Study of Testosterone and rHGH in FSHD (STARFISH): A Proof-of-Concept Study
Phase: PHASE1
Conditions: Facioscapulohumeral Muscular Dystrophy
Sponsor: University of Rochester

 
 
Official Title: Study of Testosterone and rHGH in FSHD (STARFiSH): A Proof-of-Concept 
Study 
 
NCT Number: NCT03123913 
 
Document Date: 5/4/2021 

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
CONFIDENTIAL
STUDY OF TESTOSTERONE AND RHGH IN FSHD (STARFISH): A PROOF-OF-CONCEPT STUDY
 
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STUDY PROTOCOL
Study of Testosterone and rHGH in FSHD (STARFiSH): A Proof-of-Concept Study

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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TABLE OF CONTENTS
Page
Investigative Team ........................................................................................................................5
Protocol Synopsis..........................................................................................................................7
1.0
STUDY OBJECTIVES AND MEASURES .......................................................................11
1.1
Primary Objective....................................................................................................11
1.2
Secondary Objectives.............................................................................................11
1.3
Exploratory Objectives............................................................................................11
1.4
Outcome Measures.................................................................................................11
2.0
BACKGROUND & RATIONALE ......................................................................................12
2.1
Facioscapulohumeral muscular dystrophy..............................................................12
2.2
Anabolic Effects in FSHD........................................................................................12
2.3
Proposed Therapeutic Intervention.........................................................................12
2.3.1
Human Growth Hormone ............................................................................12
2.3.2
Testosterone ...............................................................................................12
2.3.3    Combination Therapy and Implications for FSHD.......................................13
3.0
INVESTIGATIONAL PLAN ..............................................................................................15
3.1
Study Design........................................................................................................15
3.2
Rationale for Combination Therapy & Proposed Dosage....................................15
3.3
Rationale for Method of Administration................................................................16
3.4
Rationale for Effect and Sample Size ..................................................................16
4.0
SELECTION AND ENROLLMENT OF SUBJECTS ........................................................17
4.1
Subject Population ...............................................................................................17
4.2
Inclusion Criteria ..................................................................................................17
4.3
Exclusion Criteria .................................................................................................17
4.4
Recruitment Process............................................................................................17
4.5
Subject Identification Numbers ............................................................................18
4.6
Subject withdrawal ...............................................................................................18
4.7
Costs to the Subject.............................................................................................18
4.8
Payment for Participation.....................................................................................18
4.9
Return of Individual Research Results.................................................................18
5.0
STUDY DRUG ADMINISTRATION/ASSIGNMENT ........................................................18
5.1
Formulation ..........................................................................................................18
5.2
Packaging, Labeling, and Distribution..................................................................19
5.3
Storage of Study Drug .........................................................................................19
5.4
Dispensing & Administration ................................................................................19
5.5
Dosing Regimen ..................................................................................................19
5.6
Dosage Adjustments............................................................................................19
5.6.1
Dosage Reduction.......................................................................................19
5.6.2
Dosage Suspension....................................................................................20
5.6.3
Discontinued Study Drug ............................................................................20
5.6.4
Missed Doses..............................................................................................20
5.7
Accountability and Compliance of Study Drug.....................................................20
5.8
Prior and Concomitant Interventions....................................................................20
6.0
CLINICAL AND LABORATORY EVALUATIONS ............................................................20

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6.1
Schedule of Activities...........................................................................................20
6.2
Screening and Baseline Visit ...............................................................................21
6.2.1
Screening Evaluations ................................................................................21
6.2.2
Baseline Evaluations...................................................................................22
6.3
Follow Up Visits ...................................................................................................23
6.3.1
On-site Follow-up Evaluations ....................................................................23
6.3.2
Telephone-based Follow-up Evaluations....................................................25
6.4
Unscheduled Visits ..............................................................................................25
6.5     Premature Discontinuation of Study Drug ...........................................................26
6.6
Premature Withdrawal from the Study .................................................................26
               6.7    Milestones and Study Calendar……………………………………………………...26
7.0
ASSESSMENTS & OTHER EVALUATIONS...................................................................29
7.1
Efficacy Assessments ..........................................................................................29
7.1.1
Neuromuscular Assessments .....................................................................29
7.1.2
Functional Assessments .............................................................................29
7.1.3    Self-reported Assessments.........................................................................30
7.2
Feasibility Assessments.......................................................................................30
7.3
Safety Assessments ............................................................................................30
7.3.1
Adverse Event Assessments ......................................................................30
7.3.2
Clinical safety Laboratory Tests..................................................................31
7.3.3
Treatment-specific Assessement................................................................31
8.0
STATISTICAL CONSIDERATIONS.................................................................................32
8.1
Analysis of Safety Ouctomes..................................................................................32
8.2
Analysis of Outcome Measures of Efficacy.............................................................33
8.3
Analysis of Pharmacokinetic Outcomes..................................................................33
8.4
Analysis of Feasibility..............................................................................................33
8.5
Missing Data ...........................................................................................................34
8.6
Sample Size Consideration………………………………………………………….….34
8.7
Data and Safety Monitoring……………………………………………………………..34
9.0
ADVERSE EVENT REPORTING, MONITORING & REPORTABLE EVENTS...............35
9.1
Definition of an Adverse Event................................................................................35
9.1.1
Classification...............................................................................................36
9.1.2
Grade of Intensity........................................................................................36
9.1.3
Relationship to Study Drug .........................................................................36
9.1.4
Adverse Event Assessment ........................................................................37
9.1.5
Reporting of Adverse Events ......................................................................38
9.1.6
Follow-Up of Adverse Events at Permanent Withdrawal or End of Study...38
9.2
Definition of Serious Adverse Event (SAE).............................................................38
9.2.1
Reporting Serious Adverse Events .............................................................38
9.2.2
Monitoring of Serious Adverse Events........................................................39
9.3
Reportable Events (Incidents).................................................................................39
9.4
Risk/Benefit Assessment ........................................................................................39
9.5
Potential Risks…………….………………………………………………………….….39
9.6
Protection Against Risks….……………………………………………………………..41
9.7    Potential Benefits to Subjects…………………………………………………….........42
9.8    Alternatives to Participation…………………………………………………………….42
10.0
ETHICS............................................................................................................................42
10.1 Guidelines for Good Clinical Practices....................................................................42
10.2 Informed Consent ...................................................................................................42
10.3 Protocol Compliance/Amendments/Discontinuation...............................................43

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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10.4 Subject Confidentiality ............................................................................................43
10.5 Research Information in Medical Records…………………………………………….43
11.0
TRIAL MANAGEMENT....................................................................................................43
11.1 Coordination Efforts ................................................................................................43
11.2 Quality Assurance...................................................................................................43
11.3 Data Handling & Record Keeping...........................................................................43
11.4 Retention of Study Records....................................................................................44
12.0
PUBLICATION OF RESEARCH FINDINGS....................................................................44
REFERENCES............................................................................................................................45

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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INVESTIGATIVE TEAM
Investigators
Chad R. Heatwole, M.D.
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 673
Rochester, NY 14642
Office: (585) 275-2559 
Fax: (585) 273-1255 
Email:Chad_Heatwole@URMC.Rochester.edu
Charles Thornton, M.D.
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 645
Rochester, NY 14642
Office: (585) 275-2542 
Email: Charles_Thornton@urmc.rochester.edu
Johanna Hamel, M.D.
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 673
Rochester, NY 14642
Office: (585) 275-1200
Email: Johanna_Hamel@URMC.Rochester.edu
Principal 
Investigator 
Sponsor of IND 
Chad R. Heatwole, M.D.
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 673
Rochester, NY 14642
Office: (585) 275-2559 
Fax: (585) 273-1255 
Email:Chad_Heatwole@URMC.Rochester.edu
Primary Study 
Biostatistician
Michael P. McDermott, Ph.D.
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 630
Rochester, NY 14642
Office: (585) 275-6685 
Fax: (585) 273-1031
Email:  mikem@bst.rochester.edu
Investigative Drug 
Pharmacist
Stephen A. Bean, Pharmacist
Pharmacy, Strong Memorial Hospital, Box 638
601 Elmwood Ave
Rochester, NY 14642
Office: (585) 275-6153
Email: Steve_bean@urmc.rochester.edu
Trial Coordination 
and Data 
Management 
Center 
Elizabeth Luebbe (Health Project Coordinator)
University of Rochester Medical Center
Department of Neurology, Box 673
601 Elmwood Ave

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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Rochester, NY 14642
Office: (585) 275-7867
Email:  elizabeth.leubbe@.rochester.edu 
William Martens (Data Manager)
University of Rochester Medical Center
Department of Neurology, Box 673
601 Elmwood Ave
Rochester, NY 14642
Office: (585) 275-2483
Email:  bill_martens@urmc.rochester.edu
Clinical Safety 
Monitor 
Cardiologist 
Consultant
Urology 
Consultant
Emma Ciafaloni, MD
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 630
Rochester, NY 14642
Phone: 585-275-4568
Email: Emma_Ciafaloni@URMC.Rochester.edu
Spencer Rosero, MD
University of Rochester Medical Center
School of Medicine and Dentistry
Department of Cardiology
601 Elmwood, Ave
Rochester, NY 14642
Phone: 585-275-2475 
Email: Spencer_Rosero@urmc.rochester.edu
Hani Rashid, MD
University of Rochester Medical Center
Department of Urology
601 Elmwood Ave
Rochester, NY 14642
Phone: 585-424-6490
Email: Hani_Rashid@urmc.rochester.edu
Endocrinologist
Consultants
Shalender Bhasin, MD
Director, Research Program in Men’s Health: Aging and Metabolism
Brigham and Women’s Hospital
670 Albany St
Boston, MA 02118
Phone: (617) 414-2950
Email: SBHASIN@Partners.org
David Weber, MD, MS
University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, 
Rochester, NY 14642
Email: David_Weber@urmc.rochester.edu

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
CONFIDENTIAL
STUDY OF TESTOSTERONE AND RHGH IN FSHD (STARFISH): A PROOF-OF-CONCEPT STUDY
 
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Protocol Synopsis
Protocol Title
Study of Testosterone and rHGH in FSHD: A Proof-of-Concept 
Study
Acronym
STARFiSH
Clinical Phase
Phase 1
Study Population
Subjects will be ambulatory men (ages 18 to 65) with FSHD 
Funding
Planned NIH 
Study Drug
Recombinant human growth hormone (Genotropin®)
Testosterone enanthate injection (generic)
Study Drug Supplier
Pfizer (Genotropin®)
Number of Subjects
20 subjects
Number of Study 
Centers
1 – University of Rochester Medical Center  FSHD clinic
Duration of Study
36 weeks total (24 weeks on study drug)
Primary Objective
To examine the safety and tolerability of rHGH and testosterone in 
adult male patients with FSHD.
Secondary Objectives
To examine the pharmacokinetic effects of rHGH and testosterone 
on serum levels of free and total testosterone, IGF-1, thyroid 
function, luteinizing hormone and follicle stimulating hormone.  
To examine the effect of rHGH and testosterone on total and 
regional lean body mass.
Exploratory Objectives
To examine the effects of rHGH and testosterone on multiple 
measures of clinical function including ambulation, strength, 
pulmonary function, and patient reported disease-burden.
Evaluations
Exploratory efficacy outcome measures:
Measures of preliminary efficacy include the following (all measured 
as the change from baseline to week 24):
1.
Composite Quantitative Muscle Testing (QMT) score
2.
Composite Manual Muscle Testing (MMT) score
3.
FSHD Clinical Outcome Measure (FSHD-COM), total and 
individual test scores
4.
FSHD-Health Index (FSHD-HI), disease-specific patient-reported 
outcome measure
5.
Forced Vital Capacity (FVC)
6.
Epworth Sleepiness Scale
7.
Fatigue Severity Scale
8.
Dual Energy X-Ray Absorptiometry (DEXA) Lean Body Mass 
(total and regional)
9.
PROMIS-57
10. FSHD daily exercise questionnaire.
11. Beck Depression Inventory (BDI)
12. Six minute walk distance
13. International Physical Activity Questionnaire
 
Feasibility outcome measures:
1.
Willingness to travel to Rochester, NY for a screening/baseline 
visit

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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2.
Number of consented subjects
3.
Number of completed rHGH injections per enrolled participant
4.
Number of completed testosterone injections per enrolled 
participant
5.
Ability of participants to administer study drug
6.
Number of completed study visits per participant
7.
Number of subjects that completed the study without drug 
discontinuation
8.
Number of subjects who completed the study
 
Safety outcome measures:
1.
Changes from baseline in laboratory test results, vital signs, and 
EKG results
2.
Occurrence of serious adverse events
3.
Occurrence of non-serious adverse events
Significance/Relevance
The most significant symptoms to FSHD patients are related to 
muscle dysfunction and may be amendable to testosterone/rHGH 
therapy.  In 2012 a cross-sectional study of 328 FSHD patients was 
completed to identify the symptoms most important to this 
population.  Six symptomatic themes were identified as having a 
prevalence of 90% or higher.  These FSHD themes included: 1) 
problems with shoulders or arms; 2) the inability to do activities; 3) 
fatigue; 4) back, chest, and abdomen weakness; 5) limitations with 
mobility or walking; and, 6) changed body image due to disease. In 
addition to being highly prevalent in FSHD, these themes were also 
identified as having the highest impact on the daily lives of FSHD 
patients.  Testosterone/rHGH therapy has been previously shown to 
improve respiratory function, lean body mass, strength, and aerobic 
endurance in healthy elderly men.  If these effects also occur in 
FSHD patients, many (if not all) of the above life altering symptoms 
could 
be 
improved. 
 
The 
proposed 
study 
will 
evaluate 
testosterone/rHGH therapy for the first time in an FSHD population.  
The intervention of testosterone paired with rHGH for FSHD is novel 
and, despite solid evidence in other human populations, has never 
been implemented in FSHD.   If safety and proof-of-concept is 
demonstrated, the data from this study will form the basis for 
initiating a larger efficacy trial of combination therapy in FSHD. The 
identification of an efficacious and safe therapeutic approach that 
reduces a decline in clinically relevant function, strength, and 
quality-of-life in muscular dystrophy would represent a significant 
advance in the clinical management of this population.
Study Design
This study is a proof-of-concept study to evaluate the potential 
efficacy of daily testosterone plus rHGH injections in men with 
FSHD.  Subjects (n=20) will be assigned to receive active drug 
(Genotropin® and testosterone) for 24 weeks while being closely 
monitored.  Analyses will be conducted after the last subject 
enrolled has completed their last scheduled study visit (at 36 weeks 
after a 12 week washout period).
Sample Size
Considerations
The primary tolerability outcome variable is the ability to take 
combination study medication for 24 weeks and complete the 24 
week treatment period. The criterion for declaring combination 

STUDY DRUG: TESTOSTERONE AND HUMAN GROWTH HORMONE
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treatment well tolerated will be based on a hypothesis test that 
compares the observed tolerability rate against a tolerability rate that 
would be considered unacceptably low.  We believe that 70% is a 
reasonable choice for the unacceptably low tolerability rate in this 
context.  A test based on the binomial distribution will be performed 
for H0: π ≤ 0.70 vs. H1: π > 0.70, where π is the true probability of 
tolerability.  The decision rule will be to reject the null hypothesis of 
unacceptable tolerability if the number of subjects tolerating the 
dosage is 18 (out of 20) or greater.  This rule will provide 80% power 
to detect that the dosage is tolerable (has a tolerability rate > 70%) if 
the true tolerability rate is 92%.  The actual significance level of this 
test is 3.6%.  
The table below provides information on the precision with which the 
incidence of a particular adverse event can be estimated as well as 
the probability of observing at least one such event during the trial 
given different values for the true incidence of the adverse event in 
the target FSHD population receiving combination therapy.  A 
sample size of 20 participants will yield a 95% upper confidence 
bound for the incidence that is within approximately 20% of the 
observed incidence.  It will also make it very likely that an adverse 
event with a true incidence ≥ 15% will be observed in at least one 
subject during the trial.
Estimation of adverse event incidence with n = 20 participants.
Observed 
Adverse 
Event 
Incidence
95% Upper 
Confidence 
Bound
True Adverse 
Event 
Incidence
Probability of 
Observing at 
Least 1 
Adverse Event
5%
21.6%
5%
26.1%
10%
28.3%
10%
60.8%
15%
34.4%
15%
82.4%
20%
40.1%
20%
93.1%
25%
45.6%
25%
98.0%
30%
50.8%
30%
99.2%
For lean body mass, an estimated standard deviation of 1.6 kg was 
derived using data on 24-week change from participants in our 
ongoing longitudinal study of FSHD progression (PI: Heatwole, 
U01AR065119).  Assuming a standard deviation of 1.6 kg meters for 
the this outcome variable, a sample size of 18 participants will 
provide 85% power to detect a mean change of 1.2 kg , using a t-
test and a 5% significance level (two-tailed).  A sample size of 20 
participants will allow for an anticipated attrition rate of 10%.
For the 6MWT, an estimated standard deviation of 42.3 meters was 
derived using data on 24-week change from participants in our 
ongoing longitudinal study of FSHD progression.  Assuming a 
standard deviation of 40 meters for this outcome variable, a sample 
size of 18 participants will provide 85% power to detect a mean 
change of 30 meters, using a t-test and a 5% significance level (two-
tailed).  Recent studies in chronic obstructive pulmonary disease1,2, 
coronary artery disease3, and Duchenne muscular dystrophy4 

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support a distance of 25-35 meters as representing a minimal 
clinically important change.  A sample size of 20 participants will 
allow for an anticipated attrition rate of 10%.
Route & Dosage Form
Testosterone enanthate (in oil) will be delivered via intramuscular 
injections every 2 weeks.  rHGH (Genotropin®) will be given by 
subcutaneous injections
Dosage
Testosterone enanthate, 140 mg every two weeks.
Genotropin®, 5.0 µg/kg/day (calculated using the patient’s pre-entry 
weight)
Inclusion Criteria
Males ages 18 to 65 years
Moderately affected, symptomatic, ambulatory, FSHD (genetically 
confirmed or clinical symptoms suggestive of FSHD with a first 
degree relative with genetically confirmed FSHD)
Hematocrit of ≤ 50%
Prostate-specific antigen ≤ 4.0 ng/ml (or ≤ 3.0 ng/ml if the 
participant is at elevated risk of prostate cancer (e.g. the 
participant has a first-degree relative with prostate cancer)
Fasting blood glucose <126 mg/dl
Participants will be able to walk continuously for six minutes (cane, 
orthoses allowed) and be able to independently administer an IM 
and SC injection (or have a family member who is capable and 
willing to administer these injections 
Exclusion Criteria
Diabetes, obesity (BMI>35 kg/m2), or cardiovascular disease 
(heart failure, coronary artery disease, uncontrolled hypertension, 
untreated hypercholesterolemia)
Untreated thyroid disease
Deep vein thrombosis
Untreated severe sleep apnea
Past pituitary disease
Significant musculoskeletal injury and/or pain that affects walking
A systolic blood pressure over 160 or a diastolic pressure over 100
Plans to dramatically change exercise habits
Liver disease
Psychiatric disease
Renal disease
Severe lower urinary tract symptoms (International Prostate 
Symptom Score (IPSS)> 19)
Cancer (other than basal cell skin cancer)
An active desire to conceive, heavy alcohol use (greater than 50 
g/day)
Current testosterone or HGH use

Testosterone level of ≥ 1100 ng/dl 
Current use of medications that interfere with the growth hormone 
or gonadal endocrine axis.

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1.0 STUDY OBJECTIVES AND MEASURES
1.1
Primary Objective
To examine the safety and tolerability of rHGH and testosterone in adult male patients with 
FSHD.
1.2
Secondary Objectives
1) To examine the pharmacokinetic effects of rHGH and testosterone on serum levels of free 
and total testosterone, IGF-1, thyroid function, luteinizing hormone and follicle stimulating 
hormone.  
2) To examine the effect of rHGH and testosterone on total and regional lean body mass.
1.3
Exploratory Objectives
To examine the effects of rHGH and testosterone on multiple measures of clinical function 
including ambulation, strength, pulmonary function, and patient reported disease-burden.
1.4   Outcome measures
Feasibility outcome measures:
1. Willingness to travel to Rochester, NY for a screening/baseline visit
2. Number of consented subjects
3. Number of completed rHGH injections per enrolled participant
4. Number of completed testosterone injections per enrolled participant
5. Ability of participants to administer study drug
6. Number of completed study visits per participant
7. Number of subjects that completed the study without drug discontinuation
8. Number of subjects who completed the study
Safety outcome measures:
1.   Changes from baseline in laboratory test results, vital signs, and EKG results
2.   Occurrence of serious adverse events
3.   Occurrence of non-serious adverse events
Exploratory efficacy outcome measures:
Composite Quantitative Muscle Testing (QMT) score
Composite Manual Muscle Testing (MMT) score
FSHD Clinical Outcome Measure (FSHD-COM), total and individual test scores
FSHD-Health Index (FSHD-HI), disease-specific patient-reported outcome measure
Forced Vital Capacity (FVC)
Epworth Sleepiness Scale
Fatigue Severity Scale
Dual Energy X-Ray Absorptiometry (DEXA) Lean Body Mass (total and regional)
PROMIS-57
FSHD daily exercise questionnaire.
Beck Depression Inventory (BDI)
Six minute walk distance
International Physical Activity Questionnaire

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2.0  BACKGROUND & RATIONALE
2.1  Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) is the second most common form of adult 
muscular dystrophy with a prevalence of 1:15,000-1:20,000.5,6  The clinical manifestations of 
FSHD include steady progressive weakness of the face, shoulders, arms, and hip girdle 
muscles and life altering fatigue, impaired ambulation, respiratory decline, social limitations, and 
activity impairment related to muscle weakness.  In a recent paper of functional impairment in 
FSHD, patients were reported to have a loss of strength between 1 and 4% per year and a 24% 
chance of developing a need for a wheelchair over a six year interval.7  Currently, there is no 
known disease modifying therapy for FSHD that can improve or limit functional decline in 
ambulation.  
2.2 Anabolic Effects in FSHD
We hypothesize that the anabolic benefits of testosterone and human growth hormone 
observed in healthy adults will also occur in FSHD participants.  Indeed, our studies of albuterol 
in FSHD demonstrate that FSHD muscle is responsive even to mildly anabolic agents.8,9   We 
hypothesize that the side effect profile of combination therapy in FSHD will be acceptable and 
comparable to that previously demonstrated in healthy adults.  If treatment is ultimately found to 
limit the rate of functional decline in FSHD, it would represent a significant therapeutic advance 
for patients who currently struggle with this muscular dystrophy. 
2.3 Proposed Intervention
2.3.1
Human Growth Hormone
Human Growth Hormone (HGH) is a naturally occurring peptide hormone that is produced in the 
pituitary gland of men and women.  Like testosterone, HGH can stimulate cell growth and 
regeneration.10 In HGH deficient states, patients experience exercise intolerance, low bone 
mineral density, changes in body composition, and a worsening cholesterol profile.11  HGH 
supplementation can ameliorate these impairments.  Recombinant HGH (rHGH) is a 
synthesized preparation of HGH that has been used to treat children and adults with growth 
hormone deficiency, as well as those with muscle wasting, Turner syndrome, Prader-Willi 
syndrome, chronic renal failure, and idiopathic short stature.10,12-15
2.3.2
Testosterone
Testosterone is a naturally occurring androgen that is produced in both men and women.  
Testosterone promotes protein synthesis and has anabolic effects on both muscle and bone.16  
It is commonly utilized for men with hypogonadism and conditions associated with low or no 
endogenous testosterone.17  It is also recommended for men to improve libido and erectile 
dysfunction.18  In women, testosterone supplementation has been used for muscle atrophy 
associated with acquired immune deficiency syndrome, inoperable metastatic breast cancer, 
low libido, sexual dysfunction, muscle wasting, and as a postmenopausal therapy.19-25  The 
Endocrine Society currently recommends testosterone to: 1) increase muscle strength and lean 
body mass in patients with HIV; and 2) improve bone mineral densities in patients receiving high 
dosages of glucocorticoids.18  In a prior study, testosterone in isolation has been shown to be 
safe and increase lean body mass, reduce body fat, and improve basal metabolic rate in a 
heterogeneous group of adult muscular dystrophy population (including a FSHD participant) 
with normal baseline testosterone levels.  In this study, results were seen after 3 months of 
treatment and were comparable to the results demonstrated in a group of normal men receiving 
the same therapy.26  In a second study of 40 patients with myotonic dystrophy, testosterone in 
isolation was found to be safe, tolerable, and able to improve both creatinine excretion and lean 
body mass while not statistically improving overall strength.27 

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2.3.3
Combination Therapy and Implications for FSHD
Over the last 12 years, researchers have studied the utility of testosterone combined 
with recombinant human growth hormone to increase strength and lean muscle mass.  Large 
scale clinical trials, mostly in men, have found testosterone and rHGH in combination to be well 
tolerated and effective in improving respiratory function, lean body mass, strength, and aerobic 
endurance.20,28-31  Between 2002 and 2009, three large placebo-controlled human trials 
evaluating 323 participants were conducted with results demonstrating the safety and benefit of 
combination therapy over monotherapy or placebo (Table 1).20,28,29   Results from these studies 
suggest a synergistic effect of these two agents for improving muscle function in humans.20,28,29
In the HORMA (Hormonal Regulators of Muscle and Metabolism in Aging) study, 
researchers compared six different dosage combinations of testosterone and rHGH to identify 
the most effective dose combination.29-31  Testosterone gel at 5g/day and 10g/day was paired 
with rHGH at 0 µg/kg/day (placebo), 3µg/kg/day, and 5µg/kg/day.  The most pronounced 
benefits in body composition, strength, endurance, and reduction in fasting triglycerides were 
seen with the combined higher dosages of both medications.29-31  
The positive effects of combined testosterone/rHGH therapy have also been observed in 
younger healthy populations.  In a randomized, double-blind, placebo-controlled, 8-week trial of 
recreational trained athletes, participants were assigned testosterone, growth hormone, 
placebo, or combined therapy.  A greater improvement in sprint capacity was seen with 
combination therapy than with any other therapy.32  Still other studies have observed markedly 
increased protein synthesis in men receiving combination therapy. 18,20,32,33  This therapeutic 
approach is one of the few documented methods shown via clinical trial to reduce declines in 
both lean muscle mass and physical strength.
Despite promising effects on muscle strength, function, and metabolism, a study of 
testosterone/rHGH in a population of muscular dystrophy patients has never been performed.  
We hypothesize that reductions in strength, endurance, and lean body mass will be lessened 
overtime in response to combination therapy in FSHD.  If gains in muscular and physical 
function are of similar magnitude in FSHD as they have been in other populations, this 
discovery would significantly improve therapeutic options for FSHD patients and may provide an 
option to limit progressive muscle weakness and functional decline in other musculoskeletal 
populations.34 

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Three Clinical Studies of Testosterone/ Growth Hormone Combination Therapy 
Title
Treatment
N
Body Composition (DEXA)
Strength
Aerobic Capacity
Growth Hormone and Sex Steroid 
Administration in Healthy Aged 
Women and Men: A Randomized 
Clinical Trial (JAMA)
rHGH +placebo; sex 
steroid*+ placebo; 
rHGH + sex steroid*
131
 4.3 kg increase in lean body mass in 
men treated with T/rHGH;  T/rHGH 
produced the greatest reductions in 
body fat
6.8% increase in 
strength in men 
treated with T/rHGH 
8.6% improvement in 
graded treadmill 
exercise testing 
(Vo2Max) in T/rHGH 
Group
The Effects of Growth Hormone 
and/or Testosterone in Healthy Elderly 
Men: A Randomized Controlled Trial 
(JCEM)
rHGH +placebo; T + 
placebo; rHGH + T; 
Placebo
80
1.8 kg increase in lean body mass in 
men treated with T/rHGH;  This group 
also had the greatest reduction in body 
fat 
4.06 Nm increase in 
knee flexion torque in 
men treated with 
T/rHGH 
23% improvement of 
VO2Max in T/rHGH vs. 
placebo
Testosterone and Growth Hormone 
Improve Body Composition and 
Muscle Performance in Older Men 
(JCEM)
Low or High dose T 
groups paired with 
placebo or 1 of 2 
dosages of rHGH 
(3,5 µg/kg/day)
112
2.6 kg increase in lean body mass 
with the high dose T/rHGH;  This group 
also had the greatest reduction in body 
fat 
29% increase in 
composite strength in 
men treated with high 
dose T/rHGH 
140 second 
improvement in cycle 
endurance in high dose 
T/rHGH group 
* sex steroid= testosterone for men, estradiol/medroxyprogesterone for women; T= testosterone; rHGH= recombinant Human Growth Hormone

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3.0 INVESTIGATIONAL PLAN
3.1
Study Design 
STARFiSH is a proof-of-concept, single-center, open-label study of daily human growth hormone 
(Genotropin®, 5.0 µg/kg via subcutaneous injection) and testosterone (testosterone enanthate, 140mg via 
intramuscular injection every two weeks) for 24 weeks in men with FSHD with a 12 week washout period.  This 
protocol is based on three prior controlled clinical trials of combination therapy in humans and includes 
modifications to best accommodate the FSHD population.20,28,29  A total of 20 subjects will be enrolled at the 
University of Rochester Medical Center in Rochester, NY.  
3.2
Rationale for Combination Therapy & Proposed Dosages
We will use the equivalent dosage of testosterone and rHGH that was found to be safe and most 
effective for men in the multicenter, dose-finding HORMA study.29-31  
Additional clinical studies of combination therapy using higher average dosages of testosterone 
paired with rHGH provide support for our rHGH dosage selection.20,28  In these studies, while clinical 
benefit was observed with higher rHGH dosages, adverse events attributed to higher rHGH dosages 
limited patient tolerability.  In one trial, a mean dosage of 6.52 µg/kg/day of rHGH with testosterone 
was administered to patients with an average mass of 79.7 kg.28  While clear improvements in 
strength, body composition, and aerobic capacity were seen with this combination therapy, 41% of 
patients had mild adverse events attributed to the higher dosage of rHGH. 28  With rHGH dosage 
reductions, these mild adverse events resolved.  Similarly, in another study, patients on combination 
therapy experienced improvements with graded treadmill exercise testing; however, at the higher 
mean rHGH dosage of 8.57 µg/kg/day, 32% of men experienced carpal tunnel symptoms.20  
Conversely, HORMA investigators found that the incidence of carpal tunnel symptoms occurred in 
only 1 of 37 participants (3%) using testosterone paired with an rHGH dosage of 5.0 µg/kg/day (the 
dosage selected for our study).29 
A prior dose finding study using HGH in elderly people with hypothalamic-pituitary disease also 
supports a 5.0 µg/kg/day dosing strategy.11  Researchers tried patients on different dosages of HGH 
including 0.17 mg/day, 0.33 mg/day, and 0.5 mg/day.  Patients experienced increases in lean body 
mass and IGF-1 levels using all dosages, but did not have added benefit between the 0.33 mg/day 
and the 0.5 mg/day dosing.  Furthermore, while no patients experienced a major adverse event, three 
patients on the higher 0.5 mg/day dosage had adverse events attributed to HGH.  Using an average 
baseline mass of 83 kg for the study patients, the optimal tolerated dosage of HGH in this population 
was estimated to be between 3.98 µg/kg/day and 6.02 µg/kg/day.  For adults with growth hormone 
deficiency, the recommended starting dosage of Genotropin® is 0.040 mg/kg/week (5.7 µg/kg/day); a 
dosage that is well tolerated, widely used, and above our selected dosage of 5.0 µg/kg/day. 
The use of 140 mg of testosterone enanthate IM given every two weeks is supported by prior 
research and clinical data.  In the HORMA study, researchers utilized rHGH combined with 10 grams 
of 1% testosterone transdermal gel.29   This combination created the most pronounced therapeutic 
response in adult males while being found to be both safe and well tolerated.  At a 10% systemic 
absorption this equates to a total dosage of 140 mg of testosterone enanthate over 14 days (the 
exact dosage that we have chosen for our study).  This dosage of testosterone is also similar to what 
is commonly utilized in clinical practice.  The Endocrine Society recommends that men with reduced 
testosterone levels be treated with testosterone supplementation.  Specifically, the Endocrine Society 
recommends a starting dosage of 150-200 mg of testosterone enanthate given every 2 weeks via 
intramuscular injection.18   While our selected dosage is slightly lower (140 mg every two weeks) it will 
be administered via the identical mechanisms and frequencies commonly used in clinical practice.  

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3.3
Rationale for Method of Administration
Participants will receive testosterone enanthate (in oil) via intramuscular injection every two weeks.  This 
preparation and its intramuscular delivery mechanism has been extensively studied, utilized broadly for 
patients with hypogonadism, and is the exact preparation/delivery mechanism that was paired with rHGH and 
utilized in a study of 131 healthy men and women published in JAMA.1  In general, intramuscular preparations 
of testosterone have several advantages over topical (i.e., buccal, cream, patch, mucoadhesive) testosterone 
preparations.  Namely, intramuscular preparations are substantially more affordable and have a more 
predictable therapeutic absorption rate compared to topical preparations.  rHGH (Genotropin®) will be given by 
subcutaneous injections using the Genotropin Pen® delivery device. This device has a dial to select the proper 
dose of study drug and a dose display directly on the Pen.  Participants will be given a document detailing the 
use of the Genotropin Pen® and will be taught how to use the Pen during their inpatient visits.
3.4
Rationale for Effect and Sample Size
The primary tolerability outcome variable is the ability to take combination study medication for 24 weeks and 
complete the 24 week treatment period. The criterion for declaring combination treatment well tolerated will be 
based on a hypothesis test that compares the observed tolerability rate against a tolerability rate that would be 
considered unacceptably low.  We believe that 70% is a reasonable choice for the unacceptably low tolerability 
rate in this context.  A test based on the binomial distribution will be performed for H0: π ≤ 0.70 vs. H1: π > 
0.70, where π is the true probability of tolerability.  The decision rule will be to reject the null hypothesis of 
unacceptable tolerability if the number of subjects tolerating the dosage is 18 (out of 20) or greater.  This rule 
will provide 80% power to detect that the dosage is tolerable (has a tolerability rate > 70%) if the true 
tolerability rate is 92%.  The actual significance level of this test is 3.6%.  
The table below provides information on the precision with which the incidence of a particular adverse event 
can be estimated as well as the probability of observing at least one such event during the trial given different 
values for the true incidence of the adverse event in the target FSHD population receiving combination 
therapy.  A sample size of 20 participants will yield a 95% upper confidence bound for the incidence that is 
within approximately 20% of the observed incidence.  It will also make it very likely that an adverse event with 
a true incidence ≥ 15% will be observed in at least one subject during the trial.
 Estimation of adverse event incidence with n = 20 participants.
Observed Adverse Event 
Incidence
95% Upper Confidence 
Bound
True Adverse Event 
Incidence
Probability of Observing 
at Least 1 Adverse Event
5%
21.6%
5%
26.1%
10%
28.3%
10%
60.8%
15%
34.4%
15%
82.4%
20%
40.1%
20%
93.1%
25%
45.6%
25%
98.0%
30%
50.8%
30%
99.2%
For lean body mass, an estimated standard deviation of 1.6 kg was derived using data on 24-week change 
from participants in our ongoing longitudinal study of FSHD progression (PI: Heatwole, U01AR065119).  
Assuming a standard deviation of 1.6 kg meters for the this outcome variable, a sample size of 18 participants 
will provide 85% power to detect a mean change of 1.2 kg , using a t-test and a 5% significance level (two-
tailed).  A sample size of 20 participants will allow for an anticipated attrition rate of 10%.
For the 6MWT, an estimated standard deviation of 42.3 meters was derived using data on 24-week change 
from participants in our ongoing longitudinal study of FSHD progression.  Assuming a standard deviation of 40 
meters for this outcome variable, a sample size of 18 participants will provide 85% power to detect a mean 
change of 30 meters, using a t-test and a 5% significance level (two-tailed).  Recent studies in chronic 
obstructive pulmonary disease1,2, coronary artery disease3, and Duchenne muscular dystrophy4 support a 

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distance of 25-35 meters as representing a minimal clinically important change.  A sample size of 20 
participants will allow for an anticipated attrition rate of 10%.
4.0 SELECTION AND ENROLLMENT OF SUBJECTS
4.1
Subject Population
Experienced investigators will be responsible for recruitment and follow-up of 20 subjects for this clinical trial.  
Participants will be moderately affected, ambulatory, FSHD men ages 18 to 65.  All patients will be 
symptomatic and have genetically confirmed FSHD or clinical symptoms suggestive of FSHD with a first 
degree relative with genetically confirmed FSHD.  Complete inclusion and exclusion eligibility criteria are listed 
in Sections 4.2 & 4.3. To be eligible for enrollment into this study, subjects must meet all of the following 
eligibility criteria. 
4.2
Inclusion Criteria

Males ages 18 to 65 years

Moderately affected, symptomatic, ambulatory, FSHD (genetically confirmed or clinical symptoms 
suggestive of FSHD with a first degree relative with genetically confirmed FSHD)

Hematocrit of ≤ 50%

Prostate-specific antigen ≤ 4.0 ng/ml (or ≤ 3.0 ng/ml if the participant is at elevated risk of prostate cancer 
(e.g. the participant has a first-degree relative with prostate cancer)

Fasting blood glucose <126 mg/dl

Participants will be able to walk continuously for six minutes (cane, orthoses allowed) and be able to 
independently administer an IM and SC injection (or have a designated person such as a family member, 
caregiver, or friend who is capable and willing to administer these injections
4.3
Exclusion Criteria

Diabetes, Obesity (BMI>35 kg/m2), or cardiovascular disease (Heart failure, coronary artery disease, 
uncontrolled hypertension, untreated hypercholesterolemia)

Untreated thyroid disease

Deep vein thrombosis

Untreated severe sleep apnea

Past pituitary disease

Significant musculoskeletal injury and/or pain that affects walking

A systolic blood pressure over 160 or a diastolic pressure over 100

Plans to dramatically change exercise habits

Liver disease

Psychiatric disease

Renal disease

Severe lower urinary tract symptoms (International Prostate Symptom Score (IPSS)> 19)

Cancer (other than basal cell skin cancer)

Plans to conceive, heavy alcohol use (greater than 50 g/day)

Current testosterone or HGH use

Testosterone level of ≥ 1100 ng/dl 

Current use of medications that interfere with the growth hormone or gonadal endocrine axis.
4.4
Recruitment Process
Volunteers from diverse ethnic and racial backgrounds will be recruited using local and nationwide recruitment 
tools.  These individuals will be evaluated at the University of Rochester.  Recruitment media will include: 
recruitment websites and newsletters (e.g., Strong Health’s Clinical Trials website, websites and newsletters 
for the Fields Center for FSHD & Neuromuscular Research, the Muscular Dystrophy Association, and the FSH 
Society), clinicaltrials.gov, and direct mailings through the National Registry of Myotonic Dystrophy and 

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Facioscapulohumeral Dystrophy Patients and Family Members (RSRB #12163).35  This National registry is 
headquartered at the University of Rochester and has ~748 members with FSHD 228 meet age and gender 
eligibility criteria.  Participants will also be recruited through The University of Rochester FSHD clinic 39/75 
active patients meet age and gender eligibility criteria] and through their participation in current and prior 
research initiatives at the University of Rochester.  One such study is a NIH-funded disease progression 
evaluation of 40 FSHD patients at the University of Rochester (PI: Heatwole: U01AR065119). To date, we 
have successfully recruited and obtained consent for the full number of FSHD patients for this study and 21 of 
these participants currently meet gender and age eligibility criteria.  The University of Rochester has a history 
of successfully recruiting patients for FSHD clinical trials.  In one such instance, University of Rochester 
researchers working with The Ohio State University enrolled 90 FSHD patients for a clinical trial of albuterol.8  
The male patients from that study met comparable (albeit not identical) eligibility criteria to those proposed in 
our study.  If needed, we will also request referrals from our neuromuscular collaborators including researchers 
from Boston, Baltimore, Columbus, Salt Lake City, Seattle, Kansas City, Gainesville, and Stanford.
    
4.5
Subject Identification Numbers
The participants will assigned a unique, coded identification number at the Screening visit.  This Subject ID will 
be included on all data forms for all visits.
4.6
Subject Withdrawal
Subjects have the right to discontinue study drug and/or study participation at any time and for any reason.  
The investigator also has the right to discontinue study drug or subject’s participation if he/she feels it is in the 
subject’s best interest (e.g. clinical condition worsening, adverse events, subject is not following protocol 
requirements, etc).  A subject will be considered to have withdrawn from the study in the following 
circumstances: death, lost-to-follow-up, withdrawal of informed consent or if site investigator feels study 
participation should be discontinued.  If discontinuation of study drug is related either to an adverse event or 
serious adverse event, details must be documented per Adverse Event Reporting guidelines in Section 9.0.
4.7 Costs to the Subject
Subjects and their insurance will not incur any costs as a result of participating in this study. A grant through 
the National Institutes of Health (NIH) will pay for the procedures associated with the study as well as 
testosterone. Genotropin will be provided by Pfizer.
4.8 Payment for Participation
Study participants will be reimbursed for travel and lodging expenses (up to $500.00 per visit). Patients will 
receive a payment of $100 per visit for four of the five study visits (for a total of $400). Patients must complete 
a visit to receive payment for that visit. Patients will not receive a payment for the screening/baseline visit. If a 
family member will be assisting with study drug administration, their travel expenses will also be reimbursed up 
to $500 (for the initial visit only).
The study will use a subject payment system called Advarra Participant Payments. The system allows three 
ways to provide payment: a reloadable debit card; direct deposit; or mailed paper checks. The study team will 
help patients create a subject profile which will include their name and date of birth. Depending on which 
payment method a patient chooses, email address and banking information may be required.  If patients 
already have an Advarra account (because they’re in another study that uses this system), their existing profile 
will be used to provide payment.  An ‘Information Sheet for Advarra Participant Payments” will be provided 
to patients for their reference. 
4.9 Return of Individual Research Results
Laboratory results including results from blood tests, urinalysis, ECGs, and DEXA scans will be provided to 
subjects at their study visit. Patients will be informed if their results suggest that they are in need of further 
testing.  The study doctor/staff will talk with patients about their findings and options. Patients may be asked to 
follow up with their regular doctor or other specialists for future care.
5.0 STUDY DRUG ADMINISTRATION / ASSIGNMENT

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5.1
Formulation 
Genotropin® will be supplied by Pfizer Inc.  The generic form of testosterone enanthate will be purchased by 
the investigational pharmacy from a local vendor.  Both drugs will be received and dispensed by the 
Investigational Drug Services unit at the University of Rochester.
5.2
Packaging, Labeling, and Distribution
The University of Rochester, Investigational Drug Services unit will provide packaging, labeling, and 
distribution to the investigational unit to ensure that each subject has an adequate and appropriate supply of 
study drug.    
5.3
Storage of Study Drug
The investigator will ensure that all study drug supplies are kept in a locked, safe area under appropriate 
storage conditions with access limited to those directly involved in the study. Drug supplies should not be 
repackaged in any way. Genotropin® should be stored at controlled refrigerated temperature, 2-8° C (36-46° 
F).  Testosterone should be stored at room temperature.
5.4
Dispensing & Administration 
Participants will be given study medication during their baseline visit to take home with them.  Compliance will 
be tracked using a compliance questionnaire and used vials will be collected at each study visit. Medications 
will be provided by the Investigational Drug Service (IDS) at the University of Rochester.  Sharp boxes, 
syringes, needles, vials, alcohol swabs, and Genotropin Pens and cartridges will be provided to each 
participant.  Administration of therapy will be taught to participants by trained personnel and will fully comply 
with each medication’s labeling instructions.  A designated person such as a family member, caregiver, or 
friend, will also be instructed on study drug administration, if needed. Participants will be given documents, will 
watch video tutorials, and will be instructed on drug administration at the baseline visit.   
Testosterone enanthate:  Subjects will receive vials of testosterone enanthate to be administered as one 
intramuscular injection into the gluteal or thigh muscle.  When properly given, intramuscular injections of 
testosterone enanthate are well tolerated. Care should be taken to slowly inject the preparation deeply into the 
gluteal or thigh muscle, being sure to follow the usual precautions for intramuscular administration, such as the 
avoidance of intravascular injection.
Genotropin®:  Subjects will be given Genotropin Pen® delivery devices with 5 or 12 mg cartridges.  This 
device has a dial to select the proper dose of study drug and a dose display directly on the Pen.  Participants 
will be instructed on how to use the dial to administer the correct medication dose.  Participants will receive 
Genotropin® using these Pens via subcutaneous injection, as calculated based on body weight at the 
Screening/Baseline Visit.  Subjects will pinch a fold of skin at the injection site, insert the pen at a 90 degree 
angle, push the black/white injection knob until it clicks, wait 5 seconds, then withdraw Pen.  Participants will 
be given a document detailing the use of the Genotropin Pen® and will be taught how to use the Pen during 
their inpatient visit.
5.5
Dosing Regimen
Subjects will receive 5ug/kg/day of Genotropin® and 140mg every two weeks of testosterone enanthate for 24 
weeks.  Subjects will be instructed to administer the Genotropin® after an evening meal.
5.6
Dosage Adjustments
Dosage reductions are permitted at any time during the study.

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5.6.1 Dosage Reduction
The investigator should be consulted prior to the subject reducing the dosage of study drug.  The safety 
monitor will review all safety data and based on adverse effects, laboratory profiles, vital signs, or EKG results 
will recommend that a subject’s dosage of study medication be reduced or make recommendations regarding 
potential withdrawal from the study.  Elevations of IGF-1 higher than 400 ng/mL, a total testosterone higher 
than 1100 ng/dL, or a HCT ≥54% will warrant a reduction in study medication.  The Safety Monitor will provide 
the Investigator with guidance on recommendations to reduce a dosage.  A dosage reduction is accomplished 
by lowering the total daily dosage by 25%, 50%, 75%, or 100% based on the type of adverse event noted and 
if it was attributed to rHGH and/or testosterone (or more as deemed necessary by the investigator) until 
symptoms resolve or reduced dosage is tolerated by the subject.  Dosage reductions are to be documented on 
the Dose Management Log.
5.6.2
Dosage Suspension
Administration of the study drug may be interrupted for intolerable adverse effects thought to be related to 
study drug, intercurrent illnesses or surgery at any time during the study.  These situations will be handled on a 
case-by-case basis.  A suspension may last up to two weeks.  If a longer suspension is required, the Safety 
Monitor will be contacted and the situation will be reviewed and approved if appropriate.  Subjects will be 
considered to have permanently discontinued study drug for suspensions lasting longer than 2 weeks without 
prior approval by the safety monitor.  Multiple suspensions throughout the study are allowable in consultation 
with the safety monitor.  Dosage suspensions are to be documented on the Dose Management Log.
5.6.3
Discontinued Study Drug
Subjects who permanently discontinue study drug may be followed in the study per intention to treat.  There is 
no downward titration necessary when the study drug is permanently discontinued.  Study drug 
discontinuations are to be documented on the Dose Management Log.
5.6.4
Missed Doses
Participants will record missed dosage on their medication log.  Missed doses will not be replaced and 
participants will be instructed to continue their dosing regimen as instructed.  Missed doses and methods for 
mitigating future missed doses will be discussed on weekly participant calls.  
5.7
Accountability and Compliance of Study Drug
The site investigator or coordinator must maintain accurate records (including dates) of receipt of all study drug 
from IDS.  Drug accountability records must be completed to account for the dispensing of the study drug.  
Compliance will be assessed by tracking dispensed and unused packets at each in-person visit and by subject 
self-report at weekly telephone contacts. Subjects will be instructed to return unused study drug to be collected 
at each in-person visit. The subject will be counseled and, as necessary, re-instructed on proper administration 
of study drug.  Additionally, laboratory studies (e.g. IGF-1 levels and testosterone levels) will be expected to 
rise with medication use.  The absence of a laboratory response will suggest noncompliance with study 
medication.
5.8
Prior and Concomitant Interventions
Prior and concomitant drugs taken by subjects up to 90 days before the Baseline visit and throughout the 
duration of the study will be documented and followed for any changes at all visits including in-person and 
telephone contacts. Documentation of the use and daily dosing of other dietary supplements, including those 
hypothesized to affect the endocrine access will be employed. 
6.0 CLINICAL AND LABORATORY EVALUATIONS
6.1
Schedule of Activities
An overview of the schedule of activities and evaluation is provided in Table 2.  Following informed consent, 
participants will have a screening visit.  Participants who meet all eligibility requirements will be enrolled and 
will receive serial in-person assessments at baseline, 8 weeks, 16 weeks, 24 weeks, and 36 weeks.  16 weeks 
has been shown to be an adequate time to demonstrate both increases in strength and function.29-31 32  

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Throughout the study, participants will receive weekly phone calls from a clinical coordinator to address any 
study-related difficulties.  All subjects will be followed for the full 36 weeks, if they are willing, regardless of 
protocol violations or withdrawal of study drug.
Schedule of Study Activities and Testing
Screening
Baseline
8w
16w
24w
36w
Activity
On Combination Therapy
 
 
 
 
Washout Period
 
Informed consent
X
Documentation of Inclusion/Exclusion criteria
X
 
Clinic Visits
X
X
X
X
X
X
Laboratory Testing *
X
X
X
X
X
Study Medication Dispensed
X
X
X
 
Dual Energy X-Ray Absorptiometry (DEXA)
X
X
X
X
Six Minute Walk Test
X
FSHD-COM
X
X
X
X
X
Strength and Functional Testing
X
X
X
X
X
Exercise Log Review
X
X
X
X
Patient-Reported Outcome Measures
X
X
X
X
X
Safety Monitoring
Vitals **
X
X
X
X
X
X
Physical Exam
X
 
X
X
X
X
Fundoscopic Exam
X
X
X
X
X
Digital Rectal Exam
X
 
X
X
X
X
International Prostate Symptom Score
X
 
X
X
X
X
Quantitative Insulin Sensitivity Check Index
 
X
X
X
X
X
Side effect questionnaire
X
X
X
X
X
EKG
X
 
X
X
X
X
Weekly Phone Calls 
 
 
 
 
 
* Free and total T levels,  IGF-1 (Free/ total), PSA,  fasting glucose, chem 14, CK, lipid profile
luteinizing hormone, Insulin levels, HGA1c, FSH, CBC, CRP, TSH, and Free T4 levels, urinalysis
** Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature
6.2
Screening and Baseline Visit
The Screening Evaluations can take place at the same visit or within two weeks of the Baseline visit. The 
Baseline visit will require an overnight stay at the Clinical Research Center at the University of Rochester.  
Screening and baseline evaluations will take place after the subject has signed the informed consent 
document.  Study drug will be administered only after the inclusion/exclusion criteria have been fulfilled (e.g. 
fasting serum glucose, liver function tests, testosterone, hematocrit, serum prostate specific antigen, and 6 
minute walk test).  

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6.2.1
Screening Evaluations
During this visit, the subject will be thoroughly informed about all aspects of the study, including all scheduled 
visits and activities, and will be requested to sign and date the informed consent prior to performing any study-
related procedures.
Subjects will be assessed for study eligibility by the Investigator or Coordinator.  All the inclusion criteria must 
be met and none of the exclusion criteria may apply.  All the results from the screening procedures must be 
available before determining a subject’s eligibility for the study.
The following procedures will be performed at the screening visit:

Obtain written informed consent (if not already obtained)

Subject Identification Number assigned 

Inclusion/exclusion criteria review

Medical history review

Demographics

Review concomitant medication usage

Obtain vital sign measurements (Height, weight, blood pressure, body mass index, pulse, respiratory 
rate, temperature, waist circumference)

Obtain blood sample for laboratory testing (Total testosterone levels, free testosterone levels, IGF-1, 
PSA,  fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, 
TSH, and Free T4 levels, lutenizing hormone, FSH, CBC, CRP)

Urinalysis

Physical Exam

6 Minute Walk Test

International Prostate Symptom Score

Rectal exam

Electrocardiogram (EKG)
6.2.2
Baseline Evaluations
The following procedures will be performed at the baseline visit:

Enrollment of subject into study

Conduct final review of eligibility

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Fatigue Severity Scale

Dual Energy X-Ray Absorptiometry (DEXA)

Fundoscopic exam

Laboratory studies (if not done within 7 days as part of the screening visit)

Quantitative Insulin Sensitivity Check Index

Side Effect Questionnaire 

International Physical Activity Questionnaire

Instruct subject about correct administration of study drug

Administration of first dosage of each therapy

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Both study drugs will be administered after all screening procedures have been completed and 
eligibility has been determined. Testosterone and rHGH will be administered at time points separated 
by greater than one hour. This time is sufficient to identify any immediate site reaction related to either 
study medication.  Both medications have been extensively studied in humans and the likelihood of any 
significant reaction is low. The following activities will also occur

Obtain vital signs (blood pressure, pulse, respiratory rate, temperature)

Inquire about any immediate side effects (e.g., nausea, dizziness, GI discomfort)

Instruct subjects to bring unused study drug to each study visit, and to immediately report any adverse 
events to the investigator or coordinator. 
6.3
Follow Up Visits
After the subject has completed the Screening/Baseline Visit, they will return to the Clinical Research Center 
for an in-person visit at 8 weeks, 16 weeks, and 24 weeks, and 36 weeks (after 12 weeks of washout). 
Subjects will also be contacted weekly to inquire about their general status and resolve any study medication 
issues.  The in-person visits will take about 6 hours.
6.3.1
On-site Follow up Evaluations
The following activities will be completed during the on-site follow up visits.  These visits may be conducted 
within + 7 days of the target date.  The last study visit while on drug (the 24 week visit) will be conducted 
before the 24 week has expired while the patient is still on study medication.
Week 8 Visit
An in-person visit at Week 8 will involve:

Blood specimen for clinical safety (total testosterone levels, free testosterone levels, IGF-1, PSA,  
fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, TSH, 
and Free T4 levels, LH, FSH, CBC, CRP)

Urinalysis

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Fatigue Severity Scale

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Fundoscopic exam

Physical exam

Rectal exam

International Prostate Symptoms Score

Quantitative Insulin Sensitivity Check Index

Side effect questionnaire

International Physical Activity Questionnaire

Domain Delta

EKG

Review of concomitant medications and adverse events

Exercise log review

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Participants with no clinically significant adverse events or lab abnormalities will remain on their daily dosage of 
study medication.  
Week 16 Visit
An in-person visit at Week 16 will involve:

Blood specimen for clinical safety (Total testosterone levels, free testosterone levels, IGF-1, PSA,  
fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, TSH, 
and Free T4 levels, LH, FSH, CBC, CRP)

Urinalysis

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Fatigue Severity Scale

Dual Energy X-Ray Absorptiometry (DEXA)

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Fundoscopic exam

Physical exam

Rectal exam

International Prostate Symptoms Score

Quantitative Insulin Sensitivity Check Index

Side effect questionnaire

International Physical Activity Questionnaire

Domain Delta

EKG

Review of concomitant medications and adverse events

Exercise log review
Those participants with no clinically significant adverse events or lab abnormalities will remain on their daily 
dosage of study medication.
Week 24 Visit
An in-person visit at Week 24 will involve:

Blood specimen for clinical safety (Total testosterone levels, free testosterone levels, IGF-1, PSA,  
fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, TSH, 
and Free T4 levels, LH, FSH, CBC, CRP)

Urinalysis

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Fatigue Severity Scale

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
Dual Energy X-Ray Absorptiometry (DEXA)

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Fundoscopic exam

Physical exam

Rectal exam

International Prostate Symptoms Score

Domain Delta

Quantitative Insulin Sensitivity Check Index

side effect questionnaire

International Physical Activity Questionnaire

EKG

Review of concomitant medications and adverse events

Exercise log review
After this visit, participants will go off of study medication.
Week 36 Visit (12 weeks after washout)
An in-person visit at Week 36 will involve:

Blood specimen for clinical safety (Total testosterone levels, free testosterone levels, IGF-1, PSA,  
fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, TSH, 
and Free T4 levels, LH, FSH, CBC, CRP)

Urinalysis

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Fatigue Severity Scale

Dual Energy X-Ray Absorptiometry (DEXA)

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Fundoscopic exam

Physical exam

Rectal exam

International Prostate Symptoms Score

Quantitative Insulin Sensitivity Check Index

Side effect questionnaire

International Physical Activity Questionnaire

Domain Delta

EKG

Review of concomitant medications and adverse events

Exercise log review
6.3.2
Telephone-based Follow up Evaluations
Participants will receive a weekly phone call to evaluate for any side effects or interval changes in medical 
health.  Each participant will be asked if they have any questions regarding the study or the study medications.  

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Participants will be asked if they have been compliant with the study medications.  Reasons for non-
compliance will be discussed as will scheduling for upcoming in-person assessments.
6.4
Unscheduled Visits 
Unscheduled in-person visits may occur at any time during the study. Assessments listed below will be 
completed and any data generated, including that from unscheduled telephone contacts, should be 
documented on appropriate study evaluation forms.  These evaluations may take place at the Clinical 
Research Center:

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Specimen collection for safety laboratory tests (if deemed necessary by the site Investigator to assess 
adverse events)

Assessment of adverse events

Review of concomitant medications

Assessment of study drug compliance
If a subject has an Unscheduled Visit between the scheduled visits he/she should be instructed to attend 
his/her next visit according to the study schedule as planned.
6.5
Premature Discontinuation of Study Drug
In the event of adverse events, non-compliance, protocol violation, intolerability, or other safety reason there 
may be a need for a premature discontinuation of study drug. Subjects will be allowed to permanently 
discontinue study drug but still be followed in the study per the intent-to-treat principle.  If a subject prematurely 
discontinues study drug, the reason for discontinuation will be recorded.  Protocol assessments should be 
conducted per the schedule of activities for subjects who continue to be followed off study drug.  A participant 
who has discontinued study drug will be sent postage and shipping materials to return the remainder of their 
study medication.  This medication will be destroyed and not used in another study participant.  
6.6
Premature Withdrawal from the Study
In the event a subject is unwilling or unable to continue to be followed off study drug, when possible, a 
complete final evaluation using the Premature Withdrawal visit assessments will be conducted (if the subject is 
willing) and all unused study drug returned to the site coordinator:

Blood specimen for clinical safety (Total testosterone levels, free testosterone levels, IGF-1, PSA,  
fasting glucose, comprehensive metabolic panel, CK, lipid profile, HGA1c, fasting insulin level, TSH, 
and Free T4 levels, LH, FSH, CBC, CRP)

Urinalysis

Quantitative Muscle Testing

Manual Muscle Testing

FSHD Clinical Outcome Measure (FSHD-COM)

Forced Vital Capacity

FSHD-Health Index (FSHD-HI)

PROMIS-57

Beck Depression Inventory (BDI)

Epworth Sleepiness Scale

Vital signs (Height, weight, blood pressure, body mass index, pulse, respiratory rate, temperature, waist 
circumference)

Fundoscopic exam

Physical exam

Rectal exam

Prostate symptom scale

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
International Prostate Symptoms Score

Quantitative Insulin Sensitivity Check Index

Side effect questionnaire

International Physical Activity Questionnaire

Domain Delta

EKG

Review of concomitant medications and adverse events

Exercise log review
If a subject does not return for an in-person evaluation, adverse events, concomitant medications, reason for 
withdrawal and method of study drug return will be reviewed by phone when possible and the conclusion of 
study participation page will be completed. 
6.7  Milestones and Study Calendar
We will obtain local IRB approval and train all clinical site staff in quarter 1 of year 1 (Q1Y1); enroll our first 
patient by Q2Y1; have 25% of participants enrolled by Q4Y1; 50% by Q3Y2; 75% by Q2Y3; and 100% by 
Q1Y4.  We will complete all data collection by Q3Y4 and complete our study analysis and final NIH study 
report by Q4Y4 (See figure below).
FIGURE 1: STUDY TIMELINE
Year
Year 1
2
3
4
Quarter
Q1
Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Post-Award
PRIMARY OBJECTIVES:
Obtain Institutional Review Board Approval and Train Staff
Recruitment of FSHD Patients
Enrollment of FSHD Patients
Participant Study Visits
Analysis of Data and Completion of Final Study Report
Presentation and Publication of Study Results
A planned enrollment table is provided below

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Visit
APRMAYJUN JUL AUGSEPOCTNOVDECJANFEBMAR
Screening
1
2
3
4
5
6
Baseline
1
2
3
4
5
6
Week 8
1
2
3
4
5
Week 16
1
2
3
4
Week 24
1
2
3
Week 36
1
Visit
APRMAYJUN JUL AUGSEPOCTNOVDECJANFEBMAR
Screening
7
8
9
10
11
12
13
Baseline
7
8
9
10
11
12
13
Week 8
6
7
8
9
10
11
12
Week 16
5
6
7
8
9
10
11
Week 24
4
5
6
7
8
9
10
Week 36
2
3
4
5
6
7
8
Visit
APRMAYJUN JUL AUGSEPOCTNOVDECJANFEBMAR
Screening
14
15
16
17
18 19
20
Baseline
14
15
16
17
18 19
20
Week 8 13
14
15
16
17 18
19
20
Week 16 12
13
14
15
16
17
18
19
Week 24
11
12
13
14
15
16
17
Week 36
9
10
11
12
13
14
15
Visit
APRMAYJUN JUL AUGSEPOCTNOVDECJANFEBMAR
Screening
Baseline
Week 8
Week 16 20
Week 24 18
19
20
Week 36 16
17
18
19
20
Y1
Y2
Y3
Y4
6
7
7
0
6
7
7
0
5
7
8
0
4
7
8
1
3
7
7
3
1
7
7
5
25
42
44
9
Week 36
Total Visits
Screening
Baseline
Week 8
Week 16
Week 24
Year 3 (2019-2020)
Year 4 (2020-2021)
STARFiSH Enrollment Timeline (Estimated)
Year 1 (2017-2018)
Year 2 (2018-2019)

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7.0 ASSESSMENTS & OTHER EVALUATIONS
7.1
Efficacy Assessments
7.1.1
Neuromuscular Assessments
6 Minute Walk Test: The six minute walk test (6MWT) measure has been extensively studied and utilized in 
neuromuscular populations36-38.  It represents patient function and one of the most prevalent issues that 
impairs FSHD quality-of-life.39,40
Quantitative Muscle Testing (QMT):  Maximum Voluntary Isometric Contraction Testing of the limb muscles 
will be performed using the Quantitative Muscle Assessment (QMA) system.  This system uses an adjustable 
cuff to attach the patient's arm or leg to an inelastic strap that is connected to a force transducer with a load of 
0.5 to 1,000 Newtons.  Measurements resulting from this method of strength testing have been used for 
several neuromuscular diseases. 8,41-43 Six selected muscle groups will be tested bilaterally (biceps, triceps, 
quadriceps, hamstrings, handgrip, shoulder external rotators).  These particular muscles were chosen because 
they show excellent test-retest reliability in neuromuscular patients and normal volunteers and they reflect 
affected muscle groups in FSHD amenable to therapeutic intervention.8  A composite QMT score will be 
generated by expressing each muscle strength score as a percent of predicted normal given the subject’s age, 
gender, and height and averaging across muscles.8,44  Additional analysis of QMT strength will include 
absolute strength analysis, and analysis of upper and lower limb strength individually.
Manual Muscle Testing (MMT):   Manual muscle testing will be performed on 34 muscle groups (bilateral 
shoulder abductors, shoulder external rotators, elbow flexors, wrist flexors, wrist extensors, hip flexors, hip 
abductors, knee extensors, hip extensors, knee flexors, hip adductors, elbow extensors, ankle dorsiflexors, 
plantar flexors, common finger extensors, and thumb flexors, plus neck extensor and neck flexors).  
Measurements resulting from this method of strength testing have been utilized in prior clinical trials of 
musculoskeletal disease.41,43,45,46
The FSHD Clinical Outcome Measure (FSHD-COM):  The FSHD-COM is an evaluator-administered test that 
measures multiple aspects of physical function known to be impaired in FSHD.  Tests included in the FSHD-
COM evaluate leg function, arm/shoulder function, trunk function, hand function, and balance.  Leg function is 
evaluated using sit to stand times,47 the six minute walk test,36-38 self-selected gait speed,48,49 time to go 30 
feet,50 and time to ascend stairs.50  Arm and shoulder function are measured using range of motion 
determinations at the shoulders and elbows, 51 and the time it takes a participant to don and doff a coat.52  
Trunk function is measured using the time it takes a participant to pick up a penny from the floor,52 sit up with 
the feet held, and go from a supine to sitting position.  Hand function is measured using QMT grip strength 
determinations.  Lastly, balance is approximated using the timed up and go test.53  The composite FSHD-COM 
is currently being validated in our longitudinal study of 40 FSHD patients.  Each of individual tests of the FSHD-
COM (and the FSHD-COM total score) will be analyzed.   
   
7.1.2
Functional Assessments
Forced Vital Capacity:  Respiratory function will be measured using forced vital capacity.
Epworth Sleepiness Scale will be completed to estimate subject daytime sleepiness.  
Fatigue Severity Scale will be completed to estimate subject fatigue. 
Dual Energy X-Ray Absorptiometry (DEXA).  Lean body mass (LBM) will be measured via Dual Energy X-
Ray Absorptiometry (DEXA).  DEXA provides a practical and effective approach to determine lean muscle 
mass, and has been extensively utilized in prior neuromuscular clinical trials.54,55   Both total LBM and regional 
LBM will be measured.56  DEXA measurement has multiple advantages over the more recently described and 

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debated MRI techniques.  Specifically, compared to MRI, DEXA has a more extensive history of use, a more 
standardized analysis, is not as dependent on perfect participant positioning, and is more accessible, more 
affordable, and can be utilized in patients with metallic foreign bodies, aneurysm clips, pacemakers, 
claustrophobia, and metallic implants, and has a better correlation with change in six minute walk distances 
compared to MRI thigh measurements.57,58  Most importantly, the use of DEXA as a biomarker is supported by 
a prior study of combination therapy where LBM increases (measured by DEXA) occurred prior to later 
observable marked improvements in patient strength and function.59
7.1.3
Self-reported Assessments
The FSHD-Health Index (FSHD-HI): The FSHD-HI is a disease-specific patient reported outcome measure 
designed to assess patient-relevant effects during therapeutic trials.39,40  The instrument measures a patient’s 
assessment of their: 1) Mobility; 2) Hand and arm function; 3) Emotional issues; 4) Cognitive impairment; 5) 
Decreased satisfaction in social situations; 6) Decreased performance in social situations; 7) Specific activity 
impairment; 8) Fatigue; 9) Pain; 10) Eating problems; 11) Communication difficulty; 12) Problems with 
shoulders and arms; 13) Weakness of the back, chest, or abdomen; and, 14) Body image and has been 
created to satisfy FDA recommendations for use in supporting drug labeling applications.  The FSHD-HI is 
currently being validated in NIH sponsored longitudinal study of 40 FSHD patients at the University of 
Rochester. 
PROMIS-57: The PROMIS-57 generates scores for depression, anxiety, fatigue, pain interference, pain 
intensity, physical function, sleep disturbance, and satisfaction with participation in social roles.60  
Beck’s Depression Inventory (BDI):  The BDI is a widely used instrument for monitoring change in 
depressive symptoms.61
International Physical Activity Questionnaire (IPAQ)62 will be completed at each visit.  In addition, 
participants will complete a daily exercise log that we developed for FSHD patients in U01AR065119.  
This exercise log will highlight the type and duration of activities that the FSHD participate in on a 
daily basis.
7.2
Feasibility Assessments
Several outcome measures have been incorporated to evaluate recruitment and retention for this particular 
study.  These include the subject’s willingness to travel to Rochester, NY for a screening/baseline visit and the 
number of consented subjects.  Information regarding retention will be captured by recording the number of 
completed study visits, the number of subjects that completed the study without drug discontinuation, and the 
number of subjects who completed the study.  Whenever possible, reasons for refusal to participate will be 
recorded.  
Compliance will be measured as the percentage of distributed packs and vials that were used out of those 
scheduled to be used.  Additionally, the subjects will be asked whether or not they required assistance with 
administration of the study drug or if they were able to self-administer all doses.
7.3
Safety Assessments
7.3.1
Adverse Event Assessment 
Adverse events, attribution of the adverse event to study drug, actions taken with respect to study drug (i.e. 
dosing changes), and classification of seriousness will be systematically documented. Serious adverse events 
(death, life-threatening adverse event, persistent or significant disability/incapacity, or subject hospitalization or 
prolongation of existing hospitalization) will be specifically noted and adjudicated for relationship to study drug.

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7.3.2
Clinical Safety Laboratory Tests
Blood and urine samples will be obtained for clinical safety lab assessments (complete metabolic panel, 
complete blood count, and urinalysis) at each in-person visit as described in Sections 6.0. A centralized clinical 
research organization will manage laboratory specimen. The following clinical safety lab tests will be 
performed: 
COMPREHENSIVE 
METABOLIC PANEL
COMPLETE BLOOD 
COUNT
HORMONE ANALYTES
Other Tests
Sodium (Na)
White Blood Cell Count 
(WBC)
Total testosterone
Total Cholesterol
Potassium (K)
Red Blood Cell Count 
(RBC)
Thyroid Stimulating 
Hormone
Low Density Lipoprotein 
Cholesterol
Chloride (Cl)
Hemoglobin (Hb)
Free T4
High Density Lipoprotein 
Cholesterol
Carbon Dioxide (CO2)
Hematocrit (HCT)
Luteinizing Hormone
Triglycerides
Blood Urea Nitrogen 
(BUN)
Mean Corpuscular 
Volume (MCV)
Follicle Stimulating 
Hormone
Non-HDL-C
Glucose 
Mean Corpuscular 
Hemoglobin (MCH)
IGF-1
Cholesterol-HDL-C ratio
CK
PSA
Calcium (Ca) 
Mean Corpuscular 
Hemoglobin 
Concentration (MCHC)
Insulin (Fasted)
Creatinine (Crn)
Red Blood Cell 
Distribution Width (RDW)
Bilirubin Total
MVP 
Free Testosterone
HGA1c
Albumin
Platelet Count (PLT)
Protein (NOS) Total
Glutamic-Oxaloacetic 
Transferase (AST, 
SGOT)
Glutamic-Pyruvate 
Transferase  (ALT, 
SGPT)
Alkaline Phosphatase 
NOS
CRP
7.3.3
Treatment-specific Assessments
Subjects will be monitored for the following treatment-related events:

peripheral edema

carpal tunnel syndrome

gynecomastia

insulin resistance

arthralgia

increased erythropoiesis

reduced HDL cholesterol

elevated prostate specific antigen

elevated blood pressure

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Physical exams will be implemented to evaluate for peripheral edema, carpal tunnel symptoms, and joint pain, 
and will include a fundoscopic examination using a pan-optic ophthalmoscope.  Participants will also be 
monitored with the International Prostate Symptom Scale63, and the quantitative insulin sensitively check index 
(Quicki) to evaluate for signs of prostate dysfunction or diabetes.20,29  Patients will serially complete a treatment 
specific questionnaire at each study visit designed for early detection of adverse events associated with study 
drug and will be contacted on a weekly basis by study personnel to monitor for any adverse events.28
8.0 STATISTICAL CONSIDERATIONS
Statistical analysis of the study will be performed by the Department of Biostatistics and Computational Biology 
at the University of Rochester under the direction of the Primary Study Biostatistician, Dr Michael P. 
McDermott. 
8.1 Analysis of Safety Outcomes: The primary measures of safety and tolerability will consist of: 1) the 
occurrence of any serious or non-serious adverse events; and, 2) the ability of participants to complete a 24-
week period on combination therapy without having to discontinue either therapy.  An adverse event will be 
defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a medical treatment or procedures that may or may not be 
considered related to the medical treatment or procedure (ICH E-6 Guidelines for Good Clinical Practices). 
Stable chronic conditions that are present prior to the start of the study and do not worsen during the trial are 
not considered adverse events. Minor fluctuations in signs or symptoms of the disease under study are also 
not considered adverse events, but significant worsening of the disease beyond what is expected will be 
reported.   
Adverse events are detected in two ways:
Clinical: Symptoms reported by the participant or signs detected on examination.
Ancillary Tests: Abnormalities of vital signs, EKG, laboratory tests, and other diagnostic procedures.
The research team (including the safety monitor and PI) will assess whether each adverse event is unexpected 
or related (or possibly related) to the study medication. The adverse event may be a new illness, a worsening 
of a sign or symptom of the condition under treatment, a worsening of concomitant illness, an effect of the 
study medication or a combination of these factors.  Each event will be classified as mild, moderate, or severe 
and serious vs. non-serious based on preset rules. Participants will specifically be monitored for the following 
events that have been previously associated with treatment: peripheral edema, carpal tunnel syndrome, 
gynecomastia, insulin resistance, arthralgia, increased erythropoiesis, reduced HDL cholesterol, elevated 
prostate specific antigen, and elevated blood pressure.  Physical exams will be implemented to evaluate for 
peripheral edema, carpal tunnel symptoms, and joint pain, and will include fundoscopic and rectal 
examinations.  Participants will also be monitored with the International Prostate Symptom Scale46, and the 
quantitative insulin sensitivity check index (Quicki) to evaluate for signs of prostate dysfunction or diabetes. 
Patients will serially complete a treatment specific questionnaire at each study visit designed for early detection 
of adverse events associated with study drug and will be contacted on a weekly basis by study personnel to 
monitor for any adverse events. 
The primary tolerability outcome variable is the ability to take combination study medication for 24 weeks and 
complete the 24 week treatment period. The criterion for declaring combination treatment well tolerated will be 
based on a hypothesis test that compares the observed tolerability rate against a tolerability rate that would be 
considered unacceptably low.  We believe that 70% is a reasonable choice for the unacceptably low tolerability 
rate in this context.  A test based on the binomial distribution will be performed for H0: π ≤ 0.70 vs. H1: π > 
0.70, where π is the true probability of tolerability.  The decision rule will be to reject the null hypothesis of 
unacceptable tolerability if the number of subjects tolerating the dosage is 18 (out of 20) or greater.  This rule 
will provide 80% power to detect that the dosage is tolerable (has a tolerability rate > 70%) if the true 
tolerability rate is 92%.  The actual significance level of this test is 3.6%.  Adverse events will be tabulated 
overall and by severity.  For each adverse event, a 95% confidence interval will be computed for the incidence 
using the Wilson score method.  This will be repeated excluding all mild symptoms.  Similar analyses will be 
performed after grouping adverse events by body system.  Individual adverse events will be listed, with 

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particular attention paid to serious adverse events.  Laboratory tests, vital signs, and EKG abnormalities will be 
summarized similarly; continuous values may be analyzed using the methods described below for lean body 
mass. A complete accounting of subject disposition will be summarized, including a tabulation of subject 
withdrawals, dosage reductions, dosage suspensions, and early discontinuations of study medication (with 
reasons for each).  Concomitant medication usage for each participant will be listed for review.
8.2 Analysis of Outcome Measures of Efficacy: 
Analysis of Lean Body Mass: Lean body mass obtained using DEXA will be the objective primary marker used 
to determine whether combination treatment shows sufficient promise to consider further studies in FSHD.  
The analysis of this outcome will involve the use of a repeated measures analysis of variance model (i.e., the 
so-called “mixed model repeated measures”, or MMRM, analysis strategy81), with time (treated as a 
categorical variable) as the factor of interest.  The covariance matrix for the within-subject observations will be 
modeled using an unstructured pattern.  Ninety-five percent confidence intervals for mean changes from 
baseline to each visit will be computed using this model, with the 24-week time point being of primary interest.  
A test for significance of the mean change from baseline to 24 weeks will likewise be performed with this model 
using a significance level of 5% (two-tailed).  The analyses will be performed according to the intention-to-treat 
principle and will include all enrolled participants.  The repeated measures analysis of variance model to be 
used for these analyses uses a direct-likelihood approach to estimate the parameters of interest using all 
available data from all participants.  A key assumption underlying this analysis is that the missing data are 
“missing at random” (MAR), i.e., the probability that the responses are missing for a subject depends only on 
the set of observed data for that subject and not on the specific missing values that were not obtained.  The 
underlying assumptions of the statistical model (e.g., normality) will be thoroughly checked and remedial 
measures (e.g., transformations, use of non-parametric methods) may be necessary if serious violations of 
these assumptions are detected, but this is not expected for the lean body mass outcome based on our 
previous experience with its use in clinical trials of FSHD.40  A similar model that also includes amount of 
exercise (a dichotomous baseline variable based on exercise log data) and the interaction between amount of 
exercise and time will be used to explore differences between exercise subgroups with respect to changes in 
lean body mass after combination treatment.
Exploratory Analyses of Potential Efficacy: Outcome measures that will be used to explore potential efficacy 
include changes from baseline in the distance walked in 6 minutes, MVICT scores, FSHD-COM (total score 
and individual tests), FVC, Epworth Sleepiness Scale, Fatigue Severity Scale, FSHD-HI scores, PROMIS-57 
scores, and BDI score. The analyses of these outcomes will be performed as above for lean body mass.  It 
should be emphasized that these analyses will be considered to be purely exploratory, although the distance 
walked in 6 minutes will be given higher priority in terms of interpreting the potential functional benefit of 
combination treatment.
8.3 Analysis of Pharmacokinetic Outcomes:  Changes from baseline in all serum markers will be 
summarized descriptively.  Formal analyses of changes from baseline will also be performed using the 
methods described above for lean body mass.
8.4  Analyses for Feasibility
Measures of feasibility will be tabulated as part of our total data analysis.  These measures will include:
1. Willingness to travel to Rochester, NY for a screening/baseline visit
2. Number of consented subjects
3. Number of completed rHGH injections per enrolled participant
4. Number of completed testosterone injections per enrolled participant
5. Ability of participants to administer study drug
6. Number of completed study visits per participant
7. Number of subjects that completed the study without drug discontinuation
8. Number of subjects who completed the study

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8.5 Missing Data
A key assumption underlying this analysis is that the missing data are “missing at random” (MAR), i.e., the 
probability that the responses are missing for a subject depends only on the set of observed data for that 
subject and not on the specific missing values that were not obtained.64  
8.6 Sample Size Considerations
The primary tolerability outcome variable is the ability to take combination study medication for 24 weeks and 
complete the 24 week treatment period. The criterion for declaring combination treatment well tolerated will be 
based on a hypothesis test that compares the observed tolerability rate against a tolerability rate that would be 
considered unacceptably low.  We believe that 70% is a reasonable choice for the unacceptably low tolerability 
rate in this context.  A test based on the binomial distribution will be performed for H0: π ≤ 0.70 vs. H1: π > 
0.70, where π is the true probability of tolerability.  The decision rule will be to reject the null hypothesis of 
unacceptable tolerability if the number of subjects tolerating the dosage is 18 (out of 20) or greater.  This rule 
will provide 80% power to detect that the dosage is tolerable (has a tolerability rate > 70%) if the true 
tolerability rate is 92%.  The actual significance level of this test is 3.6%. The Table below provides information 
on the precision with which the incidence of a particular adverse event can be estimated as well as the 
probability of observing at least one such event during the trial given different values for the true incidence of 
the adverse event in the target FSHD population receiving combination therapy.  A sample size of 20 
participants will yield a 95% upper confidence bound for the incidence that is within approximately 20% of the 
observed incidence.  It will also make it very likely that an adverse event with a true incidence ≥ 15% will be 
observed in at least one subject during the trial.
Observed Adverse Event 
Incidence
95% Upper Confidence 
Bound
True Adverse Event 
Incidence
Probability of Observing 
at Least 1 Adverse Event
5%
21.6%
5%
26.1%
10%
28.3%
10%
60.8%
15%
34.4%
15%
82.4%
20%
40.1%
20%
93.1%
25%
45.6%
25%
98.0%
30%
50.8%
30%
99.2%
For lean body mass, an estimated standard deviation of 1.6 kg was derived using data on 24-week change 
from participants in our ongoing longitudinal study of FSHD progression (PI: Heatwole, U01AR065119).  
Assuming a standard deviation of 1.6 kg meters for the this outcome variable, a sample size of 18 participants 
will provide 85% power to detect a mean change of 1.2 kg , using a t-test and a 5% significance level (two-
tailed).  A sample size of 20 participants will allow for an anticipated attrition rate of 10%.
For the 6MWT, an estimated standard deviation of 42.3 meters was derived using data on 24-week change 
from participants in our ongoing longitudinal study of FSHD progression.  Assuming a standard deviation of 40 
meters for this outcome variable, a sample size of 18 participants will provide 85% power to detect a mean 
change of 30 meters, using a t-test and a 5% significance level (two-tailed).  Recent studies in chronic 
obstructive pulmonary disease, coronary artery disease, and Duchenne muscular dystrophy support a distance 
of 25-35 meters as representing a minimal clinically important change.  A sample size of 20 participants will 
allow for an anticipated attrition rate of 10%.
8.7  Data and Safety Monitoring
Participants will be monitored in accordance with current Endocrine Society Guidelines.18  The independent 
medical safety monitor (Dr. Emma Ciafaloni) is a board certified physician with knowledge of both FSHD and 
endocrine therapies.  In addition to the PI, the safety monitor will directly review all laboratory values, vital 
signs, EKG results (e.g., PR, QRS, and corrected QT intervals, rhythm, conduction, and waveform analysis), 

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adverse events, and all other safety related data on a quarterly basis.  Any safety concerns identified by the PI 
will be addressed by the safety monitor in real time. The safety monitor will have the final determination if any 
medication needs to be stopped or reduced or if a participant needs to be withdrawn from the study.  Our study 
endocrinologists (Dr. Bhasin and Dr. Weber), the study cardiologist (Dr. Rosero), and the study urologist (Dr. 
Rashid) will also assist with any questions throughout the study.  If an adverse event occurs, the safety monitor 
will have the option to reduce one or both of the medications by 25%, 50%, 75%, or 100% based on the type of 
adverse event noted and if it was attributed to rHGH and/or testosterone.  Elevations of IGF-1 higher than 400 
ng/mL, a total testosterone level higher that 1100 ng/dL or a HCT ≥54% will warrant study medication 
reduction.20  One of our endocrinologist consultants, Dr. Bhasin, has written protocols for the safe adjustment 
of testosterone supplementation and will advise on each individual case in whom elevated levels are noted.65  
The report of any serious adverse event will comply with both FDA and IRB requirements.  All participants will 
be followed and evaluated as scheduled (as they are willing) regardless of the dosages of the study 
medications. 
Testosterone enanthate and rHGH are both approved therapeutics for use in human populations.  We will 
carefully monitor for all potential adverse events associated with these therapies throughout the study.  In 
rHGH, reported side effects include: peripheral edema, carpal tunnel syndrome, gynecomastia, insulin 
resistance, papilledema, and arthralgia.  Although stimulation of existing carcinomas with rHGH has been 
hypothesized, no evidence has yet been produced to support this hypothesis.10,66  For testosterone, reported 
side effects include: erythropoiesis (increased hematocrit), reduction in HDL cholesterol, elevation in prostate 
specific antigen, worsening of sleep apnea, and elevation in blood pressure.  In men over 65, there may be a 
higher risk of cardiovascular events associated with testosterone use.67  Higher rates of adverse events have 
been claimed in Veterans Affairs patients receiving testosterone after coronary angiography; however these 
results have been refuted.68,69  In contrast, other studies have demonstrated that mortality rates are higher in 
patients with a deficiency of testosterone compared to those treated with testosterone70,71, and that 
testosterone is not associated with any cardiovascular risk.72,73,74,75  There are no data to suggest that FSHD 
patients will experience any disease-specific side effects that have not previously been identified in studies 
involving healthy adults.  Regardless, as a precaution, FSHD patients over the age of 65 and those with known 
coronary artery disease will not be included in this study.  In addition, we will serially monitor CK and CRP 
levels to evaluate for any unexpected evidence of increasing muscle inflammation.  Cosmetic side effects may 
occur with testosterone use and include hirsutism, acne, voice changes, gynecomastia and alopecia.  While 
there is no evidence to support a causative role in prostate cancer in men, androgens may enlarge an occult 
prostate tumor that has androgen sensitivity.10,76   No patients with known prostate cancer will be enrolled, and 
all men will be screened for signs of prostate change throughout their involvement.  Prior trials of combination 
therapy have not observed significant adverse events that have not been observed with single agent 
approaches.20,28,29  In the majority of cases, the adverse events observed with combination therapy during prior 
clinical trials were mild and responsive to medication dosage reductions.20,28,29  
Patients will be monitored for suicide risk through use of the Beck Depression Inventory and safety measures 
will be taken to mitigate risk if a patient discloses suicidal thoughts. A standard operating procedure for safety 
triage is in place to assess and address the patient’s safety. The patient will be connected with care if needed 
and continuously monitored.
9.0  ADVERSE EVENT REPORTING, MONITORING & REPORTABLE EVENTS
9.1
Definition of an Adverse Event
An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporarily associated with the use of a medical treatment or procedures that 
may or may not be considered related to the medical treatment or procedure (ICH E-6 Guidelines for Good 
Clinical Practices). Stable chronic conditions that are present prior to the start of the study and do not worsen 
during the trial are not considered adverse events. Minor fluctuations in signs or symptoms of the disease 
under study are also not considered adverse events, but significant worsening of the disease should be 
reported.   

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Adverse events are detected in two ways:
Clinical: Symptoms reported by the subject or signs detected on examination
Ancillary Tests: Abnormalities of vital signs, EKG, lab tests, and other diagnostic procedures.
Adverse events are typically associated with physical or psychological, rather than social or economic harm.  
The investigator must assess whether the adverse event is unexpected and related (or possibly related). The 
adverse event may be a new illness, a worsening of a sign or symptom of the condition under treatment, a 
worsening of concomitant illness, and an effect of the study medication or a combination of these factors. 
Planned surgical procedures for pre-existing conditions are not adverse events.  
9.1.1
Classification
Adverse events are to be classified by the investigator as serious or non-serious. 
9.1.2
Grade of Intensity
The maximum intensity of an adverse event will be graded as follows:
GRADE 
LEVEL
DEFINITION
1
Mild (awareness of a sign or symptom that is easily tolerated)
2
Moderate (sign or symptom intense enough to interfere with usual 
activity)
3
Severe (interferes significantly with ability to do work or usual activity)
9.1.3
Relationship to Study Drug
With careful medical consideration at the time of evaluation, the reasonable possibility of an adverse event’s 
relationship to study medication is to be assessed.  The Safety Monitor’s opinion may be sought in those cases 
in which the site investigator is unable to make an independent judgment.  The Safety Monitor may in turn 
consult with the principal investigator as needed. The following definitions are general guidelines only to help 
assign grade of attribution:
GRADE LEVEL
DESCRIPTOR
DEFINITION
1
Unrelated
Adverse event is clearly not related to the investigational drug (s)
2
Unlikely
Adverse event is doubtfully related to the investigational drug (s)
3
Possible
Adverse event may be related to the investigational drug (s)
4
Probable
Adverse event is likely related to the investigational drug (s)
5
Definite
Adverse event is clearly related to the investigational drug (s)
Definite
This category applies to those adverse events, which after careful medical consideration at the time 
they are evaluated, are felt with certainty to be related to study medication.
An adverse event may be considered definitely related if or when (at least three of the following):

It follows a direct temporal sequence from administration of the study medication.

It cannot be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors or other modes of therapy administered to the subject.

It disappears or decreases on cessation or reduction in dosage.  There are important exceptions 
when an adverse event does not disappear upon the discontinuation of study medication, yet drug-
relatedness clearly exists.

It follows a known pattern of response to the test drug.
Probable
This category applies to those adverse events, which after careful medical consideration at the time 
they are evaluated, are felt with a high degree of certainty to be likely related to study medication.

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An adverse event may be considered probably related if or when (at least three of the following):

It follows a reasonable temporal sequence from administration of the study medication.

It could not be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors or other modes of therapy administered to the subject.

It disappears or decreases on cessation or reduction in dosage.  There are important exceptions 
when an adverse event does not disappear upon the discontinuation of study medication, yet drug-
relatedness clearly exists.

It follows a known pattern of response to the test drug.
Possible
This category applies to those adverse events for which, after careful medical consideration at the time 
they are evaluated, a connection with administration of study medication appears unlikely but cannot be 
ruled out with certainty.
An adverse event may be considered possibly related if or when (at least two of the following):

It follows a reasonable temporal sequence from administration of the study medication.

It could not readily have been produced by the subject’s clinical state, environmental or toxic factors 
or other modes of therapy administered to the subject.

It follows a known pattern of response to the test drug.
Unlikely
In general, this category can be considered applicable to those adverse events, which, after careful 
medical consideration at the time they are evaluated, are judged to be doubtfully related to study 
medication.
An adverse event may be considered unlikely related if or when (must have two):

It does not follow a reasonable temporal sequence from the administration of the test drug.

It could readily have been produced by the subject’s clinical state, environmental or toxic factors or 
other modes of therapy administered to the subject.

It does not follow a known pattern of response to the test drug.

It does not reappear or worsen when the drug is re-administered.
Unrelated
In general, this category can be considered applicable to those adverse events, which, after careful 
medical consideration at the time they are evaluated, are judged to be clearly unrelated to study 
medication.
An adverse event may be considered unrelated if or when (must have three):

It does not follow the temporal sequence from the administration of the test drug.

It was most likely produced by the subject’s clinical state, environmental or toxic factors or other 
modes of therapy administered to the subject.

It does not follow a known pattern of response to the test drug.

It does not reappear or worsen when the drug is re-administered.
9.1.4
Adverse Event Assessment
At each in-person visit and telephone contacts, occurrence of adverse events will be assessed by verbally 
asking subjects if they have had any problems or symptoms since their last visit.
If the subject reports an adverse event, the investigator/coordinator will probe further to determine:

Time of onset and resolution

Frequency

Causality/relation to study treatment

Intensity

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
Action taken regarding study medication

Outcome
9.1.5
Reporting of Adverse Events
Adverse events encompass both physical and psychological harms. During the clinical trial, all adverse events 
encountered must be reported on the Adverse Event log, whether considered to be related to study medication 
or not. Adverse events must be evaluated by the site investigator for seriousness and causality prior to entry 
on the electronic Case Report Form (eCRF). All recorded adverse events should be evaluated at each 
subsequent visit until the condition has resolved or until the site investigator and/or Safety Monitor agree that 
the condition no longer needs to be followed.  At every visit the investigator must review the adverse events 
with the subject and record any new changes in status or events since the last visit. 
9.1.6
Follow-Up of Adverse Events at Permanent Withdrawal or End of Study
Adverse events ongoing at the time of a subject’s withdrawal from or completion of the study must be followed 
for 30 days or until the investigator deems the condition has resolved or the condition has stabilized (whichever 
occurs first).  
9.2
Definition of Serious Adverse Event (SAE)
Any untoward medical occurrence (adverse event) that at any dosage:

results in death;

is life-threatening event (places the subject at immediate risk of death from the event as it occurred);

requires inpatient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity;

results in congenital anomaly/birth defect; or

any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the outcomes listed above (e.g. 
allergic bronchospasm requiring intensive treatment in the emergency room or at home, convulsions not 
resulting in inpatient hospitalization, development of drug dependency or drug abuse, etc).
9.2.1
Reporting Serious Adverse Events
Responsibilities for reporting serious adverse events is outlined below:

The Investigator or Coordinator should record all serious adverse events that occur during the study 
period (commencing once informed consent has been provided) on the Adverse Event log and in the 
appropriate source documents.

Study Period:  For the purposes of reporting serious adverse events, the study period is defined as the 
time period from when the subject signs the informed consent until 30 days following the subject’s 
completion of the study. 

The following information should be supplied if available at the time of the telephone call:  study name, 
site number, subject number, and age, gender, start date of study drug, whether study drug has been 
discontinued, date of randomization, date of last study drug dosage, date of onset of event, event 
description, whether event required treatment, death and autopsy report (if available), an identification 
of which criteria for a serious event have been met, and the Investigator’s current opinion of the 
relationship between the event and the study drug or study participation.

The Investigator and Coordinator will complete the MedWatch Form and update the AE, concomitant 
medications and dose management logs within 24 hours. The MedWatch form must be completed for 
all Serious Adverse Events regardless of causality or expectedness.
9.2.2
Monitoring of Serious Adverse Events  

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Adverse events are assessed by the study staff at each visit by recording all complaints of subjects and by 
assessment of the clinical features and surveillance labs. The progress of each SAE will be followed by the  
Investigator until resolution or until an appropriate endpoint is reached (resolution or determination of event to 
be chronic and/or stabilized). 
9.3
Reportable Events (Incidents)
The following incidents will be considered reportable events and will be reported to the Independent Safety 
Monitor, the Investigator, and the IRB within 24 hours of the event, or the Investigator’s knowledge of the 
event.
o
Dosage suspension
o
Dosage rechallenge
o
Subject withdrawal
o
Early discontinuation of study drug
o
Serious adverse event (SAE)
o
Suicide attempt
o
Emergency treatment disclosure
o
Clinically significant overdosage
9.4
RISK/BENEFIT ASSESSMENT
9.5
Potential Risks
Completion of patient-reported outcome measures may cause feelings of distress. 
Muscle strength and function testing may cause bruising or temporary muscle soreness. For bedside 
respiratory testing, subjects may have difficulty breathing or may feel fatigued.  
Patients may experience minor discomfort during the DEXA scan from lying in the same position for about 15 
minutes. The amount of radiation exposure during the DEXA scans is relatively small. There is no known 
minimum level of radiation exposure that is recognized as being totally free of the risk of causing genetic 
defects (cellular abnormalities) or cancer. Patients’ risk of radiation-related injury depends on their total lifetime 
exposure, not just the radiation dose received in this study.  
Blood draws may cause pain, redness, bruising or infection at the site of the needle stick. Rarely some people 
feel lightheaded or faint.
Electrocardiogram (ECG/EKG) testing may cause minor skin irritation from the electrodes. 
 
During the rectal examination, patients may feel some discomfort or pain, especially if the prostate gland is 
swollen or irritated. This pressure may make patients feel the need to urinate. A small amount of bleeding from 
the rectum may occur after an examination, especially if hemorrhoids or anal fissures are present.  In rare 
cases, patients may feel lightheaded and faint. 
The light of the ophthalmoscope during the funduscopic examination can cause some discomfort.
There is a potential for invasion of privacy or breach in confidentiality in this study. 
The study team may be notified if patients receive other health care services at URMC or its Affiliates (e.g., 
visit to the emergency room). In addition, the following individuals may be informed of the patient’s participation 
in research and may see results of testing conducted for this study:

Staff at the University of Rochester Medical Center and its Affiliates (e.g., Strong Memorial Hospital, 
Highland Hospital, URMC primary care, specialist physician offices) who have a reason to access the 
patient’s electronic health record. 

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
Individuals who request a copy of information from the patient’s health record for activities such as 
treatment or payment (e.g., medical insurance companies, worker’s compensation). 
Risks of Testosterone:
Central Nervous 
System:
Genitourinary:
Hematologic & 
Oncologic:
Cardiovascular: 
Irritability or 
aggressive behavior
Large prostate or 
prostate cancer
Deep vein thrombosis and 
pulmonary embolism 
(blood clots in veins or the 
lungs)
Major heart problems including 
stroke and heart attack 
(inconclusive data)
Altered taste or 
sense of smell
Inflammation of the 
prostate
Decreased white blood 
cells
Hypertension 
Sleep apnea or 
worsening sleep 
apnea
Prostate lab 
abnormalities
Prostate problems 
including inflammation, 
cancer, nodules
Increased blood pressure
Insomnia
Changes in muscle 
bulk, body hair, and 
voice
Increase in the volume of 
red blood cells
Change in lipid profile (e.g., 
cholesterol and triglycerides)
Mood swings
Abnormal thyroid 
function
Increased hemoglobin in 
the blood
Swelling
Headache
Ejaculatory disorder
Bleeding
Widening of blood vessels
Fatigue
Problems urinating
 Increased blood cells
Blood clots
Suicidal ideation
Testicular atrophy
Liver inflammation or 
cancer
Dermatologic:
Abnormal dreams
Increased spontaneity 
or frequency and 
duration of erections
Anemia (decrease in red 
blood cells or hemoglobin 
in the blood)
Rash or skin reaction at the 
injection site
Amnesia
Erectile dysfunction
Neuromuscular & 
Skeletal:
Increased body hair
Anxiety
Urinary tract infections
Arthralgia
Increased sweating
Depression
Reduced sperm levels
Back pain
Baldness
Personality changes
Excessive sexual 
stimulation
Pain at the injection site
Acne
Seizure
Yellow skin
Weakness
Respiratory:
Vision changes
Abnormal liver 
function, liver failure or 
cancer
Bleeding into joint space
Upper respiratory tract infection
Voice changes
Increased bilirubin in 
the blood or jaundice
Accelerated bone growth
Cold symptoms 
Endocrine/ 
Metabolic:
Gastrointestinal:
Carpal tunnel syndrome
Shortness of breath
Hot flashes
Vomiting
restlessness
Bronchitis
Increased calcium in 
the blood
Heartburn
Other:
Sinus infection
Increased plasma 
estradiol 
concentration
Diarrhea
Increased tearing
Weight gain
Increased appetite
Increased urination
Gynecomastia 
(increased breast 
size)
Nausea
Allergic reaction
Gastrointestinal 
hemorrhage or 
Testosterone abuse

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irritation
Other serious side effects, while very rare, may include: anaphylaxis (shock) reactions, congestive 
heart failure, or other life-threatening cardiovascular events.
While testosterone has not been shown to be a cause of cancer in humans, it is not recommended in 
patients with an active malignancy. In addition, testosterone may be associated with increase 
cardiovascular events in patients older than 65 and those with preexisting cardiac, kidney, or liver 
disease.   
Risks of rHGH:
Endocrine & Metabolic
Dermatologic:
Other:
Dehydration
Sweating
Acute Critical Illness
Insulin resistance
Skin rash
Infection
Adrenal insufficiency
Acne
Candidiasis (yeast infection)
Hypothyroidism
Psoriasis (patches of abnormal 
skin)
Allergic reaction
High blood sugar
Hair loss
Intracranial Hypertension
Impaired glucose tolerance 
and diabetes mellitus
Increased growth of pre-existing 
moles
Abnormal tissue growth or tumor
Reduced serum cortisol levels
Loss of fat at the injection site
Papilledema
Central Nervous System:
Gastrointestinal:
Damage to the retinas of the eyes
Pain
Inflammation of the pancreas
Enlargement of facial features
Reduced skin sensation
Nausea
Respiratory:
Headache
Flatulence
Cough
Discomfort
Abdominal Pain
Rhinitis
Reduced sensation or 
numbness
Vomiting
Pharyngitis (inflammation of the back of 
the throat)
Dizziness
Gastritis
Flu-like symptoms
Depression
Neuromuscular and Skeletal:
Cardiovascular:
Fatigue
Joint pain
High blood pressure 
Insomnia
Joint disease
Swelling
Seizure
Muscle pain or stiffness
Chest pain
Aggressive behavior
Fracture through the growth plate
Otic:
Limb pain
Ear infection or inflammation
Scoliosis
Ear disease
Carpal tunnel syndrome
Altered hearing
Weakness
While rHGH has not been shown to be a cause of cancer in humans, it is not recommended in patients with an 
active malignancy.  
9.6
Protection Against Risks
Study personnel are trained to minimize the risks associated with participation in this trial. Patients will be 
closely monitored and may withdraw from the study or any procedure at any time for any reason. Subjects may 
be referred for treatment, counseling or other necessary follow-up if needed. Any additional treatment, 
counseling, or follow-up may be provided by the patient or his insurance. 

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Safety measures will be taken to mitigate suicide risk if a patient discloses suicidal thoughts. A standard 
operating procedure for safety triage is in place to assess and address the patient’s safety. The patient will be 
connected with care if needed and continuously monitored.
All study staff are fully trained in testing techniques and will ask patients how they are feeling throughout the 
course of the visit.  Patients will be asked to report any concerns to study staff immediately.  
To minimize the risk of invasion of privacy or breach in confidentiality, patients’ data is labelled with a study 
number. All data will be stored in a secure manner and only study team members will have access to it.  
Patients will not be eligible to participate in this study if they have any preexisting history of cancer, are known 
to have cancer, are older than 65 years old or have preexisting cardiac, kidney, or liver disease due to the risks 
of these patients receiving rHGH and/or testosterone.   
Patients will be provided with the “label” information for both testosterone and rHGH to review and discuss with 
study staff. The study team will monitor for side effects during phone calls with patients every week and at 
each study visit.  Patients will be asked to report to the study team if any adverse events occur.   
9.7
Potential Benefits to Subjects
Patients may not benefit from participation in this research study. A potential benefit might be some 
improvement in muscle strength.
9.8
Alternatives to Participation
Patients do not have to participate in this study to receive care for FSHD.  Testosterone and rHGH are FDA 
approved drugs and can be prescribed by physicians outside of the study. 
10.0  ETHICS
10.1 Guidelines for Good Clinical Practices
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting trials that involve the participation of human subjects.  Compliance with 
this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, 
consistent with principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are 
credible (ICH E-6 Guideline for GCP).  The Principal Investigator will ensure that this trial is conducted in full 
accordance with the ethical principles which have their origin in the Declaration of Helsinki or with the laws and 
regulations of the country in which the research is conducted, whichever affords greater protection to the 
individual.  The Principal Investigator will ensure that all individuals assisting with the trial are adequately 
qualified, informed about the protocol, any amendments to either the protocol, treatment or study procedures, 
and their trial-related duties and functions.   
10.2 Informed Consent
The consent form will describe the purpose of the study, procedures to be followed, and risks and benefits of 
participation.  The consent form document will contain all the elements required by the ICH E6 Guideline for 
Good Clinical Practice and any additional elements required by local regulations (i.e. HIPAA compliance). The 
document must be in a language understandable to the subject and must specify who informed the subject. 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, scope and 
possible consequences of the clinical study have been explained in a form understandable to them. After 
reading the informed consent document and any questions answered, the subject must provide consent in 
writing. The subject’s consent must be confirmed at the time of consent by the personally dated signature of 
the subject and by the personally dated signature of the person conducting the informed consent discussions.  
No research activities may be initiated until valid consent has been obtained from the subject.

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10.3 Protocol Compliance/Amendments/Discontinuation
The study may be modified or discontinued at any time by the principal investigator, FDA, NIH, IRB/IEC, OHRP 
or other government agencies as part of their duties to ensure protection of research subjects.  Deviations or 
changes to the protocol will be submitted for review and approval from all relevant oversight entities except 
where necessary to eliminate an immediate hazard to subjects (as necessary) or when the changes are only 
logistical or administrative aspects of the trial (e.g. change of telephone numbers). All such changes will be 
forwarded to the IRB/IEC at each site for approval. 
10.4 Subject Confidentiality
Subject names will not appear on any research materials.  If the subject name appears on any other document 
(e.g., pathologist report), it must be obliterated before a copy of the document is supplied to the sponsor or 
study monitors.  Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the regulatory oversight agencies or representatives of the sponsor (e.g. study 
monitors).  Only the Subject ID (a random unique code) will be recorded on relevant study documents (e.g. 
source worksheets). 
Laboratory specimens will be coded.  All samples will be used specifically for research purposes.  
Computer entry and networking programs will be created using Subject ID. No identifying information will be 
stored in the study database. Study findings stored on a computer will be stored in accordance with local data 
protection laws. The subjects will be told that representatives of the sponsor, IEC/IRB, or regulatory authorities 
may inspect their medical records (source) to verify the information collected and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. Research charts with source documents will be kept double-locked and only available to study 
staff. The file linking subject IDs to specific patients will be stored on a password-protected computer only 
available to study staff.
10.5 RESEARCH INFORMATION IN MEDICAL RECORDS
Research data from this study including indication of study participation and lab test results will be included in 
subjects’ medical records.
11.0  TRIAL MANAGEMENT
11.1 Coordination Efforts
Project coordination, data management, and biostatistical services will be provided through the Department of 
Neurology and Department of Biostatistics and Computational Biology at the University of Rochester in 
collaboration with the Principal Investigator.
11.2 Quality Assurance
To ensure optimal treatment of subjects and conduct of the research study according to Good Clinical Practice 
guidelines, study activities will be monitored for accurate, timely study progress and data collection in an 
ongoing manner. 
11.3 Data Handling & Record Keeping
The University of Rochester will also maintain regulatory documentation.  The Investigator or Coordinator 
should have the following study documents accessible during the study:

Protocol (and amendments, if applicable) 

Signed and dated IRB/IEC approval of protocol, consent forms and advertisement notices (if 
applicable), documentation of IRB/IEC composition, and all IRB/IEC correspondence

IRB/IEC approved consent form (sample) and advertisement for recruitment (if applicable)

Copies of completed source worksheets

Confidentiality agreement

Up to date signed CVs for all personnel listed on the Log of Investigators and Study Staff

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
Copy of professional licensure/registration, as applicable, for each individual named on the Log of 
Investigators and Study Staff, who has direct subject contact

Log of Investigators, Study Staff and Staff-Related Duties

Human Subject Protection Training Certificate for each individual named on the Authorization Log who 
has direct subject contact (if applicable, Health Insurance Portability and Accountability Act (HIPAA) 
Certification)

Signed and dated Indemnity/Insurance statement (Note: this may be filed in a separate business office)

Laboratory reference ranges and accreditation

Copies of laboratory reports/printouts

Signed subject consent forms

Study drug supply/receipt/shipping records

All correspondence

Subject Identification Logs

Serious adverse event report forms
11.4 Retention of Study Records
The following records must be retained by the investigator for a minimum of 2 years after the sponsor has 
notified the FDA that investigations have been discontinued or after the FDA has approved the new drug 
application:

Signed informed consent documents for all subjects

Subject identification code list, screening projections log

Record of all communications between the investigator and the IEC/IRB

Composition of the IEC/IRB or other applicable statement 

Record of all communications between the investigator and Sponsor or CTCC

Authorization Log (List of sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant trial-related duties, together with their roles in the study and their 
signatures)

Copies of study forms and of documentation of corrections for all subjects

Drug accountability records

Record of any samples retained

All other source documents (subject records, hospital records, laboratory records, etc.)

All other documents as listed in ICH Guideline E6 (Good Clinical Practice:  Consolidated Guidance) 
12.0  PUBLICATION OF RESEARCH FINDINGS
The investigator intends to publish trial results.  No research findings presented at meetings or in publication 
form will contain subject identifying information.  

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