Clinical trial NCT01428245
Conditions: Hyperandrogenemia Polycystic Ovary Syndrome
Sponsor: University of Virginia
Start date: 2011-04-22; Completion date: 2013-05-14
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Gonadotropin-releasing hormone (GnRH) is a hormone that regulates the ability of the pituitary to secrete two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH control the production of female hormones (such as estrogen and progesterone) and the development of eggs by the ovary. Progesterone and estrogen then decrease the number of GnRH pulses produced by the brain (and therefore the number of LH pulses from the pituitary). The ability to decrease GnRH pulses seems to be very important for normal menstrual function in adult women. The purpose of this study is to learn more about how GnRH and LH pulses are controlled during puberty. The information gathered in this study will hopefully allow us to learn more about how menstrual cycles are normally established in girls during puberty.

Detailed description:
In this study, the investigators will aim to discover the effect of 7 days of estrogen and progesterone on GnRH pulses in girls in early and mid puberty. Ultimately, if the investigators understand these normal processes, the investigators may be able to better understand abnormalities of puberty.

Arms: arm 1: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr to achieve mean plasma concentrations over the range of 2-8 ng/ml for seven days

oral estrace, 0.5-1 mg once a day for seven days
Interventions: intervention 1: Progesterone intervention 2: Estrace (estrogen)
Intervention descriptions: intervention 1: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days intervention 2: oral estrace, 0.5-1 mg once a day for seven days

Protocol documents:
Prot_SAP_000.pdf: 
IRBHSR# 14100 
Assessment of the sensitivity of the hypothalamic GnRH pulse generator to estradiol and progesterone 
inhibition in early pubertal girls (JCM026) 
 
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Background and Brief Summary:   
Background:   
 
Etiology of PCOS 
Polycystic ovarian syndrome (PCOS) is a common clinical disorder affecting 6-7% of reproductive aged 
women.  PCOS is associated with hyperandrogenism, multiple ovarian cysts, and oligo- or amenorrhea (Stein 
and Leventhal 1935). It is also a leading cause of infertility.  The etiology for PCOS has not yet been elucidated.  
It has been proposed that hyperinsulinemia, altered ovarian steroidogenesis, and neuroendocrine abnormalities 
may play key roles either alone or in combination.   
  
Neuroendocrine Abnormalities in PCOS and Adolescent Hyperandrogenism 
 
Neuroendocrine abnormalities, whether primary or secondary, play an important role in PCOS.  A group of 
neurons collectively known as the GnRH pulse generator control the pulsatile secretion of GnRH (gonadotropin 
releasing hormone) from the hypothalamus.  GnRH, in turn, controls the synthesis and secretion of luteinizing 
hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland.   LH and FSH are both made by 
the same gonadotrope cell, and which hormone is preferentially synthesized and secreted depends in part on the 
GnRH pulse frequency.  In primates, a GnRH pulse frequency of 1 pulse per hour favors secretion of LH, 
whereas slower pulses, on the order of 1 pulse every three hours, favor release of FSH  
(Wildt 1981). In normally cycling women, the GnRH pulse frequency in the follicular phase is relatively fast, 
favoring LH secretion.  Following the rise in estrogen and progesterone after ovulation, there is a slowing of 
GnRH pulse frequency, resulting in a decrease in LH and increase in FSH synthesis, which is important for 
subsequent follicular development.  Physiologic doses of exogenous progesterone have been shown to slow LH, 
and by inference GnRH, pulsatility when given during the follicular phase (Soules et al 1984).  Therefore, 
progesterone plays an important role in regulating the GnRH pulse generator.    
 
PCOS is characterized by persistently rapid LH (GnRH) pulse frequency without the cyclic luteal phase slowing 
seen in ovulatory women.  Our group has shown that women with PCOS have reduced hypothalamic sensitivity 
to progesterone mediated suppression of LH (GnRH) pulsatility compared to ovulatory controls (Pastor et al 
1998).  Thus, they require higher plasma progesterone concentrations to achieve the same degree of GnRH 
suppression seen in controls.  Especially when coupled to the fact that women with PCOS generally have low 
levels of progesterone secondary to infrequent ovulation, this relative insensitivity contributes to the persistently 
rapid GnRH pulsatility characteristic of PCOS.  The resultant increase in LH leads to augmented ovarian 
androgen production, while the resultant decrease in FSH leads to impaired follicular development and 
anovulation.  Androgens play an important role in mediating hypothalamic progesterone insensitivity, as 
progesterone sensitivity can be restored in women with PCOS with the use of the androgen blocker flutamide 
(Eagleson et al 2000).   
 
Adolescent hyperandrogism is thought to be a precursor to adult PCOS.  Hyperandrogenic girls have increased 
LH concentrations and pulse frequency as well as accelerated maturation of their GnRH pulse patterns during 
pubertal development (Venturoli et al, 1992; Apter et al, 1994).  A recent study (IRB-HSR# 8588/ CRU# 
JCM010) by our group found that, like adult women with PCOS, hyperandrogenic girls are less sensitive to the 
suppressive effects of progesterone on the GnRH pulse generator than normal controls (Chhabra et al, 2005). 
 


IRBHSR# 14100 
Assessment of the sensitivity of the hypothalamic GnRH pulse generator to estradiol and progesterone 
inhibition in early pubertal girls (JCM026) 
 
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In IRB-HSR# 8588, the normal girls in early puberty (Tanner stages 1-3, n=4)  had increased hypothalamic 
progesterone sensitivity compared to their older counterparts (Tanner stages 4-5, n=16) (percent reduction in 
LH pulses after 7 days of estradiol and progesterone 86.5% in Tanner 1-3 vs. 54.1% in Tanner 4-5).  Although 
only a small number of Tanner 1-3 subjects were studied and the results do not achieve statistical significance, 
the finding is quite intriguing.  Free testosterone concentrations rise 4- to 8-fold during the course of female 
puberty (McCartney et al, 2007).  As androgens mediate reduced hypothalamic progesterone sensitivity in adult 
women with PCOS, we hypothesize that the gradual increase in free testosterone across the course of female 
puberty may lead to a gradual reduction in hypothalamic progesterone sensitivity. 
 
In this study, we propose to investigate this hypothesis by assessing the relationship between hypothalamic 
progesterone sensitivity and androgen levels in normal puberty.  We will measure hypothalamic progesterone 
sensitivity and androgen levels in normal girls in early to mid puberty (Tanner 1-3).  These results will be 
compared to historic data in normal controls in late puberty (Tanner 4-5) that were collected as part of IRB-
HSR# 8588. 
 
A better understanding of neuroendocrine function during pubertal maturation may lead to insights regarding 
abnormal pubertal maturation (e.g. precocious puberty) or disorders with pubertal onset (e.g. PCOS).  Hopefully 
this research will translate into improved prevention and treatment for these disorders in the future. 
 
In addition to the main portion of the study, we will be measuring a variety of cytokines and adipokines in these 
subjects.  This is part of a larger project to try to understand the origins of adolescent hyperandrogenemia and 
the extent to which cytokines and adipokines may play a role in increasing testosterone production in 
preadolescent and adolescent girls.  These girls will be a source of normal control data for this exploratory 
project.   
 
 
Brief Summary: Please see the abstract on page 5. 
 
Additional Information 
A.  Investigators Experience 
The PI and co-investigators have extensive experience in studies of the early manifestations and 
abnormalities of pubertal maturation during research over the past 25 years. Much of this research 
has involved joint collaboration with colleagues in the Department of Pediatrics, and this continues 
in the present application with co-investigators in the Dept. of Pediatrics. These individuals are 
specialists in pediatric endocrinology and are well versed and have expertise in dealing with children 
of the age ranges included.  The group currently has 8 ongoing, IRB-approved studies in the 
adolescent population, including 6 that involve overnight admissions with frequent blood sampling.  
Over 100 girls to date have enrolled in overnight studies.   
 
 
B. Study Support  
This study will be supported by NIH funds through the General Clinical Research Center Core Grant 
and through a U54 Specialized Cooperative Centers Program for Research in Reproduction and 
Infertility (IRB# 9112) 
 


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C. International Research 
Will this study be done outside the U.S. under the oversight of a UVA PI? NO 
D. Has another IRB ever not given approval to this protocol?  
No 
 
 
Drug Information 
• Micronized progesterone powder (Spectrum Chemical Manufacturing Corporation, Irving, CA), 
IND# 64,126 
• Estrace (Warner-Chilcott, Rockaway, NJ) 
 
Please list the phase or stage of this study.  Not applicable.   
Does this study involve research on a drug, biologic, supplement or food additive? Yes 
 
If yes, is this study investigator initiated? Yes 
 
If yes, answer questions # 1 and 2 
 
If no, answer question # 2 only. 
1.  Do the following criteria apply?  
 
 
No 
The investigation is intended to be reported to FDA as a well-controlled study in 
support of a new indication for use or intended to be used to support any other significant 
change in the labeling for the drug; 
 
No 
If the drug that is undergoing investigation is lawfully marketed as a prescription 
drug product, the investigation is intended to support a significant change in the advertising 
for the product; 
 
No 
The investigation does involve a route of administration or dosage level or use in 
a patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 
 If No- please explain why you believe the risk to subjects is not increased:  Estrogen 
and progesterone are frequently prescribed to older adolescent girls (Tanner 4-5 pubertal 
stage) in the form of oral contraceptive pills.  In that setting, they are felt to be safe and 
well tolerated.  Although the proposed population here is younger than the girls typically 
treated with oral contraceptive pills (Tanner 1-3 pubertal stage), we will be administering 
physiologic doses of estradiol and progesterone for a very short time (7 days) and do not 
anticipate any adverse effects.  The dosage of progesterone is adjusted based on the 
subject’s weight. We have studied 4 Tanner 1-3 girls on a protocol with identical study 
procedures and no adverse effects were seen.   
 
YES 
The investigation will be conducted in compliance with the requirements for 
institutional review set part in part 21CFR56 and with the requirements for informed 
consent set forth in part 21CFR50 ; and 
 
YES 
The investigation will be conducted in compliance with the requirements of 
21CFR312.7 (Promotion and charging for investigational drugs)  
2.  Please answer the following questions if you are using a drug/ supplement / food additive in a 
manner not approved by the FDA. 


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• Describe pertinent animal data that is available regarding the toxicity/safety of this drug. 
Not applicable, as abundant human data is available. 
 
• Describe pertinent human data that is available regarding the toxicity/safety of this drug. 
We are using a micronized progesterone suspension which is formulated/constituted by our 
investigational pharmacy. There are no specific data regarding human toxicity/safety of the 
UVAHS’s progesterone suspension, but the progesterone used to formulate the suspension is 
FDA approved for use in adults. We have used this progesterone suspension in other protocols, 
and we have thus far administered the progesterone suspension to 37 adolescent girls and at least 
11 adult women; no adverse events have occurred. 
    Estrace has used extensively in women and has a well described safety profile.  It is FDA 
approved for use in adults.   
• Have there been any human deaths associated with this drug? 
To our knowledge, there have been no human deaths associated with micronized progesterone or 
Estrace.   
• In how many humans has this drug been used previously? 
The oral micronized progesterone suspension formulated by the University of Virginia 
Investigational Drug Pharmacy has been used in several other IRB-HSR approved protocols.  We 
have administered the progesterone suspension to at least 37 adolescent girls and at least 11 adult 
women. 
     Oral estrogens, in various formulations, have been used to treat millions of women, although 
exact numbers are unknown.   
• If this protocol will be used in minors please describe any previous use of this drug with 
minors of a similar age range.     
The oral micronized progesterone suspension formulated by the University of Virginia 
Investigational Drug Pharmacy has been given to 37 adolescent girls as part of our protocols, 4 
of whom were Tanner 1-3 pubertal stage.  All of these subjects were also given estrace.  There 
have been no adverse effects. 
     Although Estrace is not often prescribed to adolescent girls, there is significant experience 
with estrogens in the older adolescent population, generally in the form of oral contraceptive 
pills.  Oral contraceptive pills have been shown safe and effective in adolescent girls, and are 
commonly used for a number of medical conditions, including hyperandrogenism, as well as for 
contraception. However, oral contraceptive pills are generally not prescribed to the girls in early 
adolescence (Tanner 1-3 pubertal stage) that we will be studying in this protocol.      
 
Hypothesis to be Tested: 
We hypothesize that the sensitivity of the GnRH pulse generator to suppression by estradiol and progesterone 
decreases during the course of normal female puberty coincident with a rise in androgen levels.  Specifically, 
we hypothesize that the Tanner 1-3 normal subjects in this study will have a 30% greater reduction in 
LH(GnRH) pulse frequency after 7 days of estradiol and progesterone than historic Tanner 4-5 normal controls. 
 
ABSTRACT 
Women with PCOS have decreased GnRH pulse generator sensitivity to suppression by estradiol and 
progesterone, as do hyperandrogenic adolescent girls.  In adult women, hypothalamic progesterone insensitivity 
appears to be androgen mediated as sensitivity can be restored with the use of the androgen receptor blocker 


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flutamide.  Free testosterone concentrations increase 4- to 8-fold during normal female puberty. The pubertal 
rise in T, as well as E2 and P, is accompanied by a rise in gonadotropin levels.  This concurrent rise in 
gonadotropins and ovarian steroids suggests that the sensitivity of the hypothalamus to sex steroid feedback, 
which is exquisite during childhood, gradually diminishes during pubertal development.  The etiology of this 
decreased hypothalamic sensitivity is not known.  Given that androgens mediate reduced hypothalamic 
progesterone sensitivity in adult women with PCOS, we hypothesize that the gradual increase in free 
testosterone across the course of female puberty may lead to a gradual reduction in hypothalamic progesterone 
sensitivity. LH (GnRH) pulse frequency will be assessed before and after 7 days of oral estradiol and 
progesterone in normal girls in early to mid puberty. Progesterone adjusted change in 11-hour LH pulse 
frequency will be used as the measure of hypothalamic progesterone sensitivity.  Hypothalamic progesterone 
sensitivity and androgen levels in these Tanner 1-3 subjects will be compared to results from previously studied 
Tanner 4-5 normal girls. 
 
 Human Participants: 
 
Ages 8-14 years 
 
Sex 
Female 
Race All races will be recruited and enrolled.   
 
Subjects- see below 
 
1. Provide target # of subjects (at all sites) needed to complete protocol to obtain statistically significant 
results.  10 
 
2. Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
The historic dropout/withdrawal rate in JMC010/IRB#8588 which has identical study procedures is 35%.  We 
expect a similar drop-out/withdrawal rate with this protocol.  Therefore, we plan on enrolling up to 16 subjects 
in order to obtain complete, usable data on 10. 
3.  How many subjects will be enrolled at all sites? 16  
4. How many subjects will sign a consent form under this UVa protocol? 16 
 
Will you be obtaining data from the UVa Clinical Data Repository (CDR)?  No 
 
Participation of Minors 
 
1. Explain why this research topic is relevant to minors. 
 
This is a study of the effects of progesterone administration on gonadotropin (LH) dynamics during 
early puberty. It will advance our knowledge of the mechanisms of normal puberty. Moreover, it will provide 
important foundational data pertinent to our hypotheses regarding the development of polycystic ovary 
syndrome during adolescence. If our hypotheses are correct, this study could provide critical data implicating a 
specific mechanism by which hyperandrogenemia can cause abnormal gonadotropin secretion in those who may 
go on to develop PCOS. This in turn may provide a sound rationale for treatment of hyperandrogenemic girls in 
early adolescence. If hyperandrogenemic girls could be treated effectively before or during pubertal maturation, 
development of clinical PCOS as a later adolescent and adult could be potentially avoided.  
  


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2. Is the knowledge being sought in this study already available for children or is it currently being 
acquired through another ongoing study? 
 
There is very limited data on the sensitivity of the GnRH pulse generator to suppression by estradiol and 
progesterone during the early pubertal period.  A previous study (IRB#8588/JCM010) assessed hypothalamic 
progesterone sensitivity in girls ages 8-18, but the bulk of these subjects were in late puberty (Tanner 4-5).  
Four Tanner 1-3 normal control subjects were studied on that protocol, and the finding that they were 
particularly sensitive to progesterone-mediated GnRH pulse generator slowing led to the hypothesis that is the 
basis for this study.  The knowledge being sought is not currently being acquired through another ongoing 
study.   
 
3. Provide data that is available in adults in order that the IRB may judge the potential risk in minors.  If 
there is no adult data available, please provide reasons why not.  If this information is available in a 
sponsor’s protocol, you may reference the section # here and not duplicate the information. 
 
Given that the data sought in this protocol is specific to the peripubertal period of development, there are 
no similar data in adults. However, very similar studies (frequent blood sampling for LH pulse analysis before 
and after 7 d of estradiol and progesterone) have been performed by our group in adults (REF) and adolescents 
(REF) without significant adverse effects.   
Inclusion/Exclusion Criteria 
 
Criteria for inclusion: 
• Girls ages 8 to 14 
• Tanner 1-3 pubertal stage 
• Pre-menarchal 
• Normal screening labs  
 
Criteria for exclusion: 
• Abnormal screening labs 
• congenital adrenal hyperplasia. 
• Hyperandrogenism (e.g., hirsutism, elevated free testosterone level) 
• Hemoglobin <11.5 g/dL for non-African American subjects; Hemoglobin < 11.0 g/dL for African 
American subjects  
• Weight < 31 kg 
• History of peanut allergy, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer 
• On hormonal medications (including oral contraceptive pills) or on medications known to affect the 
reproductive axis  within 3 months of the study 
• Pregnant or breast feeding 
• Participation in a research study within the past 30 days that involved taking a study drug. 
• Participation in a research study that involved taking up to or greater than 473 ml’s of blood within the 
past 60 days.  
• Cigarette smoking 
• History of surgery that required bedrest within the past 30 days 
• Family history of hypercoagulability or unexplained thromboembolic disease (not in setting of bedrest, 
surgery, or malignancy) 


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• In order to ensure an adequate number of younger girls, no more than 4 enrolled subjects will be Tanner 
stage 3 
 
Restrictions (if any) on use of other drugs or treatments: 
Subjects must discontinue all hormonally-active medications at least 3 months prior to the frequent sampling 
study (and 2 months prior to screening visit) and must not take any other medications known to affect the 
reproductive axis during the study.  There are no dietary requirements for this study. 
Recruitment 
How will participants be recruited?  
__X__  Posters/Flyers 
__X__  Television 
__X__  Radio 
__X__  Newspaper Ads 
__X__  Internet 
_____  Medical Record/ Database Review.  NOTE- potential subjects will be contacted after obtaining 
the approval of their attending physician and IRB-HSR approval of method of contacting 
potential subjects ( i.e. letter) 
_____  Medical Record/ Database Review.  NOTE- subjects will not be contacted 
__X__  Referrals from other health care professionals 
__X__  Discuss protocol with patients of PI or sub-investigators during a standard clinical visit 
If subjects will be contacted, explain in detail how this will be done. 
We will not initiate direct contact with potential subjects. Subjects responding to advertisements or referred 
from other health care professionals will be given the contact information for the Center for Research in 
Reproduction.   
Do you plan to ask the subjects to do anything for the study prior to signing a consent? 
YES  We will request that subjects come to the screening visit while fasting for at least 8 hours.  We will tell 
potential subjects that only subjects who have taken no hormonally-active medications for 2 months prior to 
screening are eligible for screening study, although we will not advise anyone to stop prescription medications 
without first consulting their personal physician. 
Explain the consenting process:   
An outpatient screening visit is scheduled for volunteers who preliminarily qualify for the study. Copies 
of the approved consent and assent forms are sent to potential subjects beforehand, and we request that the 
volunteer and her parents review and discuss the forms prior to the screening visit. The screening visit is held in 
an outpatient screening room in the CRU or alternate UVA clinical unit. This allows a private conversation 
between the study physician, the potential participant, and at least one of her parents (other individuals such as 
family members are allowed in the room if desired by the potential participant). The screening visit usually 
occurs in the morning, although rarely it will occur in the afternoon. The aims, procedures, and potential risks of 
the study are first explained by the study physician.  Importantly, the potential participant and her parents are 
given an opportunity to ask any questions, and concerns are addressed. In cases where the potential participant 
wants to begin the study and her parents concur, the participant, parents, and physician sign the consent form. In 
cases where only one parent is able to come to the screening visit, we allow the second parent to sign the form 
in advance of the visit.  This is done in conjunction with a conversation during which we offer that parent an 
opportunity to ask any questions and confirm that they understand the study and are willing for their daughter to 
participate.  We routinely inform potential participants verbally that signing the consent form does not compel 
them to continue participation in the study. The remainder of the outpatient screening visit (i.e., history, 


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physical, screening blood tests) occurs immediately thereafter.  Participants generally begin the main part of the 
study within 1-2 months of the screening visit.   
 
Do you plan to enroll your own students, patients, staff, employees? Yes.     
Do you plan to enroll students, patients, staff, employees of any of the other personnel listed on this 
protocol?  Yes 
 
Do you plan to enroll yourself or any other personnel listed on this protocol? No 
If yes, which groups? Subjects may be recruited from Dr. C. McCartney’s, Dr. J. Marshall’s, Dr. M. DeBoer’s, 
Dr. C. Burt-Solorzano’s, and Dr. A. Rogol’s clinical practices. However, Drs. McCartney, Marshall, rarely if 
ever see early pubertal girls in their clinics. It is also possible that the children of our clinic patients, students, or 
employees may be enrolled.  We will not enroll children of study investigators.  
 
If yes, explain how these potential subjects will be recruited to avoid the appearance of coercion.  
 
Patients who appear to be appropriate candidates for this study will be made aware that they may qualify 
for participation in the study.  If they express interest, we will offer a very brief explanation of what is involved. 
If the patient continues to express interest, we will give them our research coordinator’s contact information.  In 
keeping with our mandate as physicians, we will discuss the study only in instances where potential 
participation would not be harmful to the patient (e.g. in cases where temporarily withholding customary 
treatments is expected to have no harmful effects).  Subjects will be informed that their participation in the 
study is entirely voluntary and their decision whether or not to participate will have no effect on their current or 
future medical care. 
 
Biomedical Research 
 
List what will be done in this protocol: 
 
All procedures performed in this protocol are being done solely to answer a research question and generate 
generalizable knowledge. 
 
Outpatient Screening 
 
After a potential subject is identified, we will arrange for her to come to the CRU or alternate UVA 
clinical unit for an outpatient screening exam.  The goals and procedures of the study will be explained to the 
potential subject and her parents, and they will be given the opportunity to ask any questions.  The potential 
subject and her parents will be asked to sign the assent and consent forms.  A physician will record a family and 
personal medical history and perform a physical exam. Subjects will need to fast for a minimum of 8 hours prior 
to screening blood draw.  Blood will be drawn for screening tests (CBC, Comprehensive metabolic panel, 
prolactin, LH, FSH, E1, E2, P, total T, androstenedione, 17-OHP, DHEA-S, fasting insulin, glucose, TSH, hCG, 
cholesterol, LDL, HDL, and SHBG).  Potential subjects must fall within the normal range on all blood tests to 
be admitted to the study.  Patients with elevated 17-OHP on screening will be referred to their pediatricians for 
further testing to rule out congenital adrenal hyperplasia.  They will only be able to continue with the study if 
the have documented normal 17-OHP levels following cotrosyn stimulation.  If the subject’s hemoglobin is low 
at the time of screening (< 11.0 g/dL for African American subects or < 11.5 g/dL for non-African American 
subjects), we will offer the option of taking oral iron supplementation at a dose of 1-2 mg/kg for 60 days.  
Subjects weighing ≤ 36 kg will be given 300-325 mg oral ferrous gluconate daily (containing 36 mg of 
elemental iron); subjects weighing >36 kg will be given 300-325 mg oral ferrous gluconate twice daily.  


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Following the course of iron supplementation, the subject will then return to the CRU or clinical unit for a 
repeat hemoglobin, and will only be able to proceed with the study if her hemoglobin is greater than or equal to 
11.5 g/dL for non-African American subjects and greater than or equal to 11.0 g/dL for African American 
subjects. 
 
If the screening tests show that the subject is eligible for the study, she will be given oral iron supplementation 
at a dose of 1-2 mg/kg for 30 days to help prevent anemia during and after the study.  Subjects weighing ≤ 36 
kg will be given 300-325 mg oral ferrous gluconate daily (containing 36 mg of elemental iron); subjects 
weighing >36 kg will be given 300-325 mg oral ferrous gluconate twice daily.  The admission can take place 
any time during or after the iron supplementation.  
 
If overnight admission is scheduled to occur greater than one month after the most recent hemoglobin (such as 
that obtained during screening), a hemoglobin will be repeated 2-5 days before the overnight admission. 
Documentation of  hemoglobin ≥ 11.5 g/dL for non-African American subjects or ≥ 11.0 g/dL for African 
American subjects in the previous month is required for the frequent sampling protocol.  If the overnight 
admission is scheduled to occur greater than 3 months after screening, then the safety labs (complete blood 
count, comprehensive metabolic panel) will be repeated at this time. 
 
Day 0: First inpatient admission 
 
The subject will be admitted to the CRU, alternate UVA hospital unit, or off-site hotel at ~1700 hr.  In 
general, parents are welcome to stay with their child at the off-site hotel if they wish.  If the overnight portion of 
the study is to be done at an off-site hotel, the subject may stay without a parent or legal guardian, as long as 
two CRU staff are present.  Whether or not a parent needs to remain during the overnight admission will be 
discussed when the visit is scheduled.A urine b-HCG will be performed to rule out pregnancy and must be 
negative for the study to continue. A small amount of topical lidocaine/prilocaine cream (EMLA cream) may be 
applied to facilitate IV line placement.  An IV line will be placed in a forearm or hand vein and blood draws 
will begin at 1900 hr.  Samples will be taken every 10 minutes.  Most samples will be 0.75 mL, used to analyze 
levels of FSH and LH.  2.5 mL samples will be taken every 2 hours to analyze levels of estradiol, progesterone, 
testosterone, cortisol and DHEA  An additional 3.0 mL sample will be analyzed for fasting insulin, Insulin-like 
Growth Factor 1 (IGF-1), fasting glucose, estrone, sex hormone binding globulin, DHEA-S, androstenedione 
and a number of cytokines and adipokines, including adiponectin, leptin, resistin, PAI-1, IL-1b, IL-6, IL-8, 
TNFa, MCP-1, HGF and NGF. (Due to new technologies adipokines and cytokines can be measured in a total 
of 25 ul of serum, thereby allowing us to measure these without substantially increasing the necessary blood 
volume).  
A formal "lights out" will occur at 2300 hr so that we may observe any nocturnal changes in LH release 
patterns. Q10 minute blood sampling will end at 0600 hr.  There will be one final blood draw at 0700 hr.  
During blood sampling, activity (e.g., awake, sleeping) will be recorded by the nurse every 10 minutes.  
Additionally, periods of sleep will be estimated using wrist actigraphy (Motionlogger Basic-L; Ambulatory 
Monitoring, Inc.).  The Motionlogger Basic-L is a watch-like device (that includes an accelerometer) that will 
be worn on the wrist by the research participant during overnight admission.  The subject will be offered meals 
at standard CRU meal times.  
 
 
Day 1: Study medications 
 
Starting the day of discharge from the first inpatient admission, subjects will be given oral estrogen 
(estrace, 0.5-1 mg once a day) and oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 


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0700, 1500, and 2300 hr to achieve mean plasma concentrations over the range of 2-8 ng/ml for seven days.  
Each subject will be instructed to eat a small snack with the medication.  It has been observed that the 
absorption of progesterone is influenced by the presence or absence of food. Subjects will continue their iron 
supplementation. 
 
Days 3, 5: Outpatient blood draws 
 
On study day 3, subjects will have blood drawn at 0900 or 1700 hr (two hours after the 0700 or 1500 hr 
progesterone dose) to check serum estrogen and peak progesterone levels.  On study day 5, subjects will have 
blood drawn at 0900 or 1700 hr (two hours after the 0700 or 1500 hr progesterone dose) to check serum 
estrogen, peak progesterone levels, and hematocrit/hemoglobin.  For the second admission to continue, subject 
must have a hemoglobin ≥ 11.0 g/dL for African American subjects or ≥ 11.5 g/dL for non-African American 
subjects. 
 
Day 7: Second inpatient admission 
 
The second inpatient admission will begin on day 8.  The procedure will be identical to the first inpatient 
admission.   
 
Follow-up 
 
Subjects will discontinue estrace, progesterone, and iron after the completion of the second inpatient 
admission.  Follow-up questionnaires and/or phone interviews will be completed by the subjects 3, 6 and 12 
months after the study asking about the onset and frequency of menses and changes in hirsutism.  During these 
interviews, we will specifically address whether pre-menarchal girls had a withdrawal bleed following the 
study, and if so, whether or not they subsequently continued menstruating.  Whenever possible we will also see 
the patients on 2-3 occasions during the 12 months to obtain blood for T, DHEA-S, E2, and P measurements 
(depending on cycle stage). 
 
If a potential subject does not meet the inclusion/ exclusion criteria will you repeat any of the 
screening procedures/ tests?   
Yes 
If yes, please explain. Patients with elevated 17-OHP on screening will be referred to their pediatricians 
for further testing to rule out congenital adrenal hyperplasia.  They will only be able to continue with the 
study if the have documented normal 17-OHP levels following cotrosyn stimulation.  Additionally if 
safety labs are abnormal during screening (e.g., abnormal liver tests, abnormal TSH), subjects will be 
asked to return once for repeat (confirmatory) labs to exclude lab error. Repeat testing will generally 
occur within one month of the original screening lab draw. If exclusionary lab values are confirmed on 
such repeat testing, subjects will be excluded from participation.  The exact amount of blood drawn will 
depend on the labs being repeated, but the total amount of blood drawn will not exceed 5 ml.  
 
If clinically meaningful results are obtained during the course of the study, explain how you will 
notify the participant. 
We will contact the custodial parent(s) via phone and make general recommendations (e.g., follow-up 
with the subject’s primary care physician). We will generate a letter to the primary care physician (with 
a copy to the subject and her parent[s]) detailing the clinically meaningful results and associated 
findings of relevance. 
 
 


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What treatments, normally used, will be omitted for the study?  
Not applicable as these are normal, healthy subjects. 
 
Will any of the treatments/ procedures be done for research purposes only? Yes 
If yes, describe:  All procedures are being done for research purposes only. 
 
What details of the study are best kept secret from the participants? 
None of the details of the study will be kept from the participants.  Study participants and their parents 
will be advised of any and all aspects of the study. They will have ready access to their individual results 
after the data has been analyzed, and they may contact us to find out the results of the entire study once 
it has been completed. 
 
Taping/Photography-N/A 
 
Payment 
 
All participants will receive a $75 Charlottesville Fashion Square Mall gift card per inpatient admission. In 
addition, participants will receive a $50 bonus for study completion, also in the form of a gift card.   Therefore, 
a participant who completes the entire study will receive a total of $200 in gift cards.  If a subject only 
completes one inpatient admission, she will be given a $75 gift card.  
 
Is money paid from UVa or State funds (including grant funds)? 
Yes 
 
 
If Yes, continue to check all that apply below 
 
 
Will researcher use any of the following to compensate participants (check all that apply)? 
_____ Check issued to participant via UVA Oracle or State system  
_____ Petty cash account 
__X__ Gift card 
_____ Other type of compensation:  specify :_______ 
 
Check all categories that apply based on each participant group in the study: 
_____  < $50 TOTAL possible compensation for participating in the research study over one year 
 
_____  >= $50 TOTAL possible compensation for participating in the research study over one year and check 
issued to participant via UVA Oracle or State system 
 
__X___  >= $50 TOTAL possible compensation for participating in the research study over one year and 
researcher unable to issue checks through UVA or State system, but able to gather IRS information  
No payments of >= $50 will be approved if IRS information cannot be obtained. 
 
Justify why you are unable to issue checks through the UVa Oracle or state system.   
 
Additional Comments/ Explanation:   
This study involves preadolescent and adolescent girls.  In past and on-going studies involving the same patient 
population, we have found that the girls prefer being given gift cards directly at the end of the study to receiving 


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a check in the mail 4-6 weeks later, and this preference is reflected in our ability to recruit subjects.  Therefore, 
we prefer to compensate these subjects with gift cards.  We obtain social security numbers for IRS purposes.   
 
Specimens: 
Type of specimen to be used: Blood 
Please list the information and identifiers that will be with the specimen when it is given to you. Name, 
medical record #, GCRC protocol #, time (date and clock hour) drawn. 
If you are using discarded tissue do you confirm that it will be obtained either from pathology, a clinical 
lab or the UVa Tissue Procurement Facility?   Not applicable. 
Will you be using viable embryos?     No 
Will you be using embryonic stem cells?     No 
Do you plan to ship any specimens outside of UVA?     No 
Will the specimen be obtained before a subject has signed a consent form?     No   
 
 
Study Design:Biomedical 
 
What kind of controls will be used?  Only normal control subjects will be studied. 
Single-blind, double-blind, other:  This study is not blinded.  
If randomized, how?   This study is not randomized.  
Does the study involve a placebo?     No 
 
Bio-statistical Analysis 
Explain bio-statistical analysis to be done:   
Sample Size Determination.   If a total of 10 normal tanner-stage 1-3 girls complete both CRU admissions, 
and the true group to group difference in the percentage change in LH pulse frequency following estradiol and 
progesterone supplementation is greater than or equal to 30%, we anticipate that we will have at least an 80% 
chance of rejecting the null hypothesis that estradiol and progesterone supplementation alters LH pulse 
frequency to the same degree in both normal tanner-stage 1-3 and normal tanner-stage 4-5 girls.  This effect size 
was determine based on the following set of assumptions: (a) the percentage change in LH pulses frequency 
following estradiol and progesterone supplementation is normally distributed in both study populations, (b) the 
within-subject measurement variability (standard deviation) in the percentage change LH pulse frequency will 
not exceed 26.6% in either group (standard deviation based on the data from IRB-HSR# 8588), (c) the two-
sided type I error rate of the statistical test will not exceed 0.05, and (d) the power of the statistical test will be at 
least 0.80.    
 
Base on our previous protocol (IRB-HSR# 8588), we anticipated that the subject dropout rate will not exceed 
35% in this study population.  Therefore, we intend to enroll 16 normal tanner-stage 1-3 girls into this study.             
 
Statistical Analyses:   We will analyze the LH pulse frequency data from the tanner stage 1-3 normal girls and 
the LH pulse frequency data from the tanner stage 4-5 normal girls, by way of a linear-mixed effects ANCOVA 
model.  The response variable will identify the change in the LH pulse frequency between the LH pulse 
frequency measured at the first overnight admission (baseline) and that measured at the second overnight 
admission (after progesterone supplementation).   The ANCOVA model will include one independent factor 
and two independent continuous covariates. The independent factor will identify the girl’s tanner stage (1-3, or 


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4-5), while the two independent continuous covariates will identify the girl’s progesterone levels at baseline and 
following estradiol and progesterone supplementation.  Based on the parameter estimates from the ANCOVA 
model, we will be able to compare the magnitude of the change in LH pulse frequency after estradiol and 
progesterone supplementation between the two groups of girls after adjusting for the girls’ progesterone 
concentration at baseline (overnight admission 1) and after adjusting for the girls’ progesterone concentration 
following estradiol and progesterone supplementation (overnight admission 2).  A generalized-F-test will be 
utilized to formally test the null hypothesis that estradiol and progesterone supplementation alters LH pulse 
frequency in tanner-stage 1-3 girls to the same degree as in normal tanner-stage 4-5 girls.  The decision rule to 
reject the null hypothesis, will be based on a P≤0.05 criterion.  Confidence interval construction, for estimating 
the true group to group difference in the percentage change in LH pulse frequency after estradiol and 
progesterone supplementation, will be base on the Students t-distribution multiplier.  The  PROC MIXED 
procedure of SAS version 9.1.3 EAS (SAS Institute Inc, Cary NC) will be used to conduct the aforementioned 
statistical analyses.   
 
In order to ensure an adequate sampling of younger girls, no more than 4 enrolled subjects will be Tanner stage 
3.  The number of subjects in each Tanner stage will be reported with the final results.   
 
What is the primary outcome variable upon which a sample size estimate is based? 
 
Do I have an adequate sample size, or is my sample size larger than necessary?  The calculation of sample 
size also allows the CRU to properly budget for adequate resources to help you complete your proposal. 
 
Risk/ Benefit Analysis: 
 
What are the potential benefits for the participant as well as benefits which may accrue to society in 
general, as a result of this study? 
Although individual subjects will not benefit from participating in this study, the results will advance our 
knowledge of normal pubertal maturation.  A better understanding of normal pubertal maturation may lead to 
insights regarding abnormal pubertal maturation (e.g. precocious puberty) or disorders with pubertal onset (e.g. 
PCOS).  Hopefully this research will translate into improved prevention and treatment for these disorders in the 
future. 
 
Analyze the risk-benefit ratio:  
This study involves minimal risks, but may provide valuable information about normal pubertal maturation and 
the origins of PCOS.  PCOS is the most prevalent reproductive disorder in young women and typically 
manifests at puberty. Enhanced understanding of normal neuroendocrine function during puberty and how these 
normal processes go awry in PCOS will be essential to design rational prevention and treatment strategies for 
PCOS.  Therefore, we feel the potential benefits to society are substantial while the risks to the participants are 
quite small. 
 
Data and Safety Monitoring Plan  
 
Note:  A Sponsor-is defined as entity that will receive data prior to publication. 
1.  Definition: 
1.1 How will you define adverse events (AE)) for this study?  


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  An adverse event will be considered any undesirable sign, symptom or medical or psychological 
condition even if the event is not considered to be related to the investigational 
drug/device/intervention. Medical condition/diseases present before starting the investigational 
drug/intervention will be considered adverse events only if they worsen after starting study 
treatment/intervention.  An adverse event is also any undesirable and unintended effect of research 
occurring in human subjects as a result of the collection of identifiable private information under the 
research.  Adverse events also include any problems associated with the use of an investigational 
device that adversely affects the rights, safety or welfare of subjects. 
 Will use definitions provided in the non IRB Protocol (Sponsor's, Investigator-Initiated, CTEP etc.) located in
Section (insert section #). 
 
 Other 
 
1.2 How will you define serious adverse events?  
 A serious adverse event will be considered any undesirable sign, symptom, or medical condition 
which is fatal, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent 
or significant disability/incapacity, constitutes a congenital anomaly or birth defect, is medically 
significant and which the investigator regards as serious based on appropriate medical judgment. An 
important medical event is any AE that may not result in death, be life-threatening, or require 
hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions of SAEs.  
OR 
Any serious psychological and emotional distress resulting from study participation (suggesting need 
for professional counseling or intervention). 
 
 
1.3 This is the definition of an unanticipated problem: 
 
  An unanticipated problem is any event, experience that meets ALL 3 criteria below: 
 Is unexpected in terms of nature, severity or frequency given the research procedures that are 
described in the protocol-related documents AND in the characteristics of the subject 
population being studies 
 Related or possibly related to participation in research.  This means that there is a reasonable 
possibility that the incident may have been caused by the procedures involved in the research 
study. 
 The incident suggests that the research placed the subject or others at greater risk of harm 
than was previously known or recognized OR results in actual harm to the subject or others 
 
1.4 This is the definition of a protocol violation: 
 
   A protocol violation is defined as any change, deviation, or departure from the study design or 
procedures of  research project that is NOT approved by the IRB-HSR prior to its initiation or 


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implementation, OR deviation from  standard operating procedures, Good Clinical Practices (GCPs), federal, 
state or local regulations. Protocol violations may or may not be under the control of the study team or UVa 
staff. These protocol violations may be major or minor violations. 
 
Major Protocol Violation: 
All major protocol violations must be reported to the IRB-HSR immediately upon discovering them, and no 
later than seven (7) calendar days from the time the study team receives knowledge of the event.     
A major violation is a protocol violation that meets the following criteria: 
 
Represent a serious or continuing failure on the part of the study team to comply with the protocol, 
standard operating procedures, GCPS, federal, state or local regulations 
 
Impacts subject safety or substantially alter risks to subjects.  May or may NOT result in actual harm 
(clinical, emotional, social, financial, etc) 
 
Significantly damages the completeness, accuracy and reliability of the data collected for the study 
 
Is under control of the investigator/study team/ UVa staff 
 
Examples of MAJOR violations may include, but are not limited to: 
 
 
Evidence of willful or knowing misconduct on the part of the investigator(s), or study team  
 
Failure to obtain informed consent, i.e., there is no documentation of informed consent, or informed consent is 
obtained after initiation of study procedures.  (Note: Data for subjects where consent is not documented may 
not be used in data analysis.) 
 
Enrollment of a subject who did not meet all inclusion/exclusion criteria which would affect subject safety or 
would negatively impact data integrity 
 
Performing study procedure not approved by the IRB-HSR  
 
Failure to report serious unanticipated problems/adverse events to the IRB-HSR and (if applicable), the sponsor  
 
Failure to perform study procedures outlined in the protocol where subject safety or data integrity may be 
negatively impacted. (Ex. Safety labs not done per protocol) 
 
Drug/study medication dispensing or dosing error under control of Investigators, study team or UVa staff. 
 
Study visit or procedure conducted outside of required time frame that may negatively affect subject safety 
 
Failure to follow Data Safety Monitoring Plan  
 
Minor Protocol Violations: 
Reporting of minor violations to IRB is not required by IRB-HSR. 
 
2.  Identified risks and plans to minimize risk 
 
 
2.1 What risks are expected due to the intervention in this protocol? 
Expected:  is identified in nature, severity or frequency in the study documentation (protocol, consent, 
Investigator Brochure, package insert etc) is considered an expected. 
 
Risk associated with frequent blood sampling:    
Expected Risks related to study participation- 
volume of blood drawn  
Frequency 
Please pick one frequency from each box below 
• 
Significant anemia related to frequent 
blood sampling (hematocrit < 30%) 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown, but likely to be very rare 
• 
Mild anemia (hematocrit < 36%) 
related to frequent blood sampling 
 Occurs frequently, 
 Occurs infrequently 


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 Occurs rarely 
 Frequency unknown 
 
 
Risk associated with micronized progesterone suspension: 
 
Expected Risks related to study participation- 
micronized progesterone  
Frequency 
 
• 
GI upset (nausea, abdominal bloating, 
diarrhea) 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown, but likely to be very rare 
• 
CNS effects (sleepiness, headache, 
dizziness, fatigue, emotional lability, 
irritability) 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
• 
Mild, short-lived vaginal bleeding 
shortly after ingestion 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
 
Risk associated with estradiol: 
 
Expected Risks related to study participation.  Frequency 
 
• 
GI upset (nausea, abdominal bloating, 
diarrhea) 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Breast Tenderness 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Deep vein thrombosis 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown, however occurs very rarely 
with long-term estrogen use (as with oral 
contraceptive pills), so would expect to be 
exceedingly rare with the short term administration 
in this protocol 
 
Risk associated with IV needle placement: 
 
Expected Risks related to study participation- 
IV placement 
Frequency 
 
• 
Infection at needle site 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown, but likely to be very rare 
• 
Bleeding at needle site 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 


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 Frequency unknown 
• 
Blood clot at needle site 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
• 
Pain at needle site 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
• 
Bruise at needle site 
  Occurs frequently, 
  Occurs infrequently 
  Occurs rarely 
  Frequency unknown 
 
Risk associated with iron supplementation 
 
Expected Risks related to study participation- 
iron supplementation 
Frequency 
Please pick one frequency from each box below 
• 
nausea 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
• 
constipation 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
• 
dark or black stools 
 Occurs frequently, 
 Occurs infrequently 
 Occurs rarely 
 Frequency unknown 
 
 
Risk associated  with EMLA cream (topical lidocaine and prilocaine, used to alleviate pain):  The risks of lidocaine 
and prilocaine in general may include (frequency not defined) hypotension, angioedema, shock, hyperpigmentation, 
erythema, itching, rash, burning, urticaria, burning, stinging, edema bronchospasm, and hypersensitivity reactions.  
However, in the case of topical lidocaine/prilocaine use, the non-dermatologic adverse events mentioned above would be 
extremely unlikely unless large amounts of topical lidocaine/prilocaine were used (allowing significant systemic 
absorption). 
 
Risk regarding wrist actigraphy:  There are no known risks associated with the use of wrist actigraphy. 
 
Risk of not being able to take hormonal medications: Fertility in premenarcheal girls is exceedingly unlikely. Thus, the 
risk of pregnancy related to inability to take hormonal birth control medication is virtually absent.   
 
 
2.2   List by bullet format a summary of safety tests/procedures/observations to be performed.  
 
• Sterile technique will be used.   
• Before participation in the study, all participants will be required to have a normal hemoglobin (≥11.0 
g/dl for African American subjects or ≥ 11.5 g/dL for non-African American subjects).  Hemoglobin 
levels will be measured prior to every admission, and the admission will only continue if the 


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hemoglobin level is >11.0 g/dl for African American subjects or > 11.5 g/dL for non-African 
American subjects.   
• Blood loss will be carefully recorded and limited to a maximum of 7cc/kg (10% of estimated total 
blood volume) in 8 weeks.  A total of  216.5 ml of blood will be drawn  during the study (including 
estimated waste from frequent blood draws).  Therefore, girls weighing less than 31 kg will not be able 
to participate.  Iron supplementation (325 mg once or twice a day dependent on weight) will be 
prescribed to all participants. 
• β-hCG levels will be measured at screening and prior to each admission; if the β-hCG is positive, the 
study will be discontinued. 
• Topical lidocaine and prilocaine (EMLA) cream may be used to lessen pain associated with IV needle 
insertion. 
 
 
2.3 Check the criteria below under which an INDIVIDUAL SUBJECT’S study treatment or study 
participation would be stopped or modified  
 
 
        At subject, PI or sponsor’s  request 
 
 Treatment would be stopped if the subject had a Serious adverse event deemed related to study 
 
 The study would be stopped in the patient has a positive pregnancy test or a hematocrit <36 and 
hemoglobin <12 prior to any of the 4 admissions. 
 
 
2.4 Check the criteria under which THE ENTIRE STUDY would need to be stopped.  These are called 
stopping rules for early termination of the entire study.  
 
Per IRB, PI, DSMB, or sponsor discretion 
 
 Other: If there are an excessive number of unexpected adverse events that significantly alter the 
risk/benefit ratio for the study, the study will be terminated.  All adverse events will be evaluated both 
individually and cumulatively by the study team and principal investigator as they arise, allowing for 
timely decisions regarding study continuation/termination.   
 
2.5 Describe the criteria for breaking the blind/mask  
 NA – Not blinded/masked 
 
2.6 How will subject withdrawals/dropouts be reported to the IRB prior to study completion?  
  IRB-HSR continuation status form  
 
3.  Adverse Event / Unanticipated Problem Recording and Reporting 
 
3.1 Will all adverse events, as defined in section 1.1, be collected/recorded? 
 
 
   Yes 
 


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3.2 How will adverse event data be collected/recorded?  
 
 Paper AE forms/source documents (please attach a copy of this form if possible) 
 Spreadsheet - electronic 
 
3.3. How will AEs be classified/graded?  
 
 World Health Organization Criteria (WHO) 
 NCI Common Toxicity Criteria, Version 2.0/ NCI Common Terminology Criteria, Version 3.0 
 Mild/Moderate/Severe 
Serious/Not serious (required for all protocols) 
 
 
3.4 What scale will the PI use when evaluating the relatedness of adverse events to the study participation?  
(Check all that apply.) 
  
 The PI will determine the relationship of adverse events to the study 
 using the following scale: 
 
Related:      
 
AE is clearly related to the intervention 
Possibly related: 
AE may be related to the intervention 
Unrelated:  
 
AE is clearly not related to intervention 
 
 
3.5 When will recording/reporting of adverse events/unanticipated problems begin? 
 
 After subject begins study drug/ device placement/intervention /study-related procedure/specimen 
collection 
 
3.6 When will the recording/reporting of adverse events/unanticipated problems end? 
 
 End of study drug/device/intervention/participation  
 30 days post study drug/device/intervention 
 Subject completes intervention and follow up period of protocol 
 
3.7 Please complete the following table to describe details of Adverse event, Unanticipated Problem, and 
Protocol Violation reporting  
 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting in death that is deemed 
DEFINITELY related to (caused by) study 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 


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participation 
(Note:  An internal event is one that occurs in a 
subject enrolled in a UVa protocol.) 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected adverse event  
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that are not adverse events 
or protocol violations  
 
IRB-HSR 
 
 
 
 
 
 
GCRC  
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vprgs/ir
b/HSR_docs/Forms/Reporting_R
equirements-
Unanticipated_Problems.doc ) 
 copy of report to IRB 
  
Protocol Violations (Note the IRB-HSR only 
requires that MAJOR violation be reported, unless 
otherwise required by your sponsor, if applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
 
 
 
 
 
GCRC  
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
 
Protocol Violation and 
Enrollment Exception Reporting 
Form 
 
 
http://www.virginia.edu/vprgs/ir
b/hsr_forms.html 
 
copy of report to IRB 
 
Life-threatening and/or fatal unexpected events 
related or possibly related to the use of the 
investigational agent. 
FDA 
Within 7 calendar 
days of the study 
team learning of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 
Serious, unexpected and related or possibly related 
adverse events 
FDA 
Within 15 calendar 
days after the study 
team receives 
knowledge of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 


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4.    How will the endpoint data be collected/recorded.  
 
 Database: The endpoint data will be collected and maintained in a database kept on the CRU server.   
5. Data and Safety Oversight Responsibility 
 
5.1. Who is responsible for overseeing safety data for this study  
 
 No additional oversight body other than PI (skip question 5.2) 
 The UVa Cancer Center Data and Safety Monitoring Committee (If your study involves cancer patients, 
see Question # 6 to help you decide if you should check this box) 
 Industry Sponsored-designated DSMB/DSMC/Medical Monitor  
 Non-Industry Sponsored (other academic center, NIH) designated DSMB/DSMC/Medical 
Monitor (If your study is NIH funded, please check with the center to determine if they require a 
DSMB for this study) 
 
 
5.2. What is the composition of the reviewing body and how is it affiliated with the sponsor? N/A   
  
 
5.3. Please check aggregate reviews that will occur by the PI  
 
 All adverse events 
 Unanticipated Problems 
 Protocol violations 
 Audit results 
 Application of dose finding escalation/de-escalation rules  
 Application of study designed stopping/decision rules 
 Early withdrawals 
 Whether the study accrual pattern warrants continuation/action 
 Endpoint data 
 
5.4. How often will aggregate review occur? 
 
 Annually 
 
5.5. How often will a report, regarding the outcome of the reviews, be sent to the PI from the oversight 
body listed in 5.1.  Not applicable. 
 
5.6. How will a report of the information discussed in question 5.4 OR 5.5 be submitted to the IRB?   
 


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 Part of IRB-HSR continuation status form 
 
Bibliography  
 
Apter, D., Butzow, G.A., Laughlin, G.A., Yen, S.S.C. (1994). Accelerated 24-hour lutenizing hormone pulsatile 
activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic 
ovarian syndrome. Journal of Clinical Endocrinology and Metabolism 79(1):119-125. 
 
Apter, D., and Vihko, R. (1990). Endocrine determinants of fertility: serum androgen concentrations during 
follow-up of adolescents into the third decade of life. Journal of Clinical Endocrinology and Metabolism 
71:970-974. 
 
Chhabra S, McCartney CR, Yoo RY, Eagleson CA, Chang RJ, Marshall JC (2005).  Progesterone inhibition of 
the hypothalamic GnRH pulse generator: Evidence for varied effects in hyperandrogenemic adolescent girls.  
Journal of Clinical Endocrinology and Metabolism 90(5):2810-5. 
 
Daniels, T.L. and Berga, S.L. (1997). Resistance of GnRH drive to sex steroid induced suppression in 
hyperandrogenemic anovulation. Journal of Endocrinology and Metabolism 82:4179. 
 
Eagleson CA, Gingrich  MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC (2000).  Polycystic ovary 
syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to 
inhibition by estradiol and progesterone.  Journal of Clinical Endocrinology and Metabolism 85: 4047-4052.   
 
McCartney, C.R., Blank, S.K., Prendergast, K.A., Chhabra, S., Helm, K.D., Yoo, R., Chang, R.J., Foster, C.M., 
Caprio, S., Marshall, J.C. (2007). Obesity and sex steroid changes across puberty: evidence for marked 
hyperandrogenemia in pre- and early pubertal obese girls. Journal of Clinical Endocrinology and Metabolism 92 
(2): 430-6. 
 
Pastor, C.L., Griffin-Korf, M.L., Aloi, J.A., Evans, W.S., Marshall, J.C. (1998). Polycystic ovary syndrome: 
evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by 
estradiol and progesterone. Journal of Clinical Endocrinology and Metabolism 83 (2): 582-590. 
 
Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremmer WJ (1984). Progesterone modulation of 
pulsatile luteinizing hormone secretion in normal women.  Journal of Endocrinology and Metabolism 58:378-
383.   
 
Speroff, L. and Vande Weile, R. (1971). Regulation of the human menstrual cycle. American Journal of 
Obstetrics and Gynecology 109:234. 
 
Venturoli, S., Paradisi, R., Porcu, E., Pallotti, G., Fabbri, R., Gammi, L., Magrini, O., Flamigni, C. (1987). 
Postmenarchal evolution of endocrine pattern and ovarian aspects in adolescents with menstrual irregularities. 
Fertility and Sterility 48(1):78-85.  
 
Wildt, L. Hausler, A., Marshall, G. et al. (1981). Frequency and amplitude of GnRH stimulation and 
gonadotropin secretion in the rhesus monkey. Endocrinology 109:376-385. 


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inhibition in early pubertal girls (JCM026) 
 
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Version Date: 2-29-12 
 
 
 
 
 
 
____________________________ ____________________________ _______ 
Principal Investigator 
Principal Investigator 
Date 
(Print) 
(Signature) 


IRBHSR# 14100 
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inhibition in early pubertal girls (JCM026) 
 
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ICF_001.pdf: 
IRB-HSR#14100 
Assessment of the sensitivity of the hypothalamic GnRH pulse generator to estradiol and progesterone 
inhibition in early pubertal girls (JCM026)  
 
 
Page 1 of 11 
Version Date: 7-1-11 
Parents’ or Guardians’ Permission for Your Child  
to Be in a Research Study  
 
In this form “you” means the person (your child) who is being asked to be in this study. As the parent or 
guardian, you are being asked to give permission for your child to be in this study. 
 
1. Participant’s Name______________________________ 
 
2. Medical Record # _______________________________ 
 
What is the Purpose of this Form? 
This form will help you decide if you want to be in the research study. You need to be informed about the study, 
before you can decide if you want to be in it. You do not have to be in the study if you do not want to. You 
should have all your questions answered before you give your permission or consent to be in the study.  
 
Please read this form carefully.  If you want to be in the study, you will need to sign this form. You will get a 
copy of this signed form.   
  
Why is this research being done? 
Background 
Below is a list of terms and information to help you understand why we are doing this study. 
 Hormone: A substance made in the body that is sent directly out into the bloodstream to increase or 
decrease the function of certain organs, glands, or other hormones.  
 Puberty: The time that the body is growing and changing from a girl into a woman and boys are 
growing and changing into men. 
 Gonadotropin releasing hormone (GnRH): GnRH is a hormone made in a part of the brain called the 
hypothalamus. GnRH tells the pituitary gland to make LH and FSH (see below). 
 Testosterone: Testosterone is a hormone that plays an important role in boys growing and changing into 
men.  Although testosterone levels are much higher in men and boys, healthy girls and women make 
some testosterone too. 
 Luteinizing hormone (LH): LH is a hormone made in a gland underneath your brain called the 
pituitary. LH is needed for puberty. 
 Follicle Stimulating Hormone (FSH): FSH is a hormone made in a gland underneath your brain called 
the pituitary. FSH is needed for puberty.  
 Progesterone: A hormone made by the ovaries. Progesterone is important for a lot of things. For 
example, progesterone helps control GnRH release from the hypothalamus.   
 Ovary: Small oval organ in the pelvis that makes hormones (such as progesterone and testosterone) and 
eggs. 
 


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Gonadotropin-releasing hormone (GnRH) is a hormone from the brain. GnRH causes a gland called the 
pituitary to secrete two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  
• GnRH is produced in pulses from the brain, and this causes the pituitary to release LH and FSH in 
pulses.   
• LH and FSH control the production of female hormones (such as estrogen and progesterone) and the 
development of eggs by the ovary.   
• Progesterone and estrogen then decrease the number of GnRH pulses produced by the brain (and 
therefore the number of LH pulses from the pituitary).   
• The ability to decrease GnRH pulses seems to be very important for normal menstrual function in adult 
women. 
 
The purpose of this study is to learn more about how GnRH and LH pulses are controlled during puberty.  
• In this study, we will aim to discover the effect of 7 days of estrogen and progesterone on GnRH pulses 
in girls in early and mid puberty.  
• The information gathered in this study will hopefully allow us to learn more about how menstrual cycles 
are normally established in girls during puberty. Ultimately, if we understand these normal processes, 
we may be able to better understand abnormalities of puberty. 
 
In this study, we will use the drugs progesterone and estradiol.  The progesterone syrup that we use is made in 
the UVa Investigational Pharmacy.  The progesterone used to make the syrup is approved by the Food and Drug 
Administration (FDA)  but there are no specific data regarding human toxicity and safety of the UVA Health 
System progesterone syrup.  Over 35 girls have taken the progesterone syrup as made by the UVa pharmacy 
and there have not been any unexpected side effects.  The use of estradiol and progesterone are considered to be 
experimental in this study. 
 
You are being asked to be in this study, because you are a normal girl in early to mid-puberty, with normal 
levels of testosterone in your blood. 
 
Up to 16 people will be in this study at UVA.   
 
How long will this study take? 
The study involves a total of 3 outpatient visits and 2 overnight admissions.  The screening visit will last about 
1 hour.  The other 3 outpatient visits will last 15 minutes.  The 2 overnight admissions will last 14 hours each.  
The study will last 1 week (not including the screening visit). 
 
What will happen if you are in the study? 
 
All study tests, procedures, and exams are being done specifically for research purposes.   
 
 
 
 


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SCREENING (will take approximately 1 hour to complete): 
If you agree to participate, you will sign this consent form before any study related procedures take place.  
Before you can start in the study, there will be a screening period.  You will have tests and procedures during 
this time to make sure you are eligible and it is safe for you to participate.  These include the following:  
• Review of your medical history 
• Physical exam and vital signs (blood pressure, heart rate, etc.) 
• We will also check to see how far along into puberty you are.  To do this, we will do a quick breast 
exam. 
• Standard blood tests (less than 2 tablespoons of blood) to check: salts, sugars, blood counts, liver 
function, kidney function, pregnancy test, and a variety of hormones.  We will ask that you not have 
anything to eat or drink except for water for 8 hours before having this blood work drawn.  
 
If one or more of your blood tests are abnormal, we may ask you to return to the Clinical Research Unit (CRU) 
or alternate UVA clinic so we can repeat the abnormal blood test.  The repeat test will generally occur within 
one month and will help exclude lab error.  If repeat lab tests are still abnormal, you will not be able to continue 
in the study. 
 
If the tests at this screening visit show that your blood counts are borderline, we will ask that you take1-2 iron 
tablets per day (based on her weight) for 60 days and then return to the CRU or clinic to recheck you blood 
counts to ensure that it is safe for you to take part in the study. 
 
If these tests show you are eligible, you will return to the GCRC to begin the study.  You may be asked to do 
the overnight portion of the studies in a different hospital unit or in a hotel.  If you are unable to begin the study 
within 30 days, you will need to come back to have your blood counts checked prior to the first admission.  If 
you are unable to begin the study within 90 days, all of the screening blood tests will need to be repeated before 
taking part in the study. We will ask that you starting taking 1-2 tablets of iron per day (based on your weight) 
to prevent low blood counts during the study.  You will take these for a total of 30 days.   
 
STUDY TESTS AND PROCEDURES: 
 
Day 0 - Admission #1 (will take approximately 14 hours to complete): 
• You will be admitted to the CRU, alternate UVA hospital unit, or hotel at about 5:00 pm on the day 
of the admission.  If the overnight visit occurs at a hotel, your parent or guardian may stay with you 
but it is not required, as long as two CRU staff members are at the hotel with you.  Whether or not a 
parent or legal guardian is required to stay during the overnight admission will be discussed when 
your admission is scheduled. 
•  During your overnight stay, you will wear an actigraph.  It looks like a watch and it is worn on your 
wrist.  The actigraph will help us know when you are awake and when you are asleep.  
• An intravenous (IV) line will be placed in your arm. An IV is a small flexible tube that is inserted 
into a vein using a needle. Once the tube is in place, the needle is removed and replaced with a cap 
that allows blood to be drawn or medication or fluid to be given. This means you will only have the 
needle stick you in the arm once 


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• A medicine, called EMLA cream, may be applied to the skin prior to the IV insertion to try to make 
it hurt as little as possible..    
• We will do a urine pregnancy test.  If you are pregnant, you will not be able to continue in the study. 
• Starting at 7:00 PM, blood samples will be taken by a nurse every 10 minutes.  Each of the blood 
draws will be no more than 1/2 of a teaspoon  
• You will be given dinner at standard CRU mealtimes.  You will not be able to eat or drink anything 
except water from 11:00 pm until 7:00 AM.  
• A formal "lights out" will take place at 11:00 pm.  At this point the lights and the television will be 
turned off to allow you to sleep. 
• At 6 AM, the nurses will stop taking blood every 10 minutes.   
• At 7 AM, the nurses will take one final blood sample. 
• After the blood draws are complete at 7:00 AM, you will be served breakfast.   
• The nurse will take out the IV and you will be able to go home.  
• A total of 7 tablespoons of blood will be drawn during this admission. 
• Before you go home from the overnight admission, you will be given a supply of estrogen (estradiol) 
pills and progesterone syrup with instructions on how to take them.  
 
Day 1 - Start estrogen and progesterone: 
• Estrogen and progesterone are natural hormones.  The amount of these hormones given in this study 
is similar to the amounts that are produced by girls’ bodies as they develop.   
• The estrogen pills should be taken by mouth once a day for seven days.   
• The progesterone syrup should be taken by mouth three times a day at 7:00 am, 3:00 pm, and 11:00 
pm for seven days.  If your school schedule makes it difficult to take the syrup at 3:00 pm, please 
discuss this with the study doctor and we will adjust the dosing schedule.  Usually, this will mean 
that instead of taking the syrup at 3:00 pm, you will take it immediately upon arriving home from 
school. 
• The progesterone needs to be refrigerated and should be shaken well before you take it.   
• When you take the progesterone syrup, you should also eat a small snack such as peanut butter 
crackers and juice or a half of a sandwich and 2% milk.  It is important that the snack is eaten as it 
helps the medicine get absorbed. 
 
Day 3 & 5 - Outpatient Blood Draws (will take approximately 15-30 minutes to complete): 
• Three days and then five days after the admission, you will return to the CRU or clinic for an 
outpatient blood draw at 5:00 pm.  This appointment should take no longer than 30 minutes. 
• A small amount will be drawn (less than 1/3 teaspoon) to make sure the estrogen and progesterone 
are being absorbed into the blood stream.   
• On Day 5, we will check your red blood cell counts.  If they are too low, you will not be able to 
continue with the second admission. 
 
 Day 7 - Admission #2 (will take approximately 14 hours to complete): 


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• After seven days of taking the estrogen and progesterone, you will return to the CRU, hospital unit, 
or hotel for the second overnight inpatient admission.  You will bring your estrogen and 
progesterone bottles and any unused medicine to the admission and give them to the nurses. 
• The second admission will be identical to the first inpatient admission. 
• A total of 7 tablespoons of blood will be drawn during this admission. 
• At the end of the second admission, you will: 
o stop taking the estradiol and progesterone  
o keep taking the iron supplements if you have not yet take a full 30 days of the iron. 
 
FOLLOW UP: 
• 
If possible, we would like to follow-up with you 3, 6, and 12 months after the study.  This may be 
done by outpatient visits or phone calls and will include questionnaires and interviews.  We would 
also like to take a small amount of blood (less than 1 tablespoon) at this time to measure hormone 
levels. These visits are optional. 
 
Study Schedule table: 
 
Day of Study 
Type of Visit 
Estradiol Progesterone 
 
Screening visit. 
 
 
Day 0 
Admission #1 
Overnight with frequent blood draws 
 
 
Day 1 
 
X 
x 
Day  2 
 
X 
x 
Day 3 
Blood draw 
X 
x 
Day 4 
 
X 
x 
Day 5 
Blood draw 
X 
x 
Day 6 
 
X 
x 
Day 7 
Admission #2 
Overnight with frequent blood draws 
X 
x 
 
If you want to know about the results before the study is done: 
The study leader will tell you, during the study, of any results that are important to your health. That 
information is important for you to know, because it may help you decide whether you want to continue being 
in this study. We cannot tell you any other information until the results have been studied.  At that time you can 
ask for more information. 
If we take any blood or tissue: 
The blood we take will be tested to measure salts, sugar, blood counts, kidney function, liver function, 
pregnancy tests, and a variety of hormones.  


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• A total of 15 tablespoons of blood will be drawn during the study. 
• After the study is complete, any left over blood/tissue will be thrown away.  It will not be stored for any 
future testing. 
 
What are the risks of being in this study?  
Risks and side effects related to the study procedures, drugs, and interventions include: 
 
Likely 
• Iron supplements can cause dark or black bowel movements.   
 
 Less Likely   
• Estradiol and progesterone can cause nausea, fluid retention/swelling, breast tenderness, and 
moodiness/irritability.   
• After you stop taking the estrogen and progesterone, you may have some menstrual bleeding if 
your own body was ready to start a period within a few months.  If you do have a period, you 
may continue to have periods.  
• Iron supplements can cause nausea and constipation.  
• Frequent blood draws may result in mildly low red blood cell counts (mild anemia).  Mildly low 
red blood cell counts usually do not cause symptoms in healthy girls, and the body is able to 
rapidly build red blood cells to bring the counts back to normal within 1-2 months.    
 
Rare but serious 
• Frequent blood draws could lead to significantly low red blood cell counts (significant anemia) if 
precautions were not taken to avoid this.   
• Significantly low red blood cell counts can cause fatigue, lightheadedness, and shortness of 
breath, particularly with exercise.  In order to prevent low red blood cell counts, we will give you 
iron supplements to make sure that your body has the necessary building blocks to make new red 
blood cells.   
• We will check the red blood cell levels during the screening and before each overnight 
admission.  If the level is too low, we will not continue the study.  We carefully limit the amount 
of blood drawn to an amount that is safe for someone of your size.   
• Long-term (over months to years) use of estrogen has been associated with the formation of 
blood clots in the deep veins of the body.  This risk is similar to the risk of taking birth control 
pills.   
• Long-term (5 years) use estrogen and progesterone in postmenopausal women is associated with 
a slightly increased risk of heart disease, stroke, and breast cancer.  However, there is no 
evidence that the use of estrogen and progesterone as given in this study would increase these 
risks in young girls.  
   
Do not share the study drug with anyone. It is prescribed only for you and could hurt someone else. Keep it out 
of reach of children and people not able to read or understand the label. 
 


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Risks of having your blood drawn: 
Having blood drawn may cause: 
 pain (common), 
 a bruise (sometimes), 
 fainting or passing out (not very often), and  
 infection (rare). 
 
If the people doing the study are exposed to your blood or body fluids in a way that could give them a disease, 
your blood may be tested. The tests might check for: 
 hepatitis,  
 HIV (Human Immunodeficiency Virus), or  
 other infections.   
 
You and the person exposed would be told the test results. However, your name would be kept private. If your 
test is positive for hepatitis or HIV, we will tell you how to find counseling. You may want help in 
understanding what the results mean for you. 
 
Risks of taking blood with a catheter: 
Sometimes the catheter stops working.  In order to get the blood we need, we may have to stick you with 
another needle. 
 
A caution about giving too much blood: 
Because of the amount of blood being taken, you should not give blood for other reasons for 8 weeks. For 
example, avoid giving blood at a blood bank or in another research study. 
 
Risks of EMLA numbing cream: 
Common Risks are: 
 
Temporary redness or paleness of the skin 
 
Mild itching, burning, or swelling   
 
Change in skin temperature, which may cause mild discomfort 
Rare Risks are: 
 
Skin discoloration 
 
Severe allergic reaction 
 
EMLA overdose (lightheadedness, nervousness, confusion, dizziness, drowsiness, blurred or double 
vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, 
unconsciousness, respiratory depression, low blood pressure, cardiac arrest). 
 
Risks for women: 
If you are pregnant now, or get pregnant during the study, please tell us. Being in this study might hurt your 
unborn baby, so you will not be able to join or stay in the study.  Also, you should be sure you do not get 
pregnant for 1 month after the study. Use an effective method of birth control during this time. If you have 
questions about birth control, please ask the study leader. 
 


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Other unexpected risks: 
You may have side effects that we do not expect or know to watch for now.  Call the study leader if you have 
any symptoms or problems.  
 
Could you be helped by being in this study? 
You will not benefit from being in this study.  However the information researchers get from this study may 
help others in the future.  
 
 
What are your other choices if you do not join this study? 
The only choice is not to be in this study. 
 
Will you be paid for being in this study? 
You will be paid a $75 Simon Mall Visa gift card per inpatient admission.  In addition you will receive a $50 
bonus, also in the form of a gift card, for completing the medication regimen and outpatient blood draws. 
Therefore, if you complete the entire study you will receive a total of $200 in gift cards.  
 
If you do not finish the study, but complete one overnight admission, you will be paid $75. If you are admitted 
for an overnight admission, but the study leader says you cannot continue, you will be paid the full amount for 
the admission.  
 
You should get your payment at the final overnight admission. The income may be reported to the IRS as 
income.  
 
If you owe money to any Virginia state agency, the state can use the money you earn in this study to pay those 
debts.  These state agencies include the UVa Medical Center, VCU Medical Center or a college or university.  
The money may be withheld to pay back debt for such things as unpaid medical bills, taxes, fines, child support. 
Even if this happens, the money you earn may be reported to the IRS as taxable income.   
 
Will being in this study cost you any money? 
The following procedures/tests which are being done solely for research purposes will be provided to you at no 
cost: lab tests, study drugs (estradiol, progesterone, iron supplements) outpatient visits, and hospital admissions.  
 
You or your insurance company must pay for any tests or care given beyond what is required in this study.  In 
addition, you and your health plan may also have to pay for other drugs or treatments that are given to help you 
control any side effects.  You will have to pay for any costs not covered by your health plan. 
 
What if you are hurt in this study? 
If you are hurt as a result of being in this study, we have no plans to pay you for lost wages, disability, or 
discomfort. If you are hurt in the study in a way that is unexpected (meaning in a way that is not listed in the 
risks part of this form), your insurance company may pay for your treatment. If they do not pay, University of 


IRB-HSR#14100 
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Virginia will treat you free of charge. If you have questions about what will be covered if you are hurt in the 
study, talk to the study leader. You do not give up any legal rights by signing this form.  
 
What happens if you leave the study early? 
You can change your mind about being in the study any time. You can agree to be in the study now and change 
your mind later. If you decide to stop, please tell us right away. You do not have to be in this study to get 
services you can normally get at the University of Virginia.  
 
Even if you do not change your mind, the study leader can take you out of the study. Some of the reasons for 
doing so may include  
a) Your study physician is concerned about your health 
            b) You do not follow your doctor’s instructions 
c) The study sponsor closes the study for safety, administrative or other reasons 
 
If you decide to stop being in the study, we will ask you to please notify Dr. John Marshall in writing.  We also 
request that you will return any unused medicine and medicine bottles.   
Please send notification to PO Box 800391, Charlottesville, VA 22908.  Please note that any information 
already obtained will continue to be used unless you request in writing that we not use your information.  
 
How will your personal information be shared? 
The UVa researchers are asking for your permission to gather, use and share information about you for this 
study.  If you decide not to give your permission, you cannot be in this study, but you can continue to receive 
regular medical care at UVA.  
 
If you sign this form, we may collect any or all of the following information about you: 
o Personal information such as name, address, date of birth, social security number 
o Your medical records and test results that relate only to this study  
 
Who will see your private information?   
o The researchers to make sure they observe the effects of the study and understand its results   
o People or committees that oversee the study to make sure it is conducted correctly   
o People who pay for the study,  including people at the National Institutes of Health  
o Tax reporting offices (if you are paid for being in the study) 
o People who evaluate study results, which can include government agencies that provide oversight such as 
the Food and Drug Administration (FDA) 
 
The information collected from you might be published in a medical journal.  This would be done in a way that 
protects your privacy.  No one will be able to find out from the article that you were in the study.  
 
What if you sign the form but then decide you don't want your private information shared? You can 
change your mind at any time.  Your permission does not end unless you cancel it.  To cancel it, please send a 
letter to the researchers listed on this form.  Then you will no longer be in the study.  The researchers will still 
use information about you that was collected before you ended your participation.  UVa researchers will do 
everything possible to protect your privacy.   


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The information collected about you will be kept confidential by UVa as required by the federal Privacy Rule.  
Your information will not be released outside of UVa unless it is permitted by law.  
 
A copy of this consent form will be put in your medical record. (This is not the same as the record of this 
research study.) This means that everyone who is allowed to see your records will be able to find out that you 
are in this study. This is done so your regular doctors will know what drugs or treatment you are getting in the 
study. If you have other health problems during the study, they will be able to treat you properly. 
 
Please contact the researchers listed below to: 
• Obtain more information about the study 
• Ask a question about the study procedures or treatments 
• Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
• Leave the study before it is finished 
• Express a concern about the study 
 
      Principal Investigator:  John Marshall 
      Internal Medicine, School of Medicine 
      Box 800391 
      Charlottesville, VA 22908           
      Telephone:  (434)924-2431 
 
What if you have a concern about a study?  
You may also report a concern about a study or ask questions about your rights as a research subject by 
contacting the Institutional Review Board listed below. 
 
 
University of Virginia Institutional Review Board for Health Sciences Research 
PO Box 800483 
Charlottesville, Virginia 22908 
Telephone: 434-924-2620 
Fax: 434-924-2932 
 
When you call or write about a concern, please give as much information as you can. Include the name of the 
study leader, the IRB-HSR Number (at the top of this form), and details about the problem.  This will help 
officials look into your concern. When reporting a concern, you do not have to give your name. 
 
Conclusion 
 
Please check one of the following: 
 
______ 
You agree to be contacted after this study is done for follow up information. 
 
_____ 
You do not agree to be contacted after this study is done for follow up information.  


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What does your signature mean? 
Before you sign this form, please ask questions about any part of this study that is not clear to you.  Your 
signature below means that you understand the information given to you about the study and in this form.  If 
you sign the form it means that you agree to join the study. 
 
 
 
By signing below you confirm you have the legal authority to sign for this minor. 
 
__________________________ 
PARENT/GUARDIAN 
(SIGNATURE) 
 ________________________ 
PARENT/GUARDIAN 
(PRINT) 
 ______ 
DATE 
 
 
 
 
  
  
  
__________________________ 
PARENT/GUARDIAN 
(SIGNATURE) 
 ________________________ 
PARENT/GUARDIAN 
(SIGNATURE) 
 ______ 
DATE 
 
 
 
 
If you are unable to obtain parental consent from both parents, explain why not: 
 
_________________________________________________________________________________________ 
 
 
 
By signing below you confirm that you have fully explained this study to the potential subject, allowed them 
time to read the consent or have the consent read to them, and have answered all their questions.  
 
_______________________________ 
PERSON OBTAINING CONSENT 
(SIGNATURE) 
 _____________________________ 
PERSON OBTAINING 
CONSENT 
(PRINT) 
 ________ 
DATE 
  
 
 
 
TRANSLATOR 
(SIGNATURE) 
 _____________________________ 
TRANSLATOR 
(PRINT) 
 ________ 
DATE 
 
 
 
If a translator was used to explain this study to a potential subject, the translator must sign and date this line.