points that are closer together than for time points that are further apart, we anticipate 
that an autoregressive or a Toeplitz covariance structure will be appropriate for these analyses. 
If correlation coefficients are approximately constant regardless of the time between 
assessment points, we expect that a compound symmetric covariance structure will fit the data 
best. Decisions about which covariance structure will be implemented will be made only after 
correlation coefficients across time have been evaluated and with appropriate considerations of 
the Schwarz-Bayesian criterion and Akaike’s Information criterion. All other things being equal, 
we will give preference to correlation structures that require the estimation of the smallest 
number of parameters. The primary analysis will be a mixed model repeated measures analysis 
of variance that evaluates statistical contrasts to determine if the change from baseline to 6 
months for EX+T are significantly different compared to EX alone and compared to EUC.  In 
addition to the primary analysis, statistical contrasts will be evaluated to determine if there are 
significant between-group differences in the change from baseline to 3 months.  Additional 
analyses of covariance will be performed that adjust for baseline values and covariates that 
differed across groups at baseline.    
 
Specific Aim 2  
The mixed model approach discussed above will be applied also to secondary endpoints.  In all 
of the analyses we perform, we will assess the appropriateness of the selected analytic 
methods by determining whether required distributional assumptions are satisfied.  Thus, when 
t-tests are performed, we will evaluate normality and equal variance assumptions before 
accepting the results of the test.  When analyses of variance and covariance are performed, 
regression residuals will be evaluated to ensure that normality assumptions are satisfied.  When 
necessary assumptions are violated, potentially useful data transformations will be considered 
and evaluated.  In some circumstances, inappropriate distributional properties in combination 
with the failure to find an appropriate data transformation may lead to a decision to use non 
parametric rather than parametric methods of analysis.  Thus, when we say above that we will 
perform a t-test, it is possible that the t-test will be performed on the log transformed data or that 
we will use Wilcoxon’s test as an alternative.  It is similarly possible that we will apply our mixed 


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model analyses to transformed data or that it will be necessary to perform these analyses semi-
parametrically using the ranks of the data rather than the data themselves.  
 
Missing data will be a particular concern in our mixed model analyses.  To address this issue, 
we will collect information about reasons for the missingness to facilitate an assessment of 
whether missing data are ignorable. To formally determine whether data are missing completely 
at random, we will use a SAS macro to implement the likelihood ratio based method of Little 
(117).  When data are missing completely at random, multiple imputation using PROC MI in SAS 
will be used to impute missing values and standard mixed model analyses will incorporate these 
imputed values. Understanding the reasons for missingness and assessments of whether 
variable values at baseline (when data are complete) are associated with the likelihood that they 
are subsequently missing will help us decide whether the data are missing at random. 
Unfortunately, it is not possible to test whether missing data are non-ignorably missing because 
the very definition of such data implies that the missing data depend on other data that are not 
available. If we believe that data may be non-ignorably missing, we will adopt a conservative 
approach to analysis and impute values that bias towards the null hypothesis.  For example, if 
evidence suggests that subjects may have dropped out for reasons related to limited response 
to the interventions, we will bias towards the null by assuming that the missing data on these 
subjects are equal to the worst value of the outcome measure that was observed for any subject 
at the time points that are missing.  To minimize the burden of missing data, we will encourage 
all subjects who withdraw from the study to undergo the final assessments that, at the very 
least, provide information about the primary endpoints.  Our experience suggests that many 
subjects who choose to drop out are willing to cooperate in this way.  Finally, when we suspect 
non-ignorable missingness, we will perform sensitivity analyses that use more than one 
approach to imputation in order to evaluate the robustness of our conclusions. 
 
Specific Aim 3  
Specific Aim 3 addresses the question of whether the effects of the interventions persist after 
three months of discontinuing them.  Analyses in this aim will be similar to those described for 
the primary specific aim in that they will employ mixed model repeated measures analysis of 
variance.  The central differences are that analyses for this aim will include the 9 month time 
point and will focus on the statistical contrast that performs a between-group comparison of 
changes from 6 to 9 months for EX+T relative to EX. In addition to p-values, we will generate 
confidence bounds that quantify the changes from 6 to 9 months within each group and the 
potential differences between the 6 to 9 month changes in different groups. We omit the details 
of these analyses and emphasize only that considerations related to determining covariance 
structures and dealing with missing data are identical to those previously discussed. 
 
 


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Section 21: 
Clinical Coordinating Center (CCC) Activities 
 
Study Protocol, Manual of Procedures, and Informed Consent  
 Study Protocol 
The CCC will be responsible for finalizing the study protocol, including securing approval of the 
DSMB.  The CCC will maintain detailed records of all protocol amendments and distribute 
amendments to clinical sites in a timely manner.  They will also ensure each clinical site’s 
compliance with protocol amendment changes.   
 Manual of Procedures 
The CCC will finalize and maintain the study Manual of Procedures (MOP).  This includes 
ensuring that the MOP is in agreement with the study protocol and any amendments.   
 Informed Consent 
The CCC will develop a study Informed Consent Form (ICF) for distribution to the clinical sites.  
Individual sites will submit contact information, injury and HIPAA language that will be placed 
into the approved consent template by the CCC. Please see Section 23.2 Informed Consent 
Forms (ICF) for more information on the ICF. 
 
Clinical Site Coordination 
 
 Budgets 
 
Budgets will be negotiated with each clinical site in accordance with NIA guidelines. 
 Regulatory 
Washington University’s IRB (WU IRB) will serve as the single IRB (sIRB) for this study.  The 
CCC will assure all reliance documents are collected and the consent form is approved with 
standard language. The CCC will coordinate with each site to verify local IRB reliance on the 
sIRB at WU, completion of the Signature and Delegation Log, and submission of Form FDA 
1572.  Further, the CCC will require that all study staff have completed the appropriate Human 
Subjects training and that each site maintain records for those staff members. The CCC can 
audit these records at any time to assure compliance. 
The CCC will also maintain a record of the study at the ClinicalTrials.gov website. 
 
Clinical Site Visits 
The CCC will coordinate all visits to study sites, including:   
 Site Initiation 
The initiation visit will serve as verification by the CCC that each clinical site is in compliance 
with the study protocol and regulatory authorities prior to enrolling participants.  The initiation 
visit will also serve as training verification for study staff at each site.  The initiation visit will be 
conducted at each site prior to the enrollment of the first subject. The initiation visit may be 
conducted in conjunction with the DCC to ensure that each site is also adequately prepared to 
collect and transmit accurate study data. 


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 Site Monitoring 
Site monitoring visits will be conducted by the CCC and DCC, to ensure that each site is in 
compliance with study procedures, regulatory approvals and documentation, and data 
collection, maintenance, and entry.  Monitoring visits will be conducted after the participant 
randomization begins at each site (as scheduling permits) and annually thereafter, unless 
routine quality control measures determine that a site is having difficulty with some aspect of the 
protocol, which would warrant more frequent visits.  The DCC may be able to perform some 
visits remotely.  Please see Section 22.3.6: Site Visits for more information on site monitoring 
visits.   
 
Communication with Clinical Sites 
The CCC will provide centralized communication with all clinical sites.  With the exception of 
information specific to the DCC, the CCC will be responsible for coordination of all information 
sent to sites, including updates to the protocol or Manual of Procedures, scheduling of meetings 
and/or conference calls, newsletters with updates on study enrollment, and other information as 
needed.   
 
 
Reportable Adverse Event (RAE) Reporting 
The CCC will collect all information on RAEs from each clinical site and provide the appropriate 
follow-up.  The CCC will be responsible for communicating between the sites and the ISM, as 
well as communicating back to the site with changes or recommendations regarding participant 
safety.  The CCC will report RAEs to the DSMB, FDA, NIA, and sIRB per the reporting 
requirements of each entity.  The CCC will also provide reports back to the clinical sites as 
recommended for participant safety by the ISM, FDA, or sIRB. 
 
Meetings and Training Sessions 
 Investigator Meeting 
Prior to study commencement, the CCC will conduct an Investigator Meeting at a location 
central to all sites.  The purpose of the meeting is to allow site PIs and select study staff to 
convene and discuss details of the protocol and conduct of the study, as well as complete 
relevant training.  The CCC will be responsible for all aspects of coordinating the meeting, 
including but not limited to: travel and accommodations, meeting agenda, and meeting 
documentation.   
 Steering Committee and DSMB Calls 
The CCC will coordinate calls for the study Steering Committee, DSMB, and any scientific 
oversight subcommittee of the Steering Committee or CCC.  The CCC will be responsible for 
scheduling calls, providing an agenda, and keeping minutes and making these available to each 
site. Steering Committee meetings will be held at least monthly, but may be more often during 
the first year of the project or when issues arise requiring more discussion by the Steering 
Committee.  
 
 


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 Training Sessions 
Training sessions for study procedures, as required per study protocol or for the purposes of the 
DCC, will be coordinated by the CCC.  This includes scheduling with appropriate staff members, 
including any necessary travel arrangements, and creation of training materials.  The CCC will 
also facilitate the transfer of training certifications between each clinical site and the DCC. 
 Clinical Site Conference Calls 
After initiation of the first clinical site, the CCC will conduct regular conference calls at least 
monthly, with study site coordinators.  The calls will allow study coordinators to receive updates 
about study progress and discuss any issues with recruitment, screening, enrollment, and 
general conduct of the study.  The CCC will also coordinate monthly phone calls with the 
Supervising Physical Therapists and exercise interventionists.  The CCC will be responsible for 
scheduling calls, providing an agenda, and keeping minutes and making these available to each 
site.  
 
Study Equipment and Website 
Standardized study equipment and supplies for physical performance testing will be distributed 
by the CCC. The CCC will procure all equipment/materials and coordinate with each site to 
ensure timely shipping and receipt. 
The CCC will maintain a study website for purposes related to recruitment. 
 
Collaboration with the Data Coordinating Center 
The CCC may conduct study activities with the DCC where necessary to ensure efficient 
conduct of the study and accurate collection of data.  Instances where the CCC and DCC 
collaborate, where not outlined above, will be at the discretion of the study Steering Committee 
and the DCC. 
 
Central Lab, Pharmacy, and DXA Coordination 
The CCC will contract with a central lab at the Washington University School of Medicine for 
laboratory testing procedures. The CCC will coordinate with the lab to detail the types of lab 
tests needed along with the time frame and reporting responsibilities.  The CCC will assure that 
only the unblinded CCC physician receives specific laboratory test results to preserve blinding. 
The CCC will coordinate with the University of Iowa Pharmaceuticals to facilitate the distribution 
of study drug and placebo to the clinical sites.  This will include finalizing contracts with the 
company and providing timelines for study milestones.  The CCC will also create a standardized 
system for supplying the University of Iowa Pharmaceuticals with information about study 
enrollment at each site.  The CCC will be responsible for coordinating drug/placebo shipment to 
the sites. 
The CCC will provide centralized oversight and analysis of DXA scans at UCD. Detailed 
procedures are described in the MOP. 
 
 


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Section 22: 
Data Coordinating Center (DCC) Activities 
In addition to its focus discussed in Sample Size and Statistical Power and Statistical Analysis, 
the DCC will be responsible for data management, quality control, randomization, and scientific 
oversight as the study progresses.  Specifically, DCC activities will include: 
 
1. Designing, testing, maintaining, and providing instructions on the use of a password 
protected web-based data entry and management system; performing quality control 
assessments of the data entered into that system, and creating and maintaining the SAS 
analysis datasets that will serve the data analytic needs of the study; 
2. Preparing regular reports which monitor adverse events and the progress of the study 
for the Steering Committee and the Data and Safety Monitoring Board; 
3. Performing ongoing quality control assessments such as annual site visits (in 
coordination with the CCC) and the sending of queries when inappropriate missing or 
potentially erroneous data are identified; 
4. Developing and maintaining WUSTL Box for report & document storage; 
5. Developing and maintaining a web based randomization scheme. 
 
DCC Responsibilities during the Study Start-Up Period 
The study start-up period is the developmental phase of the study that precedes subject 
recruitment.  During that period, the DCC will develop the data management and quality control 
systems, activities that are discussed in sections Data Management and Quality Control.  In this 
section, we discuss two other DCC activities that will take place during this period. 
 Forms Design 
During the study start-up period, the DCC will work with clinic investigators to design study 
forms.  General principles that will guide forms design and selection include ensuring that the 
data collected are relevant to study objectives, a physical appearance of forms that facilitates 
the collection of accurate and complete data, the avoidance of open ended “fill in the blank” 
questions because they may not be suitable for statistical analysis, the use of validated 
instruments wherever possible, a focus on simple and unambiguous language, the use of 
categories like “don’t know” to deal as appropriate with situations where the subject cannot 
knowledgeably answer “yes” or “no” to a question, and constant attention to the burden of data 
collection on both subjects and staff. 
 Training and Certifying Personnel   
The DCC will work closely with the CCC and the clinical sites to ensure the appropriate training 
and certification of personnel who perform study tasks.  These efforts will focus on ensuring that 
(1) investigators, clinical coordinators, and their designated backups have appropriate familiarity 
with the details of the protocol; (2) all evaluations are carried out by individuals who are certified 
as being knowledgeable about and experienced with relevant study procedures; and (3) 
personnel are familiar and comfortable with data entry and management procedures.  To 
accomplish these goals, the following procedures will be carried out: 
 
1. The DCC will work with the CCC to help facilitate the Investigator Meeting. The DCC will 
be responsible for reviewing the standardization of data collection with attendees and 
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2. Certification of data entry personnel will require that they establish familiarity with the 
system by entering sham data from appropriate forms on a set of test subjects. 
3. At least two individuals will be certified to perform every task to ensure that backup is 
always available. 
4. The identification number of the individual performing a particular assessment will be 
included on data forms and entered into the computer.  Using a DCC maintained list of 
certified personnel, it will be routinely confirmed by the DCC that assessments have 
been performed by certified individuals. 
5. Modified data on forms will be initialed and dated by the person making the change. 
6. To maximize efficiency, personnel who join the study after it begins will be certified by 
the clinic at which they work. 
 
Data Management 
A central focus of the DCC will be on the development and testing of a secure web based data 
entry and management system.  In the sections that follow, we discuss the REDCap (Research 
Electronic Data Capture) system that will serve our needs in this domain. 
 The REDCap System 
REDCap is a comprehensive data entry, management, and quality control system developed at 
Vanderbilt University.  It bridges the gap between data entry systems such as SAS that can be 
difficult to design and use and systems like Excel that are easy to use but that lack critical 
quality control capabilities.  REDCap is widely used at many Universities throughout the United 
States and Europe and has been the data entry system of choice for more than 4500 projects at 
Washington University.  The Division of Biostatistics has used REDCap in numerous studies, 
including four previous multicenter trials we have coordinated. 
 
REDCap provides secure, web-based applications with an intuitive interface for users to enter 
data with real time validations rules such as range checks for categorical and continuous 
variables, automatic branching logic, checks for internal consistency within a form, and 
calculation of derived variables. REDCap includes data access groups to limit user access to 
data records associated with their clinical site only, audit trails for tracking data manipulation, 
and data export to common statistical packages. 
 Testing the Data Management System at the DCC  
 After the REDCap data entry screens have been created, the first step in testing the system will 
be internal to the DCC where complete sets of forms containing sham data will be completed 
and entered into REDCap.  The data will then be transferred to SAS datasets and item by item 
comparisons between forms and SAS printouts will be performed.  The preliminary test forms 
will intentionally contain outlying and missing data to confirm that range checks and 
requirements for completing certain fields are functioning properly.  A second level of testing 
which will precede the enrollment of subjects will occur when data entry personnel are asked, as 
part of their training and certification, to enter sham data from simulated study visits.  As with the 
DCC data tests, item by item comparisons between forms and SAS printouts will be performed 
at the DCC.  In addition to confirming the convenience and completeness of the data entry 
screens, these procedures will evaluate all components of the data management process 
ranging from edit checking, to skip logic in the REDCap system, to the automated transfer of 
REDCap data to SAS, to the correctness of the programs that create and store the SAS 


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datasets.  As we discuss in section Quality Control of Forms and the Data Entry System, these 
procedures will be closely integrated with searches for ambiguous wording, the training of data 
entry personnel, and the modification of an original set of draft forms into a final version. 
 Data Security and Confidentiality 
Important features of REDCap and standard procedures of the Division of Biostatistics at 
Washington University provide a high degree of certainty that data will never be lost and that 
subject confidentiality will be maintained.  In accordance with the two key requirements of 
HIPAA, password protection will be required both for access into study computers and REDCap.  
Only authorized personnel will be given access to the data entry system and those personnel 
will only be able to access data from their own clinic site.  All web-based information 
transmission from and to REDCap is encrypted. Standard security and confidentiality measures 
at the DCC include the requirement that employees sign confidentiality agreements, personal 
identifiers are included in electronic databases only under strong necessity, and encryption is 
used when names, addresses, and other primary identifiers are present in SAS datasets.  The 
security of data at the DCC will be ensured by a combination of password protection and 
rigorous automated policies regarding the backup of data.  Access to all systems in our Division 
is restricted to the Division’s own faculty, staff, and collaborators.  Access to accounts which 
store data from this study will be restricted to DCC personnel and the Division’s network 
manager.  All file transfers to outside computers use secure transfer methods which ensure that 
all such traffic is encrypted over the network.  Access to all computers and to REDCap is 
automatically logged.  Finally, should problems arise with the system, a full-time, highly 
qualified, network engineer runs the system and is on call (with backup) 24 hours a day, 7 days 
a week. 
 The SAS Data Codebook 
All data collected by REDCap and data received as supplemental files will be transferred into 
SAS using automated procedures for use in future data analyses and reports.  Generally, each 
data collection form/instrument is stored in its own SAS dataset. Each dataset in the database 
will contain appropriate labels and formats.  To facilitate use of this database, the DCC will 
prepare and maintain a detailed “SAS Data Codebook”, which describes the content, structure, 
and layout of the SAS database. It is intended to be a complete and self-explanatory description 
of each variable retained in the SAS database. The DCC routinely uses such manuals in 
multicenter studies and in large program projects for a variety of reasons, the most important 
being that they greatly facilitate data management and analysis by making it very easy to find 
where, in a large database, an item on a particular form is stored.   
 Data/Resource Sharing Plan 
In the final year of the award all data will be cleaned and archived for long term storage.  After 
the completion of the final data edits, DCC staff will initiate the process of permitting qualified 
researchers to gain access to the STEP-HI dataset.  Our data/resource sharing plan includes 
the following components. 
 
1. The DCC will prepare a de-identified database that is consistent with HIPAA 
requirements. In order to protect the rights and privacy of subjects in the study, no 
identifiers that could permit linkages to individual research participants, and variables 
that could lead to deductive disclosure of the identity of individual subjects will not be 


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included nor will indirect identifiers such as infrequently occurring (e.g., fewer than 20 
patients) outwardly manifest characteristics such as limb amputation be included in the 
data file. Categories that contain small numbers of patients (e.g., unusual fracture types) 
will be combined. The data for sharing will be provided to the NIA/NIH after the end of 
the period of funding for use with other investigators according to NIH policy. 
2. The de-identified database will include all STEP-HI research data and will be stored in a 
repository at Washington University at a time that will coincide with the online publication 
of the STEP-HI primary endpoint paper. 
3. The repository will contain documentation designed to facilitate use of the database.  
That documentation will include a data dictionary that describes the content and 
structure of each dataset, that contains variable names and labels, and that maps 
specific variable names to items on questionnaires so users can see the exact wording 
of questions and precise formats that are attached to each variable. 
4. The documentation prepared for the repository will include a list and timetable for 
secondary and exploratory papers planned by STEP-HI investigators.  The purpose of 
this list is to avoid circumstances where researchers request access to the database in 
order to perform analyses that are already planned or underway by STEP-HI 
investigators. 
5. STEP-HI investigators will assume responsibility for adjudicating requests for data 
Researchers seeking access to the data will be required to complete a brief 
questionnaire.  The questionnaire will request information that describes the background 
and rationale for the work to be undertaken along with pre-specified research questions 
and/or hypotheses, the goals of the planned analyses, the analytic methods to address 
those goals, and identifies the specific variables in the database that are required for 
those analyses.  The investigator making the request and the data analyst (if not the 
same person) will be asked to provide a current CV or NIH-type biosketch. 
6. Access to the STEP-HI database will be restricted to those investigators who certify that 
they will not use the data for commercial purposes or purposes that go beyond the pre-
specified research questions and/or hypotheses. 
 
Quality Control   
The DCC has a broad view of quality control in clinical research as a multifaceted process that 
addresses concerns such as the accuracy and completeness of computerized data, the 
common administration of protocols across sites, monitoring adherence to protocol 
requirements, and the training and certification of personnel.  Other quality control measures we 
will implement include: 
 Ensuring Data Accuracy and Completeness   
REDCap has a number of built-in quality control features that are focused on ensuring the 
accuracy and completeness of the data and that are accomplished at the clinics when the data 
are entered.  Other quality control measures involve actions taken at the DCC, features of the 
data forms that help facilitate high quality data, and steps taken at the clinic as data forms are 
completed.  Because the system automatically keeps a log of who entered or changed all data, 
we will be able to discuss with the data enterer any concerns about a particular data item.  
Other quality control measures which will help ensure the accuracy and completeness of data 
include: 
 


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1. Range checks will flag values that are outside a predefined expected range but that may 
be plausible; 
2. Prevent the entry of values that are considered to be impossible; 
3. Accept only a predefined set of values for categorical measures; 
4. All data forms will contain the identification number of the person who completed the 
form, facilitating easy access to the source if there are legibility or other problems with a 
form. 
5. Forms and screens will have a “not done” option for key assessments so the associated 
missing data will be understood as appropriately missing. 
6. Investigators and study coordinators will be expected to do visual checks of all 
completed forms to confirm legibility, completeness, and reasonableness as each form is 
filled out. 
 Data Queries 
To ensure data quality, data checks will be implemented through programmed data edit checks 
implemented by the DCC and reported to the clinical sites as structured data queries. Queries 
issued by the DCC (a) will include complete data integrity checks that are impractical and/or 
impossible to generate in REDCap, (b) may overlap with data flags that were overridden in 
REDCap, but that require additional attention, and (c) will include data issues that require 
human interpretation and/or judgement. Potentially problematic data will be reported to each 
clinical site through WUSTL Box for investigation, correction, and resolution. After investigation, 
the clinical site will perform the necessary corrections and/or verifications and provide resolution 
documentation within 14 days via WUSTL Box. If data corrections are necessary, edits will be 
made by the site within REDCap. 
 Data Audits   
The DCC will conduct an annual item by item audit of data.  To that end, the DCC will randomly 
select a subset of the subjects at each clinical site.  Depending on logistical considerations, the 
audit will be performed either during site visits or remotely at the DCC using requested copies of 
the forms stored at the clinical site.  During the audit, every item on the data forms will be 
compared with the computerized data and records will be kept of error rates at each clinical site.  
It will be confirmed that changes on forms have been appropriately initialed and documented, 
and all identified problems will be discussed with the relevant clinic personnel and, if necessary, 
with the Steering Committee.  Following each audit, a detailed report will be prepared and 
distributed to all clinic sites.  Audits will be timed to precede meetings of the DSMB so that the 
DCC can respond to questions about data quality. 
 Quality Control of Forms and the Data Entry System 
In addition to the testing outlined in Section Testing the Data Management System at the DCC, 
the following series of steps will precede enrollment of the first subject. 
1. Staff at each clinic will be asked to enter data from one set of draft forms in a formal search 
for ambiguous wording. 
2. Data collection personnel will test relevant forms by entering sham data for a simulated 
study visit. These forms will be used to confirm the familiarity of data entry personnel with 
the system, as a test of the system itself, and as part of the certification process. 


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3. After these procedures yield modifications of the draft forms, the DCC will finish developing 
the REDCap screens and will perform a final set of internal tests focused on ensuring that 
any needed modifications have been correctly incorporated into the revised system. 
 Summary Reports 
The DCC will prepare summary reports of study progress in response to requests by the 
Steering Committee and the DSMB.  It will also prepare regular reports using automated 
features to be built into the SAS database.  Reports will consider such issues as (1) recruitment 
rates, (2) the proportion of recruited subjects who are study eligible, (3) the degree to which 
there are data forms that should be in REDCap, but are not, (4) the missing data rate (5) the 
time interval between completing a form and entering it in REDCap, (6) rates of compliance to 
study procedures, and (7) adverse event rates.  They will also discuss adherence to the study 
protocol based on the number of supervised exercise training sessions attended and the pump 
bottle weights recorded.  These reports will be updated routinely and made available online 
through WUSTL Box.  Because they will be site-specific as well as aggregate in their 
presentation, they will be an important component of our quality control efforts as they will help 
identify areas of inadequate performance at the clinical sites.  The adverse event report will 
differ from other reports in that severe and potentially study related adverse events will be 
reported to the sIRB, IRBs and the chair of the DSMB within the required time frame. 
 Site Visits 
Site visits will be coordinated with the CCC.  Site visitors will prepare an agenda that will include 
observations of the performance of study procedures and of the filing system that is used to 
store completed data forms.  Site visitors will confirm that data forms are correctly filed, that 
required training certificates are available, will do random data audits if these audits are not 
done remotely, will check the specific forms of subjects whose data may have been problematic 
in the past, and will confirm that changes on forms are appropriately initialed and dated by the 
person who made the changes.  Site visits will generally be conducted by a staff member from 
the DCC and a staff member from the CCC. 
 
WUSTL Box 
WUSTL Box is a secure, HIPAA compliant, cloud file storage and collaboration tool offered by 
Washington University. Password protected file stores on WUSTL Box will be designed for 
internal use by study personnel only.  General access stores will serve as a repository for study 
documents such as the Manual of Procedures, study forms, a bibliography of study publications, 
and the regular reports prepared by the DCC. Limited access file stores will be restricted by 
clinical site and contain site-specific reports and query documentation. 
 
Randomization 
The DCC will create an online, password protected, randomization system that will be used to 
facilitate the random assignment of subjects to the three study arms.  The system will be 
created using the built-in randomization module of the REDCap system that will be used for 
data entry. To avoid temporal bias, randomization will be blocked within clinical site using 
random block sizes in order to preclude the possibility that investigators might know in advance 
the assignment of the last subject in a particular block. 
 
 


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Section 23: 
Participant Rights and Confidentiality  
 
Institutional Review Board (IRB) 
Washington University’s IRB (WU IRB) will serve as the single IRB (sIRB) for this study.  
Institutions will sign a reliance agreement to document reliance on the WU sIRB.  WU sIRB will 
be responsible for IRB approval of all protocols, informed consent documents, recruitment 
documents and any other associated study documents.  Investigators will be required to report 
all reportable events to the CCC, who will in turn alert the WU sIRB within the required reporting 
timeframes.  Modifications to the protocol or informed consent documents are required to be 
approved by the WU sIRB before initiating the change.  
 
Sites must follow requirements by their local IRB policies to assure the local IRB has the 
appropriate documentation and are alerted to the pertinent modifications. The study chair will be 
responsible for sending DSMB recommendations to individual clinical site PIs, who may in turn 
be required to distribute the report to their local IRBs.  
 
Informed Consent Forms (ICF) 
It will be the sole responsibility of each clinical site PI to ensure that informed consent was 
properly obtained for every participant who entered into the study at her/his site.  The ICF will 
describe the purpose of the study, the procedures to be followed, alternatives to participation, 
and the risks and benefits of participation.  It will also be explained that signing the consent form 
allows the study to confirm eligibility before randomization to a treatment group.  Written 
informed consent will be obtained according to procedures reviewed and approved by the WU 
sIRB.  Informed consent will be obtained prior to the screening visit procedures. Consent by a 
legally authorized representative will not be accepted.   
 
The clinical sites will be responsible for ensuring that the correct version of the ICF is used at 
their site. 
 
If there is a change in any of the study procedures or risks that may affect the participant, the 
ICF must be revised and undergo appropriate sIRB review and approval.  Any participants 
enrolled in the study prior to such changes and who are still active in the study must sign the 
amended consent form. 
 
The study consent form will be provided to a potential participant for review prior to obtaining 
informed consent. The ICF may also be mailed to the participant and/or a family member so that 
she has sufficient time to read the document and, if desired, to have a family member or friend 
review the form before signing.  During the informed consent process, study staff will provide 
participants with adequate information concerning the study procedures, respond to individuals’ 
questions and concerns, and ensure that each individual understands all the information 
provided by assessing ability to provide informed consent.  A more detailed description of the 
informed consent process can be found in Section 8.3.  
 
 


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 Disposition of Informed Consent Forms 
Because ICFs contain subject identifiers and protected health information (PHI), these forms will 
not be submitted with the data collection forms.  Originals of the ICF will be filed and maintained 
by the clinical site coordinator in the participant binder which will be secured in a locked cabinet 
or office.  A copy of the signed consent form will be given to the participant and this fact will be 
documented in the participant’s record.   
 HIPAA Authorization 
The HIPAA Authorization for Research is an individual's signed permission to allow the study 
investigators to use or disclose the individual's PHI described in the authorization.  Once an 
individual has agreed to participate in the study and written informed consent has been 
obtained, the HIPAA Authorization for Research must also be explained and signed.  The 
HIPAA Authorization may be a stand-alone document or wording for the HIPAA Authorization 
may be incorporated into the text of the ICF.  The original signed authorization will be submitted 
to the study office and a signed copy will be given to the participant.   
 
Participant Confidentiality 
Potential participants will be provided with a clear understanding of how the information they 
provide will be used.  All investigators and staff involved in the study will be required to complete 
training on the protection of human subjects and HIPAA and to maintain proper certifications.    
 
To ensure confidentiality of study data, completed questionnaires and study forms will be kept in 
participant binders stored in locked offices at each clinical site, no unauthorized person will be 
permitted to see the binder or forms, names will be used only for the necessary purpose of 
making sure that the recorded information is for the person to whom it refers, and data will be 
summarized so that published results cannot be traced to individuals.  
 
On data collection forms, participants will be identified only by a unique study identification 
number. Clinical sites will record names, contact information, and other direct identifiers to 
enable them to maintain contact with participants. Logs accessible only to the local clinical site 
PIs and key study personnel will link the study identification number to names. 
 
To protect study data from theft or unauthorized perusal or alteration, access to all computer 
files will be restricted to designated personnel through the use of passwords.  Access to the 
database and programs will be on a "need to use" basis (e.g., coordination staff cannot access 
main system programs).   
 
Computer security procedures, including multiple levels of password protection will be instituted. 
The study records will be identified by a unique participant identification number. Identification 
numbers will be recorded on each page of the paper forms.  The participant's study status date 
(e.g., date of randomization) will be used as a second level of check.  Final analysis data sets 
will not contain any directly or indirectly identifying information.   Thus, dates of birth will be 
converted to age, other dates will be changed to counts of days from study entry, identification 
numbers will be replaced with sequence numbers, variables that could lead to deductive 
disclosure of the identity of individual participants will not be included nor will indirect identifiers 
such as infrequently occurring (e.g., fewer than 20 participants), outwardly manifest 
characteristics. 


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In the final year of award, after the completion of a final data edit, DCC staff will prepare a data 
file in SAS containing all study variables intended for use in publications; identifying information 
and administrative data (e.g., audit trail) will not be included in this data file. A de-identified data 
set will be created which merges all the essential data from all time points of the study. 
Documentation (including abstracts of published works and calculated variable definitions) and 
form images will be included with the data file. The data file will be provided to the NIA after the 
end of the period of funding for sharing with other investigators according to NIH policy. 
 
 
 


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Section 24: 
Research Publication Policy 
Publications will be operationally defined as manuscripts for publication; abstracts for platform 
or poster presentation at scientific and other professional meetings; slides for presentation at 
scientific and other professional meetings; doctoral dissertations; and master’s theses. 
 
The goal of our publication policy is to encourage and facilitate the publication of study results.  
The purposes of this policy are to ensure the following:  1) STEP-HI publications will be of the 
highest scientific quality; 2) STEP-HI will be described in a consistent manner across 
publications; 3) measures are reported in consistent ways across publications; 4) proper 
acknowledgements are included; and 5) appropriate authorship credit is determined prior to 
submission of manuscripts for publication consideration. 
 
Publications from STEP-HI will be overseen by the Publications Committee (PC).  The PC will 
be led by the director of the DCC and include at least one representative from the CCC and 
representatives from at least two participating clinical sites.  The PC will make 
recommendations to the SC.   
 
A document describing the STEP-HI Publication Policy and Procedures appears in the Manual 
of Procedures. 
 
 
 


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Section 25: 
Ancillary Studies Policies 
An ancillary study will be defined as a study that 1) uses supplementary data that will be 
collected on participants who are recruited in STEP-HI, over and above the data collection 
required by the STEP-HI protocol; 2) collects biological specimens (e.g., blood) or performs 
diagnostic tests (e.g., bone density scans); and/or 3) collects data on subjects not enrolled in 
STEP-HI but who may be compared to STEP-HI subjects (e.g., participants who receive an 
alternate intervention).  Ancillary studies will be distinct from databank studies, which use data 
previously collected on participants who are enrolled in STEP-HI.   
 
Ancillary studies will be reviewed and approved by the Ancillary Studies Committee (ASC) and 
ratified by the SC prior to initiation to ensure that they do not conflict with the main study 
protocol.   All approved ancillary studies will also be reviewed by the DSMB and NIA prior to 
initiation.  If approved, the ancillary study PI will report to the DSMB on the same schedule as 
the main study. Review by the ASC (and approval by the SC) will also be required for presen-
tation or publication of ancillary study results.   
 
STEP-HI investigators will be encouraged to consider ancillary studies and to involve other 
investigators, within and outside of STEP-HI personnel. Participation in an ancillary study will be 
subject to the approval of the STEP-HI ASC, SC, and DSMB. The following factors will be 
considered in determining approval of a proposed ancillary study:  
1. Participant burden  
a. The proposed study must be acceptable to the participants (e.g. in terms of time, 
discomfort, privacy).  
b. The proposed study must not reduce enrollment or hamper continued participation in 
the main study. 
2. Study interference 
a. The proposed study must not interfere with other parts of the main study.  
b. The proposed study must put no additional demand on STEP-HI resources. 
3. The proposed study must be of the highest scientific merit. 
4. The investigators must have adequate resources to effectively complete the ancillary study, 
including: 
a. Sufficient budget (including enough to offset any costs to STEP-HI). 
b. Staff having the requisite expertise to meet the objectives of the project. 
 
Concurrent Studies 
Study investigators agree not to conduct studies which would directly compete with or have a 
detrimental effect on the conduct of STEP-HI during the period of recruitment and follow-up. 
However, it is understood that each clinical site has the right to conduct concurrent studies with 
participants who do not meet criteria for enrollment into STEP-HI.  Concurrent studies of 
patients who meet eligibility criteria for STEP-HI but are not enrolled in STEP-HI must be 
disclosed and reviewed by the STEP-HI SC.   
 
 
 


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Section 26: 
Skeletal Muscle Mass using Creatine Dilution Method 
This section describes an optional ancillary study to the main STEP-HI study.  Participation is 
voluntary.  This ancillary study follows the STEP-HI protocol regarding the overall study 
organization, administration, adverse event reporting, participant rights, publication policy, and 
general activities of the CCC and DCC. 
 
General Information 
Ancillary Study Name: Assessment of Skeletal Muscle Mass Using D3-Creatine Dilution in 
Frail Female Hip Fracture Patients. 
Ancillary Study PI: Ellen Binder, MD at Washington University School of Medicine 
Ancillary Study Funding Source: NIH Administrative Supplement 
Participating Sites:  All STEP-HI Sites are able to participate 
Compounding Pharmacy: 
Greenpark Compounding Pharmacy 
4061-F Bellaire Blvd 
Houston, TX 77025 
 
Processing Laboratory: 
University of California, Berkeley 
Hellerstein Lab/Shubha Shankaran 
Dept of Nutritional Sci & Toxicology 
54 Mulford Hall 
Berkeley, CA 94720 
Phone: 
(510) 642-0646 
 
Background and Significance 
A challenge of research focused on age-associated loss of skeletal mass (sarcopenia), is that 
the relationship between muscle mass and physical performance and mobility has been 
inconsistent across a number of studies of older adults. The reported inconsistencies may be 
due to limitations of current measurement techniques. Computed tomography and magnetic 
resonance imaging usually measure select muscle groups, which do not provide an assessment 
of total body skeletal muscle. Dual x-ray absorptiometry does not directly measure muscle 
mass, but calculates it by subtracting the non-bone, non-fat components of total body mass118.  
Factors such as variations in tissue hydration can also confound accurate measurement of 
skeletal muscle and lean mass. Thus, the finding that skeletal muscle mass is only weakly 
associated with functional outcomes in older adults may be due to current muscle-specific or 
indirect techniques for measurement of skeletal muscle mass. 
The deuterated-creatine (D3-creatine, D3Cr) dilution method is a novel measurement of total 
body muscle mass. A single oral dose of D3Cr is absorbed and then diluted by entry into the 
endogenous pool of creatine in skeletal muscle. The dilution method uses similar assumptions 
as 24-hour creatinine assessment of muscle mass, i.e., that approximately 98% of total body 
creatine is sequestered in skeletal muscle, which is subsequently metabolized to creatinine and 


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excreted in the urine. Preliminary studies indicate that D3Cr dilution provides a direct and 
accurate measurement of creatine pool size and skeletal muscle mass119 and, in a recent study 
of older men, was associated with functional capacity measures and risk of falls and disability120.  
More studies are necessary to validate the use of D3Cr as an accurate measure of skeletal 
muscle mass. The STEP-HI study provides a unique opportunity to address this issue. 
Experience to date is that the D3Cr dilution protocol has been straightforward to implement in a 
clinical setting.  A recent report examined the accuracy and potential variability of the D3Cr 
dilution method121. The estimate of variability in that report is higher than what would result in 
the current application as those investigators measured the same individual 3-4 months after 
the initial assessment, a period of time when body composition may change (subjects were 
elderly and some with chronic heart failure) but did not account for time in their analyses, likely 
adding considerable variability to their estimate. 
 
Study Objectives 
 Specific Aim 1 
To determine whether post-intervention (month 6) D3-creatine (D3Cr) muscle mass is 
significantly greater for EX+T relative to EX alone, and relative to EUC, after adjusting for 
baseline D3Cr. 
 Specific Aim 2 
To obtain preliminary estimates of the associations between baseline-adjusted post-intervention 
D3Cr muscle mass with baseline-adjusted post-intervention: a) skeletal muscle strength, as 
measured by Leg-Press 1-repetition maximum (1-RM) and Chair Rise time, b) muscular 
endurance, as measured by Six-Minute Walk Distance (6MWD) and, c) global function, 
measured by the Modified Physical Performance Test (mPPT) score and the Short Physical 
Performance Battery (SPB) score. 
 Specific Aim 3 
To estimate the responsiveness of D3Cr muscle mass to change, we will compare post-
intervention D3Cr muscle mass with post-intervention DXA total body lean mass, after adjusting 
for the associated baseline values.    
 Specific Aim 4 
To compare the associations between D3Cr muscle mass and functional measures at baseline, 
with the associations between DXA total body mass and functional measures at baseline. 
 
Participants 
100 women will be recruited to this ancillary study. 
 Inclusion Criteria 
1. Women eligible for and participating in the STEP-HI study. 
2. Women who have signed the consent for this ancillary study.  
26.2.2 Exclusion Criteria 
1. Women who are ineligible for the STEP-HI Study. 
2. Women with a urinary drainage bag. 


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Study Design 
Participants will be asked to ingest a small tablet containing 30 mg of D3-creatine, which will be 
administered at the research center by study staff or sent home with instructions to self-
administer in their home. Depending on the day of the week that the dose is ingested, 
participants will be asked to provide a fasting morning void urine sample (prior to consumption 
of food) 2-6 days after ingesting the dose. Because of the challenges of collecting a fasting 
urine sample in this frail population, we will offer to obtain the urine sample from the participant 
at their home or during an assessment visit for the STEP-HI Study. Urine will be collected in a 
collection cup labeled with the participant’s ID number.  One mL of the sample will be aliquoted 
into a 2.0 mL vial which will be frozen in a -20 freezer. The samples will then be batch shipped 
to the central lab at the University of California-Berkeley for detection of labeled and unlabeled 
creatinine by LC/MS. Samples will be shipped from each clinical site to the central lab once or 
twice per year. 
 
The dose of labeled creatine will be compounded by Greenpark Compounding Pharmacy 
(Houston, TX), and shipped to each participating site.  
 
Ingestion of the D3-creatine pill will occur at 2 time points: 
• 
Baseline visit (or shortly after randomization) for the STEP-HI Study 
• 
Month 6 visit (or shortly after) for the STEP-HI Study 
Providing a fasting urine sample will occur at 3 time points: 
• 
Baseline visit (2-6 days after taking the Baseline D3-Creatine pill) 
• 
Prior to the Month 6 research visit (0-5 days before taking the Month 6 D3-creatine pill) 
• 
Month 6 visit (2-6 days after taking the Month 6 D3-Creatine pill) 
The first D3-Creatine measure will ideally be collected during the baseline visits, but can be 
obtained up to 1 week after randomization.  The second measure will be collected ideally during 
the 6 month STEP-HI assessment, but can be obtained up to 1 week after the completion of the 
Month 6 procedures. 
 
Recruitment and Retention 
 Informed Consent 
A separate written informed consent document and appropriate HIPAA authorizations will be 
obtained in compliance with procedures reviewed and approved by the sIRB.  A copy of the 
informed consent form will always be provided to potential participants to allow for adequate 
review of the information.  Prior to obtaining informed consent, time will be given to the 
participant to review the consent form and ask questions.  Study staff will summarize all 
components of the ICF and remind participants that participation in this ancillary study is 
voluntary.  The consent form for this ancillary study will not be given to participants until after 
they are deemed eligible for the STEP-HI study.  The consent review may occur any time after 
determining screening eligibility until randomization.  For women who provide informed consent, 
the original will be maintained at the clinical site and a copy will be given to the participant.  
Informed consent will be completed prior to beginning any research procedures for this ancillary 
study. 


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 Enrollment 
Date of enrollment for this ancillary study is considered the date of consent. 
 Study Withdrawal 
This ancillary study will follow the same protocol for study withdrawal as the STEP-HI study.  In 
the event that a participant voluntarily withdraws from the assessments of the STEP-HI study, 
she will be unable to continue in this ancillary study.  If a participant is willing to complete the 6 
month assessment visit or an early withdrawal visit, this ancillary study would be offered as part 
of those optional assessments.  
 Study Discontinuation 
This ancillary study will follow the same protocol for discontinuation as the STEP-HI study.  In 
the event that a participant is discontinued from the STEP-HI study, she will also be 
discontinued from this ancillary study. 
 Replacement of Subjects 
Participants who withdraw or are discontinued from this ancillary study will not be replaced. 
 
Study Measures – University of California-Berkeley 
Assessment of urinary D3-creatinine enrichment is completed by LC-MS/MS.  The assessments 
will be performed at the University of California-Berkeley under the supervision of Dr. William 
Evans. 100 µl aliquots of urine are processed independently for Cr/Crn concentration and D3-
Crn enrichment. For Cr/Crn concentration determination, 100 µl of urine or standards for the 
standard curve is added to 100 µl internal standard and 200 µl acetonitrile. Samples are 
centrifuged to precipitate proteins and aliquots of the supernatant are diluted 50 fold using 70% 
acetonitrile for LC/MS analysis. Samples are injected onto a Cogent Diamond Hydride column 
(4.0x75mm) using an Agilent 1260 UPLC and are separated on a gradient consisting of 
acetonitrile with 0.1% formic Acid (Solvent A) and water with 0.1% formic acid (Solvent B). Mass 
spectrometry is performed on a Sciex 6500 QTRAP operating in the multiple reaction monitoring 
(MRM) mode. For determining the enrichment of D3-Crn, quantitation is performed using a 
standard curve for D3-Crn and D3-Cr enrichment that spanned from 0% to 0.168% and is 
measured by MRM transitions (116.1/46.1) corresponding to the M2 peak of Crn and 117.1/47.1 
which corresponds to D3-Crn. Samples are run in duplicate and average values are reported. 
Samples with CVs greater than 10% will be subjected to reanalysis. The total body Cr pool size 
is calculated as retained (delivered) D3-Cr dose divided by D3-Crn enrichment and muscle 
mass as described previously. 
 
Safety 
 Risks 
There are no known risks of taking creatine.  Labeled creatine is a stable isotope; there is no 
radioactivity.  Creatine is a normal component of animal protein; the average person consumes 
1 gram (1,000 mg) of creatine per day.  The dose for the study is 30 mg.  There may be other 
unknown risks or risks that we did not anticipate associated with creatine.  To track these risks 
the study will record and monitor all adverse events as in the main study. 


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 Adverse Event Reporting 
This ancillary study will rely to the main study to collect all new or worsening symptoms as 
reported by participants during STEP-HI baseline and follow-up visits.  Participation in this 
ancillary study will be documented for all RAEs. 
 Site Monitoring 
Enrollment eligibility, consent disposition, and adherence to procedures will be monitored by the 
STEP-HI DCC using data entered into REDCap and by the CCC during STEP-HI study 
monitoring visits. 
 
Statistical Analysis 
 Approach for Specific Aim 1    
Aim 1 addresses the question of whether T therapy combined with supervised exercise (EX+T) 
will induce greater improvements in D3Cr relative to the EUC and EX conditions alone. Initial 
analyses will include chi -square tests and t-tests to compare baseline values of key 
demographic, clinical, and D3Cr measurements. We will compare post-treatment D3Cr muscle 
mass using analysis of covariance (ANCOVA) where month 6 D3Cr muscle mass is the 
dependent variable, treatment group is the independent variable, and baseline D3Cr muscle 
mass is the covariate. Statistical contrasts within the ANCOVA will test whether participants 
assigned to EX+T have more D3Cr muscle mass at month 6 compared to EX alone and 
compared to EUC. Analyses will be implemented using SAS and will be preceded by an 
evaluation of the data. If statistical assumptions are not satisfied, transformations will be 
explored or nonparametric covariance analysis will be used.  
 Approach for Specific Aim 2  
Aim 2 will estimate the association of month 6 D3Cr muscle mass with month 6 strength, 
endurance, and functional measures. We will use generalized linear models where month 6 
D3Cr muscle mass is the dependent variable and baseline D3Cr muscle mass and treatment 
group are covariates. Separate models will be developed in which the independent variables are 
measures of strength, endurance, and function at baseline or for the change between baseline 
and month 6. Standardized beta coefficients with 95% confidence bounds will be reported. 
 Approach for Specific Aim 3 
Aim 3 will compare D3Cr muscle mass at month 6 with DXA total body lean mass at month 6, 
after adjusting for baseline. We will use generalized linear models that are analogous to those 
described in SA 2. 
 Approach for Specific Aim 4 
Aim 4 will compare the strength of associations between D3Cr muscle mass and functional 
measures at baseline with associations between DXA total body mass and functional measures 
at baseline. Linear regression modeling and overall model r-squares will be used to quantify 
associations between variables. There will be one model for each dependent variable (i.e., D3Cr 
muscle mass and DXA total body mass) and each independent variable (i.e., functional 
measure). Additional multivariable regression models will be explored to determine if the 
strength of the associations of D3Cr muscle mass with function, and the strength of the 
associations of DXA total body mass with function are modified by other potential confounding 


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variables such as age, race, comorbidities, and nutritional intake. We will perform diagnostics of 
residuals and collinearity and take corrective action if assumptions are violated. 
 
 


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Section 27: 
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