Clinical trial NCT04177693
Conditions: Uterine Fibroids
Sponsor: Yale University
Start date: 2020-11-24; Completion date: 2022-01-31
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A trial to assess the pharmacokinetics and hepatic safety of EGCG in women with and without uterine fibroids.

Detailed description:
This will be a randomized, multi-center, pharmacokinetics and hepatic safety trial of EGCG with 36 total patients in 3 treatment arms. 36 women will be randomized to one of the following groups: EGCG daily alone, EGCG daily with clomiphene citrate and EGCG daily with letrozole. The randomization scheme will be stratified for age groups 18-29 and 30-40 and presence of uterine fibroids. The pharmacokinetics and hepatic safety of EGCG with clomiphene citrate and letrozole are unknown. The trial conducted in women with and without fibroids will allow comparisons between these groups. The results of this study will be used to confirm hepatic safety for the larger multi-center FRIEND study.

Arms: arm 1: EGCG daily alone. 800mg arm 2: EGCG 800 mg daily with clomiphene citrate 100mg for 5 days. arm 3: EGCG 800mg daily with letrozole 5mg for 5 days.
Interventions: intervention 1: Epigallocatechin gallate (EGCG) intervention 2: Clomiphene Citrate intervention 3: Letrozole
Intervention descriptions: intervention 1: 800 mg (4 capsules) of EGCG (green tea extract), taken orally on a daily basis for up to 2 months intervention 2: 100 mg for 5 days intervention 3: 5 mg for 5 days

Protocol documents:
Prot_SAP_000.pdf: 
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Pharmacokinetics and hepatic safety of EGCG 
 
 
 
Protocol Leader: Ayman Al-Hendy  MD PhD, University of Illinois at 
Chicago 
Data and Coordination Leader: Heping Zhang, PhD, Yale University 
 
Version 2.1 
 
 
 
 
National Clinical Trial (NCT) Identified Number:  NCT04177693 
IND 150951 
 
 
Funded by: The Eunice Kennedy Shriver Institute of  
Child Health and Human Development (NICHD) 
 
 
 


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Prepared by: 
Collaborative Center for Statistics in Science 
Yale University School of Medicine 
300 George Street, Suite 523 
New Haven, CT  06511 
 
(203) 785-5185 
 
dcc.c2s2@mailman.yale.edu 
 
Last updated: June 29, 2021 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Subcommittee 
 
Group email address:  
 
Member Name 
Email Address 
Ayman Al-Hendy, MD, PhD  
aalhendy@BSD.UChicago.edu 
 
Frank Gonzalez, MD 
frgz12@uic.edu 
 
James Segars, MD 
jsegars2@jhmi.edu 
 
 
Hugh Taylor, MD 
hugh.taylor@yale.edu 
 
 
Heping Zhang, PhD 
heping.zhang@yale.edu 
 


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Table of Contents  
1 
ACRONYMS ................................................................................................................................................. 1 
2 
STUDY SYNOPSIS ....................................................................................................................................... 2 
2.1 
OBJECTIVES ..................................................................................................................................................... 2 
2.2 
PATIENT POPULATION ...................................................................................................................................... 2 
2.3 
STUDY DESIGN ................................................................................................................................................. 2 
2.4 
TREATMENT ..................................................................................................................................................... 2 
2.5 
PRIMARY OUTCOME PARAMETER .................................................................................................................... 3 
2.6 
SECONDARY OUTCOME PARAMETERS.............................................................................................................. 3 
2.7 
STATISTICAL ANALYSIS ................................................................................................................................... 3 
2.8 
ANTICIPATED TIME OF COMPLETION ............................................................................................................... 4 
2.9 
REGULATORY COMPLIANCE ............................................................................................................................. 4 
3 
BACKGROUND AND SIGNIFICANCE .................................................................................................... 5 
3.1 
OVERVIEW ....................................................................................................................................................... 5 
3.2 
EGCG (GREEN TEA EXTRACT) AND UTERINE FIBROIDS................................................................................... 5 
3.3 
EGCG CLINICAL TRIAL IN WOMEN WITH SYMPTOMATIC UTERINE FIBROIDS .................................................... 6 
4 
OBJECTIVES................................................................................................................................................ 8 
4.1 
PRIMARY AIM .................................................................................................................................................. 8 
4.2 
SECONDARY AIM ............................................................................................................................................. 8 
4.3 
TREATMENT DESIGN, STUDY POPULATION, AND STUDY SUMMARY ................................................................ 8 
4.3.1 
Treatment Design ....................................................................................................................................... 8 
4.3.2 
Study Population ........................................................................................................................................ 8 
4.3.3 
Study Summary ........................................................................................................................................... 8 
4.3.4 
Inclusion Criteria ..................................................................................................................................... 10 
4.3.5 
Exclusion Criteria .................................................................................................................................... 10 
4.3.6 
Study Termination Criteria ....................................................................................................................... 11 
4.4 
RISK/BENEFIT ASSESSMENT ........................................................................................................................... 11 
4.4.1 
Possible Benefits ....................................................................................................................................... 11 
No direct benefits to participants. ........................................................................................................................... 11 
4.4.2 
Possible risks/discomforts ........................................................................................................................ 11 
5 
STUDY DESIGN ......................................................................................................................................... 13 
5.1 
TYPE OF DESIGN ............................................................................................................................................ 13 
5.2 
RATIONALE FOR DESIGN ................................................................................................................................ 13 
5.3 
RECRUITMENT ................................................................................................................................................ 13 
5.4 
INFORMED CONSENT ...................................................................................................................................... 13 
5.5 
RANDOMIZATION/TREATMENT INITIATION .................................................................................................... 14 
5.6 
PHYSICAL EXAM ............................................................................................................................................ 14 
5.7 
TRANSVAGINAL ULTRASOUND EXAM ............................................................................................................ 14 
5.8 
LABORATORY EXAM ...................................................................................................................................... 14 
5.9 
SCHEDULE OF EVALUATIONS ......................................................................................................................... 15 
6 
DATA ANALYSIS ...................................................................................................................................... 16 
6.1 
DATA ANALYSIS ............................................................................................................................................ 16 
6.2 
PRIMARY OUTCOME MEASUREMENTS ........................................................................................................... 16 
6.3 
SECONDARY OUTCOME MEASUREMENTS ...................................................................................................... 16 
6.4 
DIFFERENCE IN SERUM FOLATE LEVELS AMONG WILDTYPE MTHFR, MTHFR (C677T), AND MTHFR 
(A1298C) PATIENTS.  STATISTICAL ANALYSES ............................................................................................................ 16 
7 
TECHNICAL ASPECTS ............................................................................................................................ 17 
7.1 
STUDY AGENT PREPARATION ........................................................................................................................ 17 
7.2 
CONCOMITANT MEDICATIONS ....................................................................................................................... 17 


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7.3 
ADVERSE EXPERIENCE REPORTING ................................................................................................................ 17 
7.3.1 
Adverse Events .......................................................................................................................................... 17 
7.3.2 
Classification of an Adverse Event ........................................................................................................... 17 
7.3.3 
Time Period and Frequency for Event Assessment and Follow-up .......................................................... 19 
7.3.4 
Adverse Event Reporting .......................................................................................................................... 19 
7.3.5 
Serious Adverse Event Reporting ............................................................................................................. 20 
7.4 
UNANTICIPATED PROBLEMS........................................................................................................................... 21 
7.4.1 
Definition of Unanticipated Problems (UP) ............................................................................................. 21 
7.4.2 
Unanticipated Problem Reporting ............................................................................................................ 21 
7.5 
DATA COLLECTION AND MANAGEMENT (INCLUDING QUALITY ASSURANCE/COMPLIANCE MEASURES) ......... 22 
7.5.1 
Data Entry and Forms .............................................................................................................................. 22 
7.5.2 
Data Security ............................................................................................................................................ 22 
7.5.3 
Data Quality Control ................................................................................................................................ 22 
7.6 
STUDY MONITORING ...................................................................................................................................... 22 
7.7 
DATA AND SAFETY MONITORING BOARD ...................................................................................................... 23 
7.8 
REPORTING .................................................................................................................................................... 23 
7.9 
OBLIGATION OF THE INVESTIGATOR .............................................................................................................. 24 
7.10 
REGULATORY REQUIREMENTS ....................................................................................................................... 24 
7.11 
PROTOCOL AMENDMENTS .............................................................................................................................. 24 
7.12 
OVERALL POLICY ........................................................................................................................................... 24 
7.13 
MAIN STUDY .................................................................................................................................................. 25 
7.13.1 
Major Publications ................................................................................................................................... 25 
7.13.2 
Minor Publications ................................................................................................................................... 26 
7.13.3 
Ancillary Study ......................................................................................................................................... 27 
7.13.4 
Related Publications ................................................................................................................................. 27 
7.13.5 
Outside Studies ......................................................................................................................................... 27 
7.13.6 
Presentations ............................................................................................................................................ 28 
8 
REFERENCES ............................................................................................................................................ 29 
9 APPENDIX J: INVESTIGATOR SIGNATURE OF AGREEMENT ............................................................... 30 
9 
APPENDIX K: DSMB CHARTER ........................................................................................................... 31 
 
FIGURE 1. FLOWCHART .................................................................................................................... 7 
 
TABLE 1. SCREENING LABS OF STUDY WOMEN ............................................................................... 14 
TABLE 2. TYPES OF SERIOUS ADVERSE EVENTS AND THEIR REPORTING REQUIREMENTS ............... 20 


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1 Acronyms 
 
American College of 
Obstetricians and Gynecologists 
ACOG 
Institutional Review Board  
 
IRB 
Anti-Mullerian Hormone 
AMH 
Intramuscular 
IM 
Aromatase Inhibitors 
AI 
Intrauterine Insemination 
IUI 
Assisted Reproductive 
Technologies 
ART 
Investigational New Drug 
 
IND 
Catechol-O-methyl transferase 
COMT 
Luteinizing Hormone 
LH 
Centers for Disease Control 
 
CDC 
Methylenetetrahydrofolate 
reductase 
MTHFR 
Clinical Report Form  
CRF 
National Institute of Child 
Health and Human 
NICHD 
Clomiphene Citrate  
 
CC 
Office for Human Research 
Protections 
OHRP 
Data Coordination Center 
DCC 
Ovarian Hyperstimulation 
Syndrome 
OHSS 
Data and Safety and Monitoring 
B
d
DSMB 
Ovarian Stimulation 
OS 
Epigallocatechin gallate 
EGCG 
Principal Investigator 
PI 
Estradiol  
E2 
Progesterone 
P4 
Estrogen  
E 
Protected Heath Information 
PHI 
Estrogen Receptor  
ER 
Quality of Life 
QOL 
Follicle Stimulating Hormone 
FSH 
Serious Adverse Event 
SAE 
Health Insurance Portability and 
Accountability Act 
HIPAA Thyroid-Stimulating Hormone 
 
TSH 
Health Related Quality of Life 
HRQL 
Total and Free Testosterone 
T, FT 
Human Chorionic Gonadotropin 
hCG 
Ultrasound 
U/S 
Human Investigation 
Committee 
HIC 
World Health Organization 
 
WHO 
Identification 
ID 
 
 


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2 Study Synopsis 
2.1 
Objectives 
The objective of this study is to conduct a randomized clinical trial to determine the 
pharmacokinetics and hepatic safety of epigallocatechin gallate (EGCG).     
 
MTHFR represents the most studied enzyme in the folate pathway with strong evidence that 
polymorphisms decrease enzyme activity. Because of the potential effect of EGCG on folate 
metabolism possibly leading to folate depletion, MTHFR represents a clinically relevant target. 
We are planning to stratify subjects by wild type MTHFR, MTHFR (C677T), and MTHFR 
(A1298C). The prevalence of MTHFR mutations can range from 30 to 40% in the American 
population for C677T and ~50% for A1298C. We will evaluate if green tea catechins may have 
modulating properties that may increase the risk of folic acid depletion in women expressing 
known MTHFR polymorphisms. In this protocol we will evaluate if polymorphisms related to 
folate metabolism increase the risk for folate depletion in women receiving green tea extract. 
2.2 
Patient Population 
The population will consist of 36 women ages ≥18 to ≤40 years (at time of consent). Eighteen 
women will have intramural and/or subserosal fibroids and 18 women will be without intramural 
fibroids and/or subserosal fibroids. Participants will be recruited over approximately a 6-month 
period from the FRIEND Collaborative clinical sites (Johns Hopkins University, University of 
Illinois at Chicago, University of Chicago and Yale University). 
2.3 
Study Design 
Randomization will be stratified by age (age 18-29, 30-40) and presence of fibroids. The 
randomization scheme will be coordinated through the data coordination center (DCC). 
2.4 
Treatment 
The 36 women will be randomized to one of the following groups: 
1. EGCG daily alone. 
2. EGCG daily with clomiphene citrate 100mg for 5 days. 
3. EGCG daily with letrozole 5mg for 5 days. 
 
The purpose of studying EGCG in combination with clomiphene citrate or letrozole is to assess 
the safety of using them together prior to the initiation of the FRIEND study. It is expected that 
EGCG will decrease fibroid size and decrease humoral activity leading to improved quality of 
endometrium for implantation. Clomiphene citrate and letrozole are being used for ovulation 
stimulation as treatment for unexplained infertility. In view of the possibility of interaction and 
change in toxicity when both are used together for FRIEND study, it was suggested by our 
pharmacology reviewer to include EGCG with the addition of clomiphene citrate and letrozole 
for the safety study.  
 
The initial screening visit will include EGCG levels, liver function, folate and estrogen levels. A 
genetics sample collection, urine pregnancy test and  pelvic ultrasound will also be performed after 
informed consent.  Patient will be given the EGCG (Green Tea extract) to start after the screening 
visit.  Patients will be counseled on dietary restrictions while on EGCG. 


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Visit 1 will occur on menstrual cycle day 3 ± 2 days.  EGCG levels over 8 hours, liver function, 
and urine pregnancy testing will occur at this visit. Patients will be assigned into their groups and 
provided with their respective treatments at this visit.  
 
Patient will return between days 8-10 of the cycle for Visit 2.  EGCG levels over 8 hours, liver 
function, estrogen, and urine pregnancy testing will occur at this visit.   
 
The patient will return for Visit 3 between days 14-16 for a pelvic ultrasound evaluation of 
endometrial thickness and ovarian characteristics. 
 
The final study visit (Visit 4) will be approximately 4 weeks after initiation of the study treatment 
and will involve EGCG levels, liver function, folate, and urine pregnancy test and pill counts.   
 
The 4 lab panels (screening, Visits 1, 2, and 4) will include EGCG and metabolite analyses, liver 
panel (AST, ALT, total bilirubin, ALP) and estrogen levels, and a urine pregnancy test.  The EGCG 
analyses at visits 1 and 2 will include testing over 8 hours. 
2.5 
Primary Outcome Parameter 
The primary outcome parameter will be differences in pharmacokinetic parameters of EGCG and 
the major metabolites between the 3 groups. 
 
2.6 
Secondary Outcome Parameters 
The secondary outcome parameters will include: 
• Changes in liver function between the 3 groups. 
• Changes in estrogen levels (E2) between the 3 groups. 
• Changes in endometrial thickness and ovarian characteristics between the 3 groups. 
• Change in the pharmacokinetic parameters of EGCG and metabolites within each 
group.  
• Difference in serum folate levels among wildtype MTHFR, MTHFR (C677T), and 
MTHFR (A1298C) patients.   
2.7 
Statistical Analysis  
Since the number of patients for this study is minimal and multiple factors are of concern, 
descriptive statistics will be used, and the study is expected to be under powered to perform any 
formal statistical inference. The number, mean, standard deviation, median, interquartile range of 
the level of the pharmacokinetic parameters of EGCG and 2 of the major metabolites at different 
time points and the difference from screening to Visit 1, Visit 2 or Visit 4, and the changes in liver 
function, estrogen levels, endometrial thickness, and follicular measurements will be presented for 
the three treatment groups, and then stratified by age group and/or the presence or absence of 
uterine fibroid. For comparison, a two-way ANOVA will be used to compare the effects of the 
three treatments and the presence of fibroids on the above outcome parameters. With a sample size 
of 36 patients for the three treatment groups, which includes 18 subjects with uterine fibroids and 
18 without uterine fibroids, with an alpha of 0.05, the power of the study would be 0.44 and 0.85 
for a medium (0.25) or large (0.4) effect size, respectively. There are insufficient preliminary data 


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in the literature to support or not support the reasonableness of these effect sizes. For the 
comparison of serum folate levels among wildtype MTHFR, MTHFR (C677T), and MTHFR 
(A1298C) patients, ANOVA (unadjusted) and multivariate linear regression will be used.   
2.8 
Anticipated Time of Completion 
We estimate the study will take approximately 6-12 months to complete.  Participants will be 
recruited from each of the 4 participating FRIEND sites.  
2.9 
Regulatory Compliance  
The DCC is working with The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD), the three participating FRIEND institutions, and the single 
Institutional Review Board (Johns Hopkins University) to ensure that clinical study data and 
regulatory requirements are met regarding the Food and Drug Administration (FDA) code for 
federal regulations.  This trial is registered on http://www.clinicaltrials.gov (NCT04177693). 


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3 Background and Significance 
3.1 
Overview 
Uterine leiomyomas (fibroids) affect 30-50% of reproductive-age women and are a significant 
cause of infertility. Intramural and submucosal fibroids reduce the likelihood of pregnancy 
(RR=0.3-0.7) compared to unaffected women.  Surgical removal of fibroids can restore fertility; 
however, recurrence rates are high, and benefits are often temporary.  Importantly, serious 
postoperative consequences such as adhesions can adversely affect a woman’s fertility and health 
in general.  Hormonal therapies that induce medical menopause can be used to reduce fibroid 
size, but these therapies also prevent pregnancy.  There is a critical need for effective, non-
hormonal, non-surgical fertility treatment options for women with fibroids that may distort the 
uterine cavity. Our long-term goal is to develop novel non-hormonal treatments for uterine 
fibroids. Green Tea leaves contain polyphenols and catechins, such as epigallocatechin gallate 
(EGCG). Studies from our group and others have shown that EGCG is the most abundant and 
active compound responsible for effects of Green Tea extracts.  Notably, EGCG can be taken 
during pregnancy and there are no known teratogenic effects. EGCG polyphenols inhibit key 
pathways of tumor growth by modulating signaling pathways involved in cell proliferation, 
transformation, inflammation, apoptosis, metastasis and invasion. Prior to initiating a 
randomized, double-blind, multi-center, prospective, clinical trial of EGCG versus placebo in 
women with uterine fibroids to evaluate birth rate a pharmacokinetic and hepatic safety analysis 
must be conducted. The pharmacokinetics and hepatic safety of EGCG with clomiphene citrate 
and letrozole are unknown. A 3-arm study will be conducted in women with and without fibroids 
to allow comparisons between these groups. The results of this study will be used to confirm 
hepatic safety for the larger multi-center FRIEND study. 
  
3.2 
EGCG (Green Tea extract) and Uterine fibroids  
Green Tea leaves contain polyphenols such as catechins or flavin-3-ols that include epicatechin 
(EC), epigallocatechin (EGC), epigallocatechin gallate (EGCG), and alkaloids. Catechins are the 
major components of tea phenols and constitute about 30-42% of the dry weight of Green Tea. 
Studies have shown that the EGCG catechin is the most abundant and active compound responsible 
for most of Green Tea’s role in promoting good health and accounts for the favorable research 
result cited in the medical literature with the use of Green Tea extracts. EGCG have the highest 
level of polyphenols and makes it the major anti-oxidant agent in Green Tea. A study conducted 
by the United States Department of Agriculture reported that Green Tea has potent anti-neoplastic 
effects against a wide range of human tumor cells (4) EGCG polyphenol have been shown to 
inhibit key pathways of tumor growth. EGCG appears to block each stage of tumorigenesis by 
modulating signaling pathways involved in cell proliferation, transformation, inflammation, 
apoptosis, oxidative stress and invasion (4). Studies by Al-Hendy et al demonstrated increasing 
levels of Catechol-O-methyl transferase (COMT) in uterine leiomyoma compared to adjacent 
myometrium and described its important role in fibroid pathogenesis (5) Beside various useful 
antioxidant and anti-inflammatory effects, EGCG exerts a potent COMT inhibitor effect which 
also contribute to effective anti-fibroid action (2, 5). Additionally, published work by Dr. Al-
Hendy also demonstrated the utility of EGCG for inhibiting fibroid tumor formation in vivo in 
nude mouse model (3). Dr.  Al-Hendy’s research team (a member of this consortium) has reported 
that EGCG acting as anti-uterine fibroid agent through the modulation of multiple signal 


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transduction pathways.  The group demonstrated that EGCG works on the gene level, to inhibit 
the proliferation of Human fibroid cells and induces apoptosis (2). This study also showed an 
impressive 14-fold increase in the expression of the BMP2 gene in EGCG-treated human fibroid 
cells than in the untreated control (2). That major increase in the secretion of BMP2 from fibroids 
by EGCG treatment is likely be able to overcome the fibroid-induced endometrial BMP-resistance 
through increased binding to the BMP receptors which will lead to improvement in the 
decidualization of the endometrium and subsequently enhancement of implantation, fertility and 
pregnancy outcomes.  Furthermore, studies also demonstrated that EGCG significantly decreased 
TGF-β3 production by human fibroid cells. As TGF-β3 is the main cytokine responsible for 
endometrial BMP-resistance, such effect of EGCG would be expected to lead to improved 
endometrial receptivity. 
3.3 
EGCG Clinical trial in women with symptomatic uterine fibroids 
To  translate  the  positive  EGCG  anti-fibroid  preclinical  findings  in  human  fibroid  cell  lines  
and  fibroid  animal  models, the efficacy and safety of EGCG on uterine fibroids burden and 
quality of life in women with symptomatic uterine  fibroids  were  evaluated in  an  NIH-funded  
double-blinded,  placebo-controlled  randomized  clinical  trial(NCT 01311869) (1). A total of 39 
reproductive-age women (age 18–50 years, day 3 serum follicle-stimulating hormone  <12  IU/L)  
with  symptomatic  uterine  fibroids  were  recruited  for  this  study.  All subjects had at least one 
fibroid lesion 2 cm3 or larger in volume, as confirmed by transvaginal or transabdominal 
ultrasonography. The subjects were randomized to oral daily treatment with either 800 mg of 
decaffeinated EGCG  or placebo  (800  mg  of  brown  rice)  for  4  months,  and  uterine  fibroid  
volumes  were  measured  at  the  end  of  study,  also  by  transvaginal or transabdominal  
ultrasonography.  The  fibroid-specific  symptom  severity  and  HRQL  of  these  uterine  fibroid  
patients  were  scored at each monthly visit, using the symptom severity and quality-of-life   
questionnaires   (1).   Of   the   final   39   women   recruited for the study, 33 completed all five 
visits of the study. In  the  placebo  group  (n  =  11),  fibroid  volume  increased  (24.3%) over the 
study period; however, patients randomized to  green  tea  extract  treatment  (n  =  22)  showed  
significant  reduction (32.6%, P = 0.0001) in total uterine fibroids volume.  In  addition,  EGCG  
treatment  significantly  reduced  fibroid-specific  symptom  severity  (32.4%,  P =  0.0001)  and  
induced significant improvement in HRQL (18.53%, P = 0.01) compared   to   the   placebo   group.   
Anemia   also   significantly  improved  by  0.7  g/dL  (P =  0.02)  in  the  EGCG  treatment   group,   
while   average   blood   loss   significantly decreased (P =  0.001).  No adverse effects, endometrial 
hyperplasia, or other endometrial pathology were observed in either group (1). 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1. Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 2: Lab visit 
Screening, Consent, Enrollment 
Visit 1: Labs, randomization, clomiphene 
citrate/letrozole dispensing,  
Visit 3: Pelvic ultrasound 
Visit 4: Lab panel and return 
unused medications 


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4 Objectives 
4.1 
Primary Aim 
Our goal is to assess the pharmacokinetics and hepatic safety of EGCG in women with and without 
uterine fibroids. 
4.2 
Secondary Aim 
Not applicable. 
4.3 
Treatment Design, Study Population, and Study Summary 
4.3.1 Treatment Design 
This will be a pharmacokinetic trial involving 36 healthy adult female subjects. There will be 18 
subjects with uterine fibroids and 18 without uterine fibroids.  The randomization scheme will be 
coordinated through the DCC and the randomization will be stratified for age groups 18-29 and 
30-40 and presence of fibroids.  The population will consist of 36 women with or without uterine 
fibroids, age ≥18 to ≤40 years (at time of consent). 
 
The appropriate study candidates will be recruited from the clinics of the 4 FRIEND Collaborative 
sites after obtaining informed written consent from the female subjects.  Recruited participants 
will meet the inclusion and exclusion criteria detailed below.  Monitoring of this trial at all sites 
will be conducted by the Yale DCC.   
4.3.2 Study Population 
Thirty-six (36) patients will be equally randomized via computer-generated randomization 
schedule to receive:  
1. Two capsules of decaffeinated Green Tea extract (close to 800mg EGCG)  taken orally on 
a daily basis for up to 2 months   
2. Two capsules of decaffeinated Green Tea extract taken orally on a daily basis for up to 2 
months with clomiphene citrate 100mg for 5 days  
3. Two capsules) of decaffeinated Green Tea extract taken orally on a daily basis for up to 2 
months with letrozole 5mg for 5 days. 
4.3.3 Study Summary   
 
Recruitment and Prescreening: see Section 5 descriptions following. 
 
 
 
-30 
 
 
 
 
 
0 
 
 
 
 
 
+30 
 
 
 
Menstrual Cycle 1 
Menstrual Cycle 2 
Day 30-
35 visit 
Screening 
Day 1-5 
visit 
Day 14-
16 visit 
Day 8-
10 visit 


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Screening visit (anytime in cycle 1):  
1. Obtain informed, signed consent. 
2. Complete medical/gynecological/menstrual history and physical exam of female study 
participant.  
• Vital signs, height, weight, hip and abdominal circumference, BMI  
• Pap smear if necessary per current ACOG time-frame guidelines 
• Standard pelvic and breast exam conducted by physician or within past 12 months 
 
3. Perform radiological exams. 
• Pelvic ultrasound measuring uterine and ovarian characteristics or within past 3 months 
 
4. Laboratory tests: EGCG and metabolites, liver function, folate, estrogen levels, genetics 
    sample collection and urine pregnancy test. 
 
5. Dispense Green Tea extract and educate on dietary restrictions while taking Green Tea extract 
    and with the importance of taking food. All patients to start Green Tea extract at this visit.  
 
6. Contraception education. Patients will be counseled to use non-hormonal double-barrier 
    method: a male/female condom plus spermicidal agents, cervical cap, diaphragm or sponge.  
 
7. Concomitant medication collection. 
 
Visit 1 (Day 1-5): 
Patient will be seen on menstrual cycle day 3 ± 2 days for clomiphene citrate/letrozole initiation 
visit  
 
1. Vital signs and weight. 
2. Laboratory tests: EGCG levels over 8 hours (0.5,1,2,4,6,8),liver function, folate, estrogen 
level, and urine pregnancy testing. 
3. Concomitant medication collection and pill counts of EGCG. 
4. Randomization and dispensation of clomiphene citrate/letrozole.  
5. Contraception education. Patients will be counseled to use non-hormonal double-barrier 
method: a male/female condom plus spermicidal agents, cervical cap, diaphragm or 
sponge. 
 
Visit 2 (day 8-10): 
Patient will return several days after final clomiphene citrate/letrozole administration 
 
1. Vital signs and weight. 
2. Laboratory tests: EGCG levels over 8 hours (0.5,1,2,4,6,8), liver function, folate, estrogen 
level and urine pregnancy testing. 


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3. Concomitant medication collection and pill counts of EGCG and clomiphene citrate or 
letrozole as appropriate. 
4. Contraception education. Patients will be counseled to use non-hormonal double-barrier 
method: a male/female condom plus spermicidal agents, cervical cap, diaphragm or 
sponge. 
Visit 3 (day 14-16): 
 
1. Pelvic ultrasound via a transvaginal probe  or transabdominal transducer  evaluation of 
endometrial thickness and ovarian characteristics. 
 
Visit 4 (day 30-35): 
Patient will return for final study visit. 
 
 
1. Vital signs and weight, hip and abdominal circumference, BMI 
2. Laboratory tests: EGCG and metabolites, liver function, estrogen level, folate, and urine 
    pregnancy 
    test. 
3. Concomitant medication collection. Return unused medications and pill counts of 
     EGCG. 
 
Future Studies: One tube of blood will be collected at each visit to be stored for future analyses 
related to this study.   
4.3.4 Inclusion Criteria 
1. Healthy women ≥18 to ≤40 years of age with or without uterine fibroids 
2. Must use a double-barrier method for contraception 
4.3.5 Exclusion Criteria 
1. Subjects using Green Tea/EGCG within 2 weeks prior to study enrollment. Matcha 
(Japanese green tea), maca powder, green tea beverages and all other forms of green tea 
require a 2-week wash-out. Patients with a detectable EGCG level at the screening visit 
will be excluded. 
2. Known liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5 
mg/dL).   
3. History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks at 
one time).   
4. Subject using hormonal contraceptives: 3-month wash-out is required for all oral or cyclic 
progestins, GnRH agonists/ antagonists, gonadotropins, injectable contraceptives, oral 
contraceptives, contraceptive implants and previous use of clomiphene and letrozole. 
5. Subjects who are pregnant or breastfeeding 
6. Known hypersensitivity to the study drugs 
7. Any chronic disease 


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4.3.6 Study Termination Criteria 
Any serious adverse event considered to be related to study treatment (see section 7.3.2.1 and 
7.3.5) will be considered reason for termination of assigned intervention; participant will be 
followed up for cycle outcome and will contribute research data towards intent-to-treat analyses. 
This includes allergic reactions and liver toxicity. Women with elevation in liver function test with 
3 times the upper limit of normal will be terminated from the study and will return to site for repeat 
testing every 48 hours until resolution. 
 
 
All reports of liver toxicity will be reviewed by the DSMB (see section 7.3.4). If three (3) or 
more trial participants developed active liver disease, as defined below, this would be an 
unexpected significant risk requiring trial termination: 
  
1. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≥ 8 x upper limit 
of normal (ULN) 
2. ALT or AST ≥ 3 x ULN and total bilirubin (TBL) > 2 x ULN or International 
Normalized Ratio (INR) > 1.5 or 
3. ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
4.4 
Risk/Benefit Assessment 
4.4.1 Possible Benefits 
No direct benefits to participants.   
4.4.2 Possible risks/discomforts 
Blood draws: Discomfort, bruising, infection or bleeding at the needle puncture site 
Pelvic ultrasound: abdominal or pelvic discomfort 
EGCG: Gastrointestinal upset; rare liver toxicity. The literature supports a potential relationship 
between high-dose Green Tea extract consumption and transient changes in serum liver enzymes.  
Rare (<5%) and transient liver transaminase elevations have been documented. Hepatotoxicity 
tended to show a temporal relationship between Green Tea extract consumption and effect onset 
with Green Tea extract-induced toxicity mainly manifesting after roughly 3-4 months of 
consumption. Daily intake of 1315 mg of Green Tea catechins containing 843 mg EGCG poses 
mainly mild, transient hepatic adverse effects. The incidence and severity of hepatotoxicity 
increased when Green Tea extract or EGCG was administered under fasted conditions, while 
exposure to Green Tea under fed conditions appears to alleviate such risk. 
Clomiphene Citrate: Visual changes (such as blurring of vision, double vision, floaters), abdominal 
pain, nausea, vomiting, constipation, mood changes, headache, hot flashes, fatigue, abnormal 
endometrial thickening, multiple pregnancies, formation of ovarian cyst, breast discomfort, 
abnormal uterine bleeding, and bloating 
Letrozole: Fatigue, dizziness, nausea, hot flashes, arthritis pain in your joints, back pain, increased 
cholesterol levels, formation of ovarian cysts, multiple pregnancies 


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Other risks: There is also the risk of loss of confidentiality. Filling out the questionnaires may make 
the subjects uncomfortable or feel some anxiety. There is a risk that information about the subject 
may become known to people outside of this study. 
As this is a NIH (NICHD) funded study, your study information is protected by a Certificate of 
Confidentiality. This Certificate allows us, in some cases, to refuse to give out your information 
even if requested using legal means. 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of 
possible harm to yourself or others, or if you need medical help. 
Disclosures that you consent to in this document are not protected. This includes putting research 
data in the medical record or sharing research data for this study or future research. Disclosures 
that you make yourself are also not protected. 
 
 
 
 
 


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5 Study Design 
 
 
 
 
 
 
 
 
 
 
5.1 
Type of Design 
This will be a randomized, open-label, multi-center, pharmacokinetics and hepatic safety trial of 
EGCG with 36 total patients in 3 treatment arms. The randomization scheme will be coordinated 
through the DCC and the randomization will be stratified for age groups 18-29 and 30-40 and 
presence of uterine fibroids.   
5.2 
Rationale for Design 
The pharmacokinetics and hepatic safety of EGCG with clomiphene citrate and letrozole are 
unknown.  A 3-arm study will be conducted in women with and without fibroids to allow 
comparisons between these groups.  The results of this study will be used to confirm hepatic 
safety for the larger multi-center FRIEND study. The pharmacokinetics and hepatic safety of 
EGCG with clomiphene citrate and letrozole are unknown. A 3-arm study will be conducted in 
women with and without fibroids to allow comparisons between these groups. The results of this 
study will be used to confirm hepatic safety for the larger multi-center FRIEND study. 
 
5.3 
Recruitment 
Hospital/Local Health Care Referrals 
Subjects will be recruited at each site from individual practice(s) as well as faculty/resident clinics.   
 
Local Advertisements 
Advertisements will be placed in local newspapers and will be continued on a regular basis if 
response is good.   
 
IRB Approval  
It is expressly acknowledged that all informational material that could be construed to be 
advertising will be approved by the appropriate IRB prior to dissemination.  
5.4 
Informed Consent 
Once subjects have been identified, they will be referred to the site clinical coordinator or his/her 
designee.  The clinical protocol will be explained to potential subjects by the physician investigator 
or the coordinator depending on the clinical circumstances.  Inclusion and exclusion criteria will 
be reviewed.  After the study has been completely explained, they will be given the informed 
consent documents to review. Some individuals may wish to complete the informed consent 
process at the time of this discussion.  In these cases, the informed consent documents will be 
signed once all questions are resolved.  In other cases, the subjects may wish to take the consent 
forms home for further consideration.  In these cases, the coordinator will set up a tentative 
timeframe to be back in touch with the subjects.  The consents can be signed either with the 
coordinator or with a physician once all questions have been answered to the satisfaction of the 
potential patient.  A signed informed consent document, approved by the IRB at the study site, 
will be confirmed on all subjects prior to the baseline evaluation.  In order to be eligible for 
enrollment and randomization, all inclusion and exclusion criteria must be met.   


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5.5 
Randomization/Treatment Initiation  
Thirty-six (36) patients will be equally randomized via computer-generated randomization 
schedule to receive: 1) 800  mg  of  decaffeinated  EGCG  taken  orally  on  a  daily  basis with 
food  for  up  to  2  months;  2) 800  mg  of  decaffeinated  EGCG  taken  orally  on  a  daily  basis 
with food for  up  to  2  months with clomiphene citrate 100mg for 5 days; 3) 800  mg  of  
decaffeinated  EGCG  taken  orally  on  a  daily  basis with food  for  up  to  2  months with 
letrozole 5mg for 5 days. 
 
Treatment assignments will be randomized for age groups and presence of fibroids by a varying-
block-size design. The DCC statisticians will generate the randomization scheme for the study.   
5.6 
Physical Exam  
A physical exam with standard pelvic and breast exam will be performed on all patients by a study 
physician. Height, weight and waist and hip circumferences will be recorded to the nearest 0.1 cm, 
0.1 kg and 1 cm, respectively. Waist will be measured at the level of the umbilicus and hip 
circumference will be measured at the widest diameter. Participants will be weighed while dressed 
in light clothing, without shoes. Weight will be collected at each cycle initiation visit; however, 
height, waist and hip circumferences are only collected at the screening and end of study drug 
visits. Blood pressure will be determined in the right arm in the sitting position.  Large cuff will 
be used as necessary. Blood pressure will be assessed at each visit. Elevated blood pressures 
(≥160/100) will be repeated following acclimation to the study environment. All patients aged 21 
and older should have had a normal Pap smear in accordance with current ACOG guidelines. If 
not, one should be performed at the screening exam. Patients with cytological abnormalities will 
need to have these resolved prior to study entry.   
5.7 
Transvaginal Ultrasound Exam 
An ultrasound exam will be performed with a transvaginal probe. For subjects who cannot tolerate  
a transvaginal probe,  a transabdominal ultrasound evaluation will be performed.  The following 
measures will be obtained at screening: uterine dimensions, leiomyoma presence and size, other 
uterine abnormalities, endometrial thickness, ovarian size in three dimensions, the size of the 
largest ovarian follicle, follicle count in the largest plane and ovarian morphology. Ovarian size is 
determined by measuring the largest plane of the ovary in two dimensions and then turning the 
vaginal probe 90 degrees and obtaining a third measurement.  Endometrial thickness is the largest 
anterior-posterior measurement of the endometrium in the sagittal plane.  Ovarian volume is 
determined by the formula for a prolate ellipsoid (length x width x height x π/6)(Pache, Hop et al. 
1991).  If the patient has had no prior test of tubal patency, this may be the desired time to perform 
a sonohysterogram to determine tubal patency. Only endometrial thickness and ovarian follicular 
measurements will be measured at visit 2. 
5.8 
Laboratory Exam  
Lab tests are found in Table 1 below. Both local and central labs will be utilized.  The EGCG and 
metabolite analyses will be conducted in the lab of Dr. Jeremy Johnson at the University of Illinois.  
Dr. Jeremy Johnson is the pharmacokinetics core leader for UICentre, the academic drug discovery 
initiative at the University of Illinois at Chicago.     
Table 1. Screening labs of study women 
LOCAL LABORATORY BLOOD TESTS 
CENTRAL LABORATORY BLOOD TESTS 


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Hormones 
Liver 
EGCG and metabolites 
Estrogen 
Total Bilirubin 
EGCG 
 
ALT/AST 
EGC 
 
Alkaline Phosphatase 
ECG 
 
 
4′-O-methyl-epigallocatechin 
 
 
Genetic polymorphisms related to folate metabolism 
 
5.9 
Schedule of Evaluations 
 
Study procedure 
Cycle 1 
 
Cycle 2 
  
Screening 
Visit 1 (Day 1 
-5) 
Visit 2 (Day 8 
-10) 
Visit 3 (Day 
14-16) 
Visit 4 (Day 
30 - 35) 
Informed consent 
X 
  
  
 
  
Inclusion/exclusion 
criteria 
X 
  
  
 
  
Demographic information 
X 
  
  
 
  
Medical history 
X 
  
  
 
  
Concomitant medications 
X 
X 
X 
 
X 
Gynecological history 
X 
  
  
 
  
Menstrual history 
X 
  
  
 
  
Vital signs and weight 
X 
X 
X 
 
X 
Height 
X 
  
  
 
  
Hip and abdominal 
circumference 
X 
  
  
 
 X 
Physical examination 
X 
  
  
 
  
Pap smear 
X* 
  
  
 
  
Pelvic and breast exam 
X** 
  
  
 
  
Genetics sample, 
laboratory test 
X 
 
 
 
 
 Pelvic ultrasound 
Xǂ 
  
 
X 
  
EGCG levels and 
metabolites, laboratory 
test 
X 
X 
X 
 
X 
Liver function, laboratory 
test 
X 
X 
X 
 
X 
Folate, laboratory test 
X 
  
  
 
X 
Estrogen levels, laboratory 
test 
X 
X  
X 
 
X  
Contraceptive counseling 
X 
X 
X 
 
  
Dispense EGCG 
X 
  
  
 
  
Pill counts of EGCG 
  
X 
X 
 
X 
Randomization and 
dispensation of 
clomiphene citrate or 
letrozole 
  
X 
  
 
  


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Pill counts of clomiphene 
citrate and letrozole 
  
  
X 
 
  
Urine pregnancy test 
X 
X 
X 
 
X 
*If necessary per ACOG guidelines 
 
 
 
 
**if not done within past 12 months 
ǂ if not done within past 3 months 
 
 
 
 
6 Data Analysis 
 
 
 
 
 
 
 
 
 
 
6.1 
Data Analysis 
Data will be collected prospectively by designated research personnel at each study site, supervised 
by the site PI.  Individual data will be entered into a web-based data management system created 
by the DCC, using only a study ID number. 
6.2 
Primary Outcome Measurements 
The primary outcome parameter will be differences in pharmacokinetic parameters of EGCG and 
2 of the major metabolites between the 3 treatment groups. 
6.3 
Secondary Outcome Measurements 
The secondary outcome parameters will include: 
• Changes in liver function between the 3 groups. 
• Changes in estrogen levels (E2) between the 3 groups. 
• Changes in endometrial thickness and ovarian characteristics between the 3 groups. 
• Change in the pharmacokinetic parameters of EGCG and metabolites within each 
group.  
6.4 
Difference in serum folate levels among wildtype MTHFR, MTHFR (C677T), and 
MTHFR (A1298C) patients.  Statistical Analyses 
Since the number of patients for this study is minimal and multiple factors are of concern, 
descriptive statistics will be used, and the study is expected to be under powered to perform any 
formal statistical inference. The number, mean, standard deviation, median, interquartile range of 
the level of the pharmacokinetic parameters of EGCG and 2 of the major metabolites at different 
time points and the difference from screening to Visit 1 or Visit 2 or Visit 4, and the changes in 
liver function, hormone levels, endometrial thickness and follicular measurements  will be 
presented for the three treatment groups, and then stratified by age group and/or the presence or 
absence of uterine fibroid. Patients with a detectable EGCG level at the screening visit will be 
excluded. For comparison, a two-way ANOVA will be used to compare the effects of the three 
treatments and the presence of fibroids on the above outcome parameters. With a sample size of 
36 patients for the three treatment groups, and 18 subjects with uterine fibroids and 18 without 
uterine fibroids, with an alpha of 0.05, the power of the study would be 0.44 and 0.85 for a medium 
(0.25) or large (0.4) effect size, respectively. There are insufficient preliminary data in the literature 
to support or not support the reasonableness of these effect sizes. For the comparison of serum 
folate levels among wildtype MTHFR, MTHFR (C677T), and MTHFR (A1298C) patients, 
ANOVA (unadjusted) and multivariate linear regression will be used.   
 
 


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7 Technical Aspects 
7.1 
Study Agent Preparation  
We propose to purchase EGCG from Beehive Botanicals.  Beehive Botanicals, Inc. has the 
capacity to formulate and manufacture vegetable capsules containing  200mg of Green Tea extract. 
Beehive Botanicals is NSF certified as a cGMP facility. Per Beehive SOPs, all incoming material 
is third party tested for identity and potency to confirm compliance with Certificates of 
Authentication (COA).  The material per the COA has a shelf life of 3 years in correct holding 
conditions.  Clomiphene citrate and letrozole will be obtained through generic pharmaceutical 
companies.   
 
The study coordinator at each site will be responsible for distributing the supply drug kits, verifying 
pill/vial counts, and determining that there are adequate medication supplies for existing patients 
and new patients to be randomized.  The PI will ultimately be accountable for administration and 
accountability of the medication used in this study. 
7.2 
Concomitant Medications 
An inquiry into concomitant medications will be made at the screening visit as well as each 
subsequent visit.   
7.3 
Adverse Experience Reporting 
7.3.1 Adverse Events 
7.3.1.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
7.3.1.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
7.3.2 Classification of an Adverse Event 
7.3.2.1 Severity of Event 
The following guidelines will be used to describe severity.  
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  


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• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
7.3.2.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect.  
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
7.3.2.3 Expectedness 
The study PI will be responsible for determining whether an AE is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information listed in the package insert, or in the consent form. 
 


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7.3.3 Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an AE or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Site personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 
7.3.4 Adverse Event Reporting 
Adverse events deemed non-serious will be recorded throughout study participation from the start 
of study drug through one week after the last dose of study medication and reported to the DCC.  
Non-serious adverse events will be reported to the DSMB quarterly.  
 
Supervising Institutional Review Boards (IRBs) will be notified by local investigators of adverse 
events occurring at their institution according to their reporting requirements. Investigators also 
will notify the medical monitor and DCC within 24 hours after knowledge of a death or of an event 
that is life-threatening, that results in hospitalization or prolongation of hospitalization, or that 
involves a persistent or significant disability or incapacity. Study staff will collect information 
regarding the treatment provided, outcome, and presumed relationship to study, and a narrative 
description of the event. The study staff will provide updated reports to the DCC as new 
information becomes available. DCC personnel will review the data and query the clinical sites 
for clarification and additional information. In addition, the DCC will provide the information to 
the Data and Safety Monitoring Board (DSMB) as part of their safety review. 
 
The DCC will provide study-wide summary statistics (not filtered by treatment group) of adverse 
events to the single IRB annually and upon request to all sites on an annual basis for submission 
to their IRBs. 


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7.3.5 Serious Adverse Event Reporting 
All serious adverse events (SAEs) that occur from randomization through thirty days after the 
last dose of study medication must be reported or if the patient is pregnant, 6 weeks following 
delivery.  
 
The site PI will report the SAE by completing and signing the Serious Adverse Event Report 
Form [available in the “Study Forms” section of the FRIEND website], and then emailing the 
document in PDF format to dcc.c2s2@mailman.yale.edu. Subjects will be identified by study 
number only.  No other identifying information will be included on the form. The site PI must 
determine and record on the SAE form whether the SAE is unanticipated or anticipated, and if it 
is related, possibly related, or unrelated to participation in the research. The site coordinator will 
enter the information into the DCC database. The DCC will inform the sIRB within 24 hours of 
after knowledge of a SAE. 
 
The Safety Surveillance team, consisting of the DCC and lead PI of the protocol, will analyze the 
SAE to determine if it meets the criteria listed in the OHRP 45CFR46 and/or FDA 21CFR312.32 
& 3.14.80. 
 
These determinations will dictate timeframes for sites’ submission to the DCC, and the DCC’s 
submission to the DSMB (Table 2): 
 
Table 2. Types of Serious Adverse Events and their reporting requirements 
TYPE 
SITE 
DCC 
Unanticipated and 
related/possibly related SAE, 
fatal or life-threatening 
Report to DCC within 1 
business day of discovery 
 
Notify DSMB by end of next 
business day of receiving site 
report 
Other unanticipated and 
related/possibly related SAE 
Report to DCC within 1 
business day of discovery 
Notify DSMB 5 business 
days of receiving site report 
Anticipated and 
related/possibly related SAE 
Report to DCC within 5 
business days of discovery 
Notify DSMB 5 business 
days of receiving site report 
Unrelated SAE (anticipated or 
unanticipated 
Report to DCC within 10 
business days (no more than 
3 weeks) of discovery 
Notify DSMB within 10 
business days (no more than 
3 weeks) of receiving site 
report 
 
Upon receiving notification of an SAE, the DSMB will review it via a closed-session email or 
conference-call discussion.  The DSMB will send a report to the DCC within two weeks; reports 
for life-threatening SAEs will be submitted in one week. The DSMB report will include: statement 
indicating what related information the DSMB reviewed; the review date; the DSMB’s assessment 
of the information reviewed; and the DSMB’s recommendation, if any, for the DCC.   
The DCC will then record the DSMB report and disburse.  The DCC will forward reportable events 
to all FRIEND investigators and NIHCD. The Protocol PI will evaluate the frequency and severity 
of the SAEs and determine if modifications to the protocol and consent form are required. Site PIs 
will report the SAE to their site IRB according to local IRB requirements. For more information, 
please see the FRIEND/DSMB Communication Procedure.   


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7.4 
Unanticipated Problems 
7.4.1 Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review Board 
(IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.4.2 Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP 
report will include the following information: 
 
• Protocol identifying information: protocol title, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
The following UPs require prompt reporting: 
• Breaches of confidentiality involving risks; 
• Data and Safety Monitoring Board (DSMB) reports an interim analysis altering the 
risk/benefit profile by identification of increased risk; 
• Protocol deviations, violations, or other accidental or unintentional changes to the protocol 
or procedures involving risks or with the potential to recur; 
• Unapproved changes made to the research to eliminate an apparent immediate hazard to a 
subject; 
• Other problem or finding (e.g., loss of study data or forms) that an investigator or research 
staff member believes could influence the safe conduct of the research. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• UPs that are serious adverse events (SAEs) or require prompt reporting will be reported to 
the IRB and to the DCC/study sponsor according to the timeline laid out for other SAEs in 
Table 2. 


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Any other UP will be reported to the IRB and to the DCC/study sponsor at time of continuing 
review of the investigator becoming aware of the problem.  
 
7.5 
Data Collection and Management (including quality assurance/compliance 
measures) 
7.5.1 Data Entry and Forms 
Case Report Forms (CRFs) will be developed as the protocol is developed. All CRFs will be paper 
forms. Site coordinators will be responsible for timely CRF completion and data entry of the CRFs 
into the designated electronic data entry (EDC) system. CRF completion should occur at the time 
of the visit. Lab results sections should be completed within two weeks of results. Each site is 
asked to ensure that all data is entered into the EDC system within three weeks of the study visit. 
7.5.2 Data Security 
For security purposes, PHI, including patient names and addresses, will be locked and secured at 
the participating sites, and data will be linked through a unique identification number, which will 
be assigned after a patient is screened or enrolled. Access will be limited to authorized individuals 
(21 CFR 11.10(d)).     
7.5.3 Data Quality Control 
The site PI will be responsible for ensuring that study related tests are performed by competent 
personnel.  The criteria for determination of competency may vary between sites in the study. 
Attempts will be made to standardize protocols whenever possible to minimize inter-site variation. 
7.6 
Study Monitoring 
A monitoring plan that satisfies the Guideline for Monitoring of Clinical Investigations of the 
National Cancer Institute will be used. A Project Manager from the DCC will lead this effort, and 
report findings to the DCC PI. The Project Manager will have full knowledge of the study protocol, 
Manuals of Procedures, and is familiar with the database system and is trained to review patient 
charts. The Project Manager will be responsible for training and supervising other personnel.  
Once personnel at participating site are trained to recruit patients, the Project Manager will be sent 
to the site to help initiate the study according to the study protocol, and to ensure that the clinical 
site meets the scientific, clinical, and regulatory requirements. For example, the Project Manager 
will review all signed and dated forms required by the FDA (such as financial disclosure forms), 
the curriculum vitae and certifications of the investigators and personnel, CRF training, and the 
written IRB approval of the protocol and consent form.   
The on-site monitor will return to the clinical site after a defined number of patients are recruited 
(can be as early as the recruitment of the 2nd patient) or a certain time period has passed, depending 
on the duration of the protocol execution. The schedule of visits will be discussed and agreed upon 
by the Steering Committee and we anticipate that the Project Manager will visit each participating 
site at least once. 
During the site visit, the clinical sites should provide to the monitor a space and access to all 
relevant records including medical records and regulatory binders, and there would be immediate 
verbal feedback provided to the site after original source documents are compared to entries in the 


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CRF. The clinical sites must agree to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. The on-site monitor will conduct an 
audit of a random sample of entered information against the source documents, a review of all 
regulatory documents, a review of all informed consents, and a review of all pharmacy logs. The 
clinical site PI and coordinator should be available to meet the monitor during the visit. The 
monitor will review electronic data from all sites, providing a method for identifying systematic 
errors or problems.  
To assure Good Clinical/Laboratory Practice, the monitor will control adherence to the 
protocol at the clinical sites and evaluate the competence of the personnel at the clinical sites 
including the ability to obtain written informed consents and record data correctly. The monitor 
will inform the DCC PI, the Steering Committee, and NICHD regarding problems relating to 
facilities, technical equipment, or medical staff. A thorough written report will follow each site-
visit and will include a detailed itemization of discrepancies and items requiring follow-up or 
reconciliation. This report will also be forwarded to the Steering Committee for review. The 
monitor will be responsible for maintaining regular contact between the investigators in the clinical 
sites. When the study ends, the monitor will also visit the clinical site to provide assistance for 
close-out. 
7.7 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review and interpret data 
generated from the FRIEND sites and to review protocols prior to their implementation.  Its 
primary objectives are to ensure the safety of study subjects, the integrity of the research data and 
to provide FRIEND with advice on the ethical and safe progression of the study. The DSMB 
advises on research design issues, data quality and analysis, and research participant protections 
for each prospective and on-going study.  A copy of the DSMB Charter can be found in the 
appendix. 
The DSMB members are appointed by the FRIEND consortium in accordance with established 
NIH and NICHD policies.  DSMB members are experts in and represent the following fields: 
biostatistics, epidemiology, infertility, gynecology and ethics.  The DCC Coordinator is 
responsible for scheduling regular committee meetings, recording all meeting minutes and 
summarizing the committee recommendations for the FRIEND consortium.  Steering Committee 
members are prohibited from attending closed sessions of the DSMB.  Open sessions may be 
attended by Steering Committee members or Chairperson when requested by the DSMB.   
7.8 
Reporting  
Administrative Reports will be prepared by the DCC, and they include monthly and quarterly 
reports to the FRIEND Collaborative group on accrual, data quality and study compliance and 
reports presented in the packet produced for each Steering Committee and DSMB. Statistical 
reports include reports to the FRIEND Collaborative group from the data analysis, and special 
reports for scientific manuscripts.  
Statistical Reports will be generated in SAS. Reports are provided for DSMB reviews, and for 
final analysis of study results in preparation for scientific publications. The content of the interim 
reports will be very complete and will serve as the template for the final report of each study, 
which in turn will form the basis of the publication of the results. Our proposed reports to the 
DSMB would include the following: a protocol description and history; accrual rates; site 


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performance in terms of accrual; eligibility; protocol violations; data accuracy and minority 
representation; patient characteristics by treatment and site; and the rate of adverse experiences. 
7.9 
Obligation of the Investigator 
One of the requirements for certification of a site to begin participant activities will be IRB 
approval. Johns Hopkins will act as the IRB of record, and the protocol and informed consent 
template, including future amendments, will be submitted to the sIRB. Protocol amendments and 
changes to the consent forms will be distributed from the DCC via numbered memos. Approval 
documents and consents will be made available to the sites. Reporting local and study-wide 
adverse events will be done according to the sIRB Maintenance/Retention of site records. In order 
to comply with Good Clinical Practice (GCP) requirements, the investigators must maintain the 
master patient log that identifies all patients entered into the study for a period of two years after 
the study ends so that the subjects can be identified by audit.  The PI must maintain adequate 
records pertaining to subjects’ files and other source data for a minimum of 5 years after 
completion of the study. 
7.10 Regulatory Requirements 
The DCC will work with NICHD staff by providing them with clinical study data, reports, 
and other support as required for AE Reporting and IND submissions. The Project 
Managers will work with NICHD colleagues in meeting all regulatory requirements 
including compliance with ICH and HIPAA requirements, FDA code for federal regulations 
(Title 21), and IND applications. For example, the DCC Project Managers will register this 
clinical trial in a timely manner with ClinicalTrials.gov via a web-based data entry system called 
the Protocol Registration System (PRS). 
7.11 Protocol Amendments 
Given the scope of this trial, the protocol is not expected to be revised once the recruitment starts. 
However, if any changes do occur, Protocol amendments and changes to the consent forms will be 
distributed from the DCC via numbered memos. Approval documents and consents will be made 
available to the sites. Reporting local and study-wide adverse events will be done according to the 
sIRB. 
7.12 Overall Policy 
The publications policy proposes guidelines for publications that originate from our collaborative 
FRIEND consortium.  Decisions concerning publications shall be determined by consensus 
(majority vote) of the collaborating principal investigators (or designate) noted below as the 
"Consortium". This policy is designed to promote prompt, exact, quality publications and 
presentations of Network studies with appropriate academic recognition of those with significant 
contributions.  Protocols are classified into three types:  ‘Main Study’ (which may include major 
and minor publications), ‘Ancillary Study’, and ‘Pilot Study’.  Additionally, there may be 
publications from concepts or ideas generated by the FRIEND (“Related Publications”) or from 
other groups utilizing FRIEND data and/or specimens “Outside Studies” (those utilizing data 
and/or specimens from the FRIEND studies).  Abstract submissions to national meetings will also 
follow the publications policy below. The progress of publications (including presentations) will 
be a standing agenda note on all phone conferences and meetings. The FRIEND consortium will 
make the final disposition regarding disputes with respect to analysis request approval, 
prioritization, presentation, authorship and/or manuscript submission. 


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7.13 Main Study 
A Main Study is a consortium study designed prospectively by an investigator independent of 
other studies.  At the end of each Main Study, a primary analysis resulting in the primary 
manuscript and a number of secondary analyses is produced based on the research questions stated 
in the protocol.  The Protocol leader is the primary author of the primary analysis. A main study 
can generate major (related to the major hypotheses) and minor publications (relating to secondary 
hypotheses). 
7.13.1 Major Publications  
A major publication is defined as one reporting results of the major hypotheses tested.  (For 
example, does hMG/IUI increase cyclic fecundity in couples with unexplained or male factor 
infertility?). 
 
1. Authorship:  Publications will include the names of investigators from each FRIEND site and 
the DCC.  Each FRIEND and DCC will have up to two authors per publication, ordinarily the PI 
and the Co-PI, but this may at times involve another investigator who has contributed to the study 
at their site, in lieu of the PI or Co-PI.  The principal investigator at each FRIEND site will be 
responsible for submitting the names of the two authors from that unit and designating them as 
either the primary and secondary authors of the unit.  No more than 2 authors may represent a 
FRIEND site. An ancillary site may only have 1 investigator. 
2. First Author:  The lead investigator initiating the protocol will be the first author.  The first 
author would always be expected to prepare the initial draft of the manuscript. The author will 
prepare the first draft of the manuscript in a timely fashion after receiving all the relevant data 
analyses from the DCC. The primary author will circulate the final draft to all authors prior to 
submission, with a timely turnaround of comments from other authors expected.  Final decision of 
the manuscript content will be determined by the consortium. In the event that the initiating 
protocol investigator declines first authorship or fails to meet the timeline determined by FRIEND 
(as determined by majority vote) and monitored monthly, the next FRIEND investigator in the 
rank order of authors (described below) will be the first author. 
3. Authorship Order:  All authorships are expected to meet reasonable criteria as set forth by the 
International Committee of Medical Journal Editors. Uniform requirements for manuscripts 
submitted to biomedical journals. http://www.icmje.org. Updated February 2006. Accessed April 
4, 2007.  The overall authorship order will be 1) the primary author, 2) FRIEND investigators, 3) 
a DCC investigator, additional outside investigators with a limit of one author per site, and end 
with the DCC PI. 
 
Authorship 
Order 
Category 
Description 
1 
Lead Investigator of the Protocol (N =1) 
2 
Primary FRIEND Investigators of the Protocol (N = 
6); DCC investigator (N = 1) 
3 
Other Investigators (N to be determined) 
4 
DCC PI (N = 1) 
 


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The authorship order of the FRIEND Consortium  and outside sites will be based upon subject 
recruitment, data accuracy and promptness of data report according to the chart below:  
 
Investigative 
Sites 
# Subjects 
Rank 
Accuracy 
Rank 
Total 
Rank 
Authorship 
Order 
A 
1 
4 
5 
3 
B 
2 
7 
9 
6 
C 
3 
1 
4 
2 
D 
4 
2 
6 
4 
E 
5 
3 
8 
5 
F 
6 
5 
11 
7 
G 
7 
6 
13 
8 
 
Data accuracy will be ranked according to the rate of missing or false data entries/randomized 
subject at each site.  Inquires that show data was accurately entered will not count against this rate 
of data inaccuracy.  Each site’s PI will be responsible to document the contributions to the study 
of that site’s authors.  In the event the journal editor requires fewer authors even after written 
documentation of the authors’ contribution has been provided, the steering committee will vote on 
the authorship order which will include at a minimum the Lead Investigator and PI of the DCC (or 
his/her designate) in the positions listed above. The other authors will be referenced in the footnote 
and listed in the title page. 
 
4. Acknowledgement Section:  The acknowledgement section will include other investigators and 
study personnel who contributed substantially to the study by site, as well as members of the Data 
and Safety Monitoring Board.  The designation will list the initials of the individual followed by 
their highest degree (e.g. C. L. Gnatuk, J.A. Ober, R.N., etc.) Significant contributions include but 
are not limited to protocol review, initiation and participation at each site, subject recruitment and 
enrollment, study conduct, data analysis, and preparation of the manuscript.   
7.13.2 Minor Publications 
Minor studies are defined as those in which the hypotheses would not be the main elements of 
consortium studies, but in which the study data base would be utilized to test secondary 
hypotheses.  (One example would be testing whether metformin use spares the dose of clomiphene 
resulting in lower dose needs.)  Ideas for "minor studies" will, in general, be proposed by a single 
individual, who would direct all efforts leading to publication and representation.  The results from 
minor studies would be handled similarly to those from major studies.  The “Protocol” is defined 
as the Concept Protocol/study design of the hypothesis resulting in the publication. 
 
Authorship will follow the Major publications guidelines above with the exception that the 
individual leading the minor study would be the first author, followed by the ranked primary 
FRIEND investigators involved in developing the Concept Protocol.  The Lead Investigator of the 
minor publication can propose additional investigators who contributed to the study, whose 
inclusion in the authorship will be voted on by the FRIEND consortium (majority vote of the 
consortium required for inclusion in authorship).  Centers may wish to withdraw inclusion from 
authorship of publications of minor studies in which only data are contributed, and this will be the 
decision of the individual site PI. 


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7.13.3 Ancillary Study  
An Ancillary Study is an observational study, conducted as a supplement to a Main Study.  By 
definition, an Ancillary Study involves all or a subset of patients enrolled in a Main Study.  An 
Ancillary Study does not involve any additional participants.  To be defined as an Ancillary Study, 
there must be a need for collection of additional data not already collected in the Main Study.  An 
Ancillary Study may also be designed by another consortium investigator, who would serve as the 
lead investigator and primary author of the paper.  Ancillary Studies may be a “single-center” or 
“multi-center”.   
A “single-center” Ancillary Study is a study in which all data are collected, stored and analyzed at 
a single center.  The center bears the additional cost of such a study.  The study requires approval 
of the FRIEND consortium.  The center conducting the study is responsible for the analysis and 
reporting of the results.  Abstracts and manuscripts resulting from data from the single-center 
Ancillary Study are not subject to the FRIEND Publications Policies. 
A “multi-center” Ancillary Study is defined as one for which data or material (such as specimens) 
are collected at more than one center, or additional funds for conduct of the study are provided by 
the FRIEND and the DCC provides data analysis. Multi-center Ancillary Studies require the 
approval of the FRIEND consortium. 
Authorship will be as per Major publications above with the exception that the individual leading 
the ancillary study and writing the paper would be the first author, followed by ranked FRIEND 
primary investigators, etc. A center not participating in the ancillary study would not receive 
authorship unless by majority vote of the steering committee. 
7.13.4 Related Publications 
A related publication is one that has had significant input from members of the FRIEND 
consortium at formal meetings in terms of study significance and design. It is distinct from an 
ancillary publication in that a related publication reports on a study, concept or new methodology 
that has not been subjected to formal DSMB review and approval. Generally, “Related 
Publications” will arise from ideas and studies discussed with the FRIEND consortium, but not 
voted upon to become formal protocols.  
The investigator who initiates, conducts and writes the study and those who (s)he names will be 
the sole authors. The authors should acknowledge the contribution of the FRIEND consortium in 
the author line of the publication according to the format of the journal.  
7.13.5 Outside Studies 
Outside studies will result from the sharing of data and/or specimens with investigators whose 
protocols have been approved by the steering committee, and who comply with all components of 
those policies. All publications will acknowledge the assistance of the FRIEND consortium in 
making the database available on behalf of the project.  In addition, however, a disclaimer will 
need to be included stating, “the contents of this report represent the views of the authors and do 
not represent the views of the FRIEND consortium.”   


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7.13.6 Presentations   
FRIEND data should be presented before national organizations by the lead investigators of Main 
Studies, Ancillary, and Pilot studies.  Organizations that might be appropriate include the 
American Society of Reproductive Medicine, the Society for Gynecologic Investigation, and  
the American College of Obstetricians and Gynecologists.  All presentations will be approved by 
the P & P committee.  Once data are published in at least abstract form, all members of the FRIEND 
consortium can cite them publicly in lectures.  
However, investigators should avoid citing specific numbers in review articles and chapters, for 
this could jeopardize peer review publication. Authorship, First Author, and Author Order are as 
described for Major Publications, and if there is an authorship limit to the abstract we will follow 
the plan above under Major Publications.  Oral and poster presentations, including those resulting 
from secondary analyses at professional societies, must list all authors and participating 
institutions.  


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8 References 
 
1.  
Roshdy E, Rajaratnam V, Maitra S, Sabry M, Allah AS, Al-Hendy A. Treatment of symptomatic 
uterine fibroids with green tea extract: a pilot randomized controlled clinical study. International journal 
of women's health. 2013;5:477-86. 
2.  
Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. 
Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertility 
and sterility. 2010;94(5):1887-93. 
3.  
Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Sharan C, Rajaratnam V, et al. 
Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice. American 
journal of obstetrics and gynecology. 2010;202(3):289.e1-9. 
4.  
Khan N, Mukhtar H. Tea polyphenols for health promotion. Life sciences. 2007;81(7):519-33. 
5.  
Zhang D, Rajaratnam V, Al-Hendy O, Halder S, Al-Hendy A. Green tea extract inhibition of 
human leiomyoma cell proliferation is mediated via catechol-O-methyltransferase. Gynecologic and 
obstetric investigation. 2014;78(2):109-18. 
 
 
 


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9 Appendix J: Investigator Signature of Agreement 
 
 
Investigator Signature of Agreement 
 
 
 
Title:   
 
Version:  
 
Principal Investigator: 
 
I, [Insert PI’s name], the Principal Investigator for [Insert Institute Name], hereby certify that I 
have read and agree to conduct this study in accordance with this protocol on behalf all FRIEND 
Investigators and research staff from my site. 
 
 
____________________________________________ 
_________________ 
Signature 
 
 
 
 
Date 
 
 
 


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9 Appendix K: DSMB Charter 
 
 
DATA AND SAFETY MONITORING BOARD (DSMB) CHARTER 
 
Purpose and Responsibilities of the DSMB 
The members of the Data and Safety Monitoring Board (DSMB) identified in this Charter for the 
FRIEND study are responsible for safeguarding the interests of study participants, assessing the 
safety and efficacy of all study procedures, and shall monitor the overall conduct of the FRIEND 
trial.  This Committee will serve as an independent advisory group to the Director of NICHD, and 
is required to provide recommendations about starting, continuing, and stopping the FRIEND 
study.   
 
This Committee is responsible for identifying mechanisms to complete various tasks that will 
impact the safety and efficacy of all study procedures, and overall conduct. The table below 
identifies the key areas where oversight is necessary and the ways in which the Committee for the 
FRIEND study will complete those tasks. 
 
Basic Responsibility of DSMB 
Method DSMB for FRIEND will use to complete task 
Familiarize themselves with the 
study protocol  
 Review study protocols and informed consent forms. 
Monitor adverse events 
 Adverse Event: Review quarterly progress reports 
prepared by the DCC. 
 Serious Adverse Events: Review report submitted by 
the DCC within one week of the event if life-
threatening or fatal, or within two weeks otherwise.  
 The DSMB will submit a report of their review to the 
DCC Coordinator within 7 business days if the SAE 
is life-threatening or fatal, or within two weeks 
otherwise. 
Monitor data quality 
 Conduct interim evaluations of the data. 
Oversee participant recruitment 
and enrollment 
 Review interim progress reports prepared by the 
DCC. 
Develop an understanding of the 
Study’s risks and benefits 
 Review study protocols and related literatures. 
 Review interim reports of subject accrual and 
outcome measures provided by the DCC. 
 Assess the need to perform further in-depth 
evaluation of the benefits and risks of the study after 
reviewing each report.  
Ensure the proper reporting occurs 
 Review and approve the meeting and reporting 
schedule listed in Sections 5 and 6 of this DSMB 
charter. 
 


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Contacts 
NICHD 
Esther Eisenberg, MD, Project Scientist 
 
Data Coordination Center (DCC) 
Heping Zhang, PhD, DCC Principal Investigator 
Hao Huang, DCC Data Manager and Statistician 
 
Janet Sun, MS, Biostatistician 
Siobhan Thompson, MPH, Project Manager/Clinical Research Associate 
Donna DelBasso, DCC Sr. Administrative Assistant 
 
Lead Investigator(s) 
 
The Data Manager at the DCC will prepare the DSMB reports. The DCC Project Director will 
review all DSMB reports prior to submission to the DSMB. The DCC Data Manager will not be 
blind to treatment condition. 
 
DSMB Members, Organizational Chart, & Communications 
Members 
The DSMB for the FRIEND study is comprised of the members listed in the table below.  In 
addition, their high-level roles and responsibilities are identified in the table.  
  
Name of Member 
Role on 
DSMB 
High Level Responsibilities 
David S. Guzick, 
M.D., Ph.D. 
 
Chair of 
DSMB 
Voting 
member 
 Chair the DSMB discussion and prepare written 
recommendations to FRIEND. 
 Ensure the safety of study subjects, the integrity of 
the research data. 
 Provide FRIEND with advice on the ethical and 
safe progression of studies conducted.  
 Advises on research design issues, data quality and 
analysis, and research participant protection for 
each prospective and on-going study.  
Peter S. Bernstein, 
MD, MPH 
Voting 
member 
 Ensure the safety of study subjects, the integrity of 
the research data. 
 Provide FRIEND with advice on the ethical and 
safe progression of studies conducted.  
 Advises on research design issues, data quality and 
analysis, and research participant protection for 
each prospective and on-going study.  
 
Katherine Burns, 
Ph.D. 
Voting 
member 
Robert W. Rebar, 
M.D. 
Voting 
member 
Ming T. Tan, Ph.D. 
 
Voting 
member 
Kimberly L. 
Thornton, M.D. 
Voting 
member 
 


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Conflict of Interest and Compensation 
It is extremely important that all members of the DSMB state any real or apparent conflicts of 
interests at the onset of the study. Members of the DSMB shall read the NICHD Clinical Research 
Guidance Document regarding Conflict of Interest (COI) and provide their signed summary of any 
COI for the study, at its onset, to the DCC. A table summarizing any COI within the DSMB is 
provided in the Appendix.  
 
Prior to each meeting, all members of the FRIEND DSMB will have an opportunity to state 
whether they have developed any new conflicts of interest since the meeting. As a new COI is 
identified it must be documented in the table in the Appendix and a new signed summary of the 
COI should be provided to the DCC for record-keeping purposes. 
 
If a new conflict is reported, the DCC will determine if the conflict limits the ability of the DSMB 
member to participate in the discussion. 
 
All DSMB members will be compensated for their role in supporting the committee. 
Compensation will include an honorarium for meeting attendance and any travel costs. 
 
Meeting Schedule 
DSMB meetings will be conducted quarterly. However, the DSMB may hold a meeting at any 
time in accordance with their mission.  
 
Report Schedule and Content 
The type of reports (full or brief) is indicated below, followed by a description of the contents of 
each type. 
 
DSMB Report 
Report Submission Date 
Type of Report 
1. 
 
Brief 
2. 
 
Brief 
3. 
 
Full 
4. 
 
Brief 
5. 
 
Full 
6. 
 
Brief 
7. 
 
Full 
8. 
 
Brief 
 
Brief DSMB reports will include the following summaries: 
• overall actual versus projected enrollment accrual 
• overall randomization update 
• overall study drop-out rate 
• serious adverse events 


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• primary outcome measures update 
 
Full DSMB reports will include the following summaries: 
• recruitment update (number screened) overall and by site 
• enrollment update (enrolled defined as randomized to a treatment) overall and by site 
• accrual status including actual enrollment compared to projections overall and by site 
• randomization update (i.e., number assigned to each treatment arm) 
• study drop-out rate for enrolled patients (number, reason, time point) overall and by site) 
• pre-specified subset of baseline demographic data for enrolled patients 
• safety data, adverse events, and serious adverse events 
• number of case report forms expected 
• number/percentage of expected case report forms received – overall and by site 
• number of case report forms that are query clean 
• primary outcome measures update 
 
Efficacy Outcome Summary 
An interim analysis is planned at the mid-point of the study to assess the overall pregnancy rate 
(i.e., the three groups combined) while maintaining blinding of treatment assignment in order to 
assess whether this pregnancy rate approximates the predicted rate of 30-40%, and whether 
additional subjects may be needed to meet power targets.  Since treatment assignments will not be 
identified, it is not thought that adjustments in significance levels will be required. 
 
 
Appendix:  Summary of COI within the DSMB 
 
 
DSMB Member Name 
Date Submitted 
Signed COI  
Was a COI 
Identified? 
Will the Member Remain 
Part of the Committee? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Conflict of Interest Statement 
 
 
I, ______________________, assuming the role of _____________________________      
 
 
 
 
 
 
 
 
 
 
 
 
 
(insert role, for example: DSMB member)  
 
for the __________________________________________________________ 
 
 
 
 
 
 
(insert project or study name) 
 
agree to the following statements.   
 
□ I agree to: 
▪ protect the interests and safety of study participants; 
▪ uphold the integrity of the research process including data collection and analysis to be 
as free from bias and preconception as I am able; 
▪ adhere to the highest scientific and ethical standards, to comply with all relevant 
regulations and to eliminate or disclose, during my involvement with the proposed 
clinical research project, any real or apparent conflicts of interest. 
 
In addition: 
 
□ I declare that I, my spouse or dependent children, or organization with which I am connected, 
do/does not have any financial interest in the ___________________ study, where financial 
interested is defined by the DHHS, as anything of monetary value, including but not limited to, 
salary or other payments for services (for example, consulting fees or honoraria); equity interests 
(for example, stocks, stock options or other ownership interests); and intellectual property rights 
(for example, patents, copyrights and royalties from such rights).   
The financial interest term does not include various items which can be found in The Federal 
regulation, PHS, DHHS Part 50--Policies of General Applicability; Subpart F- Responsibility of 
Applicants for Promoting Objectivity in Research for Which PHS Funding Is Sought.  
For Federal employees, financial interests that are allowable and require disclosure are: 
 
Financial Interest Disclosure: Financial interest that require disclosure are stock holdings in 
pharmaceutical firms, medical device manufacturers, and biotechnology companies 
Allowable Financial Interests: In a company that produces a product that is being evaluated by a 
study, participants may hold up to $15,000 of stock: and, up to an aggregate of $25,000 of the 
stock of that company and its competitors who produce that (or a similar) product. As an alternative 
to individual stock holdings, participants may hold up to an aggregate of $50,000 in sector mutual 
funds-including pharmaceutical/health care sectors. 


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JUNE 29, 2021 
 
 
For holdings in excess of these de minimus levels, a conflict of interest analysis needs to be 
conducted by NIH regarding the holding, the company producing the product being evaluated 
under the study, and its competitors, and, if a conflict exists, could lead to the need to withdraw 
from the study. 
 
□ I agree to not withhold any data related to the _____________________ study or to interfere 
with the analysis or publication of the study’s results. 
 
□ I will not engage in activities that could be viewed as real or apparent COI, including but not 
limited to: 
 
□ having a part-time, full-time, paid, or unpaid employee status of any organizations that 
are: (a) involved in the study under review; (b) whose products will be used or tested in the 
study under review, or whose products or services would be directly and predictably 
affected in a major way by the outcome of the study; 
 
□ being an officer, member, owner, trustee, director, expert advisor, or consultant of such 
organizations;  
 
□ being a current collaborator or associate of the principal investigator (applicable to 
potential members of data safety and monitoring boards); 
 
□ having a scientific interest beyond that required for my role, where scientific interest is 
defined as having influence over the protocol, the study design, conducting the study 
analysis or any reporting related to the investigation (applicable to potential members of 
data safety and monitoring boards). 
 
 


37 
 
FRIEND PK PRE-FRIEND PROTOCOL V. 2.1                        
 
 
                 
JUNE 29, 2021 
 
Data and Safety Monitoring Board (DSMB) 
Confidentiality Agreement 
 
I agree to serve as a DSMB member for the FRIEND (Reproductive Medicine Collaborative 
Consortium: a randomized placebo-controlled trial of EGCG to improve fertility in women 
with uterine fibroids) consortium for which Yale University Collaborative Center for 
Statistics in Science serves as the Data Coordination Center (DCC).  
As a DSMB member I understand that I will be provided with and have access to documents 
submitted by the NICHD or the DCC as they relate to study protocols, Registries or other 
consortium-related materials, including proprietary and confidential information.  
I shall not disclose any confidential information (oral or written) unless required to do so by 
law.  Confidential documents may be distributed to an administrative assistant, who is not 
permitted to share the materials with anyone other than me. 
I agree that I will not distribute or publish the study records.  I further agree that I shall not 
make use of consortium materials except for the express purpose of advising the Consortia 
and the NICHD. 
I have read this agreement and agree to abide by its terms.  
 
Name (Print or Type): ___________________________________________________ 
 
Signature: ________________________________________ Date: _______________