Clinical trial NCT02137538
Conditions: Short Stature
Sponsor: Stanford University
Start date: 2009-11-18; Completion date: 2018-06-05
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine if there are differences in the final height or hormone profile of short pubertal boys placed on different forms of aromatase inhibitor now routinely used to increase stature: Anastrozole and Letrozole. It also should determine if there are differences in the side effect profiles of the two drugs to be used.

Detailed description:

Arms: arm 1: Letrozole 2.5 mg daily arm 2: Anastrozole 1 mg daily
Interventions: intervention 1: Letrozole intervention 2: Anastrozole
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
Randomization to Letrozole vs. Anastrozole in Short Pubertal Males   
NCT02137538 
March 26, 2019 
Laura Bachrach, Principal Investigator 
E Kirk Neely, Principal Investigator 
Stanford University 
Stanford, California 94305 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The purpose of the study is to determine if there are differences in the final height or 
hormone profile of patients placed on different forms of aromatase inhibitor now 
routinely used to increase stature; namely, Anastrozole and Letrozole. It also should 
determine if there are differences in the side effect profiles of the two drugs to be used. 
Objectives 
We hope to learn if there are differences in effects of different forms of aromatase 
inhibitors on growth. There have been 3 randomized controlled trials using aromatase 
inhibitors to improve stature in a variety of circumstances (delayed puberty, idiopathic 
short stature, growth hormone deficiency), but no actual comparative trials between the 
different forms. We hope to elucidate if there are differences in the growth rates/final 
heights between the different forms of therapy. This will certainly add to the current, 
somewhat small literature about the use of these drugs, although they are widely used. 
We also will look at the differences between the side effect profiles of the two 
medications. Rationale for Research in Humans 
Since we are looking at final adult heights, human subjects are necessary.  
2. 
STUDY PROCEDURES 
a. 
Procedures 
Patients from our endocrinology practice meeting our inclusion criteria will be consented 
into the study. They will be randomized into 1 of 2 treatment arms (Anastrozole 1 mg 
qday or Letrozole 2.5mg qday). Labs (gonadotropins, androgens, estrogens, growth 
factors, lipid profile) will be done every 6 months, bone age annually, and DEXA scans 
every 2 years. 
 
We will see the patients annually until near final height (< 2 cm growth velocity per 
year), re-consenting in those over 18 years old. We will perform physical exams, obtain 


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anthropometric data, and repeat the above blood tests at least once off medication and 
perform imaging studies as warranted. 
 
Beginning with this March 2016 renewal, we will no longer randomize to A vs L but use 
only A, continuing to collect observational data. Procedure Risks 
We will be using the standard doses for the two drugs used. We will be monitoring with 
every 6 month physical exams and laboratory evaluation for possible side effects. At the 
discretion of the investigator, the medication may be reduced or discontinued, 
specifically if growth velocity falls below normal. Use of Deception in the Study 
No deception will be used. Use of Audio and Video Recordings 
No audio or video recording will occur. Alternative Procedures or Courses of 
Treatment 
There are no alternatives to the above treatment. The only alternative would be to not 
start on the medication. Growth hormone is a theoretical option but is not standard of care 
for patients meeting these inclusion criteria. No standard treatment will be withheld. Will 
it be possible to continue the more (most) appropriate therapy for the participant(s) 
after the conclusion of the study? 
Yes 
g. 
Study Endpoint(s) 
Our end point is final height which is defined as less than 2 cm of 
growth per year. We anticipate that all patients will reach this end 
point. BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Without estrogen action, the fusion of the growth plates is postponed and longitudinal 
growth continues. This is the basic idea behind using aromatase inhibitors to augment 
growth. Aromatase inhibitors block the conversion of testosterone to estrogen leading to 
more time for skeletal growth. Although aromatase inhibitors have been used widely as a 
treatment for estrogen responsive breast cancers and in fact there is a plethora of data in 
that population, to date there have been 3 published randomized control trials using third 
generation aromatase inhibitors, and only one has been published to final height. The 
study to final height showed an increase of 6 cm in comparison to controls. The other 
studies are ongoing, but preliminary data is promising with improvements of standard 
deviation scores for height from baseline as well as improvements in predicted adult 
height based on bone ages. Finally, the available short-term data for safety are reassuring, 
however long-term data is lacking. Findings from Past Animal Experiments 
NA 
4. 
RADIOISOTOPES OR RADIATION MACHINES 
a. 
Standard of Care (SOC) Procedures 
Name of Exam 
Identify if SOC or Research 


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Bone age 
Standard of Care 
DEXA 
Standard of Care 
Lateral spine film 
Research 
b. 
Radioisotopes 
i. 
Radionuclide(s) and chemical form(s) 
NA 
ii. 
Total number of times the radioisotope and activity will be administered (mCi) and 
the route of administration for a typical study participant 
NA 
iii. 
If not FDA approved: dosimetry information and source documents (package insert, 
Medical Internal Radiation Dose [MIRD] calculation, and peer reviewed literature) 
NA 
c. 
Radiation Machines – Diagnostic Procedures 
i. 
Examination description (well-established procedures) 
Annual bone age x-ray, and lateral spine film at baseline and 2 years Setup and 
techniques to support dose modeling 
Standard radiography 
iii. 
FDA status of the machine and information on dose modeling (if procedure is not 
well-established) 
Well established clinical radiography 
d. 
Radiation Machines – Therapeutic Procedures 
i. 
Area treated, dose per fraction/number of fractions, performed as part of normal 
clinical management or due to research participation (well-established procedures) 
NA 
ii. 
FDA status of the machine, basis for dosimetry, area treated, dose per fraction and 
number of fractions (if procedure is not well-established) 
NA 
5. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
Investigational Product 1 
Name: 
NA 
Dosage: 
NA 
Administration Route: 
NA 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 


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Commercial Product 1 
Name: 
Letrozole (no longer being used) 
Dosage: 
2.5 mg 
Administration Route 
Oral 
New and different use? (Y/N) 
Yes 
Commercial Product 2 
Name: 
Anastrozole 
Dosage: 
1 mg 
Administration Route 
Oral 
New and different use? (Y/N) 
Yes 
6. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
120; boys with short stature and/or growth hormone deficiency which may be congenital 
or acquired (post surgical or chemotherapy) 
b. 
Age, Gender, and Ethnic Background 
Males 10-17.99 years old, any ethnic background (identical to our clinical population) 
were recruited; those over 18 years old at f/u are reconsented, 
c. 
Vulnerable Populations 
The study is directed towards children because the purpose of the study is to evaluate 
growth. We will be monitoring for side effects closely.   
d. 
Rationale for Exclusion of Certain Populations 
All boys who fit under our inclusion criteria, regardless of ethnic background, will be 
included. Girls are excluded as aromatase inhibitor therapy will increase testosterone, 
causing untoward effects for girls.  
e. 
Stanford Populations 
None 
f. 
Healthy Volunteers 
None  
g. 
Recruitment Details 
The first person identifying patients for recruitment will be physicians in the Pediatric 
Endocrine Division at Lucile Packard. The protocol director will then continue the 
recruitment process in more detail.  
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Outpatient males with: 
Age 10-17.99 years; re-consented if over 18 years old at follow up 
Current height less than 5th percentile OR 


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Predicted adult height (based on bone age) more than 10 cm below target height (mid 
parental height) 
Lab evidence of puberty: serum LH >0.3 IU/L and testosterone >15 ng/dl  
ii. 
Exclusion Criteria 
Bone age xray more than 14 years 
FSH >20 IU/L  
i. 
Screening Procedures 
Pediatric endocrinologists will recruit all patients who qualify based on our inclusion 
criteria. Qualifying labs and bone age xray are usually obtained as part of routine clinical 
assessment of boys with short stature and/or delayed puberty, or would be obtained after 
enrollment and consent.  
j. 
Participation in Multiple Protocols 
We will ask the patients about other studies they may be enrolled in although we do not 
anticipate that this will occur.  
k. 
Payments to Participants 
No payments 
l. 
Costs to Participants 
Clinic visits, drugs, and laboratory charges which are considered standard of care will be 
the patient's responsibility.  
m. 
Planned Duration of the Study 
We anticipate the average length of treatment to be 2-3 years. We will evaluate the 
patients every 6 months with laboratory evaluation with the same frequency. After 
treatment, follow-up visits will be scheduled annually until growth is completed, which 
will be on average an additional 3-4 years (6-7 years from start of treatment). Subjects 
will be re-consented upon reaching 18 years of age.  
7. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
None 
ii. 
Investigational drugs 
None 
iii. 
Commercially available drugs, biologics, reagents or chemicals 


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1) Arthralgia - reported in post-menopausal women at a frequency rate of 20-35%, lower 
in premenopausal women. Arthralgias have NOT been reported in the pediatric 
population. 
2) Bone health - In adult women, there has been a reported decrease in bone mineral 
density by 6-7% after 5 years of therapy. We only have short-term data for young boys. 
Preliminary 1 year data did not show a difference in DEXA- measured bone mineral 
density in growth hormone (GH) deficient boys using Anastrozole in combination with 
GH. In boys with idiopathic short stature, there was no statistical difference between the 
treatment group using Letrozole versus the control group. 
3) Fertility - In estrogen receptor knockout male mice, there is a progressive impairment 
of fertility. In one study using anastrozole in GH deficient boys, there was no difference 
in sperm parameters. 
4) Metabolic parameters: lipids, insulin - In adult men with aromatase deficiency, 
increased cholesterol and increased insulin resistence has been descibed. In one study 
using Letrozole in pubertal boys, there was a significant decrease in HDL cholesterol, but 
all other lipids were unaffected. No changes have been reported in insulin sensitivity. 
5) Higher than normal testosterone levels could cause hair loss or behavioral changes. 
Neither has been reported in studies to date. 
6) Growth velocity - excessive reduction in growth rate, which seems more likely to 
occur during the suppression of estrogen levels with Letrozole therapy. Procedures 
Blood draws at each visit. Bone age annually. DEXA scan and lateral spine film at 
baseline and two years into the study. Radioisotopes/radiation-producing machines 
DEXA scan which has less radiation than a standard chest XRAY; bone age and lateral 
spine x-ray. Physical well-being 
Routine clinical history. Psychological well-being 
Routine clinical history. Economic well-being 
None 
ix. 
Social well-being 
None 
x. 
Overall evaluation of risk 
Medium International Research Risk Procedures 
NA 
c. 
Procedures to Minimize Risk 
We will be monitoring for arthralgia with the clinical history every 6 months. We 
will also collect laboratory data every six months: lipids, insulin levels, as well as 
estrogen and testosterone, gonadotropin and growth hormone levels. We will 
perform DEXA scans at baseline and two years into study to assess for decreases in 
bone density. Access to the labs/scans are all password protected. 
d. 
Study Conclusion 


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The endpoint is final height. We will terminate when the growth rate has decreased 
to less than 2 cm per year. Since we will be monitoring clinical and performing 
physical exams every 6 months, if any of the side effects have been clinically 
significant, we will treat accordingly and/or terminate the use of the therapy. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
We will be monitoring, through laboratory evaluation, lipids, insulin sensitivity, 
gonadotropins, sex steroids, and growth hormone levels. We will monitor for changes 
in bone density through DEXA scans. Person(s) responsible for Data and Safety 
Monitoring 
Protocol Director Frequency of DSMB meetings 
All labs/scans will be monitored as soon as theyhave been received from the 
reference lab. Specific triggers or stopping rules 
Physician's clinical assessment based on laboratory evaluation. DSMB Reporting 
As needed 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
No 
f. 
Risks to Special Populations 
Short-term studies of aromatase inhibitors in this age group have not shown any significant risks, 
but there is a theoretical risk of issues with bone density, testicular function, and alterations to 
lipids/carbohydrate metabolism that is present. We will be monitoring for these risks during the 
course of the study. The direct benefit is increased ultimate height. We will be discussing these 
theoretical risks with the family in depth and will be obtaining assent from the subjects 
themselves. BENEFITS 
Greater final height for the individual participant and possibly improved treatment options for 
future patients. 
9. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 

SAP_001.pdf: 
Randomization to Letrozole vs. Anastrozole in Short Pubertal Males   
NCT02137538 
June 24, 2021 
Laura Bachrach, Principal Investigator 
E Kirk Neely, Principal Investigator 
Stanford University 
Stanford, California 94305 
 
Statistical Methods 
 
Baseline auxologic and hormonal measures were summarized by treatment arm. Laboratory measures 
over time were presented as means with standard deviation, with key measures (total testosterone, 
estradiol, IGF-1) additionally displayed as boxplots by arm. Growth velocity (cm/year), height (cm), bone 
age (months), predicted adult height (cm), and DEXA z-scores over time were similarly visualized. 
Adverse events were listed by arm, and spinal film was assessed qualitatively.  
To include all patients in an intent-to-treat approach, mixed effects linear regression was used to model 
each outcome as a function of treatment arm, indicators for follow-up timepoints, and their interaction for 
assessing effect modification of annual change by arm. Within-patient correlation was accounted for by a 
random effect. Estimated change since baseline with 95% confidence intervals were presented by arm if 
effect modification was deemed significant at the 0.05 alpha level and as an overall effect otherwise. All 
analyses were performed in the R statistical computing framework, version 4.01.   
---- 
1 R Core Team (2020). R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. URL https://www.R-project.org/