Clinical trial NCT01301183
Conditions: Anorexia Nervosa
Keywords: Anorexia Nervosa Estrogen Teenagers IGF-1
Sponsor: Massachusetts General Hospital
Start date: 2011-02-01; Completion date: 2020-03-01
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Teenage girls with anorexia nervosa (AN) are at risk for low bone density and low rates of bone accrual, raising concerns regarding acquisition of peak bone mass, an important determinant of future bone health and fracture risk. Important factors contributing to low bone density in AN include low levels of estrogen and insulin like growth factor-1 (IGF-1). While estrogen is important for preventing bone loss, IGF-1 is important for optimizing bone formation. We have shown in a previous study that replacement of estrogen is effective in increasing bone density in teenage girls with AN; however, this increase in bone density remains lower than that seen in normal-weight controls over the same duration, and residual deficits persist. Importantly, the impact of administering replacement doses of IGF-1 with estrogen replacement has not been studied in teenagers with AN.

This study will examine the impact of administering recombinant human (rh) insulin like growth factor-1 (rhIGF-1) with estrogen (to mimic pubertal levels of these hormones) versus administration of estrogen alone on bone metabolism in adolescent girls with anorexia nervosa (AN).

One aim of this proposal is to investigate whether co-administration of insulin like growth factor-1 (rhIGF-1) with physiologic estradiol replacement to adolescent girls with AN will increase BMD (bone mineral density) more than estrogen monotherapy, and whether bone mass will approach that seen in healthy adolescent girls. An additional aim is to determine whether co-administration of rhIGF-1 with estradiol to mimic the normal pubertal milieu stimulates bone formation through an IGF-1 mediated anabolic effect, increases bone density to a greater extent than estrogen monotherapy, and improves bone mass accrual to approach that in healthy controls. The impact of rhIGF-1 +estradiol versus estradiol alone on bone microarchitecture will also be assessed.

Detailed description:
Given the increasing prevalence of AN, its profound consequences on bone health, and lack of optimal treatment interventions, these studies will provide critical data needed to identify optimal treatment strategies for this severe co-morbid disease using state- of- the- art endpoints of BMD, bone microarchitecture and strength. Although both low IGF-1 and hypogonadism are associated with increased skeletal fragility in AN, the mechanisms by which these factors interact are incompletely understood. Specifically, the increased skeletal fragility that is associated with AN is poorly reflected by DXA-derived BMD. Furthermore, the magnitude and mechanisms by which IGF-1 deficiency and hypogonadism influence bone microarchitecture are not defined. The growing incidence of eating disorders in adolescent girls and their long-term effects on skeletal health provide strong rationale for studies that will provide a better understanding of these issues and the evaluation of rational therapeutic approaches. The studies described in this proposal utilize both cross-sectional and RCT approaches to achieve this goal. Additionally, our utilization of sophisticated techniques such as high resolution peripheral QCT (HR-pQCT) will improve our understanding of the relationship between IGF-1, gonadal steroids and bone quality and will aid in the development of effective therapies in the treatment of skeletal fragility in Anorexia Nervosa.

Arms: arm 1: RhIGF-1 with transdermal 17-beta estradiol arm 2: Placebo and transdermal 17-beta estradiol
Interventions: intervention 1: RhIGF-1 with transdermal 17-beta estradiol intervention 2: Placebo and transdermal 17-beta estradiol
Intervention descriptions: intervention 1: RhIGF-1 will be started at a dose of 30mcg/k/dose twice daily, and will be titrated up or down in 25% dose increments to maintain IGF-1 levels in the upper half of the normal range.

Estradiol will be delivered transdermally using a 100 mcg patch (Vivelle Dot) changed twice weekly. Subjects will receive cyclic micronized progesterone (Prometrium) 100 mg daily for the first 10 days of each month. All subjects will receive supplemental calcium and vitamin D. intervention 2: Placebo injections will be administered twice daily. Estradiol will be delivered transdermally using a patch (100 mcg) changed twice weekly. Subjects will receive cyclic micronized progesterone (Prometrium) 100 mg daily for the first 10 days of each month. All subjects will receive supplemental calcium and vitamin D.

Protocol documents:
ICF_002.pdf: 
Partners HealthCare System 
Research Consent Form 
 
 
 
Certificate of Confidentiality Template 
Version Date: January 2018 
 
 
 
Page 1 of 26 
 
 
Subject Identification 
 
Protocol Title: Effects of Anorexia Nervosa on Peak Bone Mass 
 
Principal Investigator: Madhusmita Misra, MD 
 
Site Principal Investigator:       
 
Description of Subject Population: Subjects between 14 and 22 years old 
diagnosed with anorexia nervosa 
Effects of Anorexia Nervosa on Peak Bone Mass 
NCT01301183 
Version date: March 29, 2018 
Consent Form
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form.  
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep.
 
Some of the people who are eligible to take part in this study may not be able to give consent 
because they are less than 18 years of age (a minor).  Instead we will ask their parent(s) to 
give permission for them to take part in the study and will ask them to agree (give their 


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Version Date: January 2018 
 
 
 
 
Page 2 of 26 
Subject Identification 
assent) to take part.  Throughout the consent form, “you” always refers to the person who 
takes part in the study. 
 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
 
Why is this research study being done? 
 
Anorexia nervosa is common in girls and young women.  Anorexia nervosa can lead to decreased 
bone density and increased risk of broken bones. People with anorexia nervosa often have low 
levels of hormones called insulin like growth factor-1 (IGF-1) and estradiol (a form of estrogen).  
IGF-1 stimulates bone cells to build bone.  Estradiol helps to build bone and also helps prevent 
bone breakdown.  We are doing this study to find out if giving low doses of IGF-1 and estradiol 
will help increase bone density in girls and young women with anorexia nervosa.  
 
This study will measure bone density and bone microarchitecture (tiny structures within bone) 
before and after receiving 12 months of estradiol (estrogen) supplement and placebo or 12 months 
of estradiol supplement along with IGF-1 supplement.  
 
Recombinant human IGF-1 (rhIGF-1, the IGF-1 medication) and estradiol skin patches are not 
approved by the U.S. Food and Drug Administration (FDA) to improve bone strength.  This 
means that IGF-1 can only be used in research studies. 
 
The U.S. Food and Drug Administration (FDA) has approved IGF-1 to treat conditions of short 
stature (height) due to primary IGF-1 deficiency but the FDA has not approved IGF-1 to improve 
bone strength. 
 
Estrogen has been approved by the FDA for use in children and adolescents with low estrogen 
levels.  However, it has not been approved for improving bone strength in teenagers with 
anorexia nervosa.  
 
This research study will compare rhIGF-1 to placebo.  The placebo looks exactly like rhIGF-1, 
but contains no rhIGF-1.  During this study, you may get a placebo instead of rhIGF-1.  Placebos 
are used in research studies to see if the results are due to the study drug or due to other reasons. 
You will take the study drug, either rhIGF-1 or placebo, twice a day for 12 months by using a 
small needle to put the study drug under your skin.  
 


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Subject Identification 
We are asking you to take part in this study because you have anorexia nervosa. 
 
 
 
Our approved target enrollment study wide is 272, with 222 subjects approved to be enrolled at 
Partners. We expect to enroll 200 subjects with anorexia nervosa in this research study, in order 
to find 100 subjects who can complete the entire study. We will enroll 72 subjects without 
anorexia nervosa in order to find 36 who can complete the entire study.  
 
The National Institutes of Health are paying for this research to be done. 
 
 
How long will I take part in this research study? 
 
You will be in this study for up to a total of 14 months. During this time, we will ask you to 
make 10 study visits to MGH.   
 
 
What will happen in this research study? 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures.   After signing the consent form you can decide not to participate in the 
study.   We will first ask you to come to a Screening Visit.  If you are eligible to continue taking 
part in this study, we will ask you to come back for 9 more study visits.  The study visits are 
discussed in detail below.  
 
Screening Visit (Visit 1) 
 
The screening visit will take about 3 hours. During this visit, we will do some tests to see if you 
qualify to take part in this research study. The study doctor will review the results of these tests 
and procedures. 
 
At this visit, we will:  
 
 
• Ask you questions about your health and give you a brief physical exam, 
including finding out your stage of puberty and menstrual history.  We will 
measure your vital signs (blood pressure, temperature, heart and breathing rates). 
 


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• Measure your height and weight with you standing backwards so you cannot see 
the numbers. 
 
• Draw a blood sample for routine tests.   
 
• Ask for a urine sample to test for pregnancy, or use serum from blood already 
being collected to test for pregnancy if a urine sample cannot be obtained. If you 
are pregnant, you cannot take part in this study. If your test results show that you 
are pregnant, we will let you know. If you are age 14-17, we will tell your 
parent/guardian the results of this test if you agree to let us. Even if you don't 
agree, the study doctor may decide to tell your parent/guardian based on your age 
and maturity. If you are at least 18 years old, we will tell you and not your parents 
about the results of the test. This test result will not become part of your medical 
record. It will stay a part of your research record. Every effort will be made to 
protect this information. However, there are times when the study doctor or study 
staff will legally have to release this information.  
 
• Give you a psychiatric interview after the screening visit.  This interview will be 
done by a study psychiatrist or psychologist and it may be done over the 
telephone.  
 
• Take a bone age x-ray of your left wrist.  This is a special type of x-ray scan that 
helps us find out how mature your bones are. 
 
• We will study your bone strength, body fat, and muscle content. To do this, we 
will use a special type of X-ray machine called a dual energy x-ray 
absorptiometry (DEXA) machine. During the DEXA scan, we will ask you to 
remove all metal items from your body including clothing fasteners, jewelry and 
accessories. We may ask you to wear a hospital gown if necessary. You will lie 
still on the scanning table while the arm of the DEXA machine passes over your 
body from head to toe. This will take about 20 minutes. DEXA scans are for 
research purposes only and the scans do not reliably show bone disorders such as 
tumors or other abnormalities. The results are not useful for your care and won't 
be put in your medical record. 
 
• We may do the DEXA scan at the baseline visit (Visit 2) 
 
• Give you a food diary.  A nutritionist will give you instructions on how to fill it 
out and ask you to either mail it back to us or bring it back at the next visit. 


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Although it is hoped that you will complete the food diary, you can choose not to 
do so and still participate in the study.  
 
• Give you a snack once you complete the visit   
 
 
Study Drug (rhIGF-1): 
You will be given information about the study drug, rhIGF-1, at this initial Screening Visit, but 
will not receive study drug until you have been found eligible for the study. We will give you 
instructions about how to give yourself rhIGF-1 injections at home. You will give yourself both 
rhIGF-1 and placebo injections exactly the same way.  You will need to give yourself these 
injections twice a day using a syringe and needle. These injections will need to be given under 
your skin about 30 minutes after breakfast and dinner every day for 12 months. You may give 
yourself the injection under the skin of your arm, stomach, or thigh. We will give you emergency 
contact information for a member of the study staff, in case you experience trouble giving 
yourself the injections.  The bottle containing rhIGF-1 needs to be stored in the bottom shelf of a 
refrigerator at all times (except when taken out for an injection). 
 
Half of the subjects with anorexia nervosa will receive rhIGF-1.  The other half will receive 
placebo.  The placebo looks exactly like the rhIGF-1 but does not contain any rhIGF-1.  You will 
have an equal chance (1 out of 2) of receiving either rhIGF-1 or placebo.  The MGH research 
pharmacy will randomly decide (like flipping a coin) whether you will receive placebo or IGF-1.  
Only the pharmacy will know whether you will receive IGF-1 or placebo, but your study doctor 
can find out this information if needed.  
 
We will ask you to write down the time at which you give yourself the injections at home in a 
logbook that we will give to you. You will need to bring the logbook with you to show the study 
doctor at each visit. 
 
rhIGF-1 may rarely cause your blood sugar level to drop.  We will give you instructions about 
how to recognize the symptoms of low blood sugar and what to do if you have low blood sugar. 
You should carry a juice box or glucose (sugar) pills with you at all times while you are taking 
part in the study. If you have any symptoms of low blood sugar, you should drink a juice box or 
take 2 glucose (sugar) pills and call a member of the study staff. Some symptoms of low blood 
sugar are weakness, dizziness, trembling, nausea, anxiety, hunger, and paleness.   
 
Study Drug (estrogen patches and progesterone):  
We will give you self-adhesive patches delivering estrogen (100 micrograms/day). Everyone 
taking part in this study will use patches with estrogen, not placebo.  You will apply 1 patch 
twice a week (Sunday morning and Wednesday night of every week for the next 12 months). 


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These patches are less than ¾ inch across in size and may be applied on the lower belly or back. 
The patch should be applied on a clean, dry area that is not oily, bruised or irritated. You should 
avoid putting the patches around your waistline since tight clothing may rub the patch off.  
 
You should apply the patch immediately after opening the package and removing the protective 
liner. It should be pressed firmly in place with the palm of the hand for about 10 seconds, making 
sure there is good contact, especially around the edges. If a patch falls off, it may be reapplied, or 
if necessary, a new patch may be applied. The location of application should be rotated, with at 
least 1 week between applying the patch again at the same location.  
 
You will be able to swim and shower while wearing the patch.  
 
If you are a woman who can become pregnant, we will give you a urine or serum pregnancy test 
before you start using the estrogen patch.  Pregnant women cannot take part in this study. 
 
We will continue to give you pregnancy tests during the entire study.   
 
You will also take a pill containing 100 mg of Prometrium (Progesterone) for the first 10 days of 
every month for the next 12 months. Prometrium will cause you to have menstrual periods. 
 
Study Drug Reminders: 
You will receive a paper medication calendar to keep track of each dose taken and to return to 
study staff at each visit. Additionally, we can enter medication reminders on your or your 
parent/guardian’s phone’s calendar to remind you when to take the different study drugs and how 
much. You can change the settings and frequency, or discontinue the alarms at any time. All 
patient information will remain confidential, and no identifiers will be used. Please indicate 
below if you would like to receive reminders via your phone’s calendar. 
 
 Yes 
 No 
Initials___________ 
 
Baseline Visit (Visit 2)  
 
If you are eligible and want to continue in the study, we will ask you to come to MGH in the 
morning at about 8:00 a.m. This visit will take about 4 hours. You will need to come in fasting. 
Fasting means that you cannot have anything to eat or drink, except for water, after midnight.  
 
At this visit, we will: 
 
• Ask you questions about your health and give you a brief physical exam. 
 


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• 
Ask you to bring in your food diary and review it with the nutritionist.  We will give you 
another food diary to bring back at your next study visit.     
 
• 
Measure your height and weight. 
 
• 
Ask you about your exercise schedule. 
 
• 
Draw blood to measure the amount of certain chemicals in your blood.  These include 
calcium, vitamin D, other chemicals important for bone formation, and glucose (sugar).  
 
• 
We will perform the DEXA scan at this visit, if it was not performed at the initial 
Screening Visit.  
 
• 
Teach you and your parents or guardians how to give yourself rhIGF-1 injections. 
 
• 
Give you a breakfast of your choice to eat.  
  
• 
Teach you how to give the IGF-1 injections.  You will give the first rhIGF-1 shot under 
your skin about 30 minutes after you finish eating breakfast.  
 
• 
Look at your bone structure by giving you an X-treme CT. The X-treme CT is an X-ray 
machine that can take detailed pictures of your bones.  
 
• 
Ask you to take calcium and vitamin D supplement pills daily.  These pills will help your 
bones grow while you are taking part in the study. Not getting enough calcium and 
vitamin D through food or through supplements may prevent your bones from growing 
well. We will give you 6 months worth of pills at this visit.  
 
• 
Ask for a urine sample to test for pregnancy, or use serum from blood already being 
collected to test for pregnancy if a urine sample cannot be obtained. 
 
• 
Ask you to complete an eating disorder questionnaire. This will take you about 10 
minutes.  
 
• 
Ask you to complete two questionnaires regarding your mood. These will take you about 
10 minutes total. 
 
• 
Ask you to complete questionnaires that assess cognition (if time and circumstances 
allow during the visit).  
 


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• 
Give you a snack once you complete the visit   
 
You may sometimes have the option of combining the first two visits, the screen and baseline.  
 
 
1-month (Visit 3), 4.5-month (Visit 5), 7.5-month (Visit 7), and 10.5-month 
(Visit 9) 
These visits will last about 30 minutes. You will need to come in fasting. At these visits, we will: 
 
• 
Ask you questions about your health and give you a brief physical exam 
 
• 
Measure your height and weight 
  
• 
Draw some blood to measure the amount of glucose and IGF-1 in your blood.  
 
If you do not live close to the study center, you will be able to have your blood drawn 
offsite. If you choose this option, you will also have questions about your history and 
your physical exam done by a local doctor for each offsite visit. Some of the tests will be 
done at these offsite locations, and the results will be mailed to us.  Otherwise, the 
samples themselves will be mailed to us. If you are a Hasbro patient, you can conduct 
these visits and the blood draws with your treatment team at Hasbro. 
 
• 
Ask for a urine sample to test for pregnancy, or use serum from blood already being 
collected to test for pregnancy if a urine sample cannot be obtained. 
 
3-month (Visit 4) and 9-month (Visit 8) 
These visits will last about 30 minutes. You will need to come in fasting. If you are a Hasbro 
patient, you can also conduct these visits and the blood draws with your treatment team at 
Hasbro.   
At these visits, we will: 
 
• 
Ask you questions about your health and give you a brief physical exam 
 
• 
Ask for a urine sample to test for pregnancy, or use serum from blood already being 
collected to test for pregnancy if a urine sample cannot be obtained. 
 
• 
Measure your height and weight  
 


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• 
Ask you to bring in your food diary and review it with the nutritionist.  We will give you 
another food diary to bring back at your next study visit. 
 
• 
Draw some blood to measure the amount of glucose and IGF-1 in your blood, as well as 
the amount of some chemicals that show how your bones have grown. 
 
• 
Ask you about your exercise schedule. 
 
6-month (Visit 6) and 12-month (Visit 10) 
These visits will include all of the procedures done at the baseline visit (Visit 2) listed above, 
including the DEXA scan.   
 
 
 
 
Taking You out of the Study Early 
 
The study doctor may take you out of the study without your permission.  This may happen 
because: 
• The study doctor thinks it is best for you to stop taking the study drug 
• You are unable to attend the required study visits 
• You are unable to give the study drug 
• The Sponsor decides to stop the study 
• We stop doing the study for other reasons 
• You become pregnant 
 
If this happens, the study doctor will explain why you need to stop taking part in the study.   
 
 
Review of Medical Records from Hospital Admissions or Emergency Department 
Visits 
 
MGH has an electronic system that lets your study doctors know if you are admitted to a Partners 
Hospital, or if you visit a Partners Hospital Emergency Department for any reason.  This alert 
will let the study doctors know why you are there.  We want to make sure the study doctors 
know about any possible problems or side effects you experience while you are taking part in the 
study. 
 
Sending Study Information to Research Collaborators Outside Partners 


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Subject Identification 
 
We may need to send your study samples to research collaborators at different labs. We will 
label all your study materials with a code instead of your name.  The key to the code connects 
your name to your study information and samples.  The study doctor will keep the key to the 
code here at Partners and will not share it with our research collaborators.  No one outside of 
Partners will know which study information or samples are yours. 
 
Storing Samples at MGH for Future Use 
 
We would like to store some of your samples and health information for future research related 
to eating disorders. We will label all your samples and health information with a code instead of 
your name.  The key to the code connects your name to your health information and samples.  
The study doctor will keep the key to the code in a password protected computer. 
 
About 28 tablespoons of blood will be drawn throughout the entire course of the study.    
 
Do you agree to let us store your samples and health information for future research related to 
eating disorders? 
 
 Yes 
 No 
Initials___________ 
 
If later you change your mind and want your samples destroyed, contact the study doctor. 
 
Future Studies: 
 
We would like to contact you about future research studies. Please indicate below whether or not 
we may contact you about future research studies: 
 
Yes: _____          No: _____          Initials: _____ 
 
 
 
If you turn 18 during this Study 
 
If you turn 18 years of age while you are taking part in this study, we will ask you to sign a new 
consent form at that time. 
 
 
 


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What are the risks and possible discomforts from being in this research 
study? 
 
Risks of rhIGF-1: 
 
RhIGF-1 (recombinant human IGF-1) is FDA approved for treating children with short stature.  
It has been used successfully in children with short stature (height) and in children with very low 
levels of IGF-1 in order to increase growth rate and adult height. In these children, rhIGF-1 is 
given in higher doses than what you will receive in this study with very few side effects. IGF-1 is 
not FDA approved to improve bone strength. However, rhIGF-1 has been successfully used in 
adult women with anorexia nervosa to increase bone density with very few side effects. Takign 
rhIGF-1 may cause you to have one or more of the side effects listed below. 
 
Common side effects: 
• Mild or moderate hypoglycemia (low blood sugar). Low blood sugar occurs in a number 
of people receiving rhIGF-1. This is avoided by giving rhIGF-1 30 minutes after a meal 
or snack 
 
• The most commonly seen side effects include some redness and pain at the injection site, 
which goes away on its own.  
 
Less common side effects: 
 
• Severe hypoglycemia (low blood sugar). Some symptoms of low blood sugar include 
weakness, dizziness, nausea, trembling, paleness, and hunger. Untreated low blood sugar 
(below 40 mg/dl) may cause confusion, drowsiness, changes in behavior, coma, and 
seizures.  
 
Although this is very unlikely to happen, if by any chance your glucose levels remain low 
and you feel you may pass out, please call 911.  If you have a severe and long-lasting 
headache with nausea and vision changes, and you cannot reach a member of the study 
staff right away, please go to the nearest emergency room.   
 


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• In children receiving rhIGF-1 or growth hormone to increase growth rate, too rapid 
growth can rarely cause the growth plate at the upper end of the long bone of the thigh to 
slip. This may cause a limp, and pain at the hip and knee. RhIGF-1 and growth hormone 
can also cause some worsening of a pre-exisitng curvature of the spine. 
 
Increased pressure within the brain may sometimes occur that may cause headaches, 
nausea and vision changes.  
 
Because you will receive rhIGF-1 in a smaller dose than children with low IGF-1 levels, 
and for a very short period of time, these side effects should not happen.  
 
Rare side effects include: 
 
 Enlargement of lymph nodes 
 
  Snoring 
 
  Fat deposits at the injection site (a lump of fat which forms at the injection site) 
 
  Ear problems (fluid in ear or ear pain)  
 
  Joint pain 
 
  Heart murmur or heart failure 
 
  Allergic reaction 
 
  Development of antibodies to IGF-1. Antibodies are proteins that are produced by the body 
to help fight infection and other foreign substances in the body. However, based on earlier 
studies, they do not appear to have any medical effect. 
 
There may be other risks of rhIGF-1 that are currently unknown.  
 
Risks of Estrogen: 
 
Taking estrogen is associated with occasional side effects 
 
Common side effects: 
 
  Mild headaches 


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  Abnormal bleeding patterns, changes in nature and quantity of vaginal discharge 
 
  Tenderness and enlargement of breasts 
 
  Nausea and vomiting 
 
Less common side effects:  
 
 Abdominal pain and bloating 
 
 
Rare side effects: 
 
 Gall bladder disease 
 
 Rashes 
 
 Intolerance to contact lenses 
 
 Migraines 
 
 Dizziness 
 
 Depression 
 
 Abnormal movements 
 
 Changes in weight 
 
 Hypertension (high blood pressure) and clotting disorders (this includes clotting in large veins 
and strokes). These are more commonly seen in older women and in women with a family 
history of clotting disorders 
 
• Continuously taking estrogen without taking progesterone might lead to cancer of the 
uterus. Because we will be giving you progesterone for only 10 days every month, this 
should not be a concern.  
 
• Taking estrogen during pregnancy can be harmful to the unborn baby.  
 


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• Estrogen may cause you to stop growing earlier than expected.  This is unlikely with the 
small doses of estrogen you will take in this study.  
 
 
 
Reasons not to use estrogen 
 
• 
Known or suspected pregnancy 
 
• 
Undiagnosed abnormal uterine bleeding 
 
• 
History of clotting disorders such as clots in superficial and deeply located veins in the body 
 
• 
Known or suspected cancer of the breasts , uterus or ovaries. 
 
• 
History of smoking 
 
If you have a history of any of these disorders, you will be withdrawn from this study for your own 
safety.  If you have a family history of clotting disorders, such as those mentioned above, or a 
family history of stroke or heart attack happening before the age of 50 years in a first or second 
degree relative, we will check your blood for clotting disorders.  If are identified as having an 
abnormal result that makes you more likely to develop clotting disorders, this information will be 
made available to you at your request.   
 
Risk of Progesterone: 
 
Risks of taking progesterone by mouth include:   
 
 
clotting abnormalities,  
 
 
dizziness,  
 
 
nausea,  
 
 
abdominal pain,  
 
 
fatigue,  
 
 
headaches,  
 


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insomnia,  
 
 
nervousness,  
 
 
sleepiness and  
 
 
breast tenderness and secretion.   
 
Rare cases of breast cancer have been reported in women taking combined estrogen and 
progesterone.  Rare instances of abnormal liver function have also been reported.  The doses of 
progesterone that will be given with the estrogen patch used in this study are very small and are 
less likely to cause these side effects. 
 
Risk of Calcium and Vitamin D: 
 
Calcium taken by mouth can cause constipation and a metallic taste in the mouth. 
Vitamin D in the dose you will take does not cause any side effects. 
 
Risks of an Allergic Reaction:  
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing.  If you think you are having an 
allergic reaction, call the study doctor right away.  If you are having trouble breathing, call 911 
immediately.  
 
Risks of Fasting:   
 
Fasting for long periods of time can cause your blood sugar levels to fall below normal. If this 
occurs, it may cause weakness, dizziness, sweating, headaches, or hunger. Because fasting will 
only occur between midnight and about 8 a.m. the following morning, we do not expect you to 
have any of these side effects. 
 
Risks from study procedures:  
 
There is a risk of superficial bruising and discomfort at the site where we draw blood from.  
Infection, lightheadedness, and fainting are risks involved with blood draws.  
 
As a result of your participation in this study you will be exposed to radiation from x-ray studies 
of your bones, including the bone age x-ray of the wrist, the X-Treme CT scans and the DEXA 


Partners HealthCare System 
Research Consent Form 
 
 
 
Certificate of Confidentiality Template 
Version Date: January 2018 
 
 
 
 
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Subject Identification 
scans. Please note that this radiation is not necessary for your medical care and is for research 
purposes only.   The total amount of radiation exposure you will receive from participation in 
this study is equal to a whole body exposure of about 0.16 milliSieverts (mSv).  The dose that 
you will receive from participation in this research study is about the same as you would 
normally receive in about 20 days from background radiation from the earth and the sky. 
 
Risks to an Embryo or Fetus, or to a breastfeeding Infant 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.   
 
Acceptable birth control methods for use in this study are: 
 
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm) 
• Copper-containing intrauterine device (IUD) a device that is placed inside your uterus 
through the vagina by a doctor and can prevent pregnancy 
• Abstinence (no sex) 
 
We will complete a pregnancy test at every visit, so the likelihood of receiving any ionizing 
radiation from study procedures while pregnancy is extremely low. There is no known evidence 
of harm due to using the estrogen patch during early pregnancy but because the risks are not 
fully understood, it should not be worn during pregnancy. The effect of IGF-1 on early 
pregnancy has not yet been studied.   
 
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.   
 
Emotional Risks 
 
You may feel uncomfortable discussing issues related to eating problems, depression or anxiety, 
or substance use. The study staff is sensitive to this discomfort. If you share symptoms of 
depression, suicidality, or substance use, the study psychiatrist or psychologist will communicate 
with your existing treatment team and/or help to provide you with treatment referrals.   
 
For your safety during this study, call your study doctor and your treating doctor BEFORE you 
take any new medication. 
 
 


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Certificate of Confidentiality Template 
Version Date: January 2018 
 
 
 
 
Page 17 of 26 
Subject Identification 
 
 
 
 
OPTIONAL SUB-STUDY - Regional Fat Distribution and Bone Marrow Fat Assessment 
with MRI/MRS: 
 
In this sub-study, we will study the fat content of your bone marrow. This has been shown to be 
related to bone mineral density. The fat content of your bone marrow will be studied with 
magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS). You will get these 
tests at the baseline and 12 month visits. This will take an additional 40-45 minutes.  
Risk of MRI: 
 
You will have an MRI scan of your body to quantify regional fat depots and thigh muscle area at 
baseline and again at 12 months. MRIs use powerful magnets to make images.  There are no 
known radiation risks associated with MRI.  However, persons with metal implants, such as 
surgical clips, or pacemakers should not have an MRI.  All credit cards and other items with 
magnetic strips should also be kept out of the MRI room. Any loose metal object may cause 
damage or injury if it gets pulled toward the magnet. You will need to remove these devices 
when getting the scan. People who feel uncomfortable in confined spaces (claustrophobia) may 
feel uncomfortable in the narrow tube.  The MRI makes loud banging noises as it takes images.  
Earplugs can be used to reduce the noises.  The MRI can be stopped at any time at your request.  
If you are or suspect you are pregnant, you should not participate in this study. 
 
MRI/MRS 
The magnetic resonance spectroscopy techniques that we will use with the MRI study have the 
potential to cause localized and mild warming of your skin and the underlying tissues.  For your 
safety and comfort, the use of these methods is restricted to prevent any excessive local 
warming.  You should immediately inform us if you experience discomfort due to warming and 
the procedure will be stopped. 
 
You will get additional $50 remuneration after the baseline and 12-month visits for 
participating in this sub-study.  
 
Do you agree to take part in the optional MRI/MRS imaging for bone marrow fat 
assessment? 
Yes: _____ No: _____ Initials: _____ 
 


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Subject Identification 
 
 
 
 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this study. However, you may have improved bone density 
and bone structure after taking part in this study.  
 
Others with anorexia nervosa may benefit in the future from what we learn in this study. 
 
 
What other treatments or procedures are available for my condition? 
 
Other treatments for low bone density in anorexia nervosa include:  
 
• Regaining and maintaining your normal body weight is the best treatment for prevention 
of further and continued bone loss. However, this may not normalize bone density.  
 
• Adequate daily intake of calcium and vitamin D.  Recent studies have shown that this 
may not be sufficient alone. 
 
• Bisphosphonates.  These medications are successful in improving bone density in certain 
groups of women.  Bisphosphonates are typically avoided in young girls and women of 
reproductive age because they may be harmful during pregnancy.  
 
• PTH (Teriparatide). PTH increases bone density in post-menopausal women, however, 
PTH is not recommended in young people at this time given reports of bone cancers 
when PTH has been given to animals. 
 
Talk with the study doctor if you have questions about any of these treatments or procedures. 
 
 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part? 
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 


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Version Date: January 2018 
 
 
 
 
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Subject Identification 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.
 
 
 
Will I be paid to take part in this research study? 
 
 
We will pay $910 dollars if you complete the entire study and the MRI sub-study.  If you do not 
complete the study, we will pay you $90 dollars for each visit you complete and $50 dollars for 
each MRI. Subjects do not get paid for Visit 1 (the screening visit). 
 
We will pay for your parking in the hospital garage during study visits. 
 
We will pay for the cost of your transportation up to $25 per visit. 
 
We may use your samples and information to develop a new product or medical test to be sold.   
The Sponsor, hospital, and researchers may benefit if this happens.  There are no plans to pay 
you if your samples are used for this purpose.   
 
 
What will I have to pay for if I take part in this research study? 
Study funds will pay for all of the study visits, labs, procedures, or medications.   
 
Study funds will pay for certain study-related items and services.  We may bill your health 
insurer for, among other things, routine items and services you would have received even if you 
did not take part in the research.  You will be responsible for payment of any deductibles and co-
payments required by your insurer for this routine care or other billed care.  If you have any 


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Version Date: January 2018 
 
 
 
 
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Subject Identification 
questions about costs to you that may result from taking part in the research, please speak with 
the study doctors and study staff.  If necessary, we will arrange for you to speak with someone in 
Patient Financial Services about these costs 
 
 
 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.
 
Anne Klibanski, MD is the doctor in charge of this research study.  You can call her at 617-726-
3870 Monday through Friday 9am to 5pm.  You can also call Dr. Madhu Misra at 617-724-
5602 Monday through Friday 9am to 5pm.  Dr. Misra may also be reached at any time by calling 
617-724-5700 and asking to have her paged at ID#32383.  You may contact either physician for 
questions about the consent in addition to questions about the study. 
 
If you have questions about the scheduling of appointments or study visits, call the study 
coordinator at 617-643-0266.  
 


Partners HealthCare System 
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Certificate of Confidentiality Template 
Version Date: January 2018 
 
 
 
 
Page 21 of 26 
Subject Identification 
 
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
▪ Your rights as a research subject 
▪ Your concerns about the research 
▪ A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 
If I take part in this research study, how will you protect my privacy? 
 
Federal law requires Partners to protect the privacy of health information and related information 
that identifies you.  We refer to this information as “identifiable information.” 
 
In this study, we may collect identifiable information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable information and why: 
 
• Partners researchers and staff involved in this study 
• The sponsor(s) of the study, and people or groups it hires to help perform this research  or 
to audit the research 
• Other researchers and medical centers that are part of this study 
• The Partners ethics board or an ethics board outside Partners that oversees the research 
• A group that oversees the data (study information) and safety of this study 
• Non-research staff within Partners who need identifiable information to do their jobs, 
such as for treatment, payment (billing), or hospital operations (such as assessing the 
quality of care or research) 
• People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers 


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Subject Identification 
• Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections) state agencies, and 
foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records 
• Public health and safety authorities,  if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse) 
• Other researchers within or outside Partners, for use in other research as allowed by law. 
 
Certificate of Confidentiality 
 
A federal Certificate of Confidentiality (Certificate) has been issued for this research to add 
special protection for information and specimens that may identify you.  With a Certificate, 
unless you give permission (such as in this form) and except as described above, the researchers 
are not allowed to share your identifiable information or identifiable specimens, including for a 
court order or subpoena.  
 
Certain information from the research will be put into your medical record and will not be 
covered by the Certificate.  This includes records of medical tests or procedures done at the 
hospitals and clinics, and information that treating health care providers may need to care for 
you.  Please ask your study doctor if you have any questions about what information will be 
included in your medical record.  Other researchers receiving your identifiable information or 
specimens are expected to comply with the privacy protections of the Certificate.  The Certificate 
does not stop you from voluntarily releasing information about yourself or your participation in 
this study. 
 
Even with these measures to protect your privacy, once your identifiable information is shared 
outside Partners, we cannot control all the ways that others use or share it and cannot promise 
that it will remain completely private.  
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your information does not expire.   
 
The results of this research may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission. 
 


Partners HealthCare System 
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Certificate of Confidentiality Template 
Version Date: January 2018 
 
 
 
 
Page 23 of 26 
Subject Identification 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study. 
 
You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with law or maintain the reliability of the study.   
 
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished. 
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
▪ I have read this consent form. 
▪ This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
▪ I have had the opportunity to ask questions. 
▪ I understand the information given to me. 
 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my identifiable 
information to be used and shared as described above. 
 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 


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Research Consent Form 
 
 
 
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Version Date: January 2018 
 
 
 
 
Page 24 of 26 
Subject Identification 
 
 
 
 
 
Signature of Parent(s)/Guardian for Child: 
 
I give my consent for my child to take part in this research study and agree to allow his/her 
identifiable information to be used and shared as described above. 
 
 
 
 
 
 
 
 
Parent(s)/Guardian for Child 
Date 
Time (optional) 
 
 
 
Assent 
 
Statement of Person Giving Assent 
 
▪ This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
▪ I have had the opportunity to ask questions, and my questions have been answered. 
 
 
Signature of Child: 
 
I agree to take part in this research study and agree to allow my identifiable information to be 
used and shared as described above. 
 
 
 
 
 
 
 
 
Child, Ages 14-17 
Date 
Time (optional) 
 
 
 
 
 


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Research Consent Form 
 
 
 
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Version Date: January 2018 
 
 
 
 
Page 25 of 26 
Subject Identification 
 
 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
▪ I have explained the research to the study subject. 
▪ I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
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Version Date: January 2018 
 
 
 
 
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Subject Identification 
 
 
 
 
Consent of Non-English Speaking Subjects Using the “Short Form” in the 
Subject’s Spoken Language 
 
 
Statement of Hospital Medical Interpreter 
 
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
 
 
Hospital Medical Interpreter 
Date 
Time (optional) 
 
OR 
 
Statement of Other Individual (Non-Interpreter) 
 
As someone who understands both English and the language spoken by the subject, I represent 
that the English version of the consent form was presented orally to the subject in the subject’s 
own language, and that the subject was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
Name 
Date 
Time (optional) 
 
 
 
Consent Form Version Date:  6.22.2018 
 
 

Prot_000.pdf: 
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 
Madhusmita Misra, MD, MPH 
 
 
Effects of Anorexia Nervosa on Peak Bone Mass 
NCT01301183 
Version date: March 29, 2018 
Protocol Summary 
 


BWH/MGH Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version 4:  Revised November 2001 
 
 
Page 1 
 
 


BWH/MGH Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version 4:  Revised November 2001 
 
 
Page 1 
 
Anne Klibanski, MD 
 
PROTOCOL TITLE 
Effects of Anorexia Nervosa on Peak Bone Mass 
 
 
FUNDING 
NIH, and Global Foundation for Eating Disorders 
 
 
VERSION DATE 
March 29, 2018 
 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
One of the goals of this proposal is to investigate if co-administration of rhIGF-1 with 
physiologic estradiol replacement to adolescent girls with AN will increase BMD more than 
estrogen monotherapy, and bone mass will approach that seen in healthy adolescent girls. 
An additional aim for the prospective study is to determine whether co-administration of rhIGF-1 
with estradiol to mimic the normal pubertal milieu: 
A) Stimulates bone formation through an IGF-1 mediated anabolic effect   
B) Increases bone density to a greater extent than estrogen monotherapy 
C) Improves bone mass accrual to approach that in healthy controls 
 
Further more we will investigate if co-administration of rhIGF-1 with physiological 
estradiol replacement will improve bone microarchitecture and bone strength in girls with AN. 
In a cross-sectional study of adolescent girls with AN and healthy adolescent girls, we will 
determine whether: 
A) Cortical and trabecular bone density and microarchitecture at the ultradistal radius (non-
weight bearing bone) and tibia (weight bearing bone) as assessed by HR-pQCT, and bone 
strength, as assessed by finite element analysis (FEA), are abnormal in AN compared to 
controls, and are associated positively with nutritional and hormonal predictors of bone mass, 
including BMI, body fat, fat-free mass, estradiol and IGF-1 levels 
 
In a prospective study of adolescent girls with AN we will determine whether: 
B)  Co-administration of rhIGF-1 with transdermal estrogen improves cortical and trabecular 
bone microarchitectural parameters (assessed by HRpQCT) and bone strength (assessed by 
FEA) more than estrogen alone to approach that in normal adolescent girls. Girls with AN 
receiving estradiol alone will have an increase in bone microarchitecture and strength versus 
baseline, but will not normalize compared to healthy controls 
C) Changes in IGF-1 levels are associated positively with changes in measures of bone density, 
microarchitecture and strength. 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
4 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Anorexia nervosa (AN) is the third most common chronic illness among adolescent girls 
(1), with a prevalence of 0.2-1.0% in Western societies (2, 3).  The prevalence rate of AN is 
269.9 per 100,000 for females, with a linear increase in incidence reported for the 15-24 year age 
group over the last 50 years (1). Primarily psychiatric in origin, AN results in numerous medical 
complications, which lead to increased morbidity and mortality in this young population.  
Although the endocrine and metabolic disturbances of AN typically resolve with weight gain, 
low bone mineral density (BMD) is a frequent and persistent co-morbid complication of AN.  
There are no effective approved therapies to normalize bone mass accrual in this population.  
 
Why is the low bone mass characteristic of AN of critical health importance?  (i) The 
prevalence, rapidity of development, and severity of low bone mass in adolescents and young 
women with AN have associated morbidity, (ii) low BMD acquired during adolescence may 
impose life-long increased fracture risk,  (iii) despite the increased prevalence of this disorder, 
treatment strategies in this population do not exist, and (iv) AN represents a unique model in 
which to investigate the profound consequence of nutritional deprivation and pubertal disruption 
on bone mass acquisition. The majority of adolescent girls with AN have low BMD of early 
onset involving both trabecular and cortical bone (4-6), and clinical fractures occur even in this 
young age group;  lumbar BMD is reduced >2 SD in adolescent AN girls, often after only one 
year of illness (5). A study in 170 adolescents 10-17 years old with AN found that 44% of girls 
with ≥ six months of amenorrhea had low lumbar spine bone mass (7).  Unfortunately, the time 
to recovery in adolescents with AN is long (8), and  therefore, severe bone mass deficits are 
common.  We have shown that adolescents with AN have a marked reduction in bone mass 
compared to bone age-matched controls using height-adjusted BMD calculations to eliminate 
potential bone size confounders (9).  A population-based long-term fracture risk cohort study 
from the Mayo Clinic found that the cumulative incidence of any fracture 40 years after the 
diagnosis of AN is 57% (10).  Low bone density in AN is a consequence of several hormonal 
alterations including hypogonadism, low IGF-1 levels, high levels of cortisol and alterations in 
certain hormones such as ghrelin, leptin and PYY that are altered in conditions of low energy 
availability. 
 
Why is this young population at such high risk for severe and permanent osteopenia and 
skeletal fragility?  The onset of AN most frequently occurs during adolescence, a period of 
maximal bone accretion, with > 90% of bone mass accrued by 18 years of age (11). Because 
adolescence is a critical time for attainment of peak skeletal mass, reduction of BMD during this 
crucial period may lead to long-term morbidity. Indeed, we found that in contrast to normal 
adolescents who demonstrate marked bone accretion during puberty, adolescents with AN do not 
increase their bone mass (12).  Therefore, bone mass remains low in these girls during a critical 
period in normal bone development. We have previously shown that adults with onset of AN 
during adolescence have lower spine BMD than those with adult-onset AN, despite comparable 
years of amenorrhea (13).  Furthermore, low bone mass in adolescents with AN may be 
permanent despite recovery (14).  Approximately half of young women with AN have persistent 
osteopenia, even after >10 years (15-17). Therefore, there may be a narrow “window-in-time” 
during adolescence in which maximal accrual of bone mass occurs and during which treatment 
paradigms to maximize bone accrual must be implemented. 
 
The overall significance of this problem: A large number of adolescent girls suffer from 
anorexia nervosa resulting in major deficits in bone mass and increased skeletal fragility, which 
may be permanent. Our proposed study will 1) test the efficacy of replacing a deficiency of an 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
5 
endogenous bone anabolic hormone, IGF-1, with estradiol as a unique therapy for the low bone 
formation state in adolescents with AN and 2) enable an understanding of the effects of this 
disease and its treatment by measuring not only compartment-specific changes in bone density, 
but microarchitecture and strength at weight bearing and non-weight bearing sites.   
 
Given the increasing prevalence of AN, its profound consequences on bone health, and lack of 
optimal treatment interventions, these studies will provide critical data needed to identify optimal 
treatment strategies for this severe co-morbid disease using state- of- the- art endpoints of BMD, 
bone microarchitecture and strength. Although both low IGF-1 and hypogonadism are associated 
with increased skeletal fragility in AN, the mechanisms by which these factors interact are 
incompletely understood. Specifically, the increased skeletal fragility that is associated with AN 
is poorly reflected by DXA-derived BMD. Furthermore, the magnitude and mechanisms by 
which IGF-1 deficiency and hypogonadism influence bone microarchitecture are not defined. 
The growing incidence of eating disorders in adolescent girls and their long-term effects on 
skeletal health provide strong rationale for studies that will provide a better understanding of 
these issues and the evaluation of rational therapeutic approaches. The studies described in this 
proposal utilize both cross-sectional and RCT approaches to achieve this goal. Additionally, our 
utilization of sophisticated techniques such as high resolution peripheral QCT (HR-pQCT) 
(described below) will improve our understanding of the relationship between IGF-1, gonadal 
steroids and bone quality and will aid in the development of effective therapies in the treatment 
of skeletal fragility in AN.  
 
Furthermore, in recent years, there has been an increasing awareness of the bone fat 
connection. In the marrow, osteocytes and adipocytes arise from a common progenitor. Recent 
studies have shown an increase in bone marrow fat in adults with anorexia nervosa which is also 
correlated inversely with bone mineral density. We will assess the effect of estrogen (bone anti 
resorptive hormone) and IGF-1 (bone anabolic hormone) on marrow fat in girls with AN and in 
comparison with healthy controls who receive no intervention. Also bone marrow fat and 
preadipocyte factor, Pref-1, decrease after recovery from anorexia nervosa. We will determine 
associations of changes in bone mass following therapy with changes in marrow fat and Pref-1 
levels over the same duration. This will help us delineate the physiological connection between 
bone marrow fat and bone mineral density and structure in AN. 
 
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 proposed 5 year grant, 100 girls with AN and 36 healthy controls will be 
enrolled at MGH. We will screen up to 272 subjects. Subjects with AN will be randomly 
assigned by the MGH Research Pharmacy to one of two arms: (i) IGF-1 with estrogen or (ii) 
estrogen alone with placebo for 12 months. Healthy controls will be followed prospectively for 
12 months. Control subjects will complete the screen and baseline visit only. Study staff will 
follow-up with control subjects via a telephone call at 12 months after their baseline visit. This 
telephone call will serve to inform study staff of  any medical changes or major life events that 
have occurred since the baseline study visit.  We anticipate a 20% dropout rate based on our 
previous studies. Only AN subjects will take calcium and vitamin D supplement pills daily; 
dosage of vitamin D will be based upon each subject’s serum levels.  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
6 
AN Subjects: Subjects with AN will be 14-22 years old- an age span before peak bone mass is 
achieved, with a bone age (BA) of  ≥14years and meet DSM V criteria for AN. Our inclusion 
criteria for AN refers to the diagnosis of (a) Anorexia Nervosa or (b) Atypical Anorexia Nervosa 
with significant weight loss per DSM V. We will use a BA of 14years as the cut-off because all 
epiphyses are near fusion and 98% of adult height has been attained at this skeletal age (19). 
Control Subjects: (i) Healthy adolescent girls 14-22 years with a BA of ≥14years; (ii) BMI 
between the 10th-90th percentiles for age, (iii) regular menstrual periods every 28-35 days and/or 
>9 menses within the last 12 months for subjects ≥ 2 years post-menarche. Control subjects will 
be studied during the early follicular phase of their cycles (days1-10). 
 
Inclusion Criteria: AN:  
• Subjects with AN will be 14-22 years old 
• Bone age (BA) of  ≥14 years  
• Meet DSM V criteria for AN or Atypical AN with significant weight loss 
• Subjects at MGH will be evaluated by an MGH study psychiatrist or psychologist before 
enrollment. 
Inclusion Criteria: Controls:  
• Healthy adolescent girls 14-22 years 
• BA of ≥14 years 
• BMI between the 10th-90th percentiles for age 
• Regular menstrual periods every 28-35 days and/or >9 menses within the last 12 months 
for subjects ≥ 2 years post-menarche. 
Exclusion Criteria: 
• Diseases known to affect bone metabolism including untreated thyroid disease, Cushing’s 
syndrome, diabetes, pituitary disease, renal failure and prior bone fracture within six 
months of the study.  
• Medications known to affect bone metabolism, including gonadal steroids and excluding 
oral contraceptives or estrogen/progestin containing compounds within two months. 
• Evidence of suicidality, psychosis, or substance abuse based on an interview with the 
study psychiatrist or psychologist and recommendations.  
o In the event that evidence of suicidality, psychosis or substance abuse is 
uncovered in the interview, the current treatment team for the subject will be 
contacted and informed by the current study psychologist or psychiatrist. In the 
event a subject does not have a treatment team in place, referrals will be made by 
the current study psychologist or psychiatrist. If danger is imminent and safety 
can not be guaranteed, 911 can be called.  
• Premature ovarian failure, as demonstrated by an elevated FSH. 
• Abnormal TSH.  
• Hematocrit <30%, Potassium <3.0 mmol/L, Glucose <50 mg/dl  
• Pregnancy 
• History of malignancy 
• Absolute contraindications to estrogen therapy (for girls with AN) 
 
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.


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
7 
Screening Visit: Eligibility for participation in the protocol will be determined at a screening 
visit. Evaluations on this visit will include: 
(a) History and physical exam including Tanner stage, height and weight.  
(b) Blood laboratory tests for glucose, TSH, LH, FSH, potassium and hematocrit, IGF-1, urine or 
serum pregnancy test and Bone age estimated using an x-ray of the left hand and wrist by 
standards of Greulich and Pyle (19). 
i. In cases where the family can provide records of the lab work required for 
screening performed within two months of the screening visit, we will not 
repeat those labs. 
ii. Blood laboratory tests can be done at baseline visit if unable to obtain at 
screening visit. If blood laboratory tests are done at baseline, medications 
will be withheld until laboratory results are received and assessed.  
 
Baseline Visit:  
(a) Bone age estimated using an x-ray of the left hand and wrist by standards of Greulich and 
Pyle (19) if not completed at the screening visit. 
(b) Complete History and Physical: Including growth, menstrual history, Tanner staging staging 
and fundoscopic exam. 
(c) Anthropometric Measurements:  Height will be measured in triplicate using a stadiometer, 
and weight on a single electronic scale in the Clinical Research Center (CRC).  
(d) Nutritional Assessment: CRC dieticians at MGH will evaluate nutritional status using 4-day 
food records for macro- and micronutrient intake (Nutrition Data Systems, version 4, 
Minneapolis, MN) and indirect calorimetry (metabolic cart) to determine respiratory quotient 
(RQ) and resting energy expenditure. (All subjects consent to the metabolic cart, although it 
is treated as optional during the study. A food diary log may be provided at the screening 
visit or baseline visit. Although all subjects consent to the food diary log, its completion is 
treated as optional during the study.) 
(e) EDI2:Eating Disorders Inventory-2 questionnaire, which has been validated in adolescent 
patients with eating disorders (25) and includes assessment of body image. This is a 91-item, 
11 scale, six-point forced-choice self-report inventory assessing behavioral and psychological 
traits common in AN. (This can be completed at the screen visit) 
(f) BDI-II: Beck Depression Inventory-2 questionnaire is a self-report inventory assessing 
depression and mood traits common in AN (All subjects consent to standardized psychiatric 
tests, although they are treated as optional during the study. This component can also be 
completed at the screen visit, instead of the baseline visit.). For safety concerns related to 
suicidality, after every administration of the BDI-II, a research assistant or study nurse will 
review the suicidality item of each measure. If any subject scores a “2” or “3” on the BDI-II 
“Suicidal Thoughts or Wishes” item, or if the total score corresponds to “moderate” or 
“severe” depression (see below), the study psychologist/psychiatrist will be paged for further 
assessment with the participant. BDI-II scoring ranges are as follows: 
a. 0-13: minimal depression 
b. 14-19: mild depression 
c. 20-28: moderate depression 
d. 29-63: severe depression 
(g) STAI: State Trait Anxiety Inventory questionnaire is a 40-item and four-point Likert scale 
self-report inventory assessing state and trait anxieties common in AN. (All subjects consent 
to standardized psychiatric tests, although they are treated as optional during the study. This 
component can also be completed at the screen visit, instead of the baseline visit.) 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
8 
(h) Activity Assessment: Habitual exercise and activity will be assessed using a standardized 
exercise questionnaire, which provides a good estimate of past year physical activity in 
adolescents (26, 27). (All subjects consent to the activity assessment, although it is treated as 
optional during the study.) 
(i) Bone Turnover Markers: Serum for PINP and C-telopeptide (CTX). 
(j) Calcium Metabolism: Blood for calcium, phosphorus, 25(OH) D, 1,25(OH)2D, PTH. 
(k) Hormonal Evaluation: Serum for IGF-1, IGFBP-3, SHBG, estradiol, leptin.  
(l) If not obtained at screening visit: Blood laboratory work for glucose, TSH, LH, FSH, 
potassium and hematocrit, and IGF-1. Medications will be withheld until laboratory results 
are received and assessed. 
(m) Bone Mass Density: lumbar spine (AP and lateral), hip, radius, whole body areal BMD, 
BMC and BA will be measured by dual energy x-ray absorptiometry (DXA: Hologic QDR 
4500, Waltham, MA).  
(n) Body Composition: Whole body DXA will be performed to assess fat and lean mass.  
(o) Bone morphology, microarchitecture and strength will be determined at the ultradistal radius 
and distal tibia using HR-pQCT (Xtreme CT, Scanco Medical AG).  Bone strength will be 
determined using FEA of HR-pQCT scan data (28). 
(p) Safety Evaluation: Urine or Serum HCG (to rule out pregnancy) and fasting glucose. 
(q) Thigh and abdomen MRI and an L4 MR spectroscopy will be performed to assess bone 
marrow fat. We will also add Pref-1 assessment to the already collected blood. This will only 
be repeated at 12 months for patients with anorexia nervosa. 
a. This study is optional for AN subjects and non-optional for HC subjects 
(r) Study Drug Reminders: We will set up medication reminders on phone calendars for those 
who consent to the optional reminders. Subjects may decrease or turn off reminders at any 
time. All patient information will remain confidential, and no identifiers will be used. 
Additionally, all subjects will receive paper medication calendars to keep track of each dose 
taken and to return to study staff at each visit. 
(s) Two subtests, Vocabulary and Matrix Reasoning, from the Weschler Abbreviated Scale of 
Intelligence (WASI), a Color-Word Interference Test subtest from the Delis Kaplan 
Executive Functioning Scale (DKEFS), and the California Verbal Learning Test (CVLT). 
(All subjects consent to the cognitive assessments, with the intention that they will be 
completed to the extent that time, subject schedule, and circumstances allow during the study 
visit.) 
All blood samples will be drawn fasting or at least two hours after food. Subjects who are unable 
to fast overnight will have the option to complete the metabolic test while fasting for two hours. 
 
 
Combined Screening and Baseline Visit  
For subjects who live or attend school far from Boston, we may offer to combine the first two 
visits, the screen and baseline. Because these visits occur within 8 weeks of each other, some 
subjects have difficulty with the time and expense necessary to come to Boston twice within this 
period. In the case of the combined visit, subjects will be phone-screened by a study co-
investigator prior to scheduling the visit to make sure that inclusion criteria are met and 
exclusion criteria ruled out.  Some information regarding exclusion criteria that we will not be 
able to gather prior to the combined visit would be bone age < 14 years, hematocrit<30% and an 
abnormal TSH level. Subjects with any history of thyroid disorder will not be eligible for the 
combined visit. To ensure that bone age of subjects completing the combined visit is mature 
enough to continue study participation, we will restrict the combined visit to subjects who are of 
a chronological age of 16 years or older at the time of the visit, making it very likely that the 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
9 
bone age is > 14 years.  Additionally, we will not proceed with the baseline visit if the x-ray of 
the wrist and hand at the combined visit indicates a bone age of <14 years. Study drug will be 
started only after inclusion/exclusion criteria have been confirmed at the combined visit. 
 
Subjects will complete all screening and baseline procedures at this visit. The subject will be 
consented and a complete medical history and physical exam will be performed before 
continuing with further study procedures. If subject is found to have any health concern or is 
found to meet any exclusion criterion during the history and physical, further study components 
will be canceled. Following this portion of the visit, the subject will complete the rest of the 
study procedures occurring at the screening and baseline visit, including: 
(c) History and physical exam including Tanner stage, height and weight.  
(d) Blood laboratory tests for glucose, TSH, LH, FSH, potassium and hematocrit, IGF-1, urine or 
serum pregnancy test and Bone age estimated using an x-ray of the left hand and wrist by 
standards of Greulich and Pyle (19). 
(e) Anthropometric Measurements:  Height will be measured in triplicate using a stadiometer, 
and weight on a single electronic scale in the Clinical Research Center (CRC).  
(f) Nutritional Assessment: CRC dieticians at MGH will evaluate nutritional status using 4-day 
food records for macro- and micronutrient intake (Nutrition Data Systems, version 4, 
Minneapolis, MN) and indirect calorimetry (metabolic cart) to determine respiratory quotient 
(RQ) and resting energy expenditure. (All subjects consent to the metabolic cart, although it 
is treated as optional during the study. A food diary log may be provided at the screening 
visit or baseline visit. Although all subjects consent to the food diary log, its completion is 
treated as optional during the study.) 
(g) EDI2:Eating Disorders Inventory-2 questionnaire, which has been validated in adolescent 
patients with eating disorders (25) and includes assessment of body image. This is a 91-item, 
11 scale, six-point forced-choice self-report inventory assessing behavioral and psychological 
traits common in AN. (This can be completed at the screen visit) 
(h) BDI-II: Beck Depression Inventory-2 questionnaire is a self-report inventory assessing 
depression and mood traits common in AN (All subjects consent to standardized psychiatric 
tests, although they are treated as optional during the study. This component can also be 
completed at the screen visit, instead of the baseline visit.). For safety concerns related to 
suicidality, after every administration of the BDI-II, a research assistant or study nurse will 
review the suicidality item of each measure. If any subject scores a “2” or “3” on the BDI-II 
“Suicidal Thoughts or Wishes” item, or if the total score corresponds to “moderate” or 
“severe” depression (see below), the study psychologist/psychiatrist will be paged for further 
assessment with the participant. BDI-II scoring ranges are as follows: 
a. 0-13: minimal depression 
b. 14-19: mild depression 
c. 20-28: moderate depression 
d. 29-63: severe depression 
(i) STAI: State Trait Anxiety Inventory questionnaire is a 40-item and four-point Likert scale 
self-report inventory assessing state and trait anxieties common in AN. (All subjects consent 
to standardized psychiatric tests, although they are treated as optional during the study. This 
component can also be completed at the screen visit, instead of the baseline visit.) 
(j) Activity Assessment: Habitual exercise and activity will be assessed using a standardized 
exercise questionnaire, which provides a good estimate of past year physical activity in 
adolescents (26, 27). (All subjects consent to the activity assessment, although it is treated as 
optional during the study.) 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
10 
(k) Two subtests, Vocabulary and Matrix Reasoning, from the Weschler Abbreviated Scale of 
Intelligence (WASI), a Color-Word Interference Test subtest from the Delis Kaplan 
Executive Functioning Scale (DKEFS), and the California Verbal Learning Test (CVLT). 
(All subjects consent to the cognitive assessments, with the intention that they will be 
completed to the extent that time, subject schedule, and circumstances allow during the visit) 
 
6-month and 12-month (AN Subjects Only): will include all the baseline procedures but the bone 
age x-ray. 
Eligible consented subjects will be allowed to have CT scans performed between the 
screening and baseline visits if scheduling conflicts arise with the baseline visit.  This will allow 
the subject to obtain a baseline assessment of bone microarchitecture prior to the initiation of 
rhIGF-1 supplementation.  In the event that a CT cannot be performed on the scheduled baseline 
visit date due to unforeseen issues, willing subjects will be able to return within a 1 week 
window for this test. DXA scans can also be completed at screening visit if not able to be 
performed at baseline visit. MR/MRS will be repeated at 12 month visit for patients with 
anorexia nervosa. We will also repeat the Pref-1 levels for those who enrolled in this optional 
part of the study.  
 
1-month, 4.5-month, 7.5-month and 10.5 month visits (AN Subjects Only): Evaluations on these 
visits will include: 
(a)  History and physical exam, including height and weight 
(b)  Pregnancy test 
(c)  Serum IGF-1 and glucose 
 
3-month and 9-month visits (AN Subjects Only): Evaluations on these visits will include: 
(a)  History and physical exam, including height and weight 
(b)  Pregnancy test 
(c)  Serum IGF-1 and glucose 
(d) Nutrition evaluation will be assessed by using 4-day food records for macro- and 
micronutrient intake (Nutrition Data Systems, version 4, Minneapolis, MN)  
(e) Activity assessment: Habitual exercise and activity will be assessed using a standardized 
exercise questionnaire. (All subjects consent to the activity assessment, although it is treated as 
optional during the study.)  
(f) Bone turnover markers and hormones 
Subjects who do not live locally will be able to have their blood drawn offsite for levels 
of IGF-1 and bone markers. Subjects who choose this option will also have a history and 
physical performed by a local physician for each offsite visit. Tests that need to be run in real 
time will be done at local laboratories, with the results mailed to investigators. Otherwise, the 
samples will be mailed to investigators.  
Subjects who are in residential treatment can have their visits at the treatment center with 
permission from the center, the subject’s case manager, and the subject. The consent, history, 
and physical will be done by licensed study staff. This applies to all visits except for baseline, 6 
month, and 12 month. Blood will not be drawn at the treatment center by study staff. If lab 
results are available for any labs that we need for the particular visit, we will use those labs. A 
release of information will be signed by the subject prior to obtaining any labs.  
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
11 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
No treatment thus far has been successful in increasing bone density in adolescent girls 
with anorexia nervosa. Weight gain is associated with some increase in bone density, but is 
difficult to attain (occurs in only 50%) and sustain. There are currently no FDA-approved 
therapies for anorexia nervosa-induced bone loss. 
Alternate strategies to address low bone density in AN: (1) Recovery of weight and menses: 
Although weight and menses recovery is associated with some increase in BMD, this increase is 
not sufficient to cause bone accrual to normalize, and BMD remains lower than in controls (54). 
Additionally, recovery can be hard to attain and sustain. (2) Calcium and vitamin D 
supplementation: Many studies have now shown that calcium and vitamin D supplementation is 
not sufficient to increase BMD in AN. BMD remains low in these girls despite higher calcium 
and vitamin D intake than in controls (9, 12, 54). (3) Bisphosphonates: Given their very long 
half life, bisphosphonates are typically avoided in young girls and women of reproductive age. In 
addition, data indicate that alendronate use is ineffective in increasing BMD at the spine in girls 
with AN (55). (4) PTH: Teriparatide increases BMD in post-menopausal women (56), however, 
PTH is not recommended in young people at this time given reports of osteosarcoma with PTH 
use in animal models (57, 58). 
Alternate strategies to assess bone microarchitecture and strength: MRI of the peripheral 
skeleton has lower resolution, longer scan time and increased susceptibility to image post-
processing. QCT could also be used to assess trabecular bone structure and density of the spine.  
However, its relatively high radiation dose at the spine precludes its use in adolescents. HR-
pQCT low radiation and technique precision makes it the optimal choice. We have compared 
bone structure as assessed by HR-pQCT in girls with AN and healthy adolescent girls. Finally, 
we have demonstrated our ability to perform FEA from assessments of bone structure in a 
population of women with AN, and have shown that bone strength is associated strongly with 
bone trabecular volume (59). FEA is easily derived using HR-pQCT data (28, 60-63). 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
Risks from medications: 
RhIGF-I administration in the dose being used in this study is associated with few side 
effects. This medication is approved by the FDA for use in children with primary IGF-I 
deficiency at a dose of 40-80 mcg/kg sc twice daily (up to 120 mcg/kg sc twice daily).  As per 
the package insert for rhIGF-I for this indication: mild or moderate hypoglycemia (very rarely 
severe), thought to be related to the drug's insulin-like activities, may occur in up to 42% of 
patients on this medication during the course of therapy. More severe hypoglycemia is rare. The 
peak hypoglycemic effect of IGF-I occurs 30 minutes to one hour after injection.  Risk of 
hypoglycemia is generally avoided when a meal or snack is consumed 30 minutes prior to 
rhIGF-I administration. We have not observed hypoglycemia in subjects in our pilot studies with 
rhIGF-I shots. Our subjects were instructed to take rhIGF-I within half an hour of a meal and 
these recommendations will hold in the proposed study, in which the doses we will use will be 
much lower than those used in primary IGF-I deficiency. We will also assess fasting glucose 
levels at all study visits. The safety and efficacy of rhIGF-I has been demonstrated by our group 
in a study in adult women with AN (64, 65), in which 30 adult women with AN received 30 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
12 
mcg/kg of rhIGF-I sc twice daily. RhIGF-I was well tolerated in this study (65). Other 
occasionally reported side effects of rhIGF-1 include bruising and redness at the injection site, 
lymphoid hypertrophy and snoring, lipohypertrophy, chronic middle ear effusions, raised 
intracranial pressure (headaches, vision changes, vomiting), slipped capital femoral epiphysis 
and progression of scoliosis in subjects who experience rapid growth, and arthralgias. Rotating 
injection sites will be advised and a close watch on other clinical features implemented. Also, as 
the drug is a pharmaceutical protein, anti-IGF-1 antibody formation can occur. 14 of 23 subjects 
treated for 2 years with the drug in one study experienced some degree of anti-IGF-1 antibody 
formation, though no clinical consequences (allergic reaction or loss of efficacy) were observed 
(from package insert). However, as with any exogenously administered protein, local or systemic 
allergic reactions may occur. Parents and subjects will be informed that such reactions are 
possible and that if an allergic reaction occurs, treatment should be interrrupted and prompt 
medical attention sought. Because we will be giving a smaller dose of rhIGF-1 (30 mcg/kg sc 
twice daily), we expect to see fewer side effects than indicated in the package insert. These risks 
of side effects are justified in light of the anticipated benefit of improved bone density and 
lowered immediate and lifetime fracture risk with treatment during this critical period of bone 
mass accrual. The rhIGF-1 dose will be increased or decreased by up to 25% to maintain IGF-1 
levels in the upper half of the normal range.  We will titrate the dose using a maximum of two 
dose increments. Thus the maximum dose will be 46.88 mcg/kg twice daily. 
Estrogen administration in the doses being administered is associated with minimal possible 
side effects. Occasional side effects may occur, the most common of which are mild headaches, 
and very rarely some irritation or redness at the application site for transdermal estrogen. 
Adverse reactions that have been reported with estrogen therapy include abnormal bleeding 
patterns, changes in nature and quantity of vaginal discharge, tenderness and enlargement of 
breasts, nausea, vomiting, abdominal pain, bloating, gallbladder disease, rashes, intolerance to 
contact lenses, migraines, dizziness, depression, abnormal movements, and changes in weight. 
These adverse effects are, however, rare, and seen more commonly with the estrogen taken 
orally rather than transdermally. More serious side effects include hypertension, lipid and 
clotting disorders. These are more commonly seen in older women and in women with a family 
history of clotting disorders. Continuous estrogen administration without cyclic progesterone can 
predispose the uterus to cancer. Because we will be administering progesterone for ten days 
every month, this should not be a concern.   We will monitor the subjects’ blood pressure at each 
visit and will also determine through careful questioning and examination the appearance of any 
side-effect at each visit.  Estrogen administration in pregnancy may be teratogenic. We will thus 
perform a pregnancy test prior to administering estrogen. 
We will not enroll subjects with the following absolute contraindications to estrogen therapy: 
• Known or suspected pregnancy 
• Undiagnosed abnormal uterine bleeding 
• History of clotting disorders such as thrombophlebitis and thromboembolic disorders 
• Known or suspected cancer of the breasts, uterus or ovaries. 
 
Relative contraindications such as migraines and smoking history will be decided on a case by 
case basis using history and phyical findings 
 
Subjects will be instructed to call us if they develop any side-effects of the medication.  
Subsequent management will be decided based on the severity of the side-effect. 
Use of replacement or higher doses of estrogen before epiphyseal closure could accelerate 
growth plate closure resulting in an inability to reach the full potential for adult height.  To avoid 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
13 
this possible side effect, we plan to administer replacement estrogen doses transdermally to girls 
with a bone age of 14 or more years, who have achieved 98% of their adult height.   
Oral progesterone has been associated with clotting abnormalities, dizziness, nausea, 
abdominal pain, fatigue, headaches, insomnia, nervousness, sleepiness and breast tenderness and 
secretion.  Rare cases of breast cancer have been reported in women taking combined estrogen 
and progesterone.  Rare instances of abnormal liver function have also been reported.  The doses 
of progesterone that will be given are small and are less likely to cause these side effects. 
Particularly micronized progesterone (Prometrium) is associated with few adverse effects. 
Oral calcium can cause constipation and a metallic taste in the mouth. 
Vitamin D in the doses being administered does not cause any side effects. 
Physician Availability:  A physician will be available by pager at all times during the study to 
answer any questions or address any concerns that a subject may have. All efforts will be made 
to protect the confidentiality of study subjects who will be referred to by an enrollment number 
only. 
 
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.
Subjects will be instructed to call us if they develop any side-effects from the study 
medications, or if symptoms of hypoglycemia are experienced. They will be advised to take 4 oz 
orange juice or two glucose pills if they are experiencing symptoms of hypoglycemia.  
Serious side effects related to study drug will necessitate protocol discontinuation. If a subject 
develops a minor side effect, she will be asked to continue medications as per the protocol. 
Worsening of symptoms may necessitate temporarily withholding medication until other 
potential causes of symptoms are ruled out.  Withholding medication for longer than one week 
will necessitate discontinuation of the study. 
 
To minimize the risk from radiation, DXA scans will not be performed on subjects until a 
negative pregnancy test result is obtained.  If lab abnormalities are discovered, the subject and 
their physician, if authorized by the subject, will be notified.   
If subjects are uncomfortable with any portion of any study visit, this portion will be 
discontinued or not performed. 
Discontinuation criteria for subjects: 
1. Pregnancy (for any subject) 
2. Identification of characteristics meeting criteria for exclusion (for any subject) 
 
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.
 
Complications of surgical and non-surgical procedures: There is a risk of superficial 
bruising and discomfort at the venepuncture site. Rarely, fainting (from a vasovagal episode) or a 
treatable infection may occur. An intravenous catheter will be in place for frequent sampling 
overnight at baseline and at the end of the study. This may cause discomfort for the duration of 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
14 
the study. EMLA or ELA-MAX, a numbing cream, can be used to minimize the pain and 
discomfort associated with blood sampling. 
Fasting for prolonged periods of time can cause blood sugar levels to fall resulting in 
light-headedness, dizziness, sweating, hunger or headaches. Because fasting will only occur 
between midnight and approximately 8 a.m. the following morning, a short period of time, we do 
not expect any of these side effects.  
The risks from radiation exposure are minimal due to the low doses of radiation involved 
in bone age x-rays, CT scans, and DXA (~0.16 mSv for DXAs, bone age film and fpVCT for 
each subject, which is equivalent to about 5% of the effective dose (3mSv) everyone gets from 
the background radiation per year). 
Risks from medications: 
RhIGF-I administration in the dose being used in this study is associated with few side effects. 
This medication is approved by the FDA for use in children with primary IGF-I deficiency at a 
dose of 40-80 mcg/kg sc twice daily (up to 120 mcg/kg sc twice daily).  As per the package 
insert for rhIGF-I for this indication: mild or moderate hypoglycemia (very rarely severe), 
thought to be related to the drug's insulin-like activities, may occur in up to 42% of patients on 
this medication during the course of therapy. More severe hypoglycemia is rare. The peak 
hypoglycemic effect of IGF-I occurs 30 minutes to one hour after injection.  Risk of 
hypoglycemia is generally avoided when a meal or snack is consumed 30 minutes prior to 
rhIGF-I administration. We have not observed hypoglycemia in subjects in our pilot studies with 
rhIGF-I shots. Our subjects were instructed to take rhIGF-I within half an hour of a meal and 
these recommendations will hold in the proposed study, in which the doses we will use will be 
much lower than those used in primary IGF-I deficiency. We will also assess fasting glucose 
levels at all study visits. The safety and efficacy of rhIGF-I has been demonstrated by our group 
in a study in adult women with AN (64, 65), in which 30 adult women with AN received 30 
mcg/kg of rhIGF-I sc twice daily. RhIGF-I was well tolerated in this study (65). Other 
occasionally reported side effects of rhIGF-1 include bruising and redness at the injection site, 
lymphoid hypertrophy and snoring, lipohypertrophy, chronic middle ear effusions, raised 
intracranial pressure (headaches, vision changes, vomiting), slipped capital femoral epiphysis 
and progression of scoliosis in subjects who experience rapid growth, and arthralgias. Rotating 
injection sites will be advised and a close watch on other clinical features implemented. Also, as 
the drug is a pharmaceutical protein, anti-IGF-1 antibody formation can occur. 14 of 23 subjects 
treated for 2 years with the drug in one study experienced some degree of anti-IGF-1 antibody 
formation, though no clinical consequences (allergic reaction or loss of efficacy) were observed 
(from package insert). However, as with any exogenously administered protein, local or systemic 
allergic reactions may occur. Parents and subjects will be informed that such reactions are 
possible and that if an allergic reaction occurs, treatment should be interrrupted and prompt 
medical attention sought. Because we will be giving a smaller dose of rhIGF-1 (30 mcg/kg sc 
twice daily), we expect to see fewer side effects than indicated in the package insert. These risks 
of side effects are justified in light of the anticipated benefit of improved bone density and 
lowered immediate and lifetime fracture risk with treatment during this critical period of bone 
mass accrual.  The rhIGF-1 dose will be increased or decreased by up to 25% to maintain IGF-1 
levels in the upper half of the normal range.  We will titrate the dose using a maximum of two 
dose increments. Thus the maximum dose will be 46.88 mcg/kg twice daily. Because changes in 
IGF-1 levels and bone density can occur due to multiple factors, IGF-1 results and DXA results 
after the baseline visit will not be shared with participants in order to avoid misleading 
assumptions, until after the 12 month treatment period. 
 
Estrogen administration in the doses being administered is associated with minimal 
possible side effects. Occasional side effects may occur, the most common of which are mild 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
15 
headaches, and very rarely some irritation or redness at the application site for transdermal 
estrogen. Adverse reactions that have been reported with estrogen therapy include abnormal 
bleeding patterns, changes in nature and quantity of vaginal discharge, tenderness and 
enlargement of breasts, nausea, vomiting, abdominal pain, bloating, gallbladder disease, rashes, 
intolerance to contact lenses, migraines, dizziness, depression, abnormal movements, and 
changes in weight. These adverse effects are, however, rare, and seen more commonly with the 
estrogen taken orally rather than transdermally. More serious side effects include hypertension, 
lipid and clotting disorders. These are more commonly seen in older women and in women with 
a family history of clotting disorders. Continuous estrogen administration without cyclic 
progesterone can predispose the uterus to cancer. Because we will be administering progesterone 
for ten days every month, this should not be a concern.   We will monitor the subjects’ blood 
pressure at each visit and will also determine through careful questioning and examination the 
appearance of any side-effect at each visit.  Estrogen administration in pregnancy may be 
teratogenic. We will thus perform a pregnancy test prior to administering estrogen. 
Subjects will be instructed to call us if they develop any side-effects of the medication.  
Subsequent management will be decided based on the severity of the side-effect. 
Use of replacement or higher doses of estrogen before epiphyseal closure could accelerate 
growth plate closure resulting in an inability to reach the full potential for adult height.  To avoid 
this possible side effect, we plan to administer replacement estrogen doses transdermally to girls 
with a bone age of 14or more years, who have achieved 98% of their adult height.   
Oral progesterone has been associated with clotting abnormalities, dizziness, nausea, 
abdominal pain, fatigue, headaches, insomnia, nervousness, sleepiness and breast tenderness and 
secretion.  Rare cases of breast cancer have been reported in women taking combined estrogen 
and progesterone.  Rare instances of abnormal liver function have also been reported.  The doses 
of progesterone that will be given are small and are less likely to cause these side effects. 
Particularly micronized progesterone (Prometrium) is associated with few adverse effects. 
Oral calcium can cause constipation and a metallic taste in the mouth. 
Vitamin D in the doses being administered does not cause any side effects. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
There are no direct known benefits to study volunteers from the study. However, there is the 
prospect of direct benefit to study volunteers as they may have improved bone density and bone 
microarchitecture after study treatment. This research may lead to an improved understanding of the 
disordered bone metabolism in teenage girls with AN and whether administration of IGF-1, a key bone 
anabolic factor, with low-dose estrogen therapy, is effective in increasing peak bone mass in this 
population compared with estrogen alone.  The potential benefits are thought to warrant the risks 
described above. 
 
EQUITABLE SELECTION OF SUBJECTS 


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The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
All subjects will be female as the vast majority of patients with AN are female. We will 
be recruiting adolescents and young women 14-22 years old as there have been no treatment thus 
far has been successful in increasing bone density in adolescent girls with anorexia nervosa. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
People who do not speak English will not be excluded from study participation. PHRC 
policy on Obtaining and Documenting Informed Consent of Subjects who do not speak English 
will be followed. For this study, potential subjects will be given a written translation in a 
language understandable to them of the “short form” or of the entire English version of the 
consent form approved by the Partners Human Research Committee (PHRC). 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          http://healthcare.partners.org/phsirb/nonengco.htm 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
 
1) Subjects will be recruited from a large population of patients with AN from the following 
locations: 
Dr. Anne Klibanski and Kamryn Eddy Ph.D have organized a group of over 30 AN health care 
providers in New England (The New England Eating Disorders Research Collaborative). This 
group includes the directors of 15 major eating disorders with in- and out-patient services 
throughout New England and representatives from many major colleges and University health 
services.  The group meets quarterly for two hour sessions to discuss recruitment strategies for 
MGH AN studies, review MGH research findings and discuss published data from other groups. 
This group represents a concerted and collaborative effort to recruit subjects with AN to the 
MGH studies and funnels patients into these studies from all over the New England area.  It has 
been developed into an effective recruitment tool. The group includes: 
o 
Representatives from the leadership of major eating disorder treatment centers 
and groups in the larger area, including:  1) Lori Ciotti, Clinical Director, The Renfrew Center of 


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Boston, 2) Seda Ebrahimi, PhD, Director, Cambridge Eating Disorders Center, 3) Anne 
Robinson, Director, Massachusetts Eating Disorder Association, 4) Perry Belfer, Director, 
Newton-Wellesley Behavioral Care, 5) Thomas Weigel, MD, Klarman Center for Eating 
Disorders, 6) Diane Mickley, Director, Wilkins Center for Eating Disorders, Greenwich, CT; 7) 
Mark Goldstein, M.D., Chief, Adolescent Medicine, MGH, 8) Suzanne Gleysteen, Beth Israel 
Deaconess Medical Center, 9) Patrice Lockhart, MD, Mercy Hospital Eating Disorder Treatment 
Program, Portland, ME, 10) Celina Pereira, MD, Director, University of Rhode Island Health 
Services, 11) Bethany Block, M.D., Brigham and Women’s Hospital, 12) Laura Koenigs, M.D., 
Baystate Medical Center, 13) Heather Bell, RD, Brown University Health Services, 14) Sarah 
Kelley, Harvard University, 15) Laura Clauss, ARNP-C, Center for Eating Disorders 
Management, Inc., New Hampshire. 
o Health care personnel for many of the suburban high schools and independent schools 
such as Dr. Suzanne Boulter in Concord, MA, Dr. Rebecca Niloff and Dr. John Robinson for 
Milton Pediatrics in Milton, MA, as well as various pediatric primary care practices in the 
Boston community are contacted regularly and invited to attend as well. 
(ii) The Eating Disorders Unit at Massachusetts General Hospital, which is the largest 
operating eating disorders clinic in New England.  The Eating Disorders Unit in the 
Massachusetts General Hospital Child Psychiatry Service and the Adult Eating and Weight 
Center together form the largest outpatient Eating Disorders Clinic in the New England area.  
Since its inception in 1981, the Clinic has evaluated more than 4000 patients with AN and/or 
bulimia nervosa.  Over 200 new patients are evaluated in the Clinic each year and over 150 
patients are in treatment at any one time.  Patients in the Clinic, many of whom were recruited 
for an ongoing, prospective, longitudinal study of eating disorders, are interested and willing to 
participate in research projects.  In addition, Clinic patients have participated in studies of low 
bone density, obsessive compulsive symptomatology, childhood sexual trauma, and 
pharmacological treatment. 
(iii)  The Harris Center, previously the Harvard Eating Disorders Center, in which Kamryn 
Eddy, Ph.D is involved, brings together many of the eating disorders programs at Harvard 
Hospitals, including Deaconess Waltham Hospital.  It also hosts annual dinners and sends out 
biannual newsletters that inform clinicians and families of eating disordered patients about new 
research opportunities.  The Harris Center is a national non-profit organization whose goal is to 
promote the healthy development of women and others at risk through research, training, 
outreach and prevention.  The Harris Center web-site is a frequently hit ED site, and details 
about the study will be available on that site.  The Harris Center networks regularly with major 
treatment centers for eating disorders in Connecticut, Vermont, Rhode Island, New Hampshire, 
and Maine and with the 250 college health centers in the Greater Boston area;   
(iv)   Walden Behavioral Care.  The Neuroendocrine Unit is invited to give monthly 
educational talks to patients and provide information about ongoing studies at the inpatient, 
partial hospitalization and residential programs.  The service admits about 280 in- and 
outpatients with eating disorders each year 
(v)   The Massachusetts Eating Disorders Association, which runs support groups for women 
and teenagers with eating disorders throughout eastern Massachusetts; 
(vi)   Health services at local colleges and universities such as Harvard University, 
Massachusetts Institute of Technology, Boston University, Boston College, Brandeis University, 
Emerson College, and Wellesley College 
(vii)  Facebook Advertisements. We also plan to use Facebook advertising to reach potentially 
interested subjects living in the Boston area. Women ages 18-45 living in New England will see 
advertisements for this research study in the “News Feed” section of their Facebook and be 
directed to an IRB approved RedCap prescreen survey. These advertisements will in no way be 


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designed to target individuals who indicate they may be struggling with an eating disorder on 
Facebook. The ads are shown to individuals based on the demographic requirements but have no 
link to any specific personal, profile or browsing history information. Examples of these 
advertisements are attached to this study protocol in Insight. A general Facebook page has also 
been created for this study (a Facebook requirement) and includes only basic contact and study 
information. A copy of this page is also attached to this study protocol in Insight. 
(viii) 
Hasbro Children’s Hospital at Rhode Island Hospital. We work with Dr. Abigail 
Donaldson and her team of providers to recruit subjects from Hasbro. This recruitment site will 
also function as an offsite clinic for follow up visits to provide Hasbro patients the opportunity to 
participate in the study with greater convenience. Subjects who are interested in the study can 
complete the eligibility portion of the screening visit at Hasbro and come to MGH for the 
consent process and baseline, 6 month, and 12 month visits. They will have the option to 
complete the entire 1, 3, 4.5, 7.5, 9, and 10.5 month visits at Hasbro. 
To maximize enrollment of adolescent subjects with AN, a number of referral mechanisms 
have been put into place over the past year that utilize the collegial relationships between Dr. 
Klibanski, Kamryn Eddy, Ph.D and various directors of area eating disorder programs, as well as 
the Head of Child Psychiatry and major pediatric primary care practices.  The investigators 
attend a monthly eating disorders support group at Walden Behavioral Care, which typically has 
an attendance of 70-80 patients, families, health professionals, and educators.  The investigators 
also give talks on the endocrine and metabolic complications of AN to patients on the inpatient 
eating disorders units at Walden Behavioral Care, Center for Eating Disorders at Cambridge, 
Laurel Hill and HRI on a monthly or bi-monthly basis.  Additionally, the Neuroendocrine Unit at 
Massachusetts General Hospital, in collaboration with the Harris Center, sponsors primary care 
symposia annually to educate the primary care clinician about eating disorders. These sessions 
also inform clinicians about research opportunities for eating disorder patients. 
Control subjects will be recruited from pediatric practices at MGH, MGH-affiliated health 
care centers and community practices.  Recruitment will occur through collaboration with 
physicians and caregivers at the above centers, and advertisement (i.e. posters, newsletters, and 
papers) in the community. 
All subjects 18 years and older, and guardians of subjects younger than 18 years will sign an 
approved consent form, and all subjects 14-17 years old will sign their assent in this PHRC-
approved Consent Form detailing study procedures.  The consent and assent forms will be read 
to subjects and their guardians and signed in the presence of the study investigator. Minor 
subjects who turn 18 years of age during the course of the study will be asked to sign the 
approved consent form as an adult.  In cases where the parents live out of state and find it 
difficult or inconvenient to come to Boston, we will ask the IRB for an exception to the protocol 
such that the study can be explained to parents and subjects over the phone and consent forms 
mailed/faxed to the parents/subjects to sign and send back to us.  We will conduct the consent 
interview by telephone when the parent can read the consent as it is discussed.  PHRC policy on 
Obtaining and Documenting Informed Consent of Subjects who do not Speak English will be 
followed. Potential subjects will be given a written translation in a language understandable to 
them of the “short form” of the consent form or of the entire English version of the consent form 
approved by the PHRC. 
Psychologist co-investigators who obtain consent from subjects, if they are also treating 
psychologists, will not recruit their own patients for the study.   
 
2) Subjects will also be recruited by using a REDCap survey, where all email 
correspondence will be done using encryption, as per institutional policy. Subjects can express 


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interest in the study by sharing their contact information and filling out eligibility criteria by 
using this survey. 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
 
AN subjects will receive $90 for completing each outpatient visit, except for the 
screening visit. AN subjects will also receive $50 each for completing the optional Baseline 
and 12 Month MRI, as well as reimbursement up to $25 per visit for parking and/or 
transportation costs to MGH. Healthy subjects will receive $100 for completing the study 
visit, as well as reimbursement up to $25 for parking and/or transportation costs to MGH. 
AN subjects can receive up to $910 for completing this study and its MRI sub-study, and 
healthy subjects can receive up to $100.  
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          http://healthcare.partners.org/phsirb/recruit.htm
 
          Guidelines for Advertisements for Recruiting Subjects
          http://healthcare.partners.org/phsirb/advert.htm
 
          Remuneration for Research Subjects
          http://healthcare.partners.org/phsirb/remun.htm
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
 
Parent/guardian consent and child assent will be obtained after describing the purpose of 
the study and its requirements to the subjects and their parents/guardians, and prior to performing 
any procedures.  Per institutional guidelines, those study volunteers who are 14 -17 years will 
document their written assent on the same PHRC approved consent form as their 
parents/guardians. The permission of one parent/guardian will be sufficient to document on the 
consent form.  The consent form will be signed in the presence of a licensed physician or 
psychologist investigator or study nurse practitioner. Psychologists obtaining consent will hold a 
PhD or PsyD degree, be licensed to practice psychology in Massachusetts, and be listed as co-
investigators on study staff. When consent is being obtained by a nurse practitioner or clinical 
psychologist, an optional consultation with a licensed physician investigator must be offered to 
all potential subjects before they sign the consent form. This offer, and its acceptance or refusal 
by the potential subject, must be documented in the research record. Any issues or problems with 


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the consent process must be reported to the PHRC as they occur, as “Other Event,” not logged 
and held for continuing review. Subjects will have up to 6 weeks to consider participation. Minor 
subjects who turn 18 years of age during the course of the study will be asked to sign the 
approved consent form as an adult.   
In cases where the parents live out of state and find it difficult or inconvenient to come to 
Boston, we will ask the IRB for an exception to the protocol such that the study can be explained 
to parents and subjects over the phone and consent forms mailed/faxed to the parents/subjects to 
sign and send back to us.  The consent interview will be conducted by telephone when the parent 
can read the consent as it is discussed. 
. 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
http://healthcare.partners.org/phsirb/newapp.htm#Newapp
 
For guidance, refer to the following Partners policy: 
          Informed Consent of Research Subjects
          http://healthcare.partners.org/phsirb/infcons.htm
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
Unanticipated problems or adverse events involving risks to subjects that are related to 
the study or study drugs will be reported within 5 working days or 7 calendar days of the date the 
study investigator becomes aware of the problem per PHRC guidelines. Mild and moderate 
adverse events will be reported to the Partners IRB per guidelines. 
Data Safety Monitoring Board:  One central Data Safety Monitoring Board (DSMB) will 
be convened at MGH every six months to review all adverse events at both sites.  Moreover, 
additional meetings may be called to consider urgent issues.  The following personnel have 
served on the DSMB for the current grant for the past 5 years and have agreed to continue to 
serve on the DSMB: 
• Ellen O’Donnell, PhD. Instructor of Psychology, Harvard Medical School. Staff 
Psychologist, Massachusetts General Hospital for Children 
• Dr. Harold Jueppner, MD, Pediatric Endocrine Unit, Massachusetts General Hospital 
• Eray Savgan-Gurol, M.D., Pediatric Endocrine Unit, Massachusetts General Hospital 


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• Meredith M. Regan, Sc.D., Biostatistician, Biometrics Center, Beth Israel Deaconess 
Medical Center, Instructor in Medicine, Harvard Medical School 
• Alissa S. White, RD., LDN, CNSC, Nutrition and Food Services, Massachusetts General 
Hospital  
Serious Adverse Events that are related to the study or study drugs will be telephoned 
into MGH within one working day, and forms faxed or mailed within 72 hours.  These events 
will be promptly related to the IRB and FDA by the Study Coordinator.  If the Data and Safety 
Monitoring Board wishes to be notified, we will initiate this notification as well. 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
Serious Related Adverse Events will be reported within 10 days per PHRC guidelines. These 
events will be promptly related to the IRB and FDA by the Study Coordinator. Mild and moderate 
adverse events will be reported to the Partners IRB per guidelines. All adverse events will also be 
reviewed every six months during the DSMB meetings. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
Specimens: Blood specimens and all other testing will be obtained from subjects for research 
purposes only. From the study visits, most blood samples will be frozen and stored in freezers in the 
Neuroendocrine Unit of Massachusetts General Hospital. These freezers are accessible to no one but 
the Neuroendocrine staff. Some blood samples will be sent to the chemistry laboratories of MGH for 
analysis, and left over samples will be disposed of as per institutional guidelines. 
The privacy of subjects and confidentiality of data obtained from subjects will be maintained strictly. 
In any reports or publications resulting from the study, the privacy and anonymity of individuals in the 
report will be protected. The subject's name will be removed as markers on any clinical reports 
submitted as attachments to an adverse event report. Subjects will be assigned a code, which will be 
used in all data used for analysis. 


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Adverse Events: Serious Related Adverse Events will be reported within 10 days per 
PHRC guidelines. These events will be promptly related to the IRB and FDA by the Study 
Coordinator. Mild and moderate adverse events will be reported to the Partners IRB per 
guidelines. All adverse events will also be reviewed every six months during the DSMB 
meetings. 
Data Quality Control:  All data will be recorded on specified Case Report Forms.  
Completed forms will be sent to Massachusetts General Hospital and retained at the remote site.  
As forms are received at Massachusetts General Hospital, they will be logged into a forms 
calendar, which contains all subjects’ code numbers and dates of each follow-up visit. In our 
experience, this has facilitated an easy, accurate, and global check of each subject's status, as 
well as providing recruitment and drop-out information. After each form is logged, it will be 
carefully checked for legibility and completeness and for ambiguity.  Data from the forms, 
including laboratory results, will be entered into an electronic database.  Forms that have missing 
or inconsistent data will also be entered into the database, except that a missing value indicator 
will take the place of the missing or inconsistent information. A missing information form will 
be filled out to indicate the items that are missing. 
Forms that are complete will be filed in a dedicated locked filing cabinet organized by 
subject code number. Forms that have missing data will be kept separately for ease of notifying 
coordinators. 
Accuracy of data entry will be checked using different methods at the beginning of the 
study and later when site monitoring has started.  At the start of the study, before the first site 
monitoring data is returned, the coordinator will check 100 random data items on the database 
against the case records each month.  If the error rate of data entry is worse than 2.5% overall or 
appears in crucial variables we will consider that a “data entry problem” exists and initiate 
whatever corrective action is necessary. One corrective action would be to initiate double entry 
of all data.  
 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
          http://healthcare.partners.org/phsirb/datasafe.htm
 
          Adverse Event Reporting Guidelines
          http://healthcare.partners.org/phsirb/adverse_events.htm
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.


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Most blood samples will be frozen and stored in freezers in the Neuroendocrine Unit of 
Massachusetts General Hospital. These freezers are accessible to no one but the Neuroendocrine 
staff.  Some blood samples will be sent to the chemistry and hematology laboratories of MGH 
for analysis, and left over samples will be disposed of as per institutional guidelines.  
The privacy of subjects and confidentiality of data obtained from subjects will be 
maintained strictly. In any reports or publications resulting from the study, the privacy and 
anonymity of individuals in the report will be protected. The subject's name will be removed as 
markers on any clinical reports submitted as attachments to an adverse event report. Subjects will 
be assigned a code, which will be used in all data used for analysis. 
 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
Serum will be sent to Dr. Kristina Rother and Dr. Jenny Blau at the NIH for analysis of 
INSL-5 levels in girls with anorexia nervosa for a collaborative study. All samples and clinical 
data will be coded so that only the study staff at MGH can link the identities. The NIH 
researches will only receive coding to link the samples with the clinical data and will not receive 
any subject-specific identifying information. The clinical data associated with the samples will 
include anthropometric and menstrual information.  
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
 
No data and specimens collected at MGH will be stored at other sites. 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
Subjects who do not live locally will be able to have their blood drawn in a local 
laboratory for levels of IGF-1 and bone markers, these results and/or specimens will be sent to 
MGH. 
 
 

SAP_001.pdf: 
Effects of Anorexia Nervosa on Peak Bone Mass 
NCT01301183 
Version date: March 29, 2018 
Analytical Plan 
 
 
 


ANALYTIC PLAN 
David A. Schoenfeld, Ph.D., a Professor of Biostatistics at Harvard Medical School and co-
investigator, has co-authored papers with us for more than 20 years and has been instrumental in 
our study design and will analyze these data. Data generated will be largely longitudinal. 
Measures of hormone function, bone turnover markers, nutrition, activity, body composition, 
bone density, bone microarchitecture and strength will be collected every three to six months for 
12 months. There are three study groups: AN randomized to rhIGF-1 and transdermal estrogen, 
estrogen alone with placebo, and normal adolescents.  Randomization will be performed by the 
MGH Research Pharmacy.  
Analysis and interpretation are listed below for each aim and sub-aim: 
Sample Size Determination: The study is powered to our primary endpoints, (i) change in 
lumbar spine BMD (specific Aim 1A), and (ii) change in trabecular bone density (specific Aim 
3A) in girls with AN who receive estrogen and rhIGF-1 versus estrogen alone. Specific Aim 1A: 
The primary analysis for this Specific Aim and the study is to compare the change in BMD over 
time in subjects with AN randomized to receive rhIGF-1 and estrogen (n=50) with the 
corresponding change in estrogen treated subjects (n=50). Using data from our previous study, 
we found that the variance covariance matrix of the random effects model was as follows: 
variance-intercept 0.01056, variance-slope 0.001523, covariance -0.001, and the residual 
variance around each subject’s trajectory 0.000533. Based on these parameters, with 100 
subjects with AN (50 in each group), we will have an 80% chance of detecting a significant 
(p=0.05 two sided) difference in change in lumbar spine BMD between girls who receive 
estradiol and rhIGF-1 versus estradiol alone if the true difference in slope between the groups is 
0.03 g/cm2/year.  This is a medically significant difference in that lumbar spine BMD in 
adolescents with AN is about 0.08 g/cm2 lower than that in healthy adolescents at 
baseline.  Estradiol alone has a net effect of 0.02 g/cm2.year in increasing bone density, so an 
additional effect of 0.03 g/cm2 (with rhIGF-1) added to 0.02 g/cm2 (from estradiol alone) would 
be a net effect of 0.05 g/cm2/year (from estradiol and rhIGF-1). This would allow girls with AN 
to catch up to healthy adolescents. The sample size calculation,  which assumes a 20% dropout 
rate, is based on the methods described by Yi and Panzarella (38) using the program 
http://hedwig.mgh.harvard.edu/biostatistics/node/35. The same model can be used with 
covariates and possible mediators of treatment effects such as baseline nutritional status, body 
composition, hormonal status, exercise and pubertal maturation. We will also explore the 
possibility that effects of rhIGF-1 with estradiol persist after discontinuation of treatment by 
examining bone density 12 months after stopping therapy.  
Specific Aim 1B. We will analyze the impact of rhIGF-1 with estrogen (n=50) versus estrogen 
alone (n=50) on levels of the bone turnover markers, PINP and CTX, in girls with AN at 3, 6, 9 
and 12 months using a repeated measures ANOVA. The primary planned analysis will be the 
difference in mean levels by treatment group during the 3, 6, 9 and 12 month observations. As 
for Specific Aim 1A, we will examine whether effects of combination therapy persist following 
discontinuation of therapy by examining these markers after 12 months of stopping therapy.  
Specific Aim 1C. We will use the longitudinal model described above to compare the rate of 
bone mass accrual in girls with AN who receive rhIGF-1 with estrogen (n=50) with that seen in 
healthy controls (n=36). We expect the change in BMD in AN girls to exceed that in controls 
because of a “catch up” effect when rhIGF-1 is used with estradiol. We will control for multiple 
comparisons in our analysis when comparing against controls. Both unadjusted and multiplicity 
adjusted analyses will be presented.  


Specific Aim 2A. In a cross-sectional design, we will compare the described HR-pQCT 
endpoints and bone strength (as assessed by FEA) in girls with AN (n=100) to those in healthy 
adolescents (n=36). We will use the Student t test when variables are normally distributed or 
when transformations can be performed to approximate a normal distribution; otherwise, we will 
use non-parametric tests such as the Wilcoxon rank sum test. Our preliminary data indicate lower 
trabecular bone density in 8 girls with AN compared with 6 controls (162±27 vs. 209±36 g/cm3, 
p=0.02). Based on these data, with 100 girls with AN and 36 controls in the study, we have 
>99% power for detecting a significant difference in trabecular bone density between the groups 
at an alpha level of 0.05. Another component of this specific aim is to determine the extent to 
which DXA parameters and possibly clinical parameters predict bone microarchitecture in the 
100 adolescents with AN. This will help elucidate the role of DXA in the future clinical 
evaluation of adolescents with AN.  Linear regression followed by regression modeling will be 
performed to determine hormonal, body composition, nutritional and exercise predictors of bone 
microarchitecture and bone strength in girls with AN and healthy adolescent girls.  
Specific Aim 2B. The goal of this specific aim is to determine prospectively changes in bone 
microarchitecture and bone strength in girls with AN who receive rhIGF-1 and estrogen therapy 
(n=50) compared with changes in AN receiving estrogen alone (n=50). Bone microarchitecture 
will be assessed using HR-pQCT and bone strength using FEA at baseline, six, 12 and 24 months 
of the study. Our second primary study endpoint is the change in trabecular bone density in the 
two treatment groups over the course of the study. With 100 subjects (50 in each group) we will 
have an 80% chance of detecting a significant difference (p=0.05 two sided) in change in 
trabecular bone density in girls with AN who receive rhIGF-1 and estrogen compared with 
estrogen alone if the true relative change is 3.5% over the 12 month period. This assumes a 
standard deviation of relative change of 6%, as was found in the group of AN women who 
gained weight in a study by Milos et al (39).  To understand the clinical meaning of such a 
change we note that AN women had a 20% decrease in trabecular bone density compared to 
normal women. The analysis will be accomplished using a longitudinal mixed model ANOVA 
with a random patient and time (slope) effect. The measure of interest will be the group time 
interaction. We estimate a 20% dropout rate based on our previous study. A secondary analysis 
will be a joint model with weight gain as described for Specific Aim 1. We will also compare 
changes in total cross-sectional area, cortical thickness, TbN, TbTh and TbSp between AN 
receiving rhIGF-1 and estrogen with AN receiving estrogen alone. Although this is not a specific 
aim, it will be interesting to compare the changes in BMD with the change in bone strength. An 
issue is that BMD and bone strength are measured in different units. In order to make the 
comparisons understandable, we will transform both to percent predicted using the data from 
healthy adolescent girls. Then we will fit a joint model for both measurements to assess the 
relationship between the two and which measure is affected most by treatment. In addition, we 
will examine these endpoints 12 months after stopping therapy to determine whether effects 
persist after discontinuing combination therapy. When comparing with healthy adolescent girls, 
we will adjust for multiple comparisons. Both unadjusted and multiplicity adjusted analyses will 
be presented.   
Specific Aim 2C. The random effects model can also be used where the “treatment” variable is 
replaced by a continuous variable such as IGF-1 level.  There are two possible analyses for this 
Specific Aim. One analysis would use all randomized subjects, and this would be very similar to 
the analysis for the treatment effect except that it may be more powerful if there is a large 
variation in IGF-1 levels in response to treatment with rhIGF-1.  The other is to restrict analysis 


to the group receiving IGF-1 to test whether the effect of treatment on bone microarchitecture 
parameters and bone strength is associated with the IGF-1 level. We will control for effects of 
nutrition, pubertal status, hormonal status (including estradiol and leptin), calcium metabolism 
and exercise in this analysis. As in most clinical trials, there will be measurements made during 
the trial of parameters which may or may not mediate the treatment effect.  For instance we do 
not expect short term changes in nutritional status, weight, and hormonal status to affect the 
difference between treatment effects of estrogen versus rhIGF-1 plus estrogen on BMD or bone 
strength but we may find the bone turnover markers such as P1NP do mediate the effect of 
treatment.  Mediation analysis in longitudinal trials is difficult and requires strong assumptions. 
We will explore mediation using the framework described by Ditlevsen et al (40).