Clinical trial NCT01724489
Conditions: Obesity Osteopenia
Sponsor: Massachusetts General Hospital
Start date: 2013-08-01; Completion date: 2019-04-01
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Obesity is an important risk factor for osteoporosis and fractures. With the growing prevalence of obesity in the U.S., understanding the pathophysiology of bone loss in this population is of importance to public health. Growth hormone (GH) is a critical mediator of bone homeostasis and is markedly reduced in obesity. Our preliminary data suggest an important role for the GH/insulin-like growth factor 1 (IGF-1) system in the pathogenesis of bone loss in obesity. The development of novel imaging techniques provides an opportunity to investigate the effects of GH on skeletal structure and strength, which will provide insights into the pathogenesis of obesity related bone loss. Understanding the pathophysiology of bone loss in obesity may help identify new treatment targets for this important complication. The investigator hypothesizes that low-dose GH administration for 18 months will improve skeletal health.

Detailed description:

Arms: arm 1: Growth Hormone is Genotropin, provided by Pfizer Inc. It is self administered daily for 18 months using a 5 mg injection pen device. Dose will be titrated based on IGF-1 levels. arm 2: Placebo will be provided by Pfizer Inc. It will appear identical to active growth hormone and will be administered in the same manner.
Interventions: intervention 1: Growth hormone intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Skeletal Physiology Dysregulation in Obesity: The Role of 
Growth Hormone 
 
NCT# 01724489 
 
Version Date: November 7th, 2019 


PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Karen K. Miller, MD 
 
PROTOCOL TITLE 
Skeletal Physiology Dysregulation in Obesity: The Role of Growth Hormone  
 
FUNDING 
 
 
VERSION DATE 
10.16.19 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
Specific Aim 1:  Low-dose GH administration for 18 months to osteopenic obese men and 
women will increase bone mass, improve bone microarchitecture and increase bone 
strength.  
We will investigate in osteopenic men and women with obesity and relative IGF-1 deficiency, 
whether GH administration for 18 months to increase IGF-1 levels within the normal range 
results in: 
A. Increased BMD  
B. Improved bone microarchitecture, including trabecular and cortical thickness.   
• The increase in trabecular thickness will be mediated primarily by GH and the effect on 
cortical thickness by IGF-1  
C. An increase in bone strength, as determined by finite element analysis 
 
 
Specific Aim 2:  We will investigate mechanisms responsible for the increase in bone 
strength due to GH administration.  We hypothesize that the increase in strength will be 
mediated by:  
A. A reduction in bone marrow fat mediated by a decrease in Pref-1 associated with an 
increase in osteoblast activity, assessed by markers of bone formation, including P1NP  
B. Increased insulin, in associations with an increase in undercarboxylated osteocalcin    
C. Improved body composition, including a decrease in abdominal adiposity and lipid deposits 
in muscle and liver, and an increase in muscle mass 
D. A reduction in inflammatory cytokines and improvement in the serum lipoprotein apoB  
E.  An increase in circulating vitamin D.   
 
 
 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
2 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Obesity is an important risk factor for osteoporosis and fractures. With the growing 
prevalence of obesity in the U.S., understanding the pathophysiology of bone loss in this 
population is of importance to public health. The etiopathology of obesity-associated bone loss is 
incompletely understood but includes reduced bone formation, deleterious effects of 
inflammatory cytokines, low levels of circulating vitamin D and elevated lipids and lipoproteins 
and ectopic lipid deposits.  Growth hormone (GH) is a critical mediator of bone homeostasis and 
is markedly reduced in obesity. Obesity is a state of relative GH and IGF-1 deficiency.  Our 
preliminary data suggest an important role for the GH/insulin-like growth factor 1 system in the 
pathogenesis of bone loss in obesity.  The GH-IGF-1 system is also an important regulator of 
lipolysis, inflammation and vitamin D metabolism and decreases lipids and lipoprotein levels.  
Our preliminary data demonstrate that GH administration for 6 months increases markers of 
bone formation and GH administration for 12 months increases BMD of the lumbar spine in 
obese subjects.  An 18-month study will be necessary to investigate the full effects of GH on 
skeletal physiology.  The development of novel imaging techniques, including Xtreme CT and 
FEA, provides an opportunity to investigate the effects of GH on skeletal structure and strength, 
which will provide insights into the pathogenesis of obesity related bone loss. Understanding the 
pathophysiology of bone loss in obesity may help identify new treatment targets for this 
important complication.   
An emerging area of intense interest is the role of the common mesenchymal stem cell 
bone marrow precursor of both osteoblasts and adipocytes.  Increased bone marrow fat is seen in 
subjects with morphologic evidence of bone weakness including endplate depression and 
compression fractures.  Therefore, an understanding of the factors that influence the development 
of bone marrow fat and stem cell differentiation is of clinical importance.  This will be the first 
study on the effects of GH on stem cell differentiation and bone marrow fat in humans. 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
Over the five years of this proposal, we expect to screen 300 patients in order to enroll 75 (38 
healthy women and 37 healthy men) total men and women with obesity, osteopenia and 
relatively low IGF-1, adiposity for an evaluable 50 subjects. We will attempt to replace subjects 
who have dropped out of the study to ensure 50 completers at 18 months (for which the study is 
powered). 
 
Eligibility: 
Subjects will undergo a pre-study screening visit to determine eligibility for the study. 
 
Inclusion criteria: 
• Ages 18-65 and generally healthy 
• BMI ≥ 25 kg/m2  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
3 
• BMD T or Z-score ≤ -1.0 (as measured by DXA) 
• IGF-I within or below the mean (plus 10% above the mean) for age and gender 
     Exclusion criteria 
• For women: amenorrhea for 3 months or more if premenopausal, pregnancy or 
breastfeeding, polycystic ovary syndrome 
• Elevated creatinine or TSH levels; alanine amino transferase levels greater than 2 times 
the upper limit of normal 
• History of diabetes mellitus, cancer or other serious chronic disease 
• Use of osteoporosis medications  
• Medication that could affect bone metabolism within the past three months, such as 
chronic oral glucocorticoids, gonadal steroids, or anticonvulsants 
• Hct > 5 units below the lower limit of normal 
• Routine MRI exclusion criteria including the presence of pacemaker or cerebral 
aneurysm clips 
• Osteoporosis, that, according to WHO classification (BMD T score less than or equal to -
2.5 at the AP spine, total hip or femoral neck), would warrant treatment consideration. 
• 
 
 
 
 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Screening Visit: (n=300: 150 healthy obese women and 150 healthy obese men) 
• A complete medical history, physical examination, height, weight, waist and hip 
circumferences.  Calculation of BMI, waist:hip ratio.   
• Fasting glucose, HbA1c, IGF-1, TSH, creatinine, SGPT, urine pregnancy test, HCT, 
Ghrelin 
• DXA scan to evaluate for osteopenia and body composition  
• Measurement of bone age for males 18 or 19 years old 
 
 
 
 
 
 
 
 
Study Visits: 
1. Baseline: (n=75: 38 healthy obese women and 37 healthy obese men) 
The baseline visit will occur within 8 weeks after the screening visit.  The following assessments 
will be made during the baseline visit days and will occur within a 30-day period.   
• Assessment of potential factors affecting BMD: family history of osteoporosis, alcohol, 
free testosterone, estradiol, exercise (Paffenbarger Physical Activity Questionnaire and 
Modified Activity Questionnaire (MAQ)), Calcium & Vitamin D Intake (Calcium & 
Vitamin D Frequency Questionnaire), and food diary log 
• Waist circumference, weight, and BMI 
• 2-hour GHRH-arginine GH stimulation testing 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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• CT 
• DXA scan (only if baseline occurs more than 6 weeks after screening visit) 
• Xtreme CT 
• Head x-ray if subject reports possibility of metal in face or head 
• MRI/MRS 
• Blood drawn to determine levels of hormones and other chemicals  
• Oral glucose tolerance test (OGTT)  
• Functional Strength Test 
• 
 
 
 
2. Follow-up visits: 
The following assessments will be made during the 6 week, 3 month, 4.5 month, 6 month, 9 
month, 12 month, 15 month, 18 month and 24 month visits.  The 3 week, 9 week, and 4 month 
visits will be performed during a +/- 2 week interval around the indicated return time to allow for 
potential scheduling conflicts.  The 6 month, 9 month, 12 month, 15 month, 18 month and 24 
month visits will be performed during a +/- 1 month interval around the indicated return time.  
Subjects who drop out or are discontinued from the study after participating for at least 9 months 
will be asked to come in for a final study visit that will be identical to the 18-month study visit.  
The follow-up visits involve: 
• Medical history, physical examination, weight, waist and hip. Return menses (for 
women), growth hormone dosing records, and all study medication vials.  
• DXA scan (12 month, 18 month, and 24 month visits) 
• CT scan (18 month visit) 
• Low-dose CT for body composition only (6 month visit)*  
• Xtreme CT scan (12 month, 18 month, and 24 month visits) 
• MRI/MRS (6 month visit* and 18 month visit) 
• Blood drawn to determine levels of hormones and other chemicals (3 week, 9 week, 4 
month, 6 month, 9 month 12 month, 15 month, 18 month and 24 month visits). 
• OGTT (6 month, 12 month, and 18 month and 24 month visits) 
• Paffenbarger Physical Activity Questionnaire and Calcium & Vitamin D Frequency 
Questionnaire (6-month, 12-month, 18-month, 24-month visits) 
• Functional Strength Test (6-month, 12-month, 18-month and 24-month visits) 
• Food diary log (18-month visit) 
• 
 
 
 
*discontinued performing starting in August 2017 
 
Study endpoints 
 Aim 1: 
 
   Primary Endpoint: Change in BMD over 18 months in the GH vs placebo group.  
   Secondary Endpoints:  
1. 
Bone microarchitectural parameters 
2. 
Bone strength by FEA 
 Aim 2:  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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   Primary Endpoint:  Change in bone marrow fat in the GH vs placebo group. 
   Secondary Endpoints:  
      1.    Pref-1.   
1. Bone formation markers P1NP, ucOC.  
2. Fasting and 2-hour OGTT insulin.  
3. Inflammatory markers hsCRP, TNF1 receptor, and IL-6.  
4. Serum lipoproteins.  
5. 25-OH vitamin D.  
 
Dual-energy X-ray-absorptiometry (DXA): DXA will be used to measure BMD of the 
AP and lateral spine (L1-L4), distal radius, total hip, femoral neck and total body. Total fat and 
fat-free mass measurements will also be obtained.  
Quantitative computed tomography (QCT): As DXA may overestimate BMD in 
obesity,107 we will perform volumetric QCT of L1 and L2 and of the proximal femur (GE 
LightSpeed Pro CT scanner, GEHealthcare, Waukesha, WI or Somatom Definition, Siemens 
Healthcare, Forchheim Germany) and low-dose single slice CT of the abdomen and thigh for 
body composition. 
High-resolution CT: High resolution peripheral QCT will be used to measure volumetric 
density, morphology and microarchitecture at the distal radius and distal tibia (XtremeCT, 
Scanco Medical AG®, Bassersdorf, Switzerland). The outcome variables computed by automated 
analysis will include volumetric BMD (g hydroxyapatite/cm3) for total, trabecular, and cortical 
regions; cortical thickness (µm) and porosity measures and trabecular number (mm-1), thickness 
(mm), and separation (mm). HR-pQCT measurements will be performed at the non-dominant 
wrist and leg in the absence of a history of fracture. 
Bone Strength: Finite element (FE) models will be generated and analyzed as published93 
using software provided by Scanco Medical AG (Bassersdorf, Switzerland) by converting each 
voxel to an equally-sized brick element,111 resulting in FE models with approximately 2 million 
elements.  
MR spectroscopy: Proton MR Spectroscopy of lumbar vertebral and femoral bone 
marrow (for lipid content), muscle and liver (for lipid content) will be performed with a 3.0 Tesla 
MR scanner (Siemens Trio, Siemens Medical Systems, Erlangen, Germany) as previously 
described by our group.97, 105, 106, 114-116  
Functional strength testing: Functional strength of the hand and forearm will be 
determined. Additionally, functional strength of the lower and upper extremities will also be 
determined.  
Endocrine testing:  
• fasting GHRH-arginine stimulation test  
• GH 
• IGF-1 
• Bioactive IGF-1 
• P1NP and CTX 
• Osteocalcin 
• Pref-1 
• hsCRP and apoB 
• IL-6 and TNF-)-α receptors I and II 
• Testosterone 
• Estradiol and SHBG 
• 75-g oral glucose tolerance test (OGTT)  




Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
7 
A physician will be available at all times during the study by pager to answer any questions a 
patient might have.  The physician will arrange to immediately see every patient with a concern.  
All efforts will be made to protect the confidentiality rights of the study subjects who will be 
referred to by code numbers only.  Confidentiality of the patients will always be of paramount 
importance to study investigators.  No data on patients will be shared with persons other than 
those directly involved in the study, except at the documented request of the patient.  Samples 
that are sent to laboratories outside of 
will be labeled with a non-identifying numeric code.    
 
All adverse events will be reported to the IRB in a timely manner according to the guidelines 
provided by Partner’s Human Subjects Research Committee. 
 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
Safety assessments 
1. IGF-I levels:  
a. Must have IGF-I within or below the lowest 2 quartiles for age and gender 
b. Measurements at screening, baseline, 6week, 3 month, 4.5 month, 6 month, 9 
month, 12 month, 15 month, 18 month and 24 month 
c. Dose decrease for IGF-I levels above the upper limit of normal 
2. Glucose: 2 hour 75 g OGTT: baseline, 6, 12, 18 and 24 months. Fasting glucose at 
screening, 6 week, 3 month, 4.5 month visits.  
3. Pregnancy testing: screening, baseline, 6 week, and 3, 4.5, 6, 9, 12, 15, 18 and 24 months 
(Additional testing will be arranged if lengthened menstrual cycle) 
4. HbA1c: screening, 6 month, 12 month, 18 month and 24 month 
 
 
Subjects will be discontinued from the study if they develop  
a. Glucose:  fasting > 126 mg/dl or 2h GTT > 200 mg/dl while they are taking the study 
medication (between the baseline visit and the day before the 18 month visit) 
b. Diabetes: HbA1c > 6.5% 
c. Positive pregnancy test 
d. Severe / intolerable side effects of GH 
e. Development of malignancy  
f. Initiation of the following medications: OCPs 
 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 





SAP_001.pdf: 
Skeletal Physiology Dysregulation in Obesity: The Role of 
Growth Hormone 
 
NCT# 01724489 
 
Version Date: November 7th, 2019 


Statistical Power and Statistical Analysis 
Statistical power:  For Aim 1, primary endpoint, with an n=75 and 50 completers, we will have >80% 
chance of detecting a difference in the rate of BMD AP lumbar spine increase of 0.024g/cm2/y at a 2-
sided p=0.05 level. This compares favorably with the rate of BMD AP spine increase of 0.036 g/cm2/y in 
a study by Baum et al.54 administering GH for 18 months to hypopituitary subjects with GH deficiency. 
This was calculated with software developed by co-investigator 
 for sample size for 
random slopes models, available in Matlab 
 
The variance covariance matrix of the random effects, Ψ, and residual variance, σ , were estimated from 
longitudinal data from Baum et al.54 that had originally been analyzed by 
. The variance of 
the intercept was 0.024, slope 0.000211, covariance 0.00199 and residual variance, σ , 0.00092 and an 
exponential drop-out rate of 0.36/yr, which is greater than we expect. The program uses the fact that the 
variance covariance matrix for the fixed effects of the model are: V(B) = {X’[s2] + ZYZ’]-1X}f-1. One 
incorporates drop outs by replacing X’[s2] + ZYZ’]-1X by a weighted sum for different follow-up times 
with weights equal to the follow-up probability -- a special case of the general model described in 
Pinheiro and Bates.121 For Aim 2, primary endpoint, with 50 completers we can detect 0.81 x SD of the 
difference in bone marrow fat content over a year; For secondary endpoints: for trabecular thickness 
(TbTh) and cortical thickness (CoTh), based on our preliminary data in obese men receiving placebo for 6 
months in which the standard deviation (SD) of the change in TbTh was 0.0047mm and of CoTh was 
0.0015mm, we will be able to detect an annual increase of 0.008mm and 0.012mm, respectively; for FEA 
we will have a power of 80% at a two-sided p=0.05 significance level, if the true rate of difference in 
estimated failure load between the treatments is 316 units, based on an assumption that the SD is 570 
units, as derived from Boutroy et al.89 With 50 completers, we will have an 80% power at a 2-sided 
p=0.05 level to see a difference in P1NP of 38.6 ng/ml, total abdominal fat of 50.8 cm2, lean mass of 1.2 
kg, vitamin D of 0.025 ng/ml, hsCRP of 0.025 mg/l, and apoB of 18.6 mg/dl per year. These were 
calculated from our preliminary data administering GH to obese subjects for 6 months. The power for the 
mediation analyses (see below) depends on the effect size of the treatment on BMD and on the correlation 
of the secondary endpoint on BMD. We derived a formula using the delta method. With at least 40 
subjects we will have an 80% chance of achieving significance at a two-sided p=0.05 level if the effect 
size is 2 units and the correlation is 0.5. For the 6-month withdrawal period, we will have adequate power 
to test whether the BMD remains significantly different from placebo at 24 months. We will have 80% 
power to detect a difference of 0.04 g/cm2 assuming that there are at least 43 patients still in the study at 
18 months (we expect 50).  
Data analysis plan:  We will pool data from men and women using a random slopes model; we will 
consider a model where each patient has a random slope and intercept. The mean intercept and slope may 
be different for men and women and in each treatment group.  The primary analysis is a pooled analysis 
of treatment effect across gender with weights equaling the frequency of men and women in the sample.  
A secondary analysis will test for the significance of the treatment-gender interaction on the rate of 
change of BMD and all other endpoints. For all analyses, an intent-to-treat analysis will be performed. 
We plan to apply the guidelines developed by the National Research Council regarding missing data.122 
Our primary analysis, the random slopes model, assumes that data is missing at random. We also will 
conduct two sensitivity analyses. The first assumes that the missing data is a function of the unobserved 
random effect123 and the second tests the assumptions in this model under other missingness 
mechanisms.124 We will also determine which of the secondary endpoints appears to mediate the 
treatment effect on an endpoint, such as BMD, microarchitectural parameters, and bone marrow fat by 
examining the effect of treatment on the potential mediator and of the potential mediator on the endpoint; 
examples of this will include whether Pref-1 mediates the effects of GH on bone marrow fat or strength, 
and whether bone marrow fat, body composition variables, inflammatory markers, lipids or vitamin D 
mediate the effects of GH on bone strength. The effect on one endpoint by a potential mediator is the 
product of the two effects. The Sobel test will test whether this effect is zero.125 As there are no known 
moderators of GH treatment in this population and the population has been purposely selected for 
osteopenia, we will not control for covariates other than gender in our primary analysis. We will perform 
exploratory analyses to answer the following: 1. Among an osteopenic population are there covariates 


(such as family history, smoking, alcohol, exercise, free testosterone or estradiol) that predict problems 
such as anomalies in bone microarchitecture and predicted strength? 2. Are these factors moderators of 
the treatment effect of GH?  Both of these analyses will use stepwise variable selection using a random 
effects model as above. 3. Is the effect of GH on BMD mediated by IGF1?  We will perform a mediation 
analysis using a random effects model with final GH dose and a final GH dose time interaction in the 
treated group.   
Timeline: Screening, enrollment, and study visits will occur from year 1 through year 5. Data 
management will occur in years 1-5, and analyses and manuscript preparation will be performed in years 
4-5.