Conditions: Anorexia Nervosa Osteopenia Osteoporosis
Keywords: Anorexia Nervosa Osteopenia Osteoporosis Bone density
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 148
Healthy volunteers: no

Brief summary:
Anorexia nervosa is an eating disorder that can cause thinning of the bones (a decrease in bone density). A significant decrease in bone density is called osteopenia or osteoporosis. Sometimes the loss of bone density can be severe enough to cause breaks and fractures of the bones. It is not known what causes the bones to thin in anorexia nervosa. Women who have this condition often have thin or weak bones that are more likely to break. They also have very low levels of a chemical called IGF-1 in their body. This chemical is very important for increasing bone growth in puberty and for maintaining healthy adult bones. The investigators would like to find out if giving rhIGF-1 followed by risedronate or risedronate alone can lead to an increase in bone formation, bone density, and bone strength in women with anorexia nervosa.

Detailed description:

Arms:
arm 1: Sequential therapy with rhIGF-1 (started at a dose of 30 mcg/kg subcutaneous BID and titrated) for 6 months followed by 6 months of risedronate 35mg PO once weekly arm 2: Risedronate 35mg PO once weekly for 12 months arm 3: Placebo for 12 months

Interventions: intervention 1: rhIGF-1 intervention 2: Risedronate intervention 3: Placebo
Intervention descriptions: intervention 1: Study participants will be started at a dose of 30 mcg/kg BID and will be titrated. intervention 2: Risedronate 35mg PO one time weekly intervention 3: Placebo injections 30 mcg/kg BID, Placebo tablet PO once weekly

Protocol document:
Prot_000.pdf: 
IGF-1 and Bone Loss in Women with Anorexia Nervosa  
 
NCT # 01406444 
 
Version Date: January 16, 2019 


PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Anne Klibanski, MD 
 
PROTOCOL TITLE 
IGF-1 and Bone Loss in Women with Anorexia Nervosa  
 
FUNDING 
Departmental Funds 
 
VERSION DATE 
1.16.19 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
This protocol is a randomized, double-blind, placebo-controlled clinical trial which aims to 
investigate the effect of a sequential anabolic and anti-resorptive strategy on BMD in women 
with AN receiving estrogen. We hypothesize that a sequential anabolic and anti-resorptive 
strategy in AN will maximally increase BMD by first stimulating low bone formation with rhIG-
1 administration and then decreasing bone resorption with risedronate.   
 
Specific Aim 1: Sequential therapy with physiologic rhIGF-1 followed by a bisphosphonate will 
increase bone mineral density in women with AN more than a bisphosphonate alone or placebo. 
 
Specific Aim 2: Sequential therapy with physiologic rhIGF-1 followed by a bisphosphonate will 
improve bone microarchitecture and bone strength in women with AN compared with 
bisphosphonate or placebo.  
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Anorexia nervosa (AN) is a prevalent serious disease of young women leading to severe bone 
loss at multiple skeletal sites. An increasingly common disorder among young women, AN is 
characterized by self-imposed restrictive nutritional practices and weight loss, occurring in 0.5-
1.0% of college-age women in the US. The illness can persist despite psychiatric and nutritional 
counseling. Bone loss is a severe, frequent and often permanent comorbid medical complication 
of AN resulting in debilitating vertebral crush fractures. There are a number of compelling 
reasons why bone loss in women with AN is an important health concern. First, the prevalence, 
extreme rapidity and severity of bone loss results in major morbidity. Second, osteopenia is often 
permanent, despite recovery. Third, there are no therapies that normalize BMD or that are FDA-
approved for bone loss in AN. Fourth, in contrast to postmenopausal osteoporosis in which 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
2 
 
therapy may be life-long, the goal in patients with AN is treatment during the acute illness to 
reduce further bone loss and fracture risk. We propose that an early relatively short-term 
intervention during the period of low weight and rapid bone loss may prevent significant 
osteopenia and permanent increased fracture risk in women with AN. 
 
Bone loss is prevalent and severe in young women with AN. The majority of women with AN 
have bone loss, and 50% have BMD measurements greater than 2 standard deviations (SD) 
below normative means. Bone mass in these young women may be comparable to 
postmenopausal women in their 7th and 8th decades. However, fracture risk is not fully 
explained by BMD, perhaps due to differences in bone microarchitecture between AN and 
healthy controls that is not captured by BMD. Of major importance is the fact that although 
BMD increases with weight recovery, osteopenia is often a permanent consequence of AN. 
Significant persistent osteopenia in women with AN has been shown in many studies and both 
cortical and trabecular BMD remain low more than ten years after recovery. Because bone mass 
remains persistently low despite recovery, such women remain at a high fracture risk throughout 
life, estimated to be 7.1 times that of healthy women in this age range. These data suggest that 
there may be a therapeutic window during which effective treatment should be implemented to 
prevent significant, lifelong bone mass reduction in this vulnerable population. 
 
Low bone formation and high bone resorption underlie bone loss in AN. We have shown that 
AN in adult women is characterized by a negative balance in bone metabolism, with deceased 
bone formation and increased bone resorption. Unlike many other states of estrogen deficiency, 
bone formation is profoundly suppressed and bone resorption increased. This dissociation of 
bone formation and resorption is a key mechanism underlying the severe degree of osteopenia in 
this disease. Therefore, an ideal therapy for bone loss in AN must address both low bone 
formation as well as decreased bone resorption. Our data demonstrate significant increases in 
BMD, but not to normal, with risedronate and with IGF-1, when administered separately, but 
neither alone addresses the severe degree of BMD observed in women with AN.  
 
IGF-1 deficiency is a key etiologic factor underlying low bone formation and low bone mass in 
AN. Correcting IGF-1 deficiency effectively increases bone formation and BMD in AN. Based 
on our data, the scientific rationale for IGF-1 physiologic replacement in AN, and the 
demonstrated safety of IGF-1, rhIGF-1 is an ideal strategy for use as an anabolic agent in young 
women with AN. Our recent data also provide strong evidence supporting the effectiveness of 
risedronate to decrease bone resorption and increase BMD in young women with AN. We 
hypothesize that bisphosphonates, because of their potent anti-resorptive effects, will consolidate 
the anabolic effects of rhIGF-1 to increase BMD in AN. We propose that maximal effectiveness 
to increase bone mass in AN will be achieved with sequential therapy with 6 months of rhIGF-1 
followed by 6 months of risedronate. We propose that this therapy may be effective in reversing 
bone loss and increasing BMD during a time of active disease. 
 
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.”
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
3 
 
Subjects: Over the proposed 5 years, 200 women with AN will be recruited for an evaluable 
population of 90 women, 18-45 years old (assuming a 10% drop-out rate based on our previous 
studies). Subjects with AN will be randomized 2:2:1 in a double-blind fashion for 12 months: 1) 
sequential therapy with rhIGF-1(30 mcg/kg) sc twice daily for 6 months followed by 6 months of 
risedronate 35mg, 2) risedronate 35mg or 3) double-placebo to determine effects on BMD, bone 
microarchitecture, and bone strength at trabecular and cortical sites. All subjects will meet the 
DSM-V criteria for AN and will be assessed for study suitability and monitored throughout the 
grant period for their overall psychiatric clinical state in coordination with the patients’ clinical 
care team by a study psychiatrist, psychologist or psychiatric nurse practitioner.  A standard oral 
contraceptive pill containing 35 µg of ethinyl estradiol and 0.4 mg of norethindrone or a standard 
transdermal estrogen patch containing 0.05 mg of estradiol will be offered to potential subjects 
who are otherwise eligible to participate in the study but who are not currently receiving estrogen 
orally, transvaginally, or transdermally, nor have had their menses in the past two to three 
months.  This medication will be prescribed at the lowest effective dose and for the shortest 
duration of time possible.  Oral contraceptives or an estrogen patch will not be offered to any 
potential study participant with absolute or relative contraindications to estrogen use.  We will 
not prescribe unopposed estrogen to any participant with an intact uterus.  For such women who 
are not already receiving a progestin, we will concurrently provide Prometrium 200 mg to be 
taken daily for 12 days sequentially every 28 days. 
 
 
Inclusion/Exclusion Criteria:  
Inclusion Criteria, AN: 
• Age 18-45 years 
• AN defined by DSM-V diagnostic criteria 
• Oral contraceptive use or transdermal or transvaginal administration of estrogen prior to 
the baseline visit, or willingness to start oral contraceptives or estrogen at baseline visit,  
or evidence that the patient is estrogen replete, i.e. menses within the previous two to 
three months 
• 
BMD T score or Z score < -1.0 measured within 6 months of the screening visit.  
• Normal TSH or free T4 
• Normal serum 25-OH vitamin D (>=20 ng/mL) and calcium levels 
• Ongoing care from a treatment team 
• Agree to use barrier contraception 
• Dental check up within the past year 
 
Exclusion Criteria, AN: 
• Any subject with contraindications to risedronate  
• Any subject with binge-purge subtype of anorexia nervosa who vomits regularly as their 
form of purging (vs. those who use laxatives or diuretics) and who have significant 
periodontal disease, tooth erosion or an invasive dental or periodontal procedure within 
the previous three months.    
• Any disease known to affect bone, including untreated thyroid dysfunction, Cushing’s or 
renal failure 
• Any medication known to affect bone metabolism within 3 months of the study, 
excluding oral contraceptives or other forms of estrogen administration. Bisphosphonates 
must have been discontinued for at least one year before participation 
• Serum potassium <3.0 meq/L 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
4 
 
• Serum ALT >3 times upper limit of normal 
• eGFR of less than 30 ml/min 
• Pregnant and/or breastfeeding 
• Diabetes mellitus 
• Active substance abuse, including alcohol 
• Suicidality 
• History of malignancy 
• Angioedema to transdermal patch 
• Hypersensitivity to estradiol 
• Allergy to peanuts in subjects who will take progesterone tablets 
• Breast cancer 
• Known, suspected, or history, hypersensitivity to progesterone, 
• Thromboembolic disorders 
• Significant dental procedures are probable during the study year 
 
An additional population of 50 women with AN who have BMD T score or Z score > -1.0 will 
be recruited for the bone microarchitecture substudy, for an evaluable population of 30 subjects.  
Exclusion criteria for the substudy will otherwise be the same as for the main study.   
 
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.
 
Women with AN 
 
Screening Visit:  A “Screening Visit” will be conducted by a member of the medical team to 
determine eligibility for the protocol. All subjects will be seen at the Clinical Research Center 
(CRC) at Massachusetts General Hospital (MGH) for an outpatient visit including the following: 
A complete medical history, physical examination and urine pregnancy test. History taking will 
include complete eating disorder, weight, menstrual, and medication histories. In addition, the 
following will be performed: 
 
1. Blood draw for comprehensive metabolic panel, cbc, TSH or free T4, 25-OH vitamin D, 
phosphorus, and calcium level 
2. Nutritional evaluation, including weight in a gown, height, frame size, calculation of percent 
IBW and body mass index (BMI), performed by research dieticians 
3. An optional food diary will be given to subjects to fill out. This is optional for AN subjects, 
who could potentially experience psychological stress if required to complete food diaries.  
4. DEXA scan of the spine, hip, radius, and total body if the subject has not had a DEXA scan 
within 6 months prior to the screening visit 
5. Determination of AN diagnosis and subtype (restricting or binge/purge) using DSM-V 
criteria   
6. Verification of the AN diagnosis 
7. Verification of lack of comorbid concerns (i.e. suicidality, substance use) will occur by the 
study psychiatrist, psychologist, or psychiatric nurse practitioner. Suicidality is assessed 
through a verbal conversation with a psychiatric health professional. If the subject has been 
suicidal in the past, the psychiatric professional will ask questions to assess their level of 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
5 
 
suicidality, and whether it would be a risk to their health to partake in a study. If a subject 
appears to be actively suicidal, study staff will reach out to their treatment team to alert them 
of this information and ensure that a treatment plan is in place. This plan includes if this 
information is discovered by screen via telephone. 
 
Baseline Visit:  Eligible study subjects (n=100 women with AN) will be assessed on the out-
patient CRC of the MGH for baseline testing.    
1. A complete medical history including menstrual history and instructions on keeping a 
menstrual diary, consumptive habits (smoking, alcohol, caffeinated beverages) will be 
recorded, oral temperature, height and weight in gown, pulse and blood pressure, and 
physical examination will be performed 
2. Urine pregnancy test 
3. DEXA scan of the spine, hip, radius, and total body if screen visit did not take place within 1 
month of BL visit or if a DEXA scan was not performed at the screening visit. 
4. Baseline hormone and safety blood testing:  IGF-1, glucose, ALT, potassium, PYY 
5. HR-pQCT and FEA of the radius and tibia and single slice CT mid-thigh for muscle mass 
and cross-sectional abdominal CT at L4 for both visceral and subcutaneous abdominal fat 
mass respectively   
6. MDCT of L1 to determine structural characteristics of the spine.   
7. Functional tests of strength using the handgrip dynamometer 
8. Subjects will be asked to take a standard dose of 1200 mg calcium and 800 IU Vitamin D 
supplements daily throughout the study.  
9. Eating Disorder Examination—Questionnaire 
10. Eating Disorder Inventory-2 
11. Paffenbarger Exercise Questionnaire  
 
Women with AN who are ineligible for the study because of BMD T score or Z score > -1 may 
be invited back for the bone microarchitecture substudy visit that has the same testing as a 
baseline study visit except that 1) MDCT of L1 is not be performed and 2) study medications are 
not provided.  
 
Eligible consented subjects will be allowed to have CT scans performed either 2 weeks before or 
1 week after their baseline visit 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.   
 
Randomization to treatment or placebo group will occur at the baseline visit. After the baseline 
visit, follow-up will occur at 1, 3, 4.5, 6, 7.5, 9, 10.5 and 12 months after baseline testing for 
follow-up testing. IGF-1 levels and glucose will be measured at each visit during the first 6 
months of the study and rhIGF-1 dose titrated based on IGF-1 levels; IGF-1 will also be 
measured at 12 months. Pregnancy tests and clinical evaluation will be performed at each visit. A 
nutritional evaluation will be performed at every visit. BMD at the spine, hip, radius and total 
body will be performed at 6 and 12 months after baseline. HR-pQCT and FEA of the radius and 
tibia and cross-sectional CT to measure left thigh muscle mass and to determine abdominal fat 
mass (both visceral and subcutaneous) will be performed at 6 and 12 months. CT of L1 to 
determine structural characteristics of the spine will be performed at 12 months. Markers of bone 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
6 
 
metabolism will be performed at months 1, 3, 6, 9 and 12. Functional tests of strength will be 
performed at months 6 and 12. The primary endpoint will be PA spine BMD. 
 
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. For visits which involve questionnaires, 
those will be mailed to the subject to be completed and returned to study staff. 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. In the event that a CT cannot be 
performed on the scheduled visit date due to unforeseen issues, willing subjects will be able to 
return within a 1 month window for this test.  
 
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 women with anorexia 
nervosa. Weight gain is associated with some increase in bone density, but is difficult to attain 
(occurs in only 50%) and sustain. The DXA scan is the best validated method currently used 
clinically to assess bone mass and fracture risk. This is the standard method of diagnosis at 
Partners, and is provided for free to study subjects. There are currently no FDA-approved 
therapies for anorexia nervosa-induced bone loss. 
 
Alternate strategies to address low bone density in AN  
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.  Additionally, recovery can be hard to attain and sustain.   
 
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 
women despite higher calcium and vitamin D intake than in controls    
 
PTH: Teriparatide increases BMD in post-menopausal women, however, PTH is not 
recommended in young people at this time given reports of osteosarcoma with PTH use in 
animal models.  
 
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.   
 
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.
 
The intervention being provided involves no more than two shots a day given subcutaneously for 
a period of 6 months of a medication that has been shown to be safe in both adults with anorexia 
nervosa and in children with short stature and primary IGF-1 deficiency. Side effects, including 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
7 
 
episodes of hypoglycemia, were uncommon in adult women with anorexia nervosa receiving 
rhIGF-1. Hypoglycemia is known to occur in anorexia nervosa per se, and was avoided in 
children receiving rhIGF-1 for short stature by administering the medication 30 minutes after 
meals. We plan to similarly administer rhIGF-1 30 minutes after breakfast and dinner. In a study 
performed by our group in 30 adult women with AN who received 30 mcg/kg of rhIGF-1 sc 
twice daily, rhIGF-1 was well tolerated. Nadir blood glucose remained above 50 mg/dl after 
rhIGF-1 injection in all patients, and hypoglycemic symptoms were not reported acutely after 
rhIGF-1 injection or at any time throughout the study. Two subjects reported mild joint stiffness, 
which improved with dose reduction. In our study of adolescent girls with AN who received 30-
40 mcg/kg of rhIGF-1 sc twice daily for one week, hypoglycemic symptoms were not reported. 
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 acute phase of disease. 
 
A number of procedures will be instituted to protect against potential risk involved in this 
protocol. All patients will have pregnancy tests on admission prior to receiving any radiation or 
study medication. Subjects will also have serial pregnancy tests at every study visit. All study-
related serious adverse events will be reported to the Subcommittee on Human Studies within 24 
hours of occurrence.   
 
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 of the IGF-1 or risedronate 
medication, 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.   
Subsequent management will be decided based on the severity of the side-effect.  
 
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. 
 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
8 
 
To minimize the risk from radiation, 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. 
 
Drop criteria for subjects: 
1. Pregnancy (for any subject)  
2. Medical instability, which will be determined by the study physician. Patients in this 
category will be assessed by the DSMB, and continue to be assessed according to study 
protocol   
3. Serious study–related adverse event 
 
 
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.   
   
Subjects will have DXAs to measure BMDs of the whole body, lumbar, spine, hip and radius 
during the study. This involves minimal radiation (~0.02 mSv for entire study), less than 1% of 
the background radiation received/person/year in the US. MDCT of the spine entails radiation of 
<1.8 0.9 mSv.  The radiation dose of HR-pQCT of the radius and tibia is 0.06-0.08 mSv per 
measurement which is less than 2% of the annual background radiation from the earth and sky. 
The cross-sectional CT of the abdomen and mid thigh entails two CT slices and 0.18 mSv. The 
effective dose for three such scans in one year (baseline, 6 and 12 months) is about 18% of the 
dose an average person receives from background radiation in a year. The total effective dose 
from all radiologic exams for the entire study (4 DXAs, 3 HR-pQCTs, 2 MDCTs, and 3 thigh 
and abdomen cross-sectional CTs) will be slightly about 143% of the effective dose (3mSv) an 
average person is exposed to from background radiation per year.   
 
There is no direct evidence that this amount of radiation exposure will cause harmful effects. To 
protect from scatter radiation during the MDCT, the patients will be asked to wear a lead vest 
and a lead skirt to minimize radiation to other parts of their body during scanning.  Exposure of 
sensitive pelvic organs is not expected as only the L1 vertebral body is exposed. Pregnancy 
needs to be ruled out before these tests are done to avoid the risk of radiation exposure to the 
unborn baby. A urine pregnancy test will be performed prior to the x-ray for all subjects. 
 
Complications of medications: rhIGF-1 will be administered as a twice-daily injection in a dose 
of 30 mcg/kg/day. RhIGF-1 is approved by the FDA for use in children with primary IGF-1 
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-1 for this indication: mild or moderate hypoglycemia (very rarely 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
9 
 
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. Risk 
of hypoglycemia is generally avoided when a meal or snack is consumed 30 minutes prior to 
rhIGF-1 administration. All subjects will be familiarized with signs and symptoms of 
hypoglycemia and timely management of the same. Measures to treat hypoglycemia will be 
described (carry a source of carbohydrates at all times, e.g. a juice box or glucose tablets).  
Subjects with a serum IGF-1 level that is not within the normal range for age will receive a 25% 
dose adjustment.  For those patients requiring a 25% dose increase to maintain IGF-1 levels 
within the normal range, we will contact subjects by phone to assess for side effects from the 
higher dose. We will monitor IGF-1 levels at all visits for all subjects taking rhIGF-1. 
 
The potential risk of risedronate in this study is not greater than that associated with its common 
use in clinical practice. These risks include abdominal or stomach pain, skin rash, diarrhea, 
headache and joint pain. Less common side effects include severe abdominal pain or stomach 
pain, stomach cramping, belching, bone pain, blurred vision or change in vision, chest pain, 
constipation, cough, dizziness, dry eyes, fever, general feeling of discomfort or fullness, leg 
cramps, nausea, ringing in the ears, swelling of feet or lower legs, and weakness. On rare 
occasion, red sore eyes have been reported. Risedronate was well tolerated in the 16 women with 
AN who participated in our preliminary studies; there were no cases of esophagitis, despite a 
high prevalence of concomitant bulimia. Although the long-term risk of risedronate in young 
women is unknown, bisphosphonates have been used in premenopausal women to treat 
osteopenia due to glucocorticoids. In addition, these medications are used widely in the 
community and it is essential that their efficacy be assessed.  Bisphosphonates remain in the 
bones for many years after administration, and it is unknown whether bisphosphonates may be 
secreted from bone during pregnancy or breastfeeding.   
 
 
There may be other risks of rhIGF-1 and risedronate that are currently unknown. 
 
 
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. 
Estrogen can cause headache, breast tenderness, abnormal withdrawal bleeding, bloating and 
cramping, nausea and mood swings.  The estrogen patch may also cause skin irritation.  In a very 
small percentage of patients, blood clot or stroke have been reported. 
 
 
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. 
 
Each subject will have a complete nutritional analysis and BMD performed. These data, 
including relative fracture risk, total caloric, protein and calcium intake will be made 

SAP_001.pdf: 
IGF-1 and Bone Loss in Women with Anorexia Nervosa 
 
NCT # 01406444 
 
Version Date: January 16, 2019 
 
 


VI.  Biostatistical Analysis 
 
Experimental Endpoint 
The primary endpoint will be PA spine BMD, and the primary analysis strategy will be to use a linear 
random effects model to estimate and test the effects of the three therapies on the study endpoints. The 
model that we propose is one where each patient has a linear trajectory from baseline to 6 months and 
then a possibly different linear trajectory from 6 months to a year. The 3 parameters that describe this 
trajectory are the intercept at baseline, the first slope, and the second slope. We assume that these three 
parameters have a multivariate normal distribution, with means dependent on the treatment group, the 
parameters of which we will estimate using SAS PROC MIXED. Since there are two slope parameters 
that depend on treatment, the mean slope in the first period and the mean slope in the second period, it is 
necessary to define the contrast of these parameters that will be used as the primary test of treatment 
effect. The contrast we will use will be the one that estimates the difference in the change in the 
endpoint at 12 months between the treatment groups. The advantage of using this analysis method rather 
than an analysis of covariance using only the 12 month and baseline data is that the method we propose 
will be more powerful and will also accommodate missing data better. It will give unbiased estimates 
whenever data are missing at random, while last observation carried forward (LOCF) or a complete case 
analysis would be biased (89). We will examine goodness of fit to this model using tests based on 
adding quadratic terms and by residual plots. If necessary we will add higher order terms to the model. 
We would use LOCF or complete case analysis as a secondary analysis. We use a model which has a 
break point at 6 months for all patients even for those on continuous therapy (placebo, risedronate) 
because having models that differ for the 3 treatments requires strong assumptions that lead to biases 
(90). An additional advantage of this model is that it relatively easy to add baseline covariates. The 
primary analysis would be intent to treat. Patients who wish to stop therapy will be encouraged to return 
for all evaluations. Our primary comparison for BMD is PA spine BMD, and other comparisons are 
considered secondary. In this way, we avoid having to correct each comparison using a multiple 
comparison correction such as the Bonferroni inequality. We consider the comparison of sequential 
therapy to risedronate and the comparison of each of these to placebo to be separate scientific questions, 
so we do not plan to correct these 3 planned contrasts using a multiple comparison procedure (91). 
 
Markers of bone metabolism  
The analysis will focus on 2 periods – one from 0 to 6 months, where we will have 2 post-treatment 
measurements, and one from 6 to 12 months, where we will also have 2 post-treatment measurements. 
The primary analysis will be to compare the bone markers in patients post risedronate values to the post-
rhIGF-1 values using a repeated measures analysis of covariance where the covariant is the baseline 
value for each period and the primary question is on average over the period whether there is a 
difference in markers. The significance of the analysis in the first period is whether these markers are 
affected differently by the 2 treatments, rhIGF-1 and risedronate. The second question, for the second 
period, is whether pre-treatment with rhIGF-1 changes the response to risedronate. 
 
Muscle mass 
Body composition parameters (thigh muscle mass, total, subcutaneous and visceral abdominal fat) by 
cross-sectional CT at 0, 6, and 12 months. The primary analysis of this measure will be by analysis of 
covariance with the 6-month measures as the dependent variable and the baseline measure as a 
covariate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Bone microarchitecture and strength 
There will be two analyses of these data, one comparing 6 months to baseline with an analysis of 
covariance, and one comparing 12 months to baseline. The first analysis isolates the effect of IGF-1 vs. 
risedronate and placebo. The second measures the effect of the sequential therapy. 
 
Power Analyses: Determination of an n of 100 subjects for the primary aim.  
The primary aim of the study is Specific Aim 1A, and the primary endpoint will be PA spine BMD. This 
aim will compare rhIGF-1 followed by risedronate (for anabolic consolidation and further BMD 
increases) to risedronate alone and to placebo. The study will determine 1) whether sequential therapy is 
superior to risedronate, 2) whether sequential therapy is superior to placebo and 3) whether risedronate 
administration is superior to placebo. A total of 100 patients will enter this three treatment parallel-
design study. With 36 evaluable patients in each of the two active treatment groups (assuming a 10% 
drop-out rate), the probability is >80% that the study will detect a difference between sequential therapy 
and risedronate at a two-sided 5% percent significance level, if the true difference between the 
treatments is 2.5%. This is based on the assumption that the SD of the response variable (BMD in 
women with AN receiving oral contraceptives) is 2.69%, as we found in our previous study (24) and on 
the 2.5% difference we found in our interim analysis of our preliminary study of sequential rhIGF-1 
followed by risedronate (4.8%) compared with risedronate alone (2.3%) at 12 months. In addition, it 
is consistent with the increase of 2.54% from baseline (3.05% compared with placebo) at the PA spine at 
6 months in subjects who received rhIGF-1 and OCPs (see Background and Figure 1). Risedronate 
increased BMD at 6 months followed by a decrease of 0.3% between 6 and 12 months (see Progress 
Report). Thus, we expect that the principal difference between sequential therapy and risedronate alone 
will be the 6-month effect we found of rhIGF-1 in this estrogen-treated population of 2.54% plus 0.4%. 
With 36 subjects in each treatment group and 18 subjects in the placebo group (assuming a 10% drop-
out rate), we expect the difference between the rhIGF-1 followed by risedronate and placebo groups to 
be approximately twice that between the two treatment groups and therefore we will have adequate 
power even though we have half the number of subjects in the placebo group. The power for this 
comparison will be 89%. We also have >80% power to detect a difference between the risedronate and 
placebo groups. These sample size estimates were based on using an analysis of covariance as the 
analysis method. The power calculated with this method will be somewhat less than the power achieved 
using the random effects model we propose. 
 
Markers of bone metabolism  
With 76 evaluable patients randomized between risedronate and rhIGF-I for the first six months, we will 
have an 80% chance of detecting a difference of 13 units in PINP. This represents a difference of 25% of 
the baseline value of PINP in patients with AN. For the difference between these groups 
(sequential therapy and risedronate) over the 12-month period, we will be able to detect a difference of 
0.13 units in CTX at a 5% significance level. For CTX, the difference is 19% of the baseline level. The 
power calculation was based on a repeated measures analysis of covariance with the baseline value as a 
covariate and two post baseline measurements. We used the programs provided by Muller (92). The 
variance covariance matrix of the measurements were (350,360;360,535) for PINP and 
(0.05,0.012;0.012,0.049) for CTX and are from our pilot study with 36 patient completers in the 
risedronate only and double placebo groups. 
 
 
 


Muscle mass 
With 40 women in the rhIGF-1 group and 20 in the placebo group, the probability is 80% that 
the study will detect a treatment difference at a two-sided 5.0% significance level, if the true difference 
between the treatments is 4.3%. This is based on the assumption that the SD of the response variable is 
5.2%, as we found when we examined the 6-month change from baseline in women of reproductive age 
receiving placebo (93). We conclude that this is feasible because it is smaller than the 6% change in fat-
free mass that was produced by IGF-1 in our previously published study in patient with AN (24). 
 
GH and IGF-1 
With 40 women in the rhIGF-1 group and 20 in the placebo group, the probability is 80 percent 
that the study will detect a treatment difference at a two-sided 5.0% significance level, if the true 
difference between the treatments is 0.7 times the SD of change from baseline. 
 
Bone microarchitecture: Spine 
The literature on trabecular thickness uses percent change as the unit of effect. With 36 evaluable 
patients in each treatment group the 95% confidence interval on the change in trabecular thickness of the 
spine will be 2.7% for each of the two active treatments based on Graeff et al. who estimated the 
difference between two spine microarchitectural endpoint measurements 12 months apart to be 8.8%, 
depending on the measure, and the SD of the change of 8.2% (73). Based on this we will be able to 
estimate trabecular thickness at the spine to sufficient precision to be confident as to whether the 
treatments affect this variable.  
 
Radius and Tibia 
With 40 patients in each treatment group and 20 in the placebo group entering the study and a 10% 
drop-out rate, the probability is 80 percent that the study will detect a treatment difference at 
a two-sided 5.0% significance level, if the true difference between the treatments is 2%. This assumes 
that the within subject SD is 3%, which is the interscan variation described for the instrument (94). If the 
within patient SD is twice this, e.g. 6%, we would be able to detect a change in trabecular thickness of 
4%, which is smaller than the difference between women with and without fractures of 6% (95). In 
addition, for both of the comparisons with placebo, we will be able to detect a 2.5% difference between 
groups with an 80% probability. If the within patient SD is twice this, we would be able to detect a 
change in trabecular thickness of 5%. Thus, we think that this measurement has the potential of 
detecting small clinically important differences in this parameter. The SD of 6% is greater than the SD 
found in the EUROFORS study using similar high-resolution CT scanners after 6 months of treatment 
with PTH of 5.6% (73). In the powering, we focus on the pairwise comparisons of the treatment arms 
because the scientific questions are distinct for each pairwise comparison. 
 
Bone strength (FEA) 
The literature on FEA standardizes measurements using the population SD standard deviation. We refer 
to one population SD as a unit. For strength, with 36 evaluable patients in each treatment group the 95% 
confidence interval of the change in FEA of the spine will be ± 0.33 units for each of the two 
active treatments. This is based on Graeff et al. who estimated the difference between two 
measurements 12 months apart to be 0.43 to 0.82 units, depending on the measure, and the SD of the 
change of one unit (73). Orwoll et al. demonstrated that 1 unit produces a hazard ratio of 3.196. Based 
on this, we will be able to estimate FEA to sufficient precision to be confident as to whether the 
treatments affect this variable. 


 
 
Exploratory Aim  
Sequential therapy with physiologic rhIGF-1 administration replacement followed by a 
bisphosphonate will increase spine bone strength in women with AN compared with 
bisphosphonate or placebo. We will develop a novel FEA model to determine spine strength using 
high resolution MDCT data. Dr. Gupta (co-investigator) has recently published the development and 
validation of such a model for wrist and leg strength in AN (78), and Dr. Keaveny is a world-renowned 
expert in this area (82,84,96) and will serve as a consultant on this project. For power and data analyses, 
please see sections on FEA of wrist above.