Clinical trial NCT01427595
Conditions: Polycystic Ovary Syndrome Hyperandrogenism
Keywords: hyperandrogenemia
Sponsor: University of Virginia
Start date: 2009-02-18; Completion date: 2015-01-17
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Many, but not all, girls with high levels of the male hormone testosterone go on to develop polycystic ovary syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual periods, excess facial and body hair, and weight gain. PCOS is also a leading cause of difficulty becoming pregnant. The investigators do not understand why some girls with high hormones develop PCOS and others do not. In a previous study by our group, some girls with high levels of male hormones had abnormalities in the secretion of another hormone, called luteinizing hormone (LH), that are often seen in women with PCOS. However, another group had normal LH secretion. The girls with the abnormal LH secretion had higher levels of another hormone, called insulin, than the girls with normal LH secretion. The investigators will test whether metformin, an insulin-sensitizing agent, changes the effects of high male hormone levels in adolescent girls, specifically by looking at their LH secretion response following metformin treatment.

Detailed description:
A better understanding of the factors that make adolescent girls more or less susceptible to the adverse neuroendocrine effects of elevated androgens will hopefully lead to improved prevention and treatment strategies for PCOS. In this study, we propose to explore the role of hyperinsulinemia on neuroendocrine function in hyperandrogenic adolescent girls by assessing the effect of the insulin sensitizer Metformin on hypothalamic progesterone sensitivity. Other differences between the progesterone sensitive and progesterone insensitive subgroups, including racial and ethnic differences between the two populations and a trend towards older gynecologic age in the progesterone insensitive population, are being pursued through other ongoing studies (IRB-HSR# 8588 and 12160).

Arms: arm 1: 12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X)
Interventions: intervention 1: Metformin intervention 2: Progesterone intervention 3: estrace
Intervention descriptions: intervention 1: 500-2000 mg PO BID (X12 weeks) intervention 2: oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2) intervention 3: oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2

Protocol documents:
Prot_SAP_000.pdf: 
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by 
Estradiol and Progesterone in Hyperandrogenic Adolescent Girls 
 
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IRB-HSR PROTOCOL 
Investigator Agreement 
 
BY SIGNING THIS DOCUMENT, THE INVESTIGATOR CONFIRMS: 
1. I am not currently debarred by the US FDA from involvement in clinical research studies. 
2. I am not involved in any regulatory or misconduct litigation or investigation by the FDA. 
3. That if this study involves any funding or resources from an outside source, or if you will be sharing data 
outside of UVA prior to publication that you will contact the Dean’s office regarding the need for a contract 
and letter of indemnification.  If it is determined that either a contract or letter of indemnification is needed, 
subjects cannot be enrolled until these documents are complete. 
4. The proposed research project will be conducted by me or under my close supervision.  It will be conducted 
in accordance with the protocol submitted to and approved by the IRB including any modifications, 
amendments or addendums submitted and approved by the IRB throughout the life of the protocol.  
5. That no personnel will be allowed to work on this protocol until they have completed the IRB-HSR On-line 
training and the IRB-HSR has been notified. 
6. That all personnel working on this protocol will follow all IRB-HSR Policies and Procedures as stated on 
the IRB-HSR Website http://www.virginia.edu/vprgs/irb/ and on the School of Medicine Clinical Trials 
Office Website:  http://knowledgelink.healthsystem.virginia.edu/intranet/hes/cto/sops/sop_index.cfm 
7. I will ensure that all those delegated tasks relating to this study, whether explicitly or implicitly, are capable 
through expertise, training , experience or credentialing to undertake those tasks.   
8. I confirm that the implications of the study have been discussed with all Departments that might be affected 
by it and have obtained their agreement for the study to take place.  
9. That no subjects will be recruited or entered under the protocol until the Investigator has received the signed 
IRB-HSR Approval form stating the protocol is open to enrollment 
10. That any materials used to recruit subjects will be approved by the IRB-HSR prior to use.  
11. That all subjects will sign a copy of the most current consent form that has a non-expired IRB-HSR 
approval stamp. 
12. That any modifications of the protocol or consent form will not be initiated without prior written approval 
from the IRB-HSR, except when necessary to eliminate immediate hazards to the subjects. 
13. Any significant findings that become known in the course of the research that might affect the willingness 
of subjects to enroll or to continue to take part, will be promptly reported to the IRB.   
14. I will report immediately to the IRB any unanticipated problems involving risk to subjects or to others 
including adverse reactions to biologics, drugs or medical devices.   
15. That any serious deviation from the protocol will be reported promptly to the Board in writing. 
16. That any data breach will be reported to the  IRB, the UVa Corporate Compliance and Privacy Office , UVa 
Police as applicable.  
17. That the continuation status report for this protocol will be completed and returned within the time limit 
stated on the form. 
18. That the IRB-HSR office will be notified within 30 days of a change in the Principal Investigator or of the 
closure of this study. 
19. That a new PI will be assigned if the current PI will not be at UVA for an extended period of time.  If the 
current PI is leaving UVa permanently, a new PI will be assigned PRIOR to the departure of the current PI.  
20. All study team members will have access to the current protocol and other applicable documents such as the 
IRB-HSR Application, consent forms and Investigator Brochures. 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by 
Estradiol and Progesterone in Hyperandrogenic Adolescent Girls 
 
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21. Signed consent forms and other research records will be retained in a confidential manner.  Records will be 
kept at least 6 years after completion of the study.  
22. No data/specimens may be taken from UVa without a signed Material Transfer Agreement between 
OSP/SOM Grants and Contracts Office and the new institution.  Original study files are considered 
institutional records and may not be transferred to another institution. I will notify my department 
administration regarding where the originals will be kept at UVa.  The material transfer agreement will 
delineate what copies of data, health information and/or specimens may be taken outside of UVa.  It will 
also approve which HIPAA identifiers may be taken outside of UVa with the health information or 
specimens. 
23. If any member of study team leaves UVa, they are STRONGLY ENCOURAGED to use Exit Checklist 
found on IRB-HSR website at http://www.virginia.edu/provost/facultyexit.pdf. 
 
 The IRB reserves the right to terminate this study at any time if, in its opinion, (1) the risks of further 
experimentation are prohibitive, or (2) the above agreement is breached. 
 
Investigators Experience 
 
The PI is a board certified general pediatrician and fellowship-trained board eligible pediatric endocrinologist 
who has been working with children clinically for the last 10 years. The PI has performed clinical research as a 
medical student, as a pediatric endocrinology fellow, and as a UVA faculty member (Department of Pediatrics, 
Division of Endocrinology). The PI has been actively involved in the current clinical research protocols of Dr. 
John Marshall studying the early manifestations and abnormalities of PCOS in pubertal girls. All sub-
investigators have experience via participation in the pediatric protocols of the adolescent PCOS research group 
within the UVA Center for Research in Reproduction led by Drs. John Marshall and Chris McCartney.  
 
Signatures 
 
Principal Investigator 
 
____________________________ ____________________________ _______ 
Principal Investigator 
Principal Investigator 
Date 
Signature 
Name Printed 
 
Department Chair 
BY SIGNING THIS DOCUMENT THE DEPARTMENT CHAIR AGREES: 
1. To work with the investigator and with the board as needed, to maintain compliance with this 
agreement. 
2. That the Principal Investigator is qualified to perform this study. 
3. That the protocol is scientifically relevant and sound. 
 
___________________________ 
_______________________  
_________ 
Department Chair or Designee  
Department Chair or Designee 
Date 
Signature 
Name Printed 
 
 
The person signing as the Department Chair cannot be the Principal Investigator or a sub-investigator on this 
protocol. 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by 
Estradiol and Progesterone in Hyperandrogenic Adolescent Girls 
 
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The Department Chair or Designee signature is ONLY required if this is a new protocol or a modification 
changing the Principal Investigator 
 
 
Brief Summary/Abstract 
 
Women with PCOS have decreased GnRH pulse generator sensitivity to suppression by estradiol and 
progesterone.  Adolescent hyperandrogenemia is thought to be a precursor of adult PCOS.  In previous studies, 
while some hyperandrogenic girls have decreased hypothalamic sensitivity to progesterone similar to their adult 
counterparts with PCOS, others maintain normal hypothalamic progesterone sensitivity.  The girls with 
decreased hypothalamic progesterone sensitivity have higher fasting insulin levels despite similar BMIs, 
suggesting that hyperinsulinemia may in part mediate the reduction in sensitivity.  We hypothesize that 
metformin will improve hypothalamic progesterone sensitivity in hyperandrogenic adolescent  
girls by improving insulin sensitivity and lowering insulin levels.  LH (GnRH) pulse frequency will be assessed 
before and after 7 days of oral estradiol and progesterone in hyperandrogenic adolescent girls both before and 
after 3 months treatment with Metformin 1000 mg BID.  Progesterone adjusted change in 11-hour LH pulse 
frequency will be used as the measure of hypothalamic progesterone sensitivity.   
 
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 
 
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.    


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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).  In adult women, short term treatment with the insulin sensitizer Metformin does not 
normalize hypothalamic progesterone sensitivity (Eagleson et al, 2003).   
 
Adolescent Hyperandrogenemia as a Precursor for PCOS 
 
Excess androgen production during adolescence is thought to be a precursor of adult PCOS.  Women with 
PCOS often report a history of irregular menstrual cycles during adolescence.  A study of girls with menstrual 
irregularities showed that while some subjects normalized endocrine function as they mature, the majority 
maintained hyperandrogenism along with the elevated LH levels and polycystic ovaries characteristic of PCOS 
(Venturoli et al. 1987).  Adolescent hyperandrogenemia has also been shown to be associated with higher 
androgen levels and lower fertility rates in adulthood (Apter and Vihko 1990).  
 
Similar to women with PCOS, girls with hyperandrogenemia have an increased frequency of LH pulses when 
compared to age matched controls (Apter et al. 1994). An ongoing study by our group (IRB-HSR# 8588) is 
investigating whether the progesterone insensitivity of the GnRH pulse generator in adult women with PCOS is 
also seen in adolescent girls with hyperandrogenemia.  Analysis of the data to date suggests that overall the 
hyperandrogenic adolescent girls have decreased hypothalamic progesterone sensitivity when compared to 
adolescent controls.  However, one subgroup of the hyperandrogenic girls have marked progesterone 
insensitivity similar to that seen in adult women with PCOS, while another subgroup retains relatively normal 
hypothalamic progesterone sensitivity despite similarly elevated androgen levels.  In an effort to understand the 
factors that may make some girls more susceptible to the adverse neuroendocrine consequences of 
hyperandrogenemia, we have analyzed the differences between these two subgroups.  Fasting insulin levels 
were higher in the progesterone-insensitive group than in the progesterone-sensitive group (31.2+3.3 vs. 
20.9+3.7 uIU/ml, p=0.02) despite similar BMIs (33+4 vs. 34+2 kg/m2). This suggests that hyperinsulinemia 
may have neuroendocrine actions during adolescence that are not present in adults. Alternatively, these findings 
may indicate differential sensitivity to the adverse effects of androgens on both hypothalamic P sensitivity and 
insulin resistance. 
 
A better understanding of the factors that make adolescent girls more or less susceptible to the adverse 
neuroendocrine effects of elevated androgens will hopefully lead to improved prevention and treatment 
strategies for PCOS.  In this study, we propose to explore the role of hyperinsulinemia on neuroendocrine 
function in hyperandrogenic adolescent girls by assessing the effect of the insulin sensitizer Metformin on 
hypothalamic progesterone sensitivity.  Other differences between the progesterone sensitive and progesterone 
insensitive subgroups, including racial and ethnic differences between the two populations and a trend towards 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by 
Estradiol and Progesterone in Hyperandrogenic Adolescent Girls 
 
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older gynecologic age in the progesterone insensitive population, are being pursued through other ongoing 
studies (IRB-HSR# 8588 and 12160).   
 
 
Hypothesis to be Tested 
 
We hypothesize that metformin will improve the sensitivity of the GnRH pulse generator to suppression by 
estradiol and progesterone in hyperandrogenic adolescent girls.  LH pulse frequency will be assessed before and 
after 7 days of oral estradiol and progesterone both before and after treatment with metformin. The primary 
linear contrast will compare the progesterone adjusted change in 11-hour LH pulse frequency between the 1st 
and the 2nd admissions (Δ(2-1)) (pre-metformin) to the progesterone adjusted change in the 11-hour LH pulse 
frequency between the 3rd and the 4th admissions (Δ(4-3)) (post-metformin). 
 
Study Design: Biomedical 
1.  Will controls be used? Yes. 
 
►IF YES, explain the kind of controls to be used. 
The subject will serve as her own control, as assessments will be made both before and after Metformin.  
 
2. What is the study design? This study is not blinded. 
 
3. 
Does the study involve a placebo? No. 
Human Participants 
Ages 10-17 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.30 
 
2.  Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
     In a similar study (JCM010), we have historically obtained complete, usable data in approximately 65% of 
the subjects who enrolled in the study.  However, that study was shorter in duration and did not involve taking 
metformin.  Because of the added length of this study, as well as the possibility that some participants may 
develop side effects with Metformin (most likely nausea or diarrhea) and choose to withdraw, we suspect that 
the screen failure/dropout/withdrawal rate will approach 50%.  Therefore, we plan to enroll 60 subjects, with a 
goal of obtaining complete, usable data in 30.   
 
3.  How many subjects will be enrolled at all sites?   60 
 
4.  How many subjects will sign a consent form under this UVa protocol?    60 
Inclusion/Exclusion Criteria 
 


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1.  List the criteria for inclusion  
• Girls ages 10 to 17 
• Hyperandrogenemic (free testosterone greater than 2 standard deviations above the mean for normal 
control subjects of the same Tanner Stage and/or hirsutism) 
• Creatinine clearance > 90 ml/min as calculated by the Cockcroft-Gault equation 
• Hemoglobin ≥ 11.0 g/dL for African American subjects; Hemoglobin ≥ 11.5 for non-African American 
subjects 
• Normal screening labs (with exception of the expected hormonal abnormalities inherent in 
hyperandrogenemia) 
• Sexually active subjects must agree to abstain or use double barrier contraception during the study 
• Subjects must agree not to take any other medications during the course of the study without approval 
by the study investigators. 
 
2.  List the criteria for exclusion 
• Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in 
hyperandrogenemia) 
• Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation 
• Hemoglobin <11.5 g/dL for non-African American subjects; Hemoglobin < 11.0 g/dL for African 
American subjects 
• Abnormal liver function tests (including AST, ALT, Bilirubin, Albumin, and Alkaline Phosphatase) 
• Weight < 34 kg 
• History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous thrombosis, breast 
cancer, endometrial cancer, or cervical cancer 
• Pregnant or breast feeding 
• On medications known to affect the reproductive axis  within 3 months of the study (including oral 
contraceptive pills, metformin, and spironolactone) 
• Are currently participating in another study or have been in one in the last 30 days. 
• Subjects using restricted medication (see restrictions below) are excluded unless the subject’s primary 
care provider approves stopping the medication. 
 
 
3.  List any restrictions on use of other drugs or treatments.    
  Subjects must not take medications known to affect the reproductive axis (including oral 
contraceptives, metformin, and spironolactone) for 90 days prior to and during the study.   
 
Subjects must not take medications that have the potential to increase metformin blood concentration 
(including cationic drugs such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, 
triamterene, trimethoprim, vancomycin which are eliminated by renal tubular secretion have the potential for 
interaction with metformin by competing for common renal tubular transport systems; cimetidine, which 
increases (by 60%) peak metformin blood concentrations; furosemide which can increase metformin blood 
concentration without altering metformin renal clearance; and nifedipine, which can increase metformin 
absorption).  Subjects should limit their intake of alcohol. 
 


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Statistical Considerations 
1. 
Is stratification/randomization involved? No. 
 
2.  What are the statistical considerations for the protocol?  
 
Sample Size Calculation.  The primary aim will be to compare the change in 11-hour LH pulse frequency 
between the 1st and the 2nd admissions (Δ(2-1)) to the change in the 11-hour LH pulse frequency between the 3rd 
and the 4th admissions (Δ(4-3)).  To perform the sample size calculation, we assumed that the linear contrast Δ(4-3) 
- Δ(2-1) will follow a normal distribution with standard deviation 1.02 units.  Base on the sample size formula for 
the paired one-sample standard normal z-test, our calculation indicates that if 30 subjects complete the study, 
we will have at least an 80% chance of detecting a 1.02 unit or greater difference between Δ(4-3) and Δ(2-1) with 
the two sided type I error rate of the statistical test not exceeding 0.05.  
 
Our prior studies indicate that the subject dropout rate in this study population should not exceed 50%, so 60 
subjects will be enrolled to insure that we have 30 completers. 
 
Statistical Analysis:  The 11-hour LH pulse frequency data from study admissions 1-4, will be analyzed by 
way of a mixed-effects linear model.  The four 11-hour LH pulse frequency measurements; one measurement 
from each admission, will function as the respond data. The study admission will be treated as a categorical 
explanatory factor in the analysis, while the mean 11-hour progesterone level from each admission will be 
treated as a continuous covariate.    Hypothesis testing will be conducted by constructing apriori defined within-
subject linear contrasts of the 11-hour LH pulse frequency measurements.  The primary linear contrast will 
compare the progesterone adjusted change in 11-hour LH pulse frequency between the 1st and the 2nd 
admissions (Δ(2-1)) to the progesterone adjusted change in the 11-hour LH pulse frequency between the 3rd and 
the 4th admissions (Δ(4-3)). We will base our decision whether to reject the null hypothesis that Δ(4-3) - Δ(2-1)=0 on 
a two-sided p≤0.05 decision rule.   We will used the same decision rule to determine whether Δ(2-1)=0 and Δ(4-
3)=0.  The SAS PROC-MIX procedure (SAS Institute Inc., Cary NC) will be used to conduct the 
aforementioned data analysis.                
 
3.  Do you have an adequate sample size, or is your sample size larger than necessary?  
We calculated that we will need a sample size of 60 subjects in this study in order to achieve a statistical 
significance with a power of 80% and Type 1 error rate of 0.05.  Given the historical screen 
failure/dropout/withdrawal rate for 8588/JCM010 of 35% and the additional demands of this study secondary to 
the addition of metformin, we anticipate a screen failure/dropout/withdrawal rate of around 50%.  Therefore, we 
propose enrolling up to 60 girls with the goal of obtaining complete, analyzable data in 30.  We believe this 
sample size is adequate and not excessive.   
 
4.  What is your plan for primary variable analysis? 
The primary linear contrast will compare the progesterone adjusted change in 11-hour LH pulse frequency 
between the 1st and the 2nd admissions (Δ(2-1)) to the progesterone adjusted change in the 11-hour LH pulse 
frequency between the 3rd and the 4th admissions (Δ(4-3)). 
 
5.  What is your plan for secondary variable analysis? Not applicable. 
6. Have you been working with a statistician in designing this protocol? Yes. 
 
 
IF YES, what is their name?  Jim Patrie 


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Biomedical Research 
1.  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 Consent and 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 consent and 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 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, Insulin-like Growth 
Factor 1 (IGF-1),  glucose, SHBG, TSH, hCG, cholesterol, LDL, HDL, 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).  In 
the rare event a subject has an elevated 17-OHP on screening, she will be given a repeat 17-OHP.  If the value 
remains elevated, she will be referred to her pediatrician for further testing to rule out congenital adrenal 
hyperplasia.  They will only be able to continue with the study if they have documented normal 17-OHP levels 
following cortrosyn stimulation. Potential subjects must fall within the normal range on all blood tests to be 
admitted to the study, except for hyperandrogenemic girls who will be expected to have some abnormal 
hormone levels.  Subjects will be administered 1 month of iron supplementation following screening, provided 
their screening labs show they are eligible to participate in the study.  As soon as screening lab results are 
available, and subjects are found to be eligible for study participation, subjects weighing ≤ 36 kg will be given 
1- 325 mg tablet a day and subjects weighing >36 kg will be given 2- 325 mg tablets a day.  The first overnight 
admission may occur anytime within this 30 day period or after the 30 day period.  Subjects will be given the 
option to pick up this supply of iron in the Clinical Research Unit or have it mailed to them. 
 
If 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 and documentation of 
hemoglobin ≥ 11.0 g/dL for African American subjects in the previous month is required for the frequent 
sampling protocol.  If 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:  Admission #1  
 
Note:  
• Admission #1 will occur on Day 7-11 of the cycle in girls who are cycling with some regularity and on 
day ≥7 in those with infrequent cycles (girls with < 10 cycles per year) provided they have a 
progesterone level of < 1.5 ng/mL within 3 days of their scheduled first admission.  If the progesterone 
level is >1.5 ng/mL within 3 days of the first admission, the first admission will be cancelled. 


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• At each overnight admission a urine HCG will be done to rule out pregnancy and must be negative for 
the study to continue.   
 
Subjects will be instructed to eat a diet including at least 150 gm of carbohydrate a day for the 3 days preceding 
the admission.  Written and oral instructions regarding this diet will be given at the time of the screening. 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 small 
amount of topical lidocaine/prilocaine cream (EMLA cream) may be applied to facilitate IV line placement..   If 
IV placement is found to be difficult, the IV team may be called to assist in obtaining adequate access.  
Frequent 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 5 mL sample at 6 AM will be 
analyzed for lipids, estrone, SHBG, DHEA-S, androstenedione, IGF-1, 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.  A 
formal "lights out" will occur at 2300 hr so that we may observe any nocturnal changes in hormonal secretion 
patterns. During the admission, the subject will wear a wrist actigraph (Motionlogger Basic-L; Ambulatory 
Monitoring, Inc.) to estimate periods of sleep (Motionlogger Basic-L; Ambulatory Monitoring, Inc.). The 
Motionlogger Basic-L is a watch-like device that includes an accelerometer. Q10 minute blood sampling will 
end at 0600 hr, although one additional Q2H sample will be drawn at 0700 hr. At 07:00 hr, the subject will also 
undergo a 2-hour oral glucose tolerance test.  75 grams of glucose will be administered at 07:00 (Time 0), with 
2.5 ml blood draws for glucose, insulin, and c-peptide at times 0, 10, 20, 30, 60, 90, and 120 minutes. The 
subject will be offered dinner at standard CRU meal time and will be offered breakfast following completion of 
the blood draws.  They will not have anything to eat or drink except water from 2300 hr until the completion of 
the blood draws. At the time of discharge, the subjects will be given oral estrogen, progesterone, and iron 
supplements.   
 
Day 1: Begin Estradiol and Progesterone 
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 0700, 1500, 
and 2300 hr for seven days. The first dose will be given at 1500 on the day of discharge. If the 1500 dose is 
incompatible with school schedules, alternative dosing schedules can be arranged.  Generally this will entail 
taking the afternoon dose immediately upon returning home from school without any change in the morning and 
evening dosing times.  Dosages will be based on weight.  The target mean plasma progesterone concentration is 
2-8 ng/dL. Each subject will be instructed to eat a small snack with the progesterone syrup as it has been 
observed that the absorption of progesterone is influenced by the presence or absence of food. 
 
Subjects will also be given oral iron supplementation at a dose of 1-2 mg/kg. Subjects  will be given iron tablets 
(which contains 27 - 65 mg elemental iron) with proper dose instructions.  Subjects weighing ≤ 36 kg will be 
given 1 tablet a day and subjects weighing >36 kg will be given 2 tablets a day to be taken for the duration of 
the study.   
 
Day 3 and Day 5: Outpatient blood draws 
On study days 3 subjects will have blood drawn at 1700 hr (two hours after the 1500 hr progesterone dose to 
check serum estrogen, peak progesterone levels, and hemoglobin.  On study day 5, subjects will have blood 


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drawn at 1700 hr (two hours after the 1500 hr progesterone dose) to check serum estrogen and peak 
progesterone levels. 
 
 
Day 7: Second inpatient admission 
The second inpatient admission will begin on day 7. The procedure will be identical to the first inpatient 
admission until 07:00 hr.  An OGTT will not be done during this admission; however, a fasting glucose and 
insulin will be drawn at this time and then the admission will end at 07:00 hr. Subjects will be required to bring 
any unused estrogen and progesterone (or the empty bottles) to the admission.  Subjects will discontinue the 
estradiol and progesterone after the completion of the second inpatient admission, but will continue taking iron 
supplementation.  At the time of discharge, subjects will be given Metformin. 
 
Day 8: Begin Metformin 
Starting the day of discharge from Admission #2, subjects will begin taking Metformin 500 mg daily.  
 
Day 14: Increase Metformin dose 
 
On Day 14, the dose of Metformin will be increased to 500 mg twice a day.  The subjects will be 
contacted by phone to inquire regarding adverse events related to the metformin and to remind them to increase 
the dose of the medication.   
 
Day 21: Increase Metformin dose 
 
On Day 21, the dose of Metformin will be increased to 1000 mg in the morning and 500 mg at night.  
The subjects will be contacted by phone to inquire regarding adverse events related to the metformin and to 
remind them to increase the dose of the medication.   
 
Day 28: Increase Metformin dose 
 
On Day 28, the dose of Metformin will be increased to 1000 mg twice a day.  The subjects will be 
contacted by phone to inquire regarding adverse events related to the metformin and to remind them to increase 
the dose of the medication.   
 
Day 42-49: Outpatient blood draw 
Girls will come in after an overnight (>8 hour) fast and have blood drawn for testosterone, SHBG, 
fasting insulin, fasting glucose, and comprehensive metabolic panel.  
 
Day 84: Admission #3  
 
Note: Admission #3 is timed to the subject’s cycles, and therefore is unlikely to occur exactly on Day 84.  All 
girls will take at least 11 weeks (77 days) of Metformin and will then come in for admission #3 at the first 
appropriate time in their cycle, which will be either on Day 7-11 of their cycle or day ≥7 in those with 
infrequent cycles (girls with < 10 periods per year) provided they have a progesterone level of < 1.5 ng/mL 
within 3 days of their scheduled first admission.  If the progesterone level is >1.5 ng/mL within 3 days of the 
first admission, the admission will be cancelled.   
 
Admission #3 will be identical to Admission #1.  Subjects will be instructed to eat a diet including at least 150 
gm of carbohydrate a day for the 3 days preceding the admission 
 


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Day 85: Begin Estradiol and Progesterone 
Starting the day of discharge from the third 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 0700, 1500, 
and 2300 hr for seven days.  Doses will be the same as on Days 1-7.  Subjects should continue to take 
Metformin 1000 mg twice a day and iron supplementation.  
 
Day 87 and Day 89: Outpatient blood draws 
On study days 3 subjects will have blood drawn at 1700 hr (two hours after the 1500 hr progesterone dose to 
check serum estrogen, peak progesterone levels, and hemoglobin.  On study day 5, subjects will have blood 
drawn at 1700 hr (two hours after the 1500 hr progesterone dose) to check serum estrogen and peak 
progesterone levels. 
 
 Day 91: Admission #4 
Admission #4 will be identical to Admission #2.   
Following the final blood draw for Admission #4, the patient will discontinue all study medications.  
 
Follow-up   
There is an optional 1 year follow up period. If the subject agrees to participate, she will complete follow-up 
questionnaires and/or phone interviews 6 and 12 months after the study.  These questionnaires/interviews will 
ask about the frequency of menses and changes in hirsutism.  Whenever possible we will also see the subjects 
on 1-2 occasions during the 12 months to obtain blood for T, SHBG, fasting insulin, fasting glucose, DHEA-S, 
E2, and P measurements (depending on cycle stage). 
 
2. List the procedures, in bullet form, that will be done for research as stipulated in this protocol.  
  Do NOT list those procedures which are being ordered for clinical care.  
All procedures performed in this protocol are being done solely to answer a research question and generate 
generalizable knowledge. 
 
3.  Will any of the procedures listed in item # 2 have the potential to identify an incidental finding?  Yes. 
►IF YES, check one of the following two options:  
__X___The examination(s) utilize(s) the same techniques, equipment, etc., that would be used if the 
subject were to have the examination(s) performed for clinical care.  There exists the potential for 
the discovery of clinically significant incidental findings.   
• The PI takes full responsibility for the identification of incidental findings:  
• The PI will inform the subjects verbally of all incidental findings that are of clinical 
significance or are of questionable significance.   
• A follow-up letter describing the finding should be provided to the subject with 
instructions to either show the letter to their PC or if the subject has no PCP, the subject 
should be instructed to make an appointment at UVa or at the Free Clinic.   
 
4.  Do any of the procedures listed above, under question # 2, utilize any imaging procedures ( e.g. 
ultrasound, CT scans/ x-rays etc.)?  No. 
 
5. 
Will you be using viable embryos? No. 
6. 
Will you be using embryonic stem cells? No. 
 


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Family History/Pedigree 
 
1.  What kind of information is being sought?  
Family history (no questionnaire is being used) 
 
2.  What identifiers will be recorded with the info (e.g. names, initials, relationship such as mother, 
father, brother, sister, random number)?Relationship 
 
3.  Does any of the information sought potentially expose the subject or a family member to additional 
risk?No. 
 
Specimens:  Will not be used for Genetic Research or Banking 
If the specimens in this protocol will only be used for Genetic Research and or Specimen Banking, you may 
delete the Specimen Labeling and Specimen Shipping sections below.  
If specimens will be taken for other reasons, the questions below should be answered and referenced to the 
samples taken for things other than Genetic Research and or Specimen Banking.  
 
Specimen Information 
1.  Describe the type of specimen to be used:Blood  
 
2.  Will the specimen be obtained BEFORE a subject has signed a consent form? No. 
3.  Will you be using discarded specimens?No. 
 
►IF NO, and taking a blood sample, will blood be taken more than 2 times/week? 
Yes. 
►IF NO, and taking a blood sample, check the option(s) below which match the subject 
population. 
 
_X____ non- healthy or pregnant adults and/or children  
 
_____ Amount will NOT exceed the lesser of 50ml or 3 ml/kg in an 8 week period 
___X__ Amount will exceed the lesser of 50 ml or 3 ml/kg in an 8 week period 
 
Specimen Labeling 
1.  What information/ HIPAA identifiers will be on the specimen label when it is given to the study team 
(from clinical labs or other source outside the study team) and/or what information will you put on the 
specimen? 
 
Name, medical record #, CRU protocol #, time (date and clock hour) drawn. 
 
2.  If the specimen is given to the study team with information on the label will you delete any of the 
information on the specimen label?   No. 
 
3.  Will any additional data be linked to the specimen by way of a code?  No. 
4.  Will the analysis on the specimen be done soon (within 24 hours) after it is collected? 
Yes and No.  See the explanation below. 
 


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Samples from the screening exam that are analyzed by UVA clinical labs will be run within 24 hrs.  
 
►IF NO, where will the specimen be stored until analysis is done?  
Some samples from the screening exam (TSH, LH, FSH, P, Testosterone, E2, c-peptide, and insulin) and all 
samples from the inpatient admissions will be analyzed and stored in the Center for Research in 
Reproduction Ligand Core lab.  
 
Specimen Shipping 
1.  Do you plan to ship any specimens outside of UVA?No. 
 
Data and Safety Monitoring Plan 
If you have any questions completing this section call 982-4311, 924-8660 or 243-9847 for assistance 
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?  
__X___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. 
1.2 How will you define serious adverse events? 
__X___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.  
1.3 What 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. 


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 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 What 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 a research project that is NOT approved by the IRB-HSR prior to its initiation or 
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. 
 
Additional Information: see the IRB-HSR website at  
http://www.virginia.edu/vpr/irb/HSR_docs/Forms/Protocol_Violations_%20Enrollment_Exceptions
_Instructions.doc 
 
1.5 If pregnancy occurs how will this information be managed? 
__X___  Adverse Event- will follow adverse event recording and reporting procedures outlined in 
section 3.  
 
1.6 What is the definition of a Protocol Enrollment Exception?   
__X___NA- No outside sponsor 
 
1.7 What is the definition of a data breach? 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, 
access, or use of protected health information (PHI) that compromises the security or privacy of 
such information. 
 
Additional Information may be found on the IRB-HSR Website: Data Breach 
2.  Identified risks and plans to minimize risk 
 
 
2.1 What risks are expected due to the intervention in this protocol? 
 
Risk associated with frequent blood sampling: 
 
Expected Risks related to study participation.  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 very rare 
• 
mild anemia (hematocrit < 36%) 
related to frequent blood sampling 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
 
Risk associated with IV needle placement: 
 
Expected Risks related to study participation.  Frequency 
Please pick one frequency from each box below 


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• 
Infection at needle site 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown, but very rare 
• 
Fainting 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown, but very rare 
• 
Bleeding at needle site 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
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 
 
Risks associated with iron supplementation: 
 
Expected Risks related to study participation.  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 
 
Risks associated with Progesterone: 
 
Expected Risks related to study participation.  Frequency 
Please pick one frequency from each box below 
• 
Mood changes/irritability 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Fluid retention 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 


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• 
Withdrawal bleeding 1-5 days after 
stopping progesterone 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
 
Risks associated with Estradiol: 
 
Expected Risks related to study participation.  Frequency 
Please pick one frequency from each box below 
• 
Nausea 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Fluid retention 
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 
 
Risks associated with Metformin: 
 
Expected Risks related to study participation.  Frequency 
 
• 
Diarrhea 
 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Nausea 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown 
• 
Lactic Acidosis 
Occurs frequently, 
Occurs infrequently 
Occurs rarely 
Frequency unknown, but very rare 
 
Other Risks: 
 
Expected Risks related to study 
participation. 
  
Frequency 
 
Reproductive Risks 
Minimized due to the requirements of this 


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Specify potential reproductive risks 
 
protocol.   
Violation of subject’s privacy and 
confidentiality 
Minimized due to the requirements of the 
privacy plan in this protocol 
 
NOTE: Risk of unplanned pregnancy: If a research subject is sexually active and stops using hormonal 
contraception while failing to use another non-hormonal method of contraception, there is a risk of unplanned 
pregnancy. (However, subjects will be counseled to use non-hormonal methods of contraception if sexually 
active.)  
 
NOTE regarding the 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). 
 
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 studies, all participants will be required to have a normal hemoglobin (≥11.5 
g/dL for non-African American subjects and ≥ 11.0 g/dL for African American subjects).  Hemoglobin 
levels will be measured prior to every admission.  For African American subjects, if the hemoglobin 
level is <11.0, the study will be discontinued.  For non-African American subjects, if the hemoglobin 
level is <11.5 g/dl, the study will be discontinued.   
• 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 467 ml of blood will be drawn during the study (including estimated 
waste from frequent blood draws), with no more than 243.5 being drawn during any 8 week period.  
Therefore, girls weighing less than 35 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. 
• We will warn participants against becoming pregnant during the study.  We will require that sexually 
active subjects use effective double barrier methods of birth control as needed during the study.  β-hCG 
levels will be measured at screening and prior to each admission; if the β-hCG is positive, the study will 
be discontinued. 
 
2.3 Under what criteria would an INDIVIDUAL SUBJECT’S study treatment or study participation be 
stopped or modified 
__X___At subject, PI or sponsor’s request 
 
__X___Treatment would be stopped if the subject had a serious adverse event deemed related to 
study. 
__X___ Other: The study would be stopped if the patient has a positive pregnancy test or if 
hemoglobin levels were below the required levels ( For African American subjects, they must 
have a hemoglobin of ≥ 11.0.  For non-African American subjects, they must have a hemoglobin 
of ≥ 11.5. 
 
2.4 Under what criteria would THE ENTIRE STUDY need to be stopped.   
These are called stopping rules for early termination of the entire study. 


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List criteria regardless of whether the study is sponsored or not.  
Be sure to include any criteria for which the UVa PI would halt the study at UVa. 
___X__Per IRB, PI, DSMB, or sponsor discretion 
 
___X__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 What are the criteria for breaking the blind/mask? 
___X__NA – Not blinded/masked 
 
2.6 How will subject withdrawals/dropouts be reported to the IRB prior to study completion? 
___X__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. 
 
3.2 How will adverse event data be collected/recorded?  
__X___Paper AE forms/source documents  
___X__Spreadsheet (paper or electronic) 
 
3.3. How will AEs be classified/graded?  
___X__Mild/Moderate/Severe 
__X__Serious/Not serious  
 
 
3.4 What scale will the PI use when evaluating the relatedness of adverse events to the study 
participation?   
__X___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? 
 
__X___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  


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_X____30 days post study drug 
 
3.7 How will Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches be 
reported?  Complete the table below to answer this question 
 
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 
participation 
An internal event is one that 
occurs in a subject enrolled 
in a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
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  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vp
rgs/irb/HSR_docs/Forms/R
eporting_Requirements-
Unanticipated_Problems.d
oc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by your sponsor, if 
applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
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/vp
rgs/irb/hsr_forms.html 
 
Go to 3rd bullet from the 
bottom. 
  


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Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
 
ITC:  if breach 
involves  
electronic data-  
 
 
UVa Police if 
breach includes 
such things as 
stolen 
computers.  
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/secur
ity/reporting.html 
 
 
Phone- (434) 924-7166 
  
UVa PI Held IND/IDE 
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 
 
 
4.    How will the endpoint data be collected/recorded.  
__X___Database: specify  
5. Data and Safety Oversight Responsibility 
 
5.1. Who is responsible for overseeing safety data for this study ?  
 
___X__No additional oversight body other than PI at UVa (skip question 5.2) 
 
5.2. What is the composition of the reviewing body and how is it affiliated with the sponsor?  N/A 
5.3. What items will be included in the aggregate review conducted by the PI?  
 
__X___All adverse events 
___X__Unanticipated Problems 
___X__Protocol violations 
___X__Audit results 
_____Application of dose finding escalation/de-escalation rules These should be outlined under 2.4. 
__X___Application of study designed stopping/decision rules 


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__X___Early withdrawals 
___X__Whether the study accrual pattern warrants continuation/action 
___X__Endpoint data 
 
5.4 How often will aggregate review occur? 
For additional information on aggregate review see: 
www.virginia.edu/vpr/irb/hsr/continuations.html#aggreview 
 
__X___Annually 
 
5.5. How often will a report, regarding the outcome of the review by the DSMB/DSMC, be sent to 
the UVa PI? 
A copy of these reports must be sent to the IRB if applicable as soon as they are received by the PI.  
Do not wait until the next continuation to submit them to the IRB.   
_X____ NA- there is no DSMB/ DSMC overseeing this study 
 
5.6. How will a report of the information discussed in question 5.4 OR 5.5 be submitted to the 
IRB?   
 
__X___Part of IRB-HSR continuation status form 
Payment 
 
1.  Are subjects being reimbursed for travel expenses (receipts /mileage required)? No. 
 
2.  Are subjects compensated for being in this study? Yes. 
 
2a.  What is the maximum TOTAL compensation to be given over the duration of the protocol? 
$400 
 
2b.  Explain compensation to be given. 
All participants will receive a $75 Simon Mall gift card per inpatient admission. In addition, participants will 
receive a $100 bonus, also in the form of a gift card, for completing the medication regimen and outpatient 
blood draws. Therefore, a participant who completes the entire study will receive a total of $400 in gift cards. 
This payment will not be provided to the subject until the end of study participation at the last overnight 
admission.   If a subject withdraws from the study before it is complete, she will receive a $75 gift card for each 
overnight admission she has completed.  
 
2c.  Is payment pro-rated (e.g. some compensation is given even if subjects do not complete the 
entire study)? 
Yes.  See explanation above.  
If No, explain why payment cannot be pro-rated.   
 
 


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2d.  Is money paid from UVa or State funds (including grant funds) or will items such as gift cards 
be distributed through UVa? Yes. 
 
2d(i).  How will the researcher compensate the subjects? 
___X__ 
Gift cards 
 
2d(ii).  Which category/ categories best describes the process of compensation?  
 
___X__ Compensation will include an alternative method (petty cash, gift card, other) 
and tax information will be collected, securely stored, and submitted electronically 
to Procurement Services as required.  
►If an alternate method will be used justify why you are unable to issue 
checks through the UVa Oracle or state system. 
 
This study involves 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 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 the adolescent subjects with gift cards.  We obtain social security numbers for IRS purposes.   
 
IMPORTANT:  If you check this box you will be required to submit the subjects’ name, Social Security 
number, full address and amount of payment to Procurement at the end of each calendar year.  The Office of the 
VP for Research will send you instructions on this procedure at a later date.   
Risk/ Benefit Analysis 
 
1.  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? 
The goal of this study is to advance our knowledge of the effects of adolescent hyperandrogenemia and 
the mechanisms of development of polycystic ovary syndrome.  Hopefully, this knowledge will lead to more 
effective means of preventing and treating PCOS in the future.     
While treatment is not the goal of this study, it is possible that individual subjects may experience 
improvement in symptoms during the course of the study given that Metformin is commonly used in clinical 
practice to treat adolescent hyperandrogenemia and PCOS.   
 
2.  Analyze the risk-benefit ratio. 
 
This study involves minimal risks and may provide valuable information about the development of polycystic 
ovary syndrome (PCOS).  There are no long-term risks associated with blood sampling or the short term 
administration of physiologic doses of estradiol and progesterone.  Metformin is associated with minimal risk in 
subjects with normal kidney, liver, and cardiac function, and subjects with such organ dysfunction will be 
excluded from the study.  This study offers significant potential benefits to society as a whole and girls with 
hyperandrogenemia in particular. We hope that a better understanding of the effects of hyperandrogenemia in 
adolescent girls and the role of adolescent hyperandrogenemia in the development of PCOS will lead to 
improved prevention of the disorder as well as more effective treatments.  In addition, some subjects may 
experience improvement in their hyperandrogenic symptoms while being treated with Metformin, as this 


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medication is commonly used in clinical practice to treat adolescent hyperandrogenia and PCOS.  Therefore, 
potential benefits are great while risks are small. 
Bibliography 
 
Apter D, Butzow GA, Laughlin GA, Yen SSC (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, 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. 
 
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.   
 
Eagleson CA, Bellows AB, Hu K, Gingrich MB, Marshall JC (2003). Obese patients with polycystic ovary 
syndrome: evidence that metformin does not restore sensitivity of the gonadotropin releasing hormone pulse 
generator to inhibition by ovarian steroids. JCEM 88(11):5158-62. 
 
Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall, JC (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.   
 
Stein I, Leventhal M (1935).  Amenorrhea associated with bilateral polycystic ovaries.  American Journal of 
Obstetrics and Gynecology 29: 181-191.     
 
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. 
APPENDIX:  Legal/Regulatory 
Recruitment 
The following procedures will be followed: 
• Finders fees will not be paid to an individual as they are not allowed by UVa Policy 
• All recruitment materials will be approved by the IRB-HSR prior to use.  They will be submitted to 
the IRB after the IRB-HSR has assigned an IRB-HSR # to the protocol. 


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• Only those individuals listed as personnel on this protocol will recruit and or conduct the consenting 
process with potential subjects.  
 
Retention Incentives 
Any item used by the sponsor/ study team to provide incentive to a subject to remain in the study, other than 
compensation identified in the Payment section, will be submitted to the IRB for review prior to use.  The IRB-
HSR will provide the study team with a Receipt Acknowledgement for their records.  Retention incentive items 
are such things as water bottles, small tote bags, birthday cards etc.  Cash and gift cards are not allowed as 
retention incentives.  
 
Clinical Privileges 
The following procedures will be followed:  
• Investigators who are members of the clinical staff at the University of Virginia Medical Center must 
have the appropriate credentials and been granted clinical privileges to perform specific clinical 
procedures whether those procedures are experimental or standard.  
• The IRB cannot grant clinical privileges.   
• Performing procedures which are outside the scope of the clinical privileges that have been granted 
may result in denial of insurance coverage should claims of negligence or malpractice arise. 
• Personnel on this protocol will have the appropriate credentials and clinical privileges in place before 
performing any procedures required by this protocol.  
• Contact the Clinical Staff Office- 924-9055 or 924-8778 for further information. 
 
Sharing of Data/Specimens 
Data and specimens collected under an IRB approved protocol are the property of the University of Virginia.  
You must have “permission” to share data/ specimens outside of UVa other than for a grant application and or 
publication.  This “permission” may come in the form of a contract with the sponsor or a material transfer 
agreement (MTA) with others.  A contract/ MTA is needed to share the data outside of UVa even if the data 
includes no HIPAA identifiers and no code that could link the data back to a HIPAA identifier.   
• No data will be shared outside of UVa, beyond using data for a grant application and or publication, 
without a signed contract/MTA approved by the SOM Grants and Contracts office/ OSP or written 
confirmation that one is not needed. 
• No specimens will be shared outside of UVa without a signed contract/MTA approved by the SOM 
Grants and Contracts office/ OSP or written confirmation that one is not needed. 
 
Prisoners 
If the original protocol/ IRB application stated that no prisoners would be enrolled in this study and 
subsequently a subject becomes a prisoner, the study team must notify the IRB immediately.  The study team 
and IRB will need to determine if the subject will remain in the study.  If the subject will remain in the study, 
the protocol will have to be re-reviewed with the input of a prisoner advocate.  The prisoner advocate will also 
have to be involved in the review of future continuations, modifications or any other reporting such as protocol 
violations or adverse events.   
 
Prisoner- Individuals are prisoners if they are in any kind of penal institution, such as a prison, jail, or juvenile 
offender facility, and their ability to leave the institution is restricted. Prisoners may be convicted felons, or may 
be untried persons who are detained pending judicial action, for example, arraignment or trial. 
For additional information see the OHRP website at  http://www.hhs.gov/ohrp/policy/populations/index.html 


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APPENDIX:  Recruitment 
Recruitment includes identifying, review of records to determine eligibility or any contact to determine a 
potential subjects interest in the study. 
 
*The UVa HIPAA covered entity is composed of the  UVa VP Office of Research, the Health System, School 
of Medicine, School of Nursing, the Sheila C. Johnson Center, the Exercise and Sports Injury Laboratory 
and the Exercise Physiology Laboratory.   
 
1. How do you plan to identify potential subjects? 
To "identify" a potential subject refers to steps you plan to take to determine which individuals 
would qualify to participate in your study. This does NOT include steps to actually contact those 
individuals. 
If your study involves more than one group of subjects (e.g. controls and cases or subjects and 
caregivers) note below which groups are being identified by the given method.  
 
a. __X__ Chart Review/ Clinic Schedule Review/ Database Review from a database 
established for health care operations (departmental clinical database) or quality 
improvement. 
 
DHHS: Study team requests Waiver of Consent to identify potential subjects.  
 
HIPAA- Allowed under Preparatory to Research if PHI to be accessed.  
IMPORTANT 
Keep in mind that PHI in the medical record may only be accessed by individuals 
who work under the UVa HIPAA covered entity; which means they meet one of 
the following criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 
b. __X__ Review of a database that was established to keep data to be used for future 
research such as the CDR, departmental research database or use of data from a separate 
current active research protocol.     
 
DHHS: Study team requests Waiver of Consent to identify potential subjects. 
 
HIPAA- Allowed under Preparatory to Research if PHI to be accessed.  
IMPORTANT 
Keep in mind that PHI in the medical record may only be accessed by 
individuals who work under the UVa HIPAA covered entity; which means 
they who meet one of the following criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 


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NOTE:  The information from which you are obtaining potential subjects must 
also have an IRB protocol approval.  
 
IRB# 10797 
If obtaining information from the Clinical Data Repository (CDR) insert IRB # 10797. 
 
c. ____ Patients UVa health care provider supplies the UVa study team with the patients 
contact information without patients knowledge.  
 
DHHS: Study team requests Waiver of Consent to identify potential subjects.  
 
HIPAA- Allowed under Preparatory to Research if PHI will be shared by the health care 
provider.  
IMPORTANT 
Keep in mind that PHI may only be given to individuals who work under the UVa 
HIPAA covered entity; which means they meet one of the following criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 
 
d. _X___ Patient obtains information about the study from their health care provider.  The 
patient contacts the study team if interested in participating.  
DHHS:  NA 
HIPAA:  Allowed under Health Care Operations 
If this choice is checked, check 3d-INDIRECT CONTACT below.  
 
e. __X__ Potential subjects will not be directly identified. They will respond to an 
advertisement such as a flyer, brochure etc.   
If this choice is checked, check 3d- INDIRECT CONTACT below.  
DHHS & HIPAA:  NA 
 
f. _____  Potential subjects have previously  signed a consent to have their name in a 
registry/database to be contacted for future studies of this type.   
IRB#  of registry/ database:  ________________ 
DHHS & HIPAA:  NA 
 
If item # a, b or c is checked above and if this protocol involves the use of protected health 
information you confirm the following to be true: 
• The use or disclosure is sought solely to review protected health information as necessary 
to prepare the research protocol or other similar preparatory purposes. 
• No PHI will be removed from the UVa covered entity. 
• The PHI that the researcher seeks to use or access is necessary for the research purposes. 
 
 


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2. How will potential subjects be contacted? 
To "contact" a potential subjects refers to the initial contact you plan to take to reach a potential 
subject to determine if they would be interested in participating in your study.  This may include 
direct contact by such methods as by letter, phone, email or in-person or indirect contact such as 
the use of flyers, radio ads etc.  
If your study involves more than one group of subjects (e.g. controls and cases or subjects and 
caregivers) note below which groups are being contacted by the given method.    
 
a.__X__Direct contact of potential subjects by the study team via letter, phone, direct e-
mail. Members of study team ARE NOT health care providers of patients.  Information 
will not be collected from psychotherapy notes.  
Note:  Letter, phone, direct email scripts must be approved by IRB prior to use.  
See IRB-HSR Website for templates. 
 
DHHS/HIPAA: Study team requests a Waiver of Consent and Waiver of 
HIPAA Authorization to contact potential subjects.  
IMPORTANT:   
Keep in mind that if PHI was collected during the identification phase that 
contact with potential subjects may only be performed by individuals who work 
under the UVa HIPAA covered entity; which means they meet one of the following 
criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 
b._X___Potential subjects will be approached while at UVa Hospital or Health Clinic by 
a person who is NOT a member of their health care team.  Information will not be 
collected from psychotherapy notes.  
 
DHHS & HIPAA: Study team requests a Waiver of Consent and a Waiver of 
HIPAA Authorization to contact potential subjects.  
 
IMPORTANT:   
Keep in mind that contacting individuals in a clinical setting may only be 
performed by individuals who work under the UVa HIPAA covered entity; which 
means they  meet one of the following criteria: 
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 
 
You should share the following information with the potential subject:  
1. Your name 
2. Who you are:  physician, nurse etc. at the University of Virginia.    


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3. Why you want to speak with them 
4. Ask if you have their permission to explain the study to them 
5. If asked about how you obtained their information use one of the following 
as an option for response.     
• DO NOT USE THIS RESPONSE UNLESS YOU HAVE OBTAINED 
PERMISSION FROM THEIR UVa PHYSICIAN:   
Your doctor, Dr. insert name wanted you to be aware of this research 
study and gave us permission to contact you.    
• We obtained your information from your medical records at UVa.   
Federal regulations allow the UVa Health System to release your 
information to researchers at UVa, so that we may contact you regarding 
studies you may be interested in participating.  We want to assure you that 
we will keep your information confidential.  
IF THE PERSON SEEMS ANGRY, HESITANT OR UPSET, THANK THEM 
FOR THEIR TIME AND DO NOT ENROLL THEM IN THE STUDY.  YOU 
MAY ALSO REFER THEM TO THE IRB-HSR AT 924-9634. 
 
c.__X__Direct contact of potential subjects by the study team by approaching in person 
at UVa or via letter, phone, direct e-mail. Members of study team contacting potential 
subjects ARE health care providers of patients.  
If you are not approaching them in person but using a letter, phone call or direct 
email please note that the letter, phone, direct email scripts must be approved by 
IRB prior to use.  See IRB-HSR Website for templates. 
DHHS:  Study team requests a Waiver of Consent to contact potential subjects 
HIPAA:  Allowed under Health Care Operations.  
 
d.__X__ Indirect contact (flyer, brochure, TV, broadcast emails, patient provided info 
about the study from their health care provider and either the patient contacts study team 
or gives their healthcare provider permission for the study team to contact them.) 
The indirect method used (flyer, brochure, TV, broadcast emails) must be approved by 
the IRB prior to use.    The IRB does not need to review any type of script to use when the 
potential subject responds to the indirect method.   
 
DHHS & HIPAA:  NA 
 
e. ____  Potential subjects are not patients.  The study does not include obtaining 
subjects health information.   Subjects will be contacted directly via email, phone, 
letter or presentation in group setting with consent then obtained individually in a 
private setting.  
If you are not approaching them in person but using a letter, phone call or direct 
email please note that the letter, phone, direct email scripts must be approved by IRB 
prior to use.   
See IRB-HSR Website for templates. 
DHHS: Study team requests a Waiver of Consent to contact potential subjects.  
HIPPA:  NA 
 


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3. Will any additional information be obtained from a potential subject during "prescreening"?  
Yes. 
 
Pre-screening for IRB purposes is the term used to describe activities PRIOR to obtaining Informed Consent and may not 
include any research procedures.  
  
The activities may involve pre-screening of potential subjects over the telephone or in person is generally performed to 
determine their initial eligibility for, and, interest in a study and is a common strategy in the recruitment process.  
Questions appropriate for pre-screening address the specific inclusion/exclusion criteria for the study and other issues of 
suitability, for example, an individual's ability to come to the research site multiple times.  
It is not appropriate at this point in the process (i.e. prior to obtaining informed consent/enrollment) to gather information that 
is not directly related to assessing eligibility and suitability (e.g. obtaining complete medical histories, obtaining blood 
specimens for lab tests).  
An additional telephone script is not required, for this pre-screening process, in addition to any scripts required under 
Recruitment question # 2.   
 
IF YES, submit any documents that will be used to collect pre-screening information so that 
the IRB may confirm what questions will be asked. 
NOTE: To comply with HIPAA regulations only the minimum necessary information may be 
collected at this time.  This means that only questions pertaining to the Inclusion and Exclusion 
Criteria may be asked.   
 
IF YES, 
 
DHHS:   study team requests a Waiver of Documentation of Consent for Pre-screening 
questions.  
 
HIPPA: 
 HIPAA does not apply if : 
o no PHI is collected or 
o  if PHI is collected from a potential subject  by an individual from a department 
that is not part of the HIPAA covered entity  
 HIPAA does apply if the collection occurs by individuals* who work in a department 
that is part of the HIPAA covered entity.  In this case the collection will be covered under 
Health Care Operations/ 
o These individuals are those that meet one of the following criteria:  
 a UVa student working in the UVa HIPAA Covered Entity*   
 a faculty  or staff member in a PAID appointment in  the UVA HIPAA 
Covered Entity* 
IF YES, Will any of the questions involve health information? Yes. 
 
IF YES, will you collect HIPAA identifiers with the health information?Yes. 
IF YES, which HIPAA identifiers will be recorded? 


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Name, MR#, date of birth, age, postal address, telephone number, email address (if 
applicable) 
 
Do you confirm that health information with HIPAA identifiers will not be shared 
outside of UVa until a consent form is signed or only shared in a de-identified 
manner? Yes. 
4. Do you plan to ask the subjects to do anything, other than answering questions, for the study 
prior to signing a consent? Yes. 
 
►IF YES, explain in detail what you will ask them to do. 
 
Tips to Study Team 
• You must document their verbal consent in the study records.  
• If a subject is asked to stop taking a drug, document the date and name of the person 
on the study team giving the verbal order to stop medications (again- must be a 
person with a DEA#). 
DHHS: Study team requests the use of Verbal Consent (Waiver of Documentation of 
Consent) for minimal risk screening procedures.  
 
HIPPA:  
If the individual, obtaining consent, works under the HIPAA Covered Entity this is 
covered under Health Care Operations 
If the individual obtaining consent does not work under  the HIPAA covered entity, 
HIPAA does not apply.  
 
Subjects will be asked to fast overnight prior to the screening visit.  If subjects are on hormonal 
medications (such as oral contraceptive pills, spironolactone, and metformin), they will be told that in 
order to participate in the study, they must discontinue the hormonal medications for 3 months.  They 
will be strongly urged to discuss the decision regarding whether or not to discontinue hormonal 
medications with their personal physician prior and to discontinue medications only with the agreement 
of their physician. Verbal consent for fasting and discontinuing medications will be documented in the 
study records, as will the discussion regarding consulting their personal physician.   
 
5. How will the consenting process take place?    
HIPPA:  
• If the individual, obtaining consent, works under the HIPAA Covered Entity consenting is 
covered under Health Care Operations. 
• If the individual obtaining consent does not work under the HIPAA covered entity, HIPAA 
does not apply.  
 
An outpatient consenting and screening visit is scheduled for volunteers who express interest in 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 consent and screening visit is held in an outpatient examination room in the CRU or alternate UVA clinical 
unit. This allows a private conversation between the screening physician and/or study coordinator, the potential 


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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 and/or study coordinator 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, physical, 
screening blood tests) occurs immediately thereafter.  Participants generally begin the main part of the study 
within 1-2 months of the screening visit.   
 
6. Will subjects sign a consent form for any part of the study? Yes. 
7.  Will the study procedures be started the same day the subject is recruited for the study? Yes. 
 
►IF YES, explain in detail why the subject cannot be given more time to make a decision 
to consent.  
Potential subjects are given a copy of the consent form prior to their screening visit.  Subjects are 
instructed to review the consent form, and are encouraged to ask any questions prior to 
scheduling a screening visit.  At the screening visit, subjects are lead through a discussion of the 
consent form.  Subjects are given the opportunity to ask any additional questions during this 
portion of the screening visit.  After the study team has read through the entire consent form with 
the subject, they are then given the opportunity to sign the consent form, decline to enroll in the 
study, or take more time to review the consent form before making a decision whether or not to 
enroll.  If the subject decides to enroll in the study on the day of the screening visit, then we will 
proceed with the study procedures outlined in the study visit above, unless the subject objects.   
 
Therefore, the study team feels that the subject is under no pressure to give consent at the 
screening visit without having ample opportunity to review the consent form.  In addition, 
subjects are given the option to decline consent or delay study procedures at any point during this 
initial visit. 
 
►IF YES, explain in detail what will be done to assure the potential subject has enough 
time to make an informed decision.See explanation above. 
 
8. Do you need to perform a “dry run” of any procedure outlined in this protocol?   No. 
 
APPENDIX:  Clinical Data Repository 
1.  Will you be obtaining data from the UVa Clinical Data Repository (CDR)?   Yes 
 
 
►If YES, check the categories of data elements below that you plan to obtain from the CDR.  
You are advised to talk to CDR personnel prior to completing this section.   


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CATEGORY 
DATA ELEMENTS 
CHECK  ALL THAT APPLY 
Demographics 
e.g. Gender, race, age 
X 
Administrative 
e.g. Includes payor, payscale, length 
of stay, fact of visits (inpatient or 
outpatient), locations of service 
(inpatient or outpatient), providers 
X 
Financial 
e.g. Charges or costs associated with 
care 
 
Clinical Data 
e.g. Diagnoses 
X 
e.g. Procedures 
x 
e.g. Mortality 
 
e.g. Laboratory / Microbiology 
Results 
X 
e.g. Medications 
X 
e.g. Vitals, Height / Weight, Other 
Clinical Parameters 
X 
e.g. Other (specify) 
 
Narrative Reports 
e.g. Includes discharge summaries, 
pathology reports, operative notes, 
etc.  
X 
 
APPENDIX:  Participation of Children 
In the state of Virginia a person under the age of 18 is considered a child. 
1. Explain why this research topic is relevant to children.    
PCOS is a common clinical disorder affecting 6-8% of reproductive age women and significantly affects 
women’s reproductive, metabolic, and cardiovascular health.  PCOS is generally thought to begin in 
adolescence, and is increasingly recognized and diagnosed in this age group.  Given the association between 
obesity and increased androgen levels in girls, there is concern that the childhood obesity epidemic may lead to 
a rise in the incidence of hyperandrogensim and PCOS.  By studying the origins of PCOS in adolescence, we 
hope to develop better strategies for screening and prevention of PCOS in this patient population.   
 
2. Is the knowledge being sought in this study already available for children or is it currently being 
acquired through another ongoing study?    
No.  Although other studies have treated hyperandrogenic girls with metformin, they have focused on clinical 
and metabolic parameters.  This study is unique in that it is exploring the neuroendocrine effects of metformin 
in adolescent girls.   
 
3. Provide data that is available in adults in order that the IRB may judge the potential risk in children.  
If there is no adult data available, 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.    
Please see Drug Information for data regarding the use of metformin and micronized progesterone in both adults 
and minors. 
 


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4. Is the potential subject population likely to include wards of the state or children who are more at risk 
for becoming a ward of the state?   Yes. 
If the study will enroll subjects from patients at UVa, this question MUST be answered YES 
 
►IF YES:  If the caregiver is someone other than the person providing permission for the child to 
participate, the study team may wish to consider the use of an additional form for them.  (example-a 
child is in foster care however the biological parent has not lost legal custody and provides their 
permission for the child to participate, but the foster parent will be the person involved in driving the 
child to their study visits.  This form might address things such as who will receive the compensation 
for driving the child to the visits- the foster parent or the biological parent).  
►IF YES and if neither of the items 4a or 4b listed below is answered YES, children who are wards of 
the state must be excluded from this protocol. Add” wards of state” as an additional exclusion criteria.    
 
4a.  Is the research in this protocol related to the child’s status as a ward of the state?   No. 
 
4b.  Is the research to be conducted in schools, camps, hospitals, institutions, or similar settings in 
which the majority of children involved as subjects are not wards?    Yes. 
If this study will be done at UVa, answer this question YES.   
 
If you answered YES to # 4 and YES to EITHER  4a or 4b you may NOT exclude children who 
are wards of state. 
If you answered YES to # 4 and you answered NO to both 4 a or 4b you must exclude children 
who are wards of the state from the protocol- Add “ Wards of State” as an exclusion criteria.    
 
4c.  Are you aware of the following requirement? Yes. 
If the consent form contains a signature line for both parents the study team will notify the IRB 
immediately, if at any time during the course of the research, it becomes known that a potential 
subject is a ward of the state or that a child already enrolled in this protocol becomes a ward of the 
state. 
    APPENDIX:  Drug Information 
 
1   What is the drug name, manufacturer and IND# if available?    
Micronized progesterone powder (Spectrum Chemical Manufacturing Corporation, Irving, CA), IND# 
64,126 
 
2.   If IND application has been submitted to the FDA, who is the Principal Investigator on the IND?     
John C. Marshall, MD, PhD 
 
3.  What is the phase or stage of this study?   NA 
 
APPENDIX:  Drug Information 
 
1   What is the drug name, manufacturer and IND# if available?    


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Estrace (Warner-Chilcott, Rockaway, NJ); IND # 64,126 
 
2.   If IND application has been submitted to the FDA, who is the Principal Investigator on the IND?     
John C. Marshall, MD, PhD 
 
3.  What is the phase or stage of this study?   Not applicable. 
APPENDIX:  Drug Information 
 
1   What is the drug name, manufacturer and IND# if available?    
Metformin (generic metformin manufacturers); IND # 64, 126 
 
2.   If IND application has been submitted to the FDA, who is the Principal Investigator on the IND?     
John C. Marshall, MD, PhD 
 
3.  What is the phase or stage of this study?   NA 
 
 
APPENDIX:  Pharmacy-Investigational Drugs/Biologics  
 
1.   What is the name of the investigational drug/biologic?   Estrace (Warner-Chilcott, Rockaway, NJ) IND 
#64,126 
 
2. Where will the subjects be seen for the administration/dispensing of the drug?     
___X__  Inpatient Unit:  Subject will be dispensed estrace when discharged from the first and third 
inpatient admissions.  Subject will be instructed to take the estrace tablets once daily for 7 days after the 
first and third overnight admissions. (Thus subjects will take two rounds of estrace for 7 days). ___ 
 
3.  What dose will be utilized in this study?    
Estrace, 0.5-1 mg once a day 
 
4. What will be the frequency of dosing in this study?    
Daily 
 
5.  What will be the duration of dosing in this study?    
7 days after the first overnight admission and 7 days after the second overnight admission (thus a total of 
14 days) 
 
6.  What route of administration will be utilized?    
PO 
 
7.  Will drug need to be prepared by the UVa Investigational Drug Service (IDS)?     
__X___  NO- Drug will be prepared and/or administered per package insert 
 


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8.  Are there any special handling instructions mandated by the study (e.g. weighing hazardous 
materials)?   No. 
 
9.  Does the protocol provide provisions for dose titration, dose reductions, and or re-challenged (if drug 
is stopped), etc.?   No. 
 
10.  How will missed doses be handled?     
The subject should take a dose as soon as she remembers, unless it has been a full 24 hours, at which point the 
missed dose should be skipped and the regularly scheduled daily dose should be taken. 
 
11.  Will a comparator (active or placebo) be utilized in the protocol?   No. 
 
12.  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 # 13 and 14 
 
If no, answer question # 13 only. 
 
13    Are you using a drug/supplement/ food additive in a manner not approved by the FDA?    Yes. 
 
IF YES, answer questions 13a-13f 
You may reference the non-IRB protocol to answer these questions. 
 
13a.  Describe pertinent animal data that is available regarding the toxicity/safety of this drug.    
Not applicable as sufficient human data is available.   
 
13b. Describe pertinent human data that is available regarding the toxicity/safety of this drug.    
Although Estrace is not often prescribed to adolescent girls, there is significant experience with 
estrogens in this 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.    
 
13c. Have there been any human deaths associated with this drug?    
None known. 
 
13d. In how many humans has this drug been used previously?    
Oral estrogens, in various formulations, have been used to treat millions of women, although 
exact numbers are unknown. 
 
13e. If this protocol will be used in children describe any previous use of this drug with children of 
a similar age range.    
Although Estrace is not often prescribed to adolescent girls, there is significant experience with 
estrogens in this 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.  There is no data 
for the use of estrace in pre-pubertal girls. 


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14.  Do the following criteria apply?  
 
_____  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; 
 
_____  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; 
 
_____  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 Not checked- explain why you believe the risk to subjects is not increased:   
Although Estrace is not often prescribed to adolescent girls, there is significant experience with 
estrogens in this 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. 
 
___X_  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   
This item must be checked. 
 
__X__ The investigation will be conducted in compliance with the requirements of 21CFR312.7 
(Promotion and charging for investigational drugs) 
 This item must be checked. 
 
15.  Is this a post-marketing study?      No. 
 
APPENDIX:  Pharmacy-Investigational Drugs/Biologics  
 
1.   What is the name of the investigational drug/biologic?    
• Micronized progesterone powder (Spectrum Chemical Manufacturing Corporation, Irving, CA), 
IND# 64,126 
 
2. Where will the subjects be seen for the administration/dispensing of the drug?     
__X___  Inpatient Unit: Subject will be dispensed micronized progesterone when discharged from the first 
and third inpatient admissions.  Subject will be instructed to take the progesterone suspension three times a 
day for 7 days after the first and third overnight admissions. (Thus subjects will take two rounds of 
progesterone for 7 days).  
 
3.  What dose will be utilized in this study?    
20 mg/ml, 25-100 mg 
 


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4. What will be the frequency of dosing in this study?    
Three times a day at 0700, 1500, and 2300 hr 
 
5.  What will be the duration of dosing in this study?    
7 days after the first overnight admission and 7 days after the second overnight admission (thus a total of 
14 days) 
 
6.  What route of administration will be utilized?    
PO 
 
7.  Will drug need to be prepared by the UVa Investigational Drug Service (IDS)?     
___X__  YES 
 
►IF YES, complete the following information under 7a-7d.  
If you need assistance completing this section contact the Investigational Pharmacists at 982-1048 
7a.  Concentration 
__X___ Standard 
_____  Non- Standard-  specify   
 
7b.  Diluents 
__X___ Standard 
_____  Non- Standard-  specify   
 
7c.  Stability after prepared 
__X___ Standard 
_____  Non- Standard-  specify   
 
7d. Special storage requirements 
___X__ Standard 
_____  Non- Standard-  specify   
 
8.  Are there any special handling instructions mandated by the study (e.g. weighing hazardous 
materials)?   No. 
 
9.  Does the protocol provide provisions for dose titration, dose reductions, and or re-challenged (if drug 
is stopped), etc.?   No. 
 
10.  How will missed doses be handled?     
The subject should take the missed dose when she remembers it unless she is due for the next dose.  If 
the next dose is due, it should be taken and the missed dose should be skipped. 
 
11.  Will a comparator (active or placebo) be utilized in the protocol?   No. 
 
12.  Does this study involve research on a drug, biologic, supplement or food additive?    Yes. 
 
►IF YES, is this study investigator initiated?   Yes. 


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If yes, answer questions # 13 and 14 
 
If no, answer question # 13 only. 
 
13    Are you using a drug/supplement/ food additive in a manner not approved by the FDA?    Yes. 
 
IF YES, answer questions 13a-13f 
You may reference the non-IRB protocol to answer these questions. 
 
13a.  Describe pertinent animal data that is available regarding the toxicity/safety of this drug.    
Not applicable, as abundant human data is available. 
 
13b. 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. We 
have used this progesterone suspension in other protocols, and we have thus far administered the 
progesterone suspension over 30 adolescent girls and at least 12 adult women; no adverse events have 
occurred. 
 
13c. Have there been any human deaths associated with this drug?   None known. 
 
13d. In how many humans has this drug been used previously?    
The micronized progesterone suspension, as formulated by the UVa Investigational Drug Pharmacy, has 
been administered to over 30 adolescent girls and to at least 12 adults in the context of our clinical 
studies.   
 
13e. If this protocol will be used in children describe any previous use of this drug with children of 
a similar age range.    
The oral micronized progesterone suspension formulated by the University of Virginia Investigational 
Drug Pharmacy has been given to over 30 adolescent girls as part of our protocols.  There have been no 
adverse effects. 
 
 
14.  Do the following criteria apply?  
 
_____  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; 
 
_____  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; 
 
_____  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. 


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If Not checked- explain why you believe the risk to subjects is not increased:   
 
The oral micronized progesterone suspension formulated by the University of Virginia 
Investigational Drug Pharmacy has been given to at least 30 adolescent girls as part of our protocols.  
There have been no adverse effects. 
 
_X___  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   
This item must be checked. 
 
_X___ The investigation will be conducted in compliance with the requirements of 21CFR312.7 
(Promotion and charging for investigational drugs) 
 This item must be checked. 
 
15.  Is this a post-marketing study?      No. 
APPENDIX:  Pharmacy-Investigational Drugs/Biologics  
 
1.   What is the name of the investigational drug/biologic?    
Metformin (generic metformin manufacturers); IND# 64,126 
 
2. Where will the subjects be seen for the administration/dispensing of the drug?     
__X___  Inpatient Unit:Subject will be given supply of metformin upon discharge from the second 
overnight study admission. 
 
3.  What dose will be utilized in this study?    
Subject will start a 500 mg dose and gradually increase up to 2000 mg a day.   
 
4. What will be the frequency of dosing in this study?    
Upon discharge from admission 2 (day 8 of study), subjects will take 500 mg of metformin once daily.   
On day 14 of study, subjects will begin taking 500 mg of metformin twice daily. 
On day 21 of study, subjects will begin taking 1000 mg of metformin in the morning and 500 mg of 
metformin at night. 
On day 28 of study, subjects will begin taking 1000 mg of metformin twice daily. 
 
5.  What will be the duration of dosing in this study?    
Subjects will take metformin for at least 11 weeks. 
 
6.  What route of administration will be utilized?    
PO 
 
7.  Will drug need to be prepared by the UVa Investigational Drug Service (IDS)?     
__X___  NO- Drug will be prepared and/or administered per package insert  
 
8.  Are there any special handling instructions mandated by the study (e.g. weighing hazardous 
materials)?  No. 


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9.  Does the protocol provide provisions for dose titration, dose reductions, and or re-challenged (if drug 
is stopped), etc.?   Yes.  
 
►IF YES, provide specifics.  Dose of metformin will be increased gradually (as outlined above).   
 
10.  How will missed doses be handled?     
The subject should take the missed dose when she remembers it unless she is due for the next dose.  If 
the next dose is due, it should be taken and the missed dose should be skipped. 
 
11.  Will a comparator (active or placebo) be utilized in the protocol?   No. 
 
12.  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 # 13 and 14 
 
If no, answer question # 13 only. 
 
13    Are you using a drug/supplement/ food additive in a manner not approved by the FDA?    Yes. 
 
 
IF YES, answer questions 13a-13f 
You may reference the non-IRB protocol to answer these questions. 
 
13a.  Describe pertinent animal data that is available regarding the toxicity/safety of this drug.    
Not applicable as sufficient human data is available. 
 
13b. Describe pertinent human data that is available regarding the toxicity/safety of this drug.    
 
          Metformin is widely used for the treatment of Type 2 diabetes and polycystic ovary syndrome.  In 
general, the medication is well tolerated.  The most concerning adverse effect associated with metformin 
is lactic acidosis.  This is a very rare effect, with a reported incidence of 0.03 cases per 1000 person-
years of treatment.  In over 20,000 person-years exposure to metformin in clinical trials, there were no 
reported cases of lactic acidosis.  However, when it does occur, it is associated with a mortality rate of 
50%.  The majority of cases have been described in diabetics with impaired renal function, often in the 
context of multiple other medical and surgical issues and multiple other pharmacologic agents.  
Therefore, it is recommended that metformin be avoided in patients with other risk factors for lactic 
acidosis, including renal dysfunction, hepatic dysfunction, congestive heart failure, hypoxemia, and 
sepsis.   
          There have been 3 case reports of hepatotoxicity thought to be secondary to metformin in the 
literature.  Liver function normalized following cessation of the drug, although causality was not 
definitively established. 
          Gastrointestinal adverse symptoms, including bloating, nausea, and diarrhea, are common, 
occurring in approximately 30% of patients taking metformin.  The symptoms are generally mild and 
resolve with continued treatment.  They can be minimized by starting with a low dose of metformin and 


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gradually increasing the dose. Metformin has not been associated with hypoglycemia when given in 
therapeutic doses. 
 
13c. Have there been any human deaths associated with this drug?    
Metformin has been associated with deaths secondary to lactic acidosis.  As described above, lactic 
acidosis is a very rare complication of metformin use, with the rate of fatal lactic acidosis being 
estimated at 0.015 cases per 1000 patient-years.  Reported cases occurred primarily in those with other 
risk factors for lactic acidosis, including renal insufficiency and congestive heart failure.   
 
13d. In how many humans has this drug been used previously?    
Metformin has been used in innumerable adults with Type 2 diabetes, as well as many women with 
PCOS.  Metformin is used widely for the treatment of Type 2 diabetes and PCOS in adolescence, 
although the total number of children treated to date is unclear.   
 
13e. If this protocol will be used in children describe any previous use of this drug with children of 
a similar age range.    
Metformin is approved for use in children with Type 2 diabetes from ages 10 to 16 (ages 17 or older are 
considered “adult” for this FDA-approval), and has been evaluated for safety in that population.  A 
number of small studies have evaluated Metformin as a potential treatment for adolescent girls with 
PCOS or its precursors, including hyperandrogenism and precocious puberty.  
 
Number of girls treated with metformin for PCOS 
Unfortunately, there is no registry documenting this information precisely. However, in a survey of 
pediatric endocrinologists published in 2005, 68% of surveyed pediatric endocrinologists said that they 
use metformin as first-line therapy for obese adolescents with PCOS (“Approach to adolescent 
polycystic ovary syndrome [PCOS] in the pediatric endocrine community in the U.S.A.,” Guttmann-
Bauman I, Journal of Pediatric Endocrinology and Metabolism, 2005).  The prevalence of PCOS in of 
American young women is 5-10% (“Metformin for the Treatment of the Polycystic Ovary Syndrome,” 
Nestler JE, NEJM 2008), and the onset of PCOS among these young women is commonly in 
adolescence (though exact numbers have not been published as to prevalence in adolescence). There are 
currently approximately 20 million girls in the US between 10-19 years old 
(http://en.wikipedia.org/wiki/Demographics_of_the_United_States).  Thus, if even 25% of young 
women with PCOS developed it during adolescence and if just half of these saw a pediatric 
endocrinologist for treatment of their disease, and 68% of these endocrinologists started metformin as 
treatment, that would mean that at any given time 170,000 girls in this age range would be taking 
metformin for PCOS. Therefore, in our estimation, thousands of girls in this age range have been 
prescribed metformin off-label for PCOS.  
 
Here at UVA, in Pediatric Endocrinology and the Children’s Fitness Clinic, all of our providers use 
metformin as a first-line therapy for overweight adolescent girls with PCOS (which represents hundreds 
of patient-care visits here at UVA alone). Collectively, in our experience, this medication has been safe 
in children and we have seen no serious side effects, beyond mild and reversible GI disturbances 
(nausea, abdominal discomfort, loose stools). 
 
14.  Do the following criteria apply?  
 


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_____  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; 
 
_____  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; 
 
_____  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 Not checked- explain why you believe the risk to subjects is not increased:   
 
Metformin is approved for use in children with Type 2 diabetes from ages 10 to 16, and has been 
evaluated for safety in that population.  Therefore, as this medication will be given to a similar 
population in this study, we do not believe this represents increased risk. 
 
__X__  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   
This item must be checked. 
 
_X___ The investigation will be conducted in compliance with the requirements of 21CFR312.7 
(Promotion and charging for investigational drugs) 
 This item must be checked. 
 
15.  Is this a post-marketing study?   No.    
APPENDIX:  Privacy Plan for Studies With Consent 
1.  Answer the questions below (1a-1e) to describe your/central registry’s plan to protect the 
identifiable data from improper use and disclosure.   
 
1a.  How will data be stored? 
___X__  Data, which may include health information, or other highly sensitive data will 
be stored with HIPAA identifiers.   
You MUST choose this option if case report forms will include such items as initials.  
 
1b. Will specimens be stored by the UVa study team? Yes. 
If YES, the following security precautions will be implemented:  
• Specimens will be kept in a locked freezer/ or locked room 
• __X___ Access to the freezer/room will be limited to authorized 
personnel.  Specimens with HIPAA identifiers will never be shared 
outside of UVa without the written permission of the subject.  
 
1c.  Will any of the data be stored electronically by the UVa study team? Yes. 
 


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►IF YES, will it include any HIPAA identifiers with health information or other 
highly sensitive data? 
 
►IF YES, where will it be stored?  
_X____  a Health Systems Computing Services (HS/CS) managed server that is 
configured to store data regulated by HIPAA. 
 
1d. Will any of the data be collected or stored in hard copy format by the UVa study team 
(e.g.- on paper) ?  Yes. 
 
►IF YES, where will it be stored?  
 
__X___ case report forms will be stored in a secure area with limited access.  
 
1e.  The following procedures will also be followed.  
• Only investigators for this study and clinicians caring for the patient will have access 
to the data.  They will each use a unique log-in ID and password that will keep 
confidential.  
• Each investigator will sign the University’s Electronic Access Agreement forward the 
signed agreement to the appropriate department as instructed on the form. 
If you currently have access to clinical data it is likely that you have already signed 
this form.  You are not required to sign it again.  
• UVa Institutional Data Protection Standards will be followed 
http://itc.virginia.edu/security/dataprotection.  Identifiable data is considered to be   
“Highly Sensitive”.  A Limited Data Set is usually considered to be “Moderately 
Sensitive” and de-identified data is usually considered to be “Not Sensitive”.   
• If identifiable data (data with health information and HIPAA identifiers) is transferred 
to any other location such as a desktop, laptop, memory stick, CD etc. the researcher 
must follow the University’s  “Electronic Storage of Highly Sensitive Data Policy”. 
Additional requirements may be found in the Universities Requirements for Securing 
Electronic Devices.  
• If identifiable health information is taken away from the UVa Health System, Medical 
Center Policy # 0218 will be followed.  
• The data will be securely removed from the server, additional computer(s), and 
electronic media according to the University's Electronic Data Removal Policy.  
• The data will be encrypted or removed if the electronic device is sent outside of UVa 
for repair according to the University's Electronic Data Removal Policy. 
• If PHI will be faxed, researchers will follow the Health System Policy # 0194.     
• If PHI will be emailed, researchers will follow the Health System Policy # 0193 and 
UVa Institutional Data Protection Standards . 
• The data may not be analyzed for any other study without additional IRB approval.  
• If you are using patient information you must follow Health System Policy  # 0021. 
 
Summary of Requirements to Comply with UVa Health System, Medical Center and University Policies 
and Guidance as noted above: 


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Highly Sensitive Data is: 
-personal information that can lead to identify theft if exposed or 
-health information that reveals an individual’s health condition and/or history of health services 
use.  
 
PHI- a type of Highly Sensitive Data, is health information combined with a HIPAA identifier 
 
• LIMIT- Limit the HIPAA identifiers to the minimal amount needed- e.g. use initials 
instead of name, use a code instead of initials, limit amount/type of health information 
collected, and collect and share only those items you state you will in this protocol.  
• SECURE- Secure Highly Sensitive Data 
o Because single-use electronic devices and media, such as desktops, laptops, memory 
sticks, CDs, smartphones etc., can be easily lost or stolen, the University strictly 
limits the circumstances under which Highly Sensitive Data may be stored on them. 
In accordance with the University’s Electronic Storage of Highly Sensitive Data 
Policy, you must obtain written approval from your Department AND VP or Dean 
prior to moving data to single use devices or media by using the Highly Sensitive 
Data Storage Request Form. 
  You additionally are responsible for applying all security safeguards covered 
in that policy, including but not limited to password protecting and encrypting 
any document on a single access electronic device.  
 If you use your smartphone to send email and your phone is not managed was 
not purchased and/or set up for you by the Health System, you cannot send 
Highly Sensitive Data via email.   
 In addition, do not use Outlook Web to send your email if it contains 
sensitive data.   
 Also, you are not allowed to auto forward your email to outside email 
systems like Gmail or Yahoo.   
 Do not save any email attachment containing Highly Sensitive Data to 
a single use device.   
 You are allowed to access Highly Sensitive Data stored on the University or 
Health Systems network via a VPN, however you cannot download any of the 
information onto your desktop or laptop. 
 Store files containing Highly Sensitive Data on a network drive specifically 
designated for storing this type of data, e.g. high-level security servers 
managed by Information Technology Services or the “F” and “O” managed 
by Heath Systems Computing Services.  You may access it via a shortcut icon 
on your desktop, but you are not allowed to take it off line to a local drive.  
 If data will be collected and/or viewed via a website, it is critical that the 
website and associated data file are set up in a highly secured manner. Do not 
attempt without assistance from:  
University Side:    ITCmicrosystems@virginia.edu 
Health System:   Web Development Center:   (434-243-6702) 
o Encrypt any electronic file containing Highly Sensitive Data that is not on a network 
drive specifically designated for this purpose.  . See encryption solutions guidance.  


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o Password protect any electronic device containing Highly Sensitive Data. 
o Lock up hard copies of Highly Sensitive Data. 
• PROTECT- Protect Highly Sensitive Data 
o Do not leave a hard copy file open on your desk when not using it and secure your 
computer when not attended. 
o Have discussions in private. 
o If you lose Highly Sensitive Data, you must report it in accordance with the 
Information Security Incident Reporting Policy. 
o Do not share Highly Sensitive Data with those not on the study team or those who 
do not have a need to know. 
o Do not share with sponsor unless subject has already signed a consent form or 
IRB has approved waiver of consent.  
o If faxing Highly Sensitive Data within UVa 
 Verify fax numbers before faxing, and use fax cover sheets with a 
confidentiality statement.  
 If printing to a central printer, ensure that names and identifiers on the 
documents are given to the correct patient. 
o Highly Sensitive Data may not be stored in a Drop Box. 
o If you plan to store data in the Cloud, you must consult with UVa Information 
Technology Services (ITS) to verify all essential security measures are in place.  
If you have a contract to use the cloud, the contract must include required security 
measures as outlined by ITS.   
o DO NOT email health information with name, medical record number or Social 
Security number to or from an email address that does not have an *HS in the 
address.  May use subject initials if within the UVa HIPAA covered entity:  The 
"UVA HIPAA covered entity" includes the hospital, health system, School of 
Medicine School of Nursing and the VP for Research Office.   
o Be aware:  PHI collected without consent/ HIPAA authorization will NOT be 
allowed to leave UVa in an identifiable form unless the disclosure is tracked with 
Health Information Services.   
o Any Highly/Moderately Sensitive Data sent outside of UVa (e.g. to sponsor) that 
was obtained under a consent must be encrypted and password protected.   
o If your electronic device is sent outside of UVa for repair, all institutional data, 
whether Highly Sensitive or not, must be either encrypted or removed.  
o If transporting Highly/Moderately Sensitive Data in paper format from one UVa 
building to another, take the following steps to protect it: 
1. Put paper inside a closed container such as a briefcase, or sealed 
envelope to limit the chance of a losing a piece. 
2. Do not leave Highly Sensitive Data unattended in a public area if it is 
not locked up.  
o When the study is complete, all electronic files containing Highly/Moderately 
Sensitive Data must be stored on a network drive specifically designated for that 
purpose.  They may not be stored on a single use device such as a CD. 
• STOP, THINK and BE CAREFUL- 
o If this was your Highly Sensitive Data how would you want it protected?  


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o There are significant monetary fines to the individual and the institution for loss 
or misuse of sensitive data. 
o Your job may also be on the line. 
 
 
2.  Describe your/central registry’s plan to destroy the HIPAA identifiers at the earliest opportunity 
consistent with the conduct of the research and in accordance with any stipulations in the research 
sponsor contract and UVa records management guidelines. 
 
__X___The HIPAA identifiers (except full dates and or address information if needed) will be destroyed 
as soon as all publications are complete.  
This wording would allow the researcher to keep HIPAA identifiers until all queries/ request for 
additional information from publisher are addressed 
 
3.  Do you confirm that you will not reuse the identifiable data (HIPAA identifiers or health information) 
or disclose any of this information to any other person or entity except as outlined in this protocol, except 
as required by law, for authorized oversight of the research study, or use it for other research unless 
approved by the IRB-HSR?  Yes. 
 
 
This means that after the study is closed at UVa: 
 
• You cannot contact the subject by any method (you cannot call them, send a letter, talk to them in 
person about the study, etc) without additional IRB approval 
• You cannot use the data for any research that is not already described in your IRB protocol 
without additional IRB approval (if you change your hypothesis you must modify your protocol)  
• You cannot share your research data with another researcher outside of your study team without 
additional IRB approval 
• Any health information with HIPAA identifiers will be shredded or discarded by using recycling 
bins for confidential material found in clinic settings.  For large item disposal of confidential 
material contact Environmental Services at 2-4976 or University Recycling at 2-5050.  
TABLE A:  HIPAA Identifiers (Limited Data Set)  
1.  Name 
2.  Postal address information, other than town or city, state, and zip code 
3.  Telephone numbers 
4  Fax numbers 
5.  Electronic mail addresses 
6.  Social Security number 
7.  Medical Record number 
8.  Health plan beneficiary numbers 
9.  Account numbers 
10.  Certificate/license numbers 
11.  Vehicle identifiers and serial numbers, including license plate numbers 
12.  Device identifiers and serial numbers 
13.  Web Universal Resource Locators (URLs) 
14.  Internet Protocol (IP) address numbers 
15.  Biometric identifiers, including finger and voice prints 
16.  Full face photographic images and any comparable images  
17.  Any other unique identifying number, characteristic, code that is derived from or related to information 
about the individual (e.g. initials, last 4 digits of Social Security #, mother’s maiden name, first 3 letters of last 
name.) 
 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by 
Estradiol and Progesterone in Hyperandrogenic Adolescent Girls 
 
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Version Date: 12/14/2015 
APPENDIX:  Sponsor 
Sponsor Information 
1. Explain the sponsorship for this study.  
INSTRUCTIONS:  
• List names of companies, institutes, foundations with which you have a grant or a contract from an 
entity that is not a support source.   
• Example:  This study is funded via a contract with the University of New York, which has a grant from 
the NIH to conduct this study.  We will be receiving free drug from Glaxo.  Glaxo will receive data 
prior to publication. 
• If the outside entity will be monitoring the study or receiving data prior to publication enter them as a 
sponsor.   
• If you are receiving things such as free supplies/ drug/ devices from a company   who WILL NOT be 
monitoring the study or be receiving data prior to publication do NOT enter them here- enter this 
information under Support Source below.   
Answer/Response: National Institutes of Health (NIH) 
 
2. Do you confirm that you will obtain a contract/ material transfer agreement with the sponsor via the 
School of Medicine Grants and Contracts Office or the Office of Sponsored Programs (OSP) 
ospnoa@virginia.edu? 
INSTRUCTIONS: 
You should have answered YES to the following question in Protocol Builder:  
--“Do you/will you have a contract with an outside entity to support this protocol?” 
Answer/Response: Yes 
 
 

ICF_001.pdf: 
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
Page 1 of 18 
Version Date: 12/14/2015 
Parents’ or Guardians’ Permission for Your Child  
to Be in a Research Study 
 
Agreement of a Child to Be in a Research Study 
Age 15 to <18 
 
 
In this form “you” means the child in the study and the parent or guardian.  
 If you are the parent or guardian, you are being asked to give permission for your child to be in this 
study.  
 If you are the child, you are being asked if you agree to be in this study.  
 
In this form “we” means the researchers and staff involved in running this study at the University of Virginia. 
 
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. 
Participant’s Name______________________________Medical Record # _________________________ 
 
Principal Investigator: 
Christine Burt Solorzano, MD 
Internal Medicine, School of Medicine 
Box 800391 
Charlottesville, VA 22908          Telephone:  (434) 924-9084 
 
Sponsor: 
National Institutes of Health (NIH) 
 
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.   
 
Who is funding this study? 
This study is being funded by the National Institutes of Health. 
 


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Hyperandrogenic Adolescent Girls 
 
 
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Why is this research being done? 
Introduction 
The purpose of this study is to understand whether insulin changes the effects of high male hormone levels in 
adolescent girls.   
 
Hormones are substances that are made in the body and sent directly out into the bloodstream to increase or 
decrease the function of certain organs, glands, or other hormones.  Female hormones, such as estrogen and 
progesterone, help a girl’s body develop into a woman’s body.  Male hormones, such as testosterone, help a 
boy’s body develop into a man’s body.  All girls and women make low levels of male hormones.  Some girls 
and women produce higher levels of male hormones for unclear reasons.   
 
Many, but not all, girls with high levels of the male hormone testosterone go on to develop polycystic ovary 
syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual periods, excess facial and body 
hair, and weight gain.  PCOS is also a leading cause of difficulty becoming pregnant.   We do not understand 
why some girls with high hormones develop PCOS and others do not.   
 
In a previous study by our group, some girls with high levels of male hormones had abnormalities in the 
secretion of another hormone (called LH) that are often seen in women with PCOS.  However, another group 
had normal LH secretion.  The girls with the abnormal LH secretion had higher levels of another hormone, 
called insulin, than the girls with normal LH secretion.  Insulin is a hormone that helps control blood sugars and 
women with PCOS often make high levels of insulin in order to keep their blood sugars normal.   
 
In this study we will use a drug called Metformin (Glucophage). Metformin (Glucophage) is approved by the 
U.S. Food and Drug administration (FDA) for the treatment of type II diabetes in adults and adolescents, but not 
for the treatment of the insulin resistance associated with PCOS. However, Metformin is commonly prescribed  
“off-label” as a treatment for PCOS in girls and women. “Off-label” means that Metformin is prescribed for 
PCOS even though the drug only has FDA-approval for treatment of diabetes. Metformin (Glucophage) lowers 
insulin levels and lowers high, but not normal, blood sugar levels.  So far, Metformin (Glucophage) has been 
given to thousands of girls who have elevated male hormone levels, and is thought to be safe and effective in 
these patients. The use of Metformin is considered to be experimental in this study.  
 
In this study we will also use the drugs progesterone and estradiol (estrace).  Estrogen and progesterone are 
natural hormones.  The amount of these hormones used in this study are similar to the amounts that are 
produced by girls’ bodies as they develop.  The progesterone syrup that we use is made in the 
UVa Investigational pharmacy.  The progesterone used to make the syrup is FDA approved, but there are no 
specific data regarding human toxicity and safety of the UVA Health System progesterone syrup.  Over 30 girls 
have taken the progesterone syrup as made by the UVa pharmacy and there have not been any unexpected side 
effects.  Although estradiol and progesterone are not typically given to girls as Estrace and progesterone syrup 
as is done in this study, they are frequently given in combination as birth control pills in this age group.  Birth 
control pills have been prescribed to numerous adolescent girls as part of the treatment for elevated male 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
Page 3 of 18 
Version Date: 12/14/2015 
hormone levels and PCOS and are felt to be safe and effective in this population. However, 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 an adolescent girl with elevated male hormone levels. 
 
Up to 60 people will be in this study at UVA.   
 
How long will this study take? 
 
Your participation in this study will require 6 outpatient study visits and 4 overnight admissions over 
approximately a 4 month period of time.  There will be one screening visit that will last no more than one hour.  
The other outpatient visits should last no longer than 30 minutes.  The overnight admissions will last 14-16 
hours and take place at the University of Virginia Clinical Research Unit (CRU), alternate UVA hospital unit, 
or off-site hotel (see below). 
 
What will happen if you are in the study? 
All of the procedures performed as part of the study are being done purely to answer research questions.  
 
SCREENING (will take approximately 30-60 minutes to complete): 
If you agree to participate, you will sign this consent form before any study related procedures take place.  
Before you can start 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.) 
• 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.  
• There are a number of restricted medications which cannot be used during the study.  The study 
personnel will discuss those restriction medications with you. 
 
If these tests show you are eligible, you will be given a 1 month supply of iron to take for up to 30 days.  You 
will receive instructions on the dosage of iron that you will take.  How much iron you take will be determined 
by your weight.  Your first study admission can occur anytime within this 30 day period or anytime after this 
period.  You will have the option to pick up this supply of iron from the Clinical Research Unit or have it 
mailed to your residence.  If you are unable to begin the study within 90 days following screening, you will 
need to come back to have the screening blood tests repeated before taking part in the study. 
 
 


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Hyperandrogenic Adolescent Girls 
 
 
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Version Date: 12/14/2015 
 
 
 
 
STUDY Tests and Procedures: 
 
If the overnight admission is scheduled to occur greater than one month after the screening visit you will be 
asked to return for an outpatient blood draw to make sure your red blood cell count is high enough to continue  
in the study. 
 
In Patient Overnight Admission #1 (Day 0): 
• Admission #1 will take place on day 7-11 of your cycle if you are having regular periods and greater 
than 7 days since your last cycle if your periods are infrequent, as long as your progesterone level is 
low within 3 days of the scheduled overnight admission.  Thus, for girls cycling infrequently, you 
will be asked to come to the CRU or other clinical unit for a blood draw within 3 days of your 
scheduled overnight admission to check your progesterone.  If your progesterone is found to be too 
high, then your admission will be cancelled.     
• We will ask that you eat at least 150 gm of carbohydrate a day for the 3 days prior to the admission 
and will give you instructions on how to do this at your screening visit. 
• You will be admitted to the CRU, alternate UVA hospital unit, or off-site hotel at 5:00 pm on that 
day.  If the overnight visit occurs at a hotel, your parent or guardian may stay with you but it is not 
required,.  If your parents/guardian are not available to stay with you, two CRU staff members will 
be 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 admission, 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. 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. 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.    
• A urine pregnancy test will be done to make sure you are not pregnant.  If you are pregnant you will 
not be able to continue in the study. 
• Starting at 7:00 PM, blood samples will be taken every 10 minutes.  With the exception of one blood 
draw that will be 1 teaspoon, each of the blood draws will be no more than 1/2 of a teaspoon  
• You will be given dinner at standard CRU mealtimes (approximately 6:00 pm).  You will not be able 
to eat or drink anything except water from 11:00 pm until 9:00 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.   


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Hyperandrogenic Adolescent Girls 
 
 
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Version Date: 12/14/2015 
• At 7 AM, the nurses will give you a sugary drink.  They will take blood samples (1/2 teaspoon) 
before you have the drink and 10, 20, 30, 60, 90, and 120 minutes after you drink it. 
• After the blood draws are complete at 9:00 AM, you will be served breakfast.   
• The nurse will take out the IV and you will be able to go home.  
• Before you go home from the admission, you will be given a supply of estrogen (estradiol) pills and 
progesterone syrup and instructions on when to take them. 
• A total of 8 tablespoons of blood will be drawn during this admission. 
 
Start study medication: estrogen, progesterone and iron supplements (Day 1): 
• 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. 
• You will also be given iron supplements to help your body rebuild your red blood cells.  You will 
take either one or two pills a day by mouth, depending on how much you weigh.  You will receive 
instructions on how much iron you should take.  
 
Outpatient Blood Draws (Day 3 and 5): 
• Three days and then five days after the admission, you will return to the CRU or alternate UVA 
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 medication is being 
absorbed into the blood stream.   
 
In Patient Overnight Admission #2 (Day 7): 
• After seven days of taking the estrogen and progesterone, you will return 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, except that it will end at 7:00 
AM.  You will not drink the sugary drink and have the additional blood draws during this 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 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
Page 6 of 18 
Version Date: 12/14/2015 
o start taking metformin by mouth.  You will start by taking 1 pill (500 mg) at night.   
 
 
 
Increase Metformin Dose (Day 14): 
• You will increase the metformin dose to 1 pill in the morning and 1 pill at night.  We will call you to 
see how you are feeling and to remind you to increase the dose. 
 
Increase Metformin Dose (Day 21): 
• You will increase the metformin dose to 1 pill in the morning and 2 pills at night.  We will call you 
to see how you are feeling and to remind you to increase the dose. 
 
Increase Metformin Dose (Day 28): 
• You will increase the metformin dose to 2 pills in the morning and 2 pills at night.  We will call you 
to see how you are feeling and to remind you to increase the dose. 
 
Outpatient blood draw (Between Days 42 and 49): 
• During this week, on a day that is convenient for you, you will come to the CRU or clinic for blood 
work after not eating or drinking anything except water for 8 hours.  This appointment should take 
no longer than 30 minutes. 
• A small amount of blood (less than 2 teaspoons) will be drawn to check your salts, sugar, kidney 
function, liver function, and several hormones.  
 
In Patient Overnight Admission #3 (Day 84): 
• Admission # 3 is timed to your cycles, so it may not occur exactly on day 84.  After day 77, we will 
schedule the admission for the first appropriate time in your cycle, which will be will be day 7-11 of 
your cycle if you are having regular periods or greater than 7 days since your last cycle if your 
periods are infrequent, as long as your progesterone level is low within 3 days of the scheduled 
overnight admission.  Thus, for girls cycling infrequently, you will be asked to come to the CRU or 
other clinical unit for a blood draw within 3 days of your scheduled overnight admission to check 
your progesterone.  If your progesterone is found to be too high, then your admission will be 
cancelled.   
• We will ask that you eat at least 150 gm of carbohydrate a day for the 3 days prior to the admission 
and will give you instructions in how to do this. 
• Admission #3 will be exactly the same as Admission #1. 
• A total of 8 tablespoons of blood will be drawn during this admission. 
 
Begin Estradiol and Progesterone (Day 85): 
• Before you leave, you will be given a supply of estrogen pills (estradiol) and progesterone syrup.  
These are the same medications and the same doses that you took on days 1-7.  
• The estrogen pills should be taken by mouth once a day for seven days.   


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
Page 7 of 18 
Version Date: 12/14/2015 
• 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. 
 
Outpatient Blood Draws (Day 87 and 89): 
• Three days and then five days after the Admission #3, 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 medication is being 
absorbed into the blood stream.   
 
In Patient Overnight Admission #4 (Day 91): 
• Admission #4 will be exactly the same as admission #2. You will bring your estrogen, progesterone, 
and metformin bottles and any unused medicine to the admission and give them to the nurses.  
• A total of 7 tablespoons of blood will be drawn during this admission. 
• After the admission is complete, you should stop taking the estradiol, progesterone, and metformin.  
You should continue to take the iron supplements for 1 more month. 
 
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 visit.   If you agree, we would ask you to complete questionnaires that will ask you about general 
health, progress through puberty, and menstrual periods.  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, and each visit would 
take about 30-45 minutes. 
 
__________ Yes, I agree to participate in the optional follow up visits. 
 
__________ NO, I do not agree to participate in the optional follow up visits. 
 
 
 
 
 
 
 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
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Version Date: 12/14/2015 
 
 
 
Study Schedule  
 
Day of Study 
Type of Visit 
Estradiol Progesterone Metformin 
Within 3 months of 
Day 0 
Screening visit 
 
 
 
Day 0 
In patient Admission #1 
Overnight with frequent blood draws 
Test with sugary drink 
 
 
 
Day 1 
 
x 
xx 
 
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 
In patient Admission #2 
Overnight with frequent blood draws 
x 
x 
 
Days 8-41 
 
 
 
x 
Day 42 
Blood draw 
 
 
x 
Days 43-83 
 
 
 
x 
Day 84 
In patient Admission #3 
Overnight with frequent blood draws 
Test with sugary drink 
 
 
x 
Day 85 
 
x 
x 
x 
Day 86 
 
x 
x 
x 
Day 87 
Blood draw 
x 
x 
x 
Day 88 
 
x 
x 
x 
Day 89 
Blood draw 
x 
x 
x 
Day 90 
 
x 
x 
x 
Day 91 
In patient Admission #4 
Overnight with frequent blood draws 
x 
x 
x 
 
Blood Testing 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
Page 9 of 18 
Version Date: 12/14/2015 
The blood we take will be tested to measure salts, sugar, blood counts, kidney function, liver function, 
pregnancy tests, and a variety of hormones. A total of 31 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. 
 
If you want to know about the results before the study is done: 
During the study your study leader will let you know of any test results that may be important to your health.  In 
addition, as the research moves forward, your study leader will keep you informed of any new findings that may 
be important for your health or may help you decide if you want to continue in the study.  The final results of 
the research will not be known until all the information from everyone is combined and reviewed.   At that time 
you can ask for more information about the study results.  
 
What are the risks of being in this study?  
Likely 
•  Metformin can cause nausea, diarrhea, bloating, and weakness/fatigue.  These symptoms are 
usually mild and go away if you continue to take the medication.  These side effects are less 
likely to be a problem if you start with a low dose of metformin and gradually increase it, which 
is what is being done in this study.  
• It is expected that you may have some menstrual bleeding 1-5 days after stopping the estrogen 
and progesterone. 
• 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.   
• The estradiol and progesterone may cause a temporary change in menstrual cycles. If you are 
already having periods, the timing of your cycles may be somewhat different for the next few 
cycles. Even if you have not yet started having periods, 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 
• In rare cases, Metformin can cause lactic acidosis.  This is a dangerous build-up of acid in the 
blood.  It is very rare, especially if people have normal kidney, liver, and heart function.  


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
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Version Date: 12/14/2015 
• 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.  
• The risk of heart disease, stroke, and breast cancer related to the hormones given in this study is 
extremely small. The risks are similar to those of taking birth control pills. 
 
Risks of Sharing the Drug 
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. 
 
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. 
 


IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in 
Hyperandrogenic Adolescent Girls 
 
 
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Risks of taking blood from an IV catheter: 
Sometimes the catheter stops working.  In order to get the blood we need, we may have to stick you with 
another needle. 
 
 
 
Risk of Heparin Lock Flush:  
Heparin works by preventing blood clots from forming in IV catheters when they are not in use. Allergic 
reactions and side effects are rare.  You should not use heparin lock flushes if you are allergic to heparin or pork 
products.  Symptoms of allergic reaction may include, rash, itching or swelling at the IV catheter site severe 
dizziness or trouble breathing.  Side effects though very unlikely may include, unusual bleeding or bruising and 
mild pain at the I.V. site. 
 
Risk of Saline Lock Flush:   
Saline works by preventing blood clots from forming in IV catheters when they are not in use. Saline is a salt 
solution.  There are no known risks to saline lock flush other than mild pain at the injection site.   
 
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). 
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 Stopping Hormonal Birth Control: 
You may be taking hormonal birth control (pills, patch or injection) and may not want your parents to know. 
There is a possible risk this information could be shared with parents inadvertently. 
 


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If you are sexually active and you would otherwise be taking hormonal birth control, you may be at greater risk 
for becoming pregnant because you are not allowed to take hormonal birth control medication while you are in 
this study.  
 
 
 
Risks for women: 
 
If you are pregnant, we want you to tell us and we will not include you in the study, because to do so might be 
harmful to the unborn baby.  We also want your child to avoid getting pregnant during this study and expect 
your child to abstain from sexual activity or use an effective method of birth control. Examples of non-
hormonal birth control that can be used in this study include condoms and a diaphragm.  If you have questions 
about birth control, please ask the study leader. 
 
If your child should become pregnant in spite of taking precautions, please immediately contact the investigator 
whose phone number is listed on this form and he/she will discuss with you and your child the choices which 
are available for your child’s consideration. 
 
Also, your child should be sure you do not get pregnant for 3 months after your participation in the study ends. 
 
Other unexpected risks: 
• Subjects should significantly limit their intake of alcohol while taking metformin. 
• 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? 
We cannot promise that you will be helped by being in this study.You may benefit from being in this study. 
Metformin is a treatment for excess male hormone, so it is possible that you may benefit from being in this 
study.  Possible benefits include: improvement in acne, excess hair growth, and weight loss.  In addition, 
information researchers get from this study may help others in the future.  
 
What are your other choices if you do not join this study? 
You do not have to be in this study to be treated for your illness or condition. You can get the usual treatment 
even if you choose not to be in this study.  The usual treatment for girls with elevated male hormone levels 
would include birth control pills, metformin, and spironolactone.  However, in order to do this study we must 
delay usual treatment. 
 
If you are an employee of UVa your job will not be affected if you decide not to participate in this study.  
If you are a student at UVa, your grades will not be affected if you decide not to participate in this study.   
 


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Will you be paid for being in this study? 
You will be paid with a $75 Simon Mall gift card for each of the inpatient admissions.  In addition you will 
receive a $100 Simon Mall gift card for completing the medication regimen and outpatient blood draws. 
Therefore, if you complete the entire study you will receive a total of $400 in gift cards.  
You should get your payment for all your visits at the final overnight admission.  
 
The income may be reported to the IRS as income.  
 
However, if you do not finish the study, you will be paid $75 for each overnight admission you have completed. 
If the study leader says you cannot continue, you will be paid the full amount for the study.  
 
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.   
 
By agreeing to be in this study, you are donating your blood samples for research, and giving up any property 
rights you may have in them.  The results of this research using your donated materials may have commercial 
value.  However, you will not receive any payments.   
 
Will being in this study cost you any money? 
All the tests and procedures described in this consent are being done solely for research purposes and will be 
provided to you at NO cost to you or your health insurance.  This includes: lab tests, study drugs (metformin, 
estradiol, progesterone, iron supplements) outpatient visits, and hospital admissions.  
 
You and/or your insurance company must pay for any tests or care given beyond what is required in this study.  
In addition, you and/or your health insurance 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.  You 
may be responsible for any co-payments or deductibles.  You may wish to ask for an estimate of your financial 
costs.  You may also wish to check with your insurance company before the study starts. Ask what they will 
cover and if they require you to get their permission before you decide to be in the study.  You will be 
responsible for the cost of travel to come to any study visit and for any parking costs.    
 
What if you are hurt in this study? 
 
If you are hurt as a result of being in this study, there are no plans to pay you for medical expenses, lost wages, 
disability, or discomfort. The charges for any medical treatment you receive will be billed to your insurance. 
You will be responsible for any amount your insurance does not cover.   You do not give up any legal rights, 
such as seeking compensation for injury, by signing this form.    


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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) Your disease gets worse  
c) The side effects of the treatment are too dangerous for you 
d) New information shows the treatment will not work or is not safe for you 
e) You do not follow your doctor’s instructions 
f) 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. Christine Burt Solorzano 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.   
 
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,  
o Social Security number ONLY IF you are being paid to be in this study 
o Your health information.  If required for this study, this may include a review of your medical records and 
test results from before, during and after the study from any of your doctors or health care providers (if 
required for this study, this may include mental health care records, substance abuse records, and/or 
HIV/AIDS records). 
 
Who will see your private information?   
o The researchers to make sure they can conduct the study appropriately,  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, such as the National Institutes of Health, including insurance companies  
o Tax reporting offices (if you are paid for being in the study) 


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o People who evaluate study results, which can include sponsors and other companies that make the drug or 
device being studied, researchers at other sites conducting the same study, and government agencies that 
provide oversight such as the Food and Drug Administration (FDA) if the study is regulated by the FDA.  
 
Some of the people outside of UVa who will see your information may not have to follow the same privacy 
laws that we follow.  We ask them to protect your privacy. However, they may release your information to 
others, and it may no longer be protected by those laws. 
 
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. 
 
A description of this clinical trial will be available on http:// www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
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.   
 
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:   Christine Burt Solorzano, MD 
      Internal Medicine, School of Medicine 
      Box 800391  Charlottesville, VA 22908          Telephone:  (434) 924-9084 


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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 
 
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. 
 
Signatures 
 
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 have received this information and all your questions have been answered.  If 
you sign the form it means that you agree to join the study.  You will receive a copy of this document after you 
have signed it.   
 
Assent from Child (15-17 years of age) 
Consent from the parent/guardian MUST be obtained before approaching the child for their assent.  
 
__________________________ 
PARTICIPANT 
(SIGNATURE) 
 ________________________ 
PARTICIPANT 
(PRINT) 
 _______ 
DATE 
 
 
 
To be completed for any child age 15 or above. 
 
Person Obtaining Assent of the Child 
Consent from the parent/guardian MUST be obtained before approaching the child for their assent.  
 
By signing below you confirm that the study has been explained to the child (less than 18 years of age), all 
questions have been answered and the child has voluntarily agreed to participate.  
 
__________________________ 
PERSON OBTAINING 
ASSENT 
(SIGNATURE) 
 ________________________ 
PERSON OBTAINING 
ASSENT 
(PRINT) 
 _______ 
DATE 
 
Interpreter 


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By signing below you confirm that the study has been fully explained to the potential subject in a language they 
understand and have answered all their questions. 
_____________________________ 
INTERPRETER 
(SIGNATURE) 
 _____________________________ 
INTERPRETER 
(PRINT) 
 ________ 
DATE 
If an interpreter was used to explain this study to a potential subject who is a child, the interpreter must 
sign and date the line above.  
 
 
Parental/ Guardian Permission 
By signing below you confirm you have the legal authority to sign for this child. 
 
__________________________ 
PARENT/GUARDIAN 
(SIGNATURE) 
 ________________________ 
PARENT/GUARDIAN 
(PRINT NAME) 
 ______ 
DATE 
 
 
 
 
  
  
  
__________________________ 
PARENT/GUARDIAN 
(SIGNATURE) 
 ________________________ 
PARENT/GUARDIAN 
(PRINT NAME) 
 ______ 
DATE 
 
 
 
 
If you are unable to obtain parental permission from both parents, explain why not: 
_____________________________________________________________________________________ 
 
 
Person Obtaining Parental Permission 
By signing below you confirm that you have fully explained this study to the parent/guardian, allowed them 
time to read the consent or have the consent read to them, and have answered all their questions.  
 
_______________________________ 
PERSON OBTAINING PARENTAL 
PERMISSION 
(SIGNATURE) 
 _____________________________ 
PERSON OBTAINING 
PARENTAL PERMISSION 
(PRINT NAME) 
 ________ 
DATE 
 
_________________________________________________________________________________________ 
 
Consent From Impartial Witness 
If this consent form is read to the parent(s) because the parent(s) is blind or illiterate, an impartial witness not affiliated with the 
research or study doctor must be present for the consenting process and sign the following statement.  The parent may place an X 
on the Parent Signature line above.  
 


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I agree the information in this informed consent form was presented orally in my presence to the parent(s) and 
the parent(s) had the opportunity to ask any questions he/she had about the study.   I also agree that the parent(s)  
freely gave their informed consent for their child to participate in this trial.  
 
__________________________________________________ 
 NAME OF IMPARTIAL WITNESS 
 
__________________________________________________        ________________ 
SIGNATURE OF IMPARTIAL WITNESS                                        DATE