Clinical trial NCT03229057
Conditions: PCOS
Sponsor: Anuja Dokras
Start date: 2018-01-15; Completion date: 2024-07-15
Enrollment: 240 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine the effect of Oral Contraceptive Pills (OCP) verses Metformin verses OCP and Metformin on the prevalence of Metabolic Syndrome (MetS) and its components in overweight/obese women with Polycystic Ovary Syndrome (PCOS).

The combination of OCP and metformin (OCP, through lowering androgens, and metformin, through improvement in insulin sensitivity) will affect the prevalence of MetS, thereby altering the risk profile for the development of diabetes and possible cardiovascular disease (CVD) in young women with PCOS.

Detailed description:
The intervention will consist of randomizing subjects to one of three arms. Subjects will either be assigned to OCP + Placebo, Metformin + Placebo or OCP + Metformin. Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. In regards to OCP, previous randomized clinical trials (RCTs) have shown that 20mcg ethinyl estradiol/norethindrone 1.0 mg was well tolerated. The study will utilize a 20mcg OCP but a less androgenic third generation progestin (desogestrel 0.15mg) with potentially lesser impact on lipids and insulin sensitivity. The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP or metformin only in order to maintain study blinding. Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects

Arms: arm 1: The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP only in order to maintain study blinding. arm 2: Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. Placebo pills will be administered to individuals randomized to metformin only in order to maintain study blinding. arm 3: The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg.
Interventions: intervention 1: OCP + Metformin intervention 2: OCP + Placebo intervention 3: Metformin + Placebo
Intervention descriptions: intervention 1: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned. intervention 2: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned. intervention 3: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.

Protocol documents:
ICF_002.pdf: 
The COMET-PCOS trial- Comparing the effects of Oral Contraceptive Pills versus 
Metformin in the medical management of overweight/obese women with 
Polycystic Ovary Syndrome  
Informed Consent and HIPAA Authorization
NCT03229057 
May 16, 2023


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT  
INFORMED CONSENT FORM AND HIPAA 
AUTHORIZATION 
Protocol Title: 
The COMET-PCOS trial- Comparing the effects of 
Oral Contraceptive Pills versus Metformin in the 
medical management of overweight/obese women 
with Polycystic Ovary  
Principal 
Investigator 
University of 
Pennsylvania: 
Principal 
Investigator 
Children’s 
Hospital of 
Philadelphia: 
Anuja Dokras, MD, PhD 
3701 Market Street, Suite 800 
Philadelphia, PA 19104 
215-615-0085
Monica Mainigi, MD 
The Children’s Hospital of Philadelphia 
34th Street and Civic Center Blvd. 
Philadelphia, PA 19104 
215-662-2972
Emergency 
Contact: 
Fellow On Call 
215-662-6100
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you have 
Polycystic Ovary Syndrome (PCOS) and are overweight. Your participation is 
voluntary which means you can choose whether or not you want to participate. If 
you choose not to participate, there will be no loss of benefits to which you are 
otherwise entitled. Before you can make your decision, you will need to know 
what the study is about, the possible risks and benefits of being in this study, and 
what you will have to do in this study. The research team is going to talk to you 
about the research study, and they will give you this consent form to read. You 
may also decide to discuss it with your family, friends, or family doctor. You may 
find some of the medical language difficult to understand. Please ask the 
investigator and/or the research team about this form. If you decide to participate, 
you will be asked to sign this form. Your doctor may be an investigator in this 
research study. As an investigator, your doctor is interested both in your clinical 
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welfare and in the conduct of this study. Before entering this study or at any time 
during the research, you may want to ask for a second opinion about your care 
from another doctor who is not an investigator in this study. You do not have to 
participate in any research study offered by your doctor. 
 
 
 
What is the purpose of this research study? 
This research study is being conducted to determine the if there is an effect on 
Metabolic Syndrome (MetS) in overweight/obese women with PCOS when Oral 
Contraceptive Pills (OCP) are given in combination with Metformin. Metabolic 
Syndrome is the name for a group of risk factors that raises your risk for heart 
disease and other health problems, such as diabetes and stroke. Currently, there 
are no clear recommendations for the best and most comprehensive medical 
management of overweight/obese women with PCOS. The study hopes to 
uncover whether OCP and Metformin together affect the prevalence of MetS, 
thereby altering the risk profile for the development of diabetes and 
cardiovascular disease in women with PCOS.  
 
How long will I be in the study?  
If you chose to participate in this study, your participation will last for 24 weeks 
(about 6 months).  The study is being conducted at two medical centers, the 
University of Pennsylvania (UPenn) and Pennsylvania State University-Hershey 
Medical Center (PSU).  The study hopes to recruit 240 women (approximately 
120 women at each site). We will also be recruiting women with PCOS from 
Children’s Hospital of Pennsylvania. 
 
What am I being asked to do? 
If you chose to participate in this study, you must sign this consent form.  You will 
be placed into one of three groups and asked to take the study medication for the 
duration of the study.  You will either be assigned to one of three groups: 1) OCP 
+ placebo pills, 2) Metformin + placebo pills, or 3) OCP + Metformin.  Placebo 
pills are used as a control, meaning they do not contain any active medication 
(like a sugar pill). The use of a placebo will help the investigators understand 
what medications are having the greatest effect in the study. The OCP used for 
this study is 20mcg ethinyl estradiol/desogestrel 0.15mg. This is a low dose birth 
control pill that would have a lesser impact on lipids and insulin sensitivity as 
these lab values can sometimes be reported high in women with PCOS. Since 
the assigned treatment groups are randomized and blinded we do ask that you 
use a medically accepted non hormonal method of birth control (such as 
condoms) while you participate in the study. 
You will be asked to come to the University of Pennsylvania for 6 study visits (a 
screening visit, randomization visit, 4 weeks, 8 weeks, 16 weeks and 24 weeks 
visit).  The screening visit will determine if you are eligible to participate in the 
study.  You may need to stop taking certain medications (wash-out) to participate 
in the study. A one-month wash-out period (6 month wash out in the case of 
injectable hormonal contraceptive) will be required for medications prior to 
screening (most common OCP and metformin).  Some medications will be 
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prohibited during this study. Please discuss any medications you are taking with 
the study doctor. The study doctor will inform you of any medication that you 
need to stop.  
If you are found to be eligible you will be randomized (assigned to a group by 
chance, like the flip of a coin) to one of the medication groups mentioned above.  
If you have not had a menstrual period for three months prior to the 
randomization visit, the study will induce menses through use of medication 
medroxyprogesterone acetate (MPA). Through-out the study, the research team 
will collect information about your medical and menstrual history, take your vital 
signs (height, weight, blood pressure and pulse) and draw your blood for 
screening and safety labs.   
Please refer to the study schedule below for more information on the timing of 
the events to take place during each study visits and further details of specific 
events that will occur.  
Study Visit 
Schedule 
Screening 
Visit 
Randomization 
Visit 
2 Week 
PC 
4 Week 
Visit 
8 Week 
Visit 
12 Week 
PC 
16 Week 
Visit 
20 Week 
PC 
24 Week 
Visit  
Safety 
PC 
Sign Informed 
Consent 
X 
Medical 
Assessment 
X 
Review Menstrual 
history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy 
test 
X 
X 
X 
X 
X 
X 
Vital Signs/ 
Biometrics 
X 
X 
X 
X 
X 
X 
Screening labs 
X* 
Safety labs 
X* 
X 
X 
X 
Hirsutism (F-G) 
score 
X 
X 
X 
Acne assessment 
X 
X 
DXA  
X 
X 
DNA Sample 
X 
Fasting blood 
draw 
X 
X 
X 
Lifestyle 
Modification 
Counselling 
X 
X 
ASA24 
X 
X 
TVUS 
X* 
X 
X 
oGTT 
X 
X 
Randomization 
X 
PCOSQ/STAI/CE
S-D/FSDS-
R/FSFI
X 
X 
Cognitive 
Questionnaires 
X 
X 
Review Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
Logs/Medications 
X 
X 
X 
X 
Collect 
Logs/Medications 
X 
X 
X 
X 
*As Needed
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Hirsutism Score: Hirsutism is excessive hair that commonly appears in a male 
pattern in females and it is generally associated with hyperandrogenic PCOS. 
The Ferriman-Gallwey Hirsutism Score is used to evaluate hair growth in nine 
areas of the body. 
Urine Pregnancy Test: A urine pregnancy test will be performed at all visits.  If a 
positive result is found, you will be informed by the site staff of the positive result 
and offered resources regarding prenatal care or alternative options.  
Lifestyle Modification Counseling: You will receive counseling about diet and 
exercise at the randomization and 4-month visit.  The diet will be designed to 
reduce your calorie intake by 500 calories a day. 
ASA24: The Automated Self-Administered 24-Hour Dietary Assessment Tool 
(ASA24). This 24-hour dietary recall captures detailed information about all 
foods, drinks, and supplements (including vitamins, minerals, herbals, and other 
dietary supplements) you consumed from midnight to midnight. You will be asked 
to complete this at 12 weeks and 24 weeks.  
Questionnaires (PCOSQ, STAI, CES-D, FSDS-R, FSFI): The PCOSQ is self-
administered questionnaire for measuring health-related quality of life in women 
with PCOS. The PCOSQ will be at randomization and the 24 weeks visit. The 
STAI (State-Trait Anxiety index) is a questionnaire for accessing trait anxiety and 
state anxiety.  The STAI will be administered to subjects at Randomization and 
24 week visit. The CES-D is a screening test for depressive symptoms. The 
CES-D will be administered to subjects at Randomization and 24 week visit. The 
FSDS-R (The Female Sexual Distress Scale-Revised) is a screening 
questionnaire for measuring sexually related personal distress in women with 
Female Sexual Dysfunction (FSD). The FSFI (Female Sexual Function Index) is 
a brief questionnaire measure of sexual function in women. It was developed for 
the specific purpose of assessing domains of sexual function (e.g. sexual 
arousal, orgasm, satisfaction, pain) in clinical trials. 
Transvaginal ultrasound: a transvaginal ultrasound will be performed to look at 
your ovaries (the female reproductive organ where eggs are produced).  This will 
occur at the screening (if needed), randomization visit and 24 weeks visit. 
DXA Scan: a DXA scan will be performed to take a measure of your bone 
density. 
Oral Glucose Test (oGTT): measures the body’s ability to use a type of sugar, 
called glucose, that is the body’s main source of energy.  This will be performed 
at the randomization and 24 weeks visit.  Prior to the test, you must fast 
overnight for 10-14 hours. You will receive an oral glucose solution and your 
blood will be sampled every 30 minutes for 2 hours. (An IV will be inserted if you 
desire to avoid multiple blood draws). 
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Cognitive Testing: test designed to measure an individual’s cognitive (thinking, 
reasoning or remembering) function in a specific area, such as verbal reasoning, 
spatial awareness or mathematics. Audio recording of cognitive testing is 
optional.  If you chose to be audio recorded- it will be deleted after transcription. 
 
Blood banking: If you agree, your blood will be collected and stored in the 
repository and used for future research that has not yet been defined.  
 
Genetic testing: If you agree, your blood will also be used to obtain a sample of 
your genetic material (DNA). We will use these samples for genetic research, 
which might teach us about health conditions that are passed on in families. The 
purpose of collecting your DNA and how it will be used is discussed further in this 
consent form. If you decide that you do not want your DNA collected, you will still 
be able to participate in this study 
 
What are the possible risks or discomforts?  
Risk are addressed by using trained medical staff, close observation and contact 
with you throughout the study. The possible risk of participating in this study 
include: 
 
Blood Samples: Possible side effects from blood drawing include feeling faint, 
inflammation of the vein, pain, bruising, or bleeding at the site of puncture.  There 
is a slight possibility of infection at the site or draw. The blood testing performed 
outside of Penn will be conducted at the Children’s Hospital of Pennsylvania 
(CHOP) Translational Core Lab (TCL), Michigan University, and National 
Institutes of Health. 
 
Oral Glucose Test: Possible side effects from this test include anemia (lack of red 
blood cells), infection at the site of the IV, nausea, vomiting, allergic reaction, 
hypoglycemia (low blood sugar), as well as all the standard blood draw 
discomforts and risks. 
 
Transvaginal ultrasound: Possible side effects include abdominal or pelvic 
discomfort. 
 
Reduced Calorie Diet: Possible side effects include hunger, weakness, changes 
in your electrolytes (salts in your body), mood changes, depression, gall stone 
from rapid weight loss. 
 
Oral Contraceptive Pills: Possible side effects include abdominal bloating, 
cramps, or pain, nausea, breast tenderness, mood changes, weight changes, 
headaches, breakthrough bleeding, blood clot, stoke, elevated blood pressure, 
gallbladder disease, swelling, irritated varicose vein, depression, migraine, 
absence of a cycle, breast changes, appetite changes, vomiting, fluid retention, 
temporary infertility, menstrual flow changes, spotting. 
 
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Metformin: The most common side effects of this drug are gastrointestinal 
symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, metallic 
taste in mouth and anorexia). There is a small risk of lactic acidosis (a medical 
condition when cells make lactic acid, from glucose, faster than the body can 
break it down). 
 
Medroxyprogesterone acetate (MPA): Possible side effects include abnormal 
uterine bleeding (irregular, increase, decrease), change in menstrual flow, 
breakthrough bleeding, spotting, no menses, changes in cervical erosion and 
cervical secretions, breast pain or tenderness, nausea, cholestatic jaundice, 
swelling, generalized rash, acne, hair growth, hair loss, depression, insomnia, 
sleepiness, dizziness, headache, nervousness, hypersensitivity reactions, rash 
(allergic) with and without itching of skin, change in weight (increase or 
decrease), increased body temperature, fluid retention, fatigue, decreased 
glucose tolerance. 
 
DXA Scan: Exposure to a small amount of x-ray radiation.  Therefore, you will 
receive a radiation dose.  This radiation dose is not necessary for your medical 
care and will occur only as a result of your participation in the study.  At doses 
much higher than you will receive, radiation is known to increase the risk of 
developing cancer after many years.  At the doses you will receive, it is very 
likely that you will see no effects at all. 
 
Questionnaires: Some questions may make you feel embarrassed or 
uncomfortable. You do not have to answer any questions which make you 
uneasy. 
Reproductive risks:  Because of the effects of these drugs there could be serious 
harm to unborn children or children who are breast-feeding. These effects could 
also harm the mother.  It is also possible that harmful side effects that are not yet 
known could happen to both the mother and unborn or breast-feeding child.  If 
you are currently pregnant, it is important that you inform the investigator 
because you will not be able participate in the study.  If you are able to become 
pregnant, you will be given a serum pregnancy test before entry into the study. 
Since we will not know which study participants have received an OCP, you are 
asked to use a medically accepted non hormonal method of birth control (such as 
condoms) while you participate in the study.  You should not become pregnant 
while you are taking these drugs.  If you do become pregnant, you must tell the 
investigator immediately and you will be discontinued from the study. Some 
information will be gathered from you regarding the pregnancy, including the 
completion of a transvaginal ultrasound. You will be referred to consult an 
obstetrician or maternal-fetal specialist. 
 
Risks of Genetic Testing: 
 
This research includes optional genetic testing. Even without your name or other 
identifiers, your genetic information is unique to you. The researchers believe the 
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chance that someone will identify you is very small, but the risk may change in 
the future as people come up with new ways of tracing information. 
 
There can be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or your blood relatives could be found during 
a research study. Even though your genes are unique, you share some of the 
same genes with your blood relatives. Although we are not able to know all of the 
risks from taking part in research on inherited traits, we believe that the risks to 
you and your family are very low, because your samples will be coded. Research 
results will not be returned to you or your doctor.  
 
Very rarely health or genetic information could be misused by employers, 
insurance companies, and others. For example, it could make it harder for you to 
get or keep a job or insurance, or life insurance companies may charge a higher 
rate based on this information. We believe the chance these things will happen is 
very small, but we cannot make guarantees. 
 
A federal law (Genetic Information Non-Discrimination Act, GINA) helps reduce 
the risk from health insurance or employment discrimination. The law does not 
include other types of misuse by life insurance or long term care insurance. If you 
want to learn more about GINA, you can find information about it on the internet 
or ask the study staff. 
 
Loss of Confidentiality:  There is a risk of loss of confidentiality if your information 
or your identity is obtained by someone other than the investigators, but 
precautions will be taken to prevent this from happening. The confidentiality of 
your electronic data created by you or by the researchers will be maintained to 
the degree permitted by the technology used. Absolute confidentiality cannot be 
guaranteed. 
 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. This means that the researchers cannot release or use 
information, documents, or samples that may identify you in any action or suit 
unless you say it is okay. They also cannot provide them as evidence unless you 
have agreed.  This protection includes federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. An example would be a court 
subpoena. 
   
There are some important things that you need to know.  The Certificate DOES 
NOT stop reporting that federal, state or local laws require. Some examples are 
laws that require reporting of child or elder abuse, some communicable diseases, 
and threats to harm yourself or others.  The Certificate CANNOT BE USED to 
stop a sponsoring United States federal or state government agency from 
checking records or evaluating programs. The Certificate DOES NOT stop 
disclosures required by the federal Food and Drug Administration (FDA).  The 
Certificate also DOES NOT prevent your information from being used for other 
research if allowed by federal regulations. 
   
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Researchers may release information about you when you say it is okay. For 
example, you may give them permission to release information to insurers, 
medical providers or any other persons not connected with the research.  The 
Certificate of Confidentiality does not stop you from willingly releasing information 
about your involvement in this research. It also does not prevent you from having 
access to your own information.  
 
Unforeseen Risk: Since the study is investigational there may be risks that are 
unknown.  If you experience any adverse reactions, please contact the study 
doctor/staff and seek medical help if necessary. 
 
For this study we may need to contact you via email or test message to provide 
you information about scheduling, appointments notes, or to send you 
information about your participation in the study. Email and text communications 
are often not secure and may be seen by others as a result. For test messages, 
message and data rates may apply to you while enrolled. By signing below, you 
accept these risks and potential additional costs.  
If you wish for us to use a different means to communicate with you during the 
course of this trial, please discuss this with the research team and alternative 
methods can be arranged. You can text “stop” to any text message to opt-out of 
the text messaging program. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be 
important to you.  This includes information that, once learned, might cause you 
to change your mind about being in the study.  We will notify you as soon as 
possible if such information becomes available. 
 
What are the possible benefits of the study?  
 
You may benefit as a result of your participation in this study. You may 
experience improvements in symptoms associated with PCOS. There is, 
however, no guarantee that you will benefit from your participation in this study. It 
is possible that information from the use of these study drugs may help advance 
knowledge for development of more effective treatment of women with PCOS in 
the future.  Result of this study may benefit others. 
 
What other choices do I have if I do not participate?  
You do not have to participate in this study to receive treatment of your PCOS. 
You may receive standard of care through the University of Pennsylvania PCOS 
Center or Children’s Hospital of Philadelphia. 
 
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Will I be paid for being in this study? 
For your time and inconvenience related to your participation in this study, you 
will be paid for the study visits you complete.   You will be paid as follows: 
Screening visit = $50 
Randomization visit = $125 
Week 4 visit = $50 
Week 8 visit = $50 
Week 16 visit = $50 
Week 24 visit = $125 
You may also be paid $50 for any unscheduled study visit. We will pay you by 
using a Greenphire ClinCard which is a pre-paid debit card in which your 
payment will occur  at the end of each visit you attend.  After giving you the card 
at the screening visit, the card will be loaded with additional payments at every 
scheduled visit. 
Please note: In order to be compensated for your participation in this study, you 
must provide your Social Security Number. Additionally, please note that the 
University of Pennsylvania is required to report to the IRS any cumulative 
payments for participation in research studies that exceed a total of $600 in a 
calendar year. 
 
Will I have to pay for anything? 
There will be no charge to you for your participation in the study.  The study drug, 
study-related procedures and study visits will be provided at no charge to you or 
your insurance. Please note any clinical procedure you have outside the study at 
the University of Pennsylvania will be your responsibility. 
 
What happens if I am injured from being in the study?  
We will offer you the care needed to treat injuries directly resulting from taking 
part in this research.  We may bill your insurance company or other third parties, 
if appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you 
other compensation for the injury.  You do not give up your legal rights by signing 
this form.   
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of the research study as soon as possible.  The 
researcher’s name and phone number are listed in the consent form. 
 
 
When is the Study over?  Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and 
all information has been collected.  This study may also be stopped at any time 
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by your physician, the study Sponsor, or the Food and Drug Administration (FDA) 
without your consent because: 
• 
The Primary Investigator feels it is necessary for your health or 
safety.  Such an action would not require your consent, but you 
will be informed if such a decision is made and the reason for 
this decision. 
• 
You have not followed study instructions.  
• 
The Sponsor, the study Principal Investigator, or the Food and 
Drug Administration (FDA) has decided to stop the study. 
If you decide to participate, you are free to leave the study at anytime.  
Withdrawal will not interfere with your future care.   
 
Who can see or use my information?  How will my personal 
information be protected?   
We will do our best to make sure that the personal information obtained during 
the course of this research study will be kept private.  However, we cannot 
guarantee total privacy.  Your personal information may be given out if required 
by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. The 
Institutional Review Board (IRB) at the University of Pennsylvania will have 
access to your records. If this study is being overseen by the Food and Drug 
Administration (FDA), they may review your research records.  We will use study 
ID numbers to identify your data and specimens.  The list that matches your 
name with your study ID number will be kept in a secured area in a locked filing 
cabinet or in a password-protected electronic document at University of 
Pennsylvania.  This list will be kept indefinitely.   
 
Your samples may be used to create products, including some that may be sold 
and/or make money for others.  If this happens, there are no plan to tell you, or to 
pay you, or to give any compensation to you or your family. 
 
Will information about this study be available to the public? 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify 
you. At most, the website will include a summary of the results. You can search 
this website at any time. 
 
Future use of Data and/or Specimens 
Your information and samples coded with your study ID number will be stored for 
future research purposes. Future researchers may receive information that could 
identify you. This can be done without again seeking your consent in the future, 
as permitted by law. The future use of your information and samples only applies 
to the information and samples collected on this study.  Your study ID number 
will be retained and shared with data/samples.  Your information and samples 
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may be stored and used for future research purposes for an indefinite amount of 
time.   
 
There are no plans to tell you about any specific research that will be done. 
Possible future research may include additional research on PCOS or metabolic 
syndrome. We may share your identifiable information and samples with other 
researchers. 
 
We will not follow up with you to tell you about the specific research that will be 
done. We will not give you any results from these studies. It is possible that you 
may have chosen not to participate in these future research studies, had you 
been approached for participation. 
 
There is a risk of breach of confidentiality (unintentional release of your 
information). We will do our best to make sure that this doesn’t happen. 
However, we cannot guarantee total privacy. We will protect your confidentiality 
during storage and sharing by keeping the list which matches your name with 
your study ID number in a secured area in a locked filing cabinet or in a 
password-protected electronic document at University of Pennsylvania.   
 
You will likely not directly benefit from future research with your information and 
samples. Research with your identifiable information and samples may help 
others by improving our understanding of health and disease, improving health 
care and making safer or more effective medical therapies, and developing new 
scientific knowledge. 
 
If you have questions about the storage of your information and samples or have 
changed your mind about use of your samples, you should contact Dr. Dokras in 
writing at the address on page 1 of this form. Once the samples have left the 
University of Pennsylvania or have been completely used there is no way to have 
them returned or withdrawn for testing. You will not be able to withdraw your 
permission for future use at that time. Any analysis or test results already 
performed will be kept. Information that has already been used or shared with 
others will be retained. 
         
Electronic Medical Record and Release of Study Related 
Information 
  
What is an Electronic Medical Record? 
An Electronic Medical Record (EMR) is an electronic version of your medical 
chart within a health system. An EMR is simply a computerized version of a 
paper medical record.  
 
If you have never received care within Penn Medicine and are participating in a 
University of Pennsylvania research study that uses Penn Medicine healthcare 
related services, an EMR will be created for you for the purpose of maintaining 
any information produced from your participation. The creation of this EMR is a 
requirement of your participation in this study. In order to create your EMR, the 
study team will need to obtain basic information about you that would be similar 
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to the information you would provide the first time you visit a hospital or medical 
facility (i.e. your name, the name of your primary doctor, the type of insurance 
you have). If you have been a patient at Penn Medicine in the past, information 
from your research participation will be added to your existing medical record.  
 
 
What may be placed in the EMR?  
Information related to your participation in the research (e.g., laboratory tests, 
notes from your physician, imaging studies, and clinical procedures, etc.) will be 
placed in your EMR maintained by Penn Medicine.  
 
Once placed in your EMR your information may be accessible to appropriate 
Penn Medicine workforce members that are not part of the research team.  
Information within your EMR may also be shared with others who are determined 
by Penn Medicine to be appropriate to have access to your EMR (e.g. Health 
Insurance Company, disability provider, etc.).  
 
Penn Medicine also participates in automated information sharing through Health 
Information Exchanges (HIEs). HIEs securely share parts of your electronic 
health record, including research information, with other healthcare organizations 
involved in your care. This information is shared to improve the quality, safety 
and efficiency of your healthcare. To request that your health information not be 
shared through HIEs, please call 215-662-4484. 
 
Will I, as a subject, have access to research related information within the 
EMR?  
The 21st Century Cures Act requires healthcare institutions to allow patients 
increased access to their electronic medical record. As part of your participation 
in this research, you will have access to research related information within your 
EMR through Penn Medicine’s patient portal – called MyPennMedicine (MPM).  
 
Some information specific to this clinical research study may be shared with you 
in a delayed manner, shared with you at the end of the study, or not shared with 
you.  Not sharing or delaying certain research information within your EMR may 
be necessary to protect the integrity of the trial results or for other reasons. 
 
Will I receive the results of research testing that may be relevant 
to my health? 
Many of tests done in research studies are only for research and have no clear 
impact on your healthcare. Research results for this study will not be returned to 
you because they would not be relevant to your healthcare. 
 
Who can I call with questions, complaints or if I’m concerned 
about my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research 
subject, you should speak with the Principal Investigator listed on page one of 
this form.  If a member of the research team cannot be reached or you want to 
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talk to someone other than those working on the study, you may contact the 
Office of Regulatory Affairs with any question, concerns or complaints at the 
University of Pennsylvania by calling (215) 898-2614. 
 
If you are a CHOP patient/subject and have questions about your rights or if you 
have a complaint, you can call the CHOP Office of Research Compliance at 215-
590-2830. 
 
What information about me may be collected, used or shared 
with others?   
During your participation in this research study, the study investigator and study 
staff will collect personal health information about you (for example, medical 
histories and result of any tests, examinations or procedures you undergo while 
in the study) and record it on study documents.  The study investigator will keep 
this personnel health information in your study related records.  In addition, the 
study doctor may obtain, and include in your records, information regarding your 
past, present and/or future physical or mental health and/or condition.  Your 
study investigator may ask you to sign a separate authorization to obtain some or 
all of your medical records from your study doctor. Your study records may 
include other personal information (such as name, social security number, 
medical record numbers, date of birth, address, telephone number, and email 
address) which could identify you.  Health information that could identify you is 
call “Protected Health Information” (or PHI). 
 
Under federal law (the “Privacy Rule”), your PHI that is created or obtained 
during this research study cannot be “used” to conduct the research or 
“disclosed” (given to anyone) for research purposes without your permission.  
This permission is called an “Authorization”.  Therefore, you may not participate 
in this study unless you give your permission to use and disclose you PHI by 
signing this Authorization.  By signing, you are agreeing to allow the study 
investigator and staff to use you PHI to conduct this study. 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. 
Your information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• to evaluate and manage research functions.   
 
Where may my information be stored?  
Information related to your participation in clinical research will be contained in a 
clinical trial management system (CTMS). A clinical trial management system 
(CTMS) is used to register your information as a participant in a study. This 
allows for your research data to be entered and stored for the purposes of study 
operational and financial applications and other activities required as part of the 
conduct of the research. Once placed in the CTMS your information may be 
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accessible to other authorized personnel at Penn Medicine that support research 
operations. Your information may be held in other research databases. 
 
Who may use and share information about me?   
The following individuals may use or share your information for this research 
study: 
• The investigator for the study and the study team  
• Other authorized personnel at Penn, including offices that support research 
operations 
• The investigator for the study at PSU- Hershey Medical Center  
• The investigator for the study at CHOP and the Children’s Hospital of 
Pennsylvania (CHOP) Translational Core Lab (TCL) 
• Other research personnel with access to the databases for research and/or 
study coordination and as otherwise approved by the IRB 
 
Who, outside of the School of Medicine, might receive my 
information?  
List all names or all classes of persons involved in the research at Penn, e.g.,  
• Greenphire ClinCard 
• Those working under the direction of the investigator for the study, (e.g. 
under subcontracts). 
• All research centers participating in the study, even if they are not part of 
the School of Medicine 
• The funding sponsor and organizations supporting the sponsor  
Oversight organizations 
• The Food and Drug Administration 
• The Office of Human Research Protections 
• The study data and safety monitoring board 
• Michigan University 
• National Institutes of Health. 
 
Once your personal health information is disclosed to others outside the School 
of Medicine, it may no longer be covered by federal privacy protection 
regulations.  
The Principal Investigator or study staff will inform you if there are any additions 
to the list above during your active participation in the trial. Any additions will be 
subject to University of Pennsylvania procedures developed to protect your 
privacy. 
 
How long may the School of Medicine use or disclose my 
personal health information?   
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Your authorization for use of your personal health information for this specific 
study does not expire.  
 
Your information may be held in a research database.  However, the School of 
Medicine may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants 
permission 
• As permitted by law  
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your 
health information at any time.  You do this by sending written notice to the 
investigator for the study (listed on the top of this form).  If you withdraw your 
permission, you will not be able to stay in this study. 
 
If you withdraw your permission, we will stop collecting health information about you 
for this study; we may continue to use and share your health information that we 
already have if it is necessary for safety and scientific soundness of the research 
study; and we will not be able to take back information that has already been used 
or shared with others.  
 
What if I decide not to give permission to use and give out my 
health information? 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject HIPAA Authorization 
describing your confidentiality and privacy rights for this study.  
 
By signing this document, you are permitting the School of Medicine to use and 
disclose personal health information collected about you for research purposes 
as described above. 
 
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Decisions 
 
Optional DNA, Blood Collection: 
 
As part of this study, we are obtaining, prior to you starting medication, a sample 
of your blood for DNA testing and for measure of other substances in the blood. If 
you agree, the researchers would like to use your DNA to identify certain 
sequences of key genes (called polymorphisms) that may predict a response to 
the medications used in this trial. If genes are identified, which are related to the 
response to the treatment, the sample may also be used in the development of 
diagnostic or prognostic tests to identify those who will or who will not respond to 
these medications. We also may use this DNA to identify genes that cause 
PCOS. Additionally, we are banking part of your blood that does not contain cells 
to eventually study proteins that are determined by these genes. There is no 
normal or abnormal result produced by the DNA or blood tests, and the 
researchers will not use the DNA to try to see if you have any genetic diseases or 
conditions. The testing of DNA may provide additional information that will be 
helpful in understanding the medications used in this trial and the effects on 
PCOS, but it is unlikely that these studies will have a direct benefit to you. The 
results of these tests will not have an effect on your care. Neither your doctor nor 
you will receive results of these tests, and the results will not be put in your 
medical records.  
 
If you agree to allow your DNA sample to be collected at the randomization visit, 
it will be stored in a secure laboratory at the study site. You are free to change 
your mind regarding the use of your sample. If you no longer want your DNA or 
blood to be used for testing, you should contact Dr. Dokras in writing at the 
address on page 1 of this form. Your DNA and blood sample will be destroyed at 
that time of withdrawal. If you consent to the collection of your DNA, it will be kept 
indefinitely or until the sample is used completely by the staff and collaborators of 
this study.  
 
You should initial below to indicate your preference for the collection of your DNA 
sample:  
 
Optional Consent: 
 
I agree to have an optional collection of blood which can be stored in the 
repository and used for future research that has not yet been defined.  
______YES _____ NO  
 
I agree to have an optional collection of blood for DNA testing which can be 
stored in the repository and used for future research that has not yet been 
defined.  
______YES _____ NO  
 
I agree to have an optional audio recording done during my cognitive testing to 
help assess accuracy of my answers and standardization of the test 
environment.  
______YES _____ NO  
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When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer.  Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of 
this study. 
A copy of this consent form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
 
 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 
 
IRB Approval From: 05-16-2023 To: 05-15-2024

Prot_SAP_000.pdf: 
      
The COMET-PCOS trial- Comparing the effects of Oral Contraceptive Pills versus 
Metformin in the medical management of overweight/obese women with Polycystic 
Ovary Syndrome  
 
NCT03229057 
November 30, 2021 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
 
 
 
The COMET-PCOS trial- Comparing the effects of Oral Contraceptive Pills versus 
Metformin in the medical management of overweight/obese women with Polycystic 
Ovary Syndrome 
 
(COMET-PCOS) 
 
Principal Investigator (1): Anuja Dokra, MD, PhD 
Principal Investigator (2): Richard S. Legro, MD 
Principal Investigator (3): Monica Mainigi, MD 
 
Version 10.1 
 
Supported by: 
 
Potential R01 from the NIH 
 
 
Study Intervention Provided by:  No outside support 
Sponsor of IND(IDE):  Not Applicable 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
 
Prepared by: 
The University of Pennsylvania Women’s Health Clinical Research Center 
Perelman School of Medicine  
3701 Market Street 
Philadelphia, PA 19104 
 
(215) 615-0085 
 
Last updated: November 30, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Protocol Subcommittee 
 
 
 
Name 
E-mail 
Anuja Dokras, MD 
ADokras@obgyn.upenn.edu  
Richard Legro, MD 
rsl1@psu.edu 
Christos Coutifaris, MD  
CCoutifaris@uphs.upenn.edu 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Table of Contents  
1 
STUDY SYNOPSIS ............................................................................................................................................. 7 
1.1 
OBJECTIVES ..................................................................................................................................................... 7 
1.2 
HYPOTHESIS ..................................................................................................................................................... 7 
1.3 
PATIENT POPULATION ...................................................................................................................................... 7 
1.4 
STUDY DESIGN ................................................................................................................................................. 7 
1.5 
TREATMENT ..................................................................................................................................................... 7 
1.6 
PRIMARY EFFICACY PARAMETER ...................................................................................................................... 7 
1.7 
SECONDARY EFFICACY PARAMETERS ............................................................................................................... 8 
1.8 
STATISTICAL ANALYSIS ................................................................................................................................... 8 
1.9 
ANTICIPATED TIME TO COMPLETION ................................................................................................................ 8 
1.10 
REGULATORY COMPLIANCE ............................................................................................................................. 8 
2 
STUDY OBJECTIVES ......................................................................................................................................... 9 
2.1 
PRIMARY AIM .................................................................................................................................................. 9 
2.2 
SECONDARY AIM ............................................................................................................................................. 9 
2.3 
TERTIARY AIMS ............................................................................................................................................... 9 
3 
BACKGROUND ............................................................................................................................................... 10 
3.1 
RATIONALE .................................................................................................................................................... 10 
3.2 
TREATMENT OF PCOS ................................................................................................................................... 10 
3.3 
METABOLIC SYNDROME IN PCOS.................................................................................................................. 11 
3.4 
EFFECT OF OCP ON METS .............................................................................................................................. 11 
3.5 
HDL-C FUNCTION AND LIPOPROTEIN ANALYSIS IN PCOS ............................................................................. 12 
3.6 
IMPACT OF OCP VS. METFORMIN ON HDL-C FUNCTION AND LIPOPROTEIN ANALYSIS IN PCOS .................... 12 
3.7 
PCOS AND ADIPOCYTE DYSFUNCTION ........................................................................................................... 13 
3.8 
OCP USE IN WOMEN WITH PCOS ................................................................................................................... 13 
3.9 
METFORMIN AS AN ALTERNATIVE TREATMENT FOR WOMEN WITH PCOS ...................................................... 14 
3.10 
OCP VS. METFORMIN ..................................................................................................................................... 14 
3.11 
OCP VS. METFORMIN VS. OCP + METFORMIN ................................................................................................ 14 
3.12 
EFFECTS OF OCP VS. METFORMIN VS OCP + METFORMIN ON INDIVIDUAL COMPONENTS OF METS ............... 15 
3.13 
DYSLIPIDEMIA................................................................................................................................................ 15 
3.14 
VISCERAL ADIPOSITY ..................................................................................................................................... 15 
3.15 
ADIPOKINE AND CYTOKINE SECRETION .......................................................................................................... 16 
4 
STUDY DESIGN .............................................................................................................................................. 18 
4.1 
OVERVIEW ..................................................................................................................................................... 18 
4.1.1 
Treatment Design ..................................................................................................................................... 18 
4.1.2 
Study Population ...................................................................................................................................... 18 
5 
SELECTION AND ENROLLMENT OF SUBJECTS............................................................................................... 19 
5.1 
INCLUSION CRITERIA ..................................................................................................................................... 19 
5.2 
EXCLUSION CRITERIA .................................................................................................................................... 19 
5.3 
STUDY TERMINATION CRITERIA .................................................................................................................... 20 
5.4 
STUDY ENROLLMENT PROCEDURES ............................................................................................................... 20 
5.4.1 
Recruitment............................................................................................................................................... 20 
5.5 
PROCEDURES FOR TRACKING SOURCES OF SUBJECTS AND THEIR DISPOSITION ............................................. 21 
5.6 
OBTAINING INFORMED CONSENT ................................................................................................................... 22 
5.7 
INTERVENTION GROUP ASSIGNMENT ............................................................................................................. 22 
6 
STUDY INTERVENTIONS ................................................................................................................................ 22 
6.1 
INTERVENTIONS, ADMINISTRATION AND DURATION ...................................................................................... 22 
6.2 
CONCOMITANT INTERVENTIONS .................................................................................................................... 25 
6.3 
ADHERENCE ASSESSMENT ............................................................................................................................. 25 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
7 
CLINICAL AND LABORATORY EVALUATIONS ................................................................................................ 25 
7.1 
SCHEDULE OF EVALUATIONS ......................................................................................................................... 25 
7.2 
TIMING OF EVALUATIONS .............................................................................................................................. 26 
4. 
REVIEW ADVERSE EVENTS .................................................................................................................................... 28 
6. 
COLLECT MEDICATION ................................................................................... ERROR! BOOKMARK NOT DEFINED. 
4. 
FASTING BLOOD DRAW AND SAFETY LABS ................................................................................................................ 30 
6. 
PCOSQ, CESD-R, STAI ..................................................................................................................................... 30 
10. 
REVIEW ADVERSE EVENTS .............................................................................. ERROR! BOOKMARK NOT DEFINED. 
11. 
COLLECT LOGS AND MEDICATION ..................................................................... ERROR! BOOKMARK NOT DEFINED. 
12. 
COGNITIVE QUESTIONNAIRES.......................................................................... ERROR! BOOKMARK NOT DEFINED. 
8 
STUDY RISK AND BENEFITS ........................................................................................................................... 30 
8.1 
RISK ............................................................................................................................................................... 30 
8.2 
PROTECTION AGAINST RISKS ......................................................................................................................... 32 
8.3 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO HUMAN SUBJECTS AND OTHERS ............................. 34 
8.4 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ......................................................................................... 34 
9 
STATISTICAL CONSIDERATIONS .................................................................................................................... 36 
9.1 
GENERAL DESIGN ISSUES ............................................................................................................................... 36 
9.2 
RANDOMIZATION ........................................................................................................................................... 36 
9.3 
OUTCOMES ..................................................................................................................................................... 36 
9.3.1 
Primary Outcome Measurements ............................................................................................................. 36 
9.3.2 
Secondary Outcome Measurements .......................................................................................................... 36 
9.4 
SAMPLE SIZE AND ACCRUALS ........................................................................................................................ 36 
9.4.1 
Sample Size and Power Calculations ....................................................................................................... 36 
9.4.2 
Statistical Analysis .................................................................................................................................... 37 
9.4.3 
Accrual ..................................................................................................................................................... 38 
10 
DATA COLLECTION, MONITORING AND ADVERSE EXPERIENCE REPORTING ............................................. 38 
10.1 
RECORDS TO BE KEPT ..................................................................................................................................... 38 
10.1.1 
Maintenance/Retention of site records ..................................................................................................... 39 
10.1.2 
Data Security ............................................................................................................................................ 39 
10.2 
ADVERSE EVENT REPORTING ......................................................................................................................... 39 
10.2.1 
Serious Adverse Events ............................................................................................................................. 39 
10.3 
DATA MONITORING ....................................................................................................................................... 40 
10.4 
STUDY MONITORING ...................................................................................................................................... 40 
11 
HUMAN SUBJECTS PROTECTION ................................................................................................................. 41 
11.1 
INSTITUTIONAL REVIEW BOARD (IRB) REVIEW AND INFORMED CONSENT ................................................... 41 
11.2 
SUBJECT CONFIDENTIALITY ........................................................................................................................... 41 
11.3 
STUDY MODIFICATION/DISCONTINUATION .................................................................................................... 41 
11.4 
DATA AND SAFETY MONITORING BOARD ...................................................................................................... 42 
12 
REFERENCES .................................................................................................................................................. 43 
 
FIGURE 1.  PREVALENCE OF METS IN WOMEN WITH PCOS, GEOGRAPHICALLY MATCHED CONTROLS AND AGED 
MATCHED NHANES POPULATION ................................................................................................. 10 
 
 
TABLE 2: RANDOMIZATION FASTING BLOOD TESTS ................................................................................... 28 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Acronyms 
 
American College of Cardiology 
ACC 
Adverse Event 
AE 
Cardiovascular Disease  
CVD 
Data Monitoring Committee 
DMC 
Diabetes Mellitus 
DM 
Data Safety Monitoring Board 
DSMB 
Insulin Resistance 
IR 
Lifestyle Modification 
LSM 
Metabolic Syndrome 
MetS 
Oral Contraceptive Pills 
OCP 
Polycystic Ovary Syndrome 
PCOS 
Oral Glucose Tolerance Test 
OGTT 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Study Synopsis 
 
Objectives 
To determine the effect of Oral Contraceptive Pills (OCP) verses Metformin verses OCP and Metformin on the 
prevalence of Metabolic Syndrome (MetS) and its components in overweight/obese women with Polycystic Ovary 
Syndrome (PCOS). 
 
Hypothesis 
OCPs increase the risk of MetS specifically by producing an atherogenic lipoprotein phenotype, increasing blood 
pressure and/ or body weight while metformin modestly decreases MetS risk by decreasing body weight and 
improving lipid phenotype. The combination of OCP and metformin (OCP, through lowering androgens, and 
metformin, through improvement in insulin sensitivity) will likely decrease the prevalence of MetS, thereby 
altering the risk profile for the development of diabetes and possible cardiovascular disease (CVD) in young women 
with PCOS. 
  
Patient Population 
The population will consist of 240 overweigh/obese women with hyperandrogenic PCOS, age 18-40 years old.  
Subjects must have a body mass index (BMI) between 25-48 kg/m².  Subjects will be diagnosed with PCOS defined 
by the Rotterdam criteria. 
 
Study Design 
This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial 
comparing OCP + placebo vs. Metformin + placebo vs. OCP + Metformin on the prevalence of MetS in women with 
PCOS.  This 6-month study will consist of a screening visit, followed by 5 study visits. No longer term follow-up is 
planned.   
 
Treatment 
The intervention will consist of randomizing subjects to one of three arms.  Subjects will either be assigned to OCP 
+ Placebo, Metformin + Placebo or OCP + Metformin. Metformin will be initiated in a step-up fashion using 
extended release pills as they are associated with fewer gastrointestinal side effects.  Subjects will begin with one 
tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose 
of metformin being 2000 mg. In regards to OCP, previous randomized clinical trials (RCTs) have shown that 20mcg 
ethinyl estradiol/norethindrone 1.0 mg was well tolerated.  The study will utilize a 20mcg OCP but a less androgenic 
third generation progestin (desogestrel 0.15mg) with potentially lesser impact on lipids and insulin sensitivity.  All 
subjects with no menses the 3 months prior to screening will be given medroxyprogesterone acetate, at the 
screening visit, after a negative pregnancy test (in order to induce menses).  Placebo pills will be administered to 
individuals randomized to OCP or metformin only in order to maintain study blinding.  Subjects will undergo 6 in 
person study visits and life style modification counseling regarding diet and exercise. Patient contact will be made 
via the subject’s preferred contact method after randomization and at the end of each month when there is no in 
person visit to ensure study compliance with medications, keeping study logs and to review side effects. 
 
Primary efficacy parameter 
Determine the prevalence of MetS after randomizing to OCP, metformin or OCP+metformin for 6 months. MetS 
will be defined by NCEP ATPIII criteria as the presence of at least 3 of the following 5 criteria: TG≥150mg/dl, HDL-
C<50mg/dl, BP≥130/≥85mmHg, WC>88cm and fasting glucose≥100mg/dl. 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Secondary/Tertiary efficacy parameters  
Assess change in HDL-C function, serum apolipoproteins, lipid particle size and number, body fat distribution, 
BMI, serum adipokines, HbA1c, glucose and insulin sensitivity, serum markers of inflammation, free fatty acids, 
androgens, quality of life parameters, cognitive testing and predictive factors for change in prevalence on MetS. 
 
Subjects will have the option to consent to storage of their blood for future additional analysis as related to the 
disease of interest.  No research/future analysis will take place, prior to gaining IRB approval. 
 
Statistical Analysis  
The primary analysis will use an intent-to-treat paradigm, wherein all randomized subjects are included according 
to their randomized treatment arm.  Data will be summarized using descriptive statistics for continuous variables 
and frequency statistics for categorical variables.  For the primary outcome of the presence of MetS at the end of 
the trial, logistic regression will be used with independent variables that include terms for the treatment arm and 
the 3 randomization stratification factors as covariates, with a contrast constructed to test for linear trend over 
the three treatment arms.  For secondary continuous outcomes, linear mixed-effect models will be fit to assess 
differences between the treatment arms with respect to changes in these outcomes over time.  The independent 
variables in the model will be treatment arm, time, the interaction of treatment and time and the 3 randomization 
stratification factors as covariates.    
 
Anticipated time to completion 
A total of 5 years (2017-2022) is anticipated.  3.5-year enrollment period (based on 3 subjects per site/month x 2 
sites), 6-month treatment period followed by time for analyses and interpretation of the data. 
 
Regulatory Compliance  
A data safety and monitoring board, led by Dr. Kathleen Hoeger, has been established to ensure that patient safety 
and 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   
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Study Objectives 
 
Primary Aim 
Our primary goal is to determine the effect of 6 months’ treatment with OCP vs. metformin vs. OCP + metformin 
on prevalence of MetS and its components in overweight / obese women. Implicit in the primary aim is clearly 
defining MetS, by NCEP ATPIII criteria as the presence of at least 3 of the following 5 criteria: TG≥150mg/dl, HDL-
C<50mg/dl, BP≥130/≥85mmHg, WC>88cm and fasting glucose≥100mg/dl; and the goal of tracking safety of our 
interventions throughout the study (through safety lab evaluations, vital signs and diaries). 
 
Secondary Aim 
The study will assess secondary outcomes such as defining the effects of OCP (lowering androgens) verses 
metformin (improving insulin sensitivity) verses OCP + metformin on body fat distribution, glucose tolerance, 
adipokines and markers of inflammation.  
 
1. Assess change in HDL-C function by measuring reverse cholesterol efflux capacity. 
2. Compare changes in serum apoliproteins and lipid particle size and number. 
Tertiary Aims 
 
1. Compare changes in total and visceral body fat distribution (DXA) and serum adipokines in the 3 arms and 
correlate with changes in serum and androgens and markers of insulin sensitivity. 
2. Identify changes in serum markers of inflammation and free fatty acids. 
3. Compare changes in anxiety, depression and quality of life parameters in all 3 arms. 
4. Compare changes in cognitive function scores in all 3 arms.  
5. Comparing response to treatment with presence of DNA polymorphisms 
 
 


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Background  
 
Rationale  
 
Treatment of PCOS 
Controversy exists regarding the optimal, long term management of overweight/obese women with polycystic 
ovary syndrome not attempting pregnancy.  It is well known that these women are at increased risk for 
development of Type 2 diabetes, dyslipidemia, metabolic syndrome and possibly cardiovascular disease due to 
insulin resistance (IR) and maybe hyperandrogenism.  In addition, the extent that racial differences in body fat 
distribution and dyslipidemia contribute to the differential burden of chronic disease in PCOS is unclear.  Although 
preventive treatments with oral contraceptive pills or metformin are widely used, international surveys show 
prescribing patterns differ amongst treating physicians (i.e. gynecologist, endocrinologist, or pediatricians).  In 
addition to different effects on menstrual cyclicity and hyperandrogenism, it is now clear that these different 
medical approaches also have varied metabolic effects possibly leading to adverse health consequences.  For 
example, in a NICHD-funded study, the University of Pennsylvania, PCOS Center recently uncovered a greater 
than 2-fold increase in MetS after treatment with low dose OCP for 4 months in overweight/obese women with 
PCOS. 
 
The few randomized clinical trials (RCTs) comparing OCP versus metformin use in overweight/obese women with 
PCOS show that with improvement in menstrual irregularity and hirsutism, OCP may increase metabolic risk by 
increasing triglycerides, blood pressure, body fat and weight.  Metformin on the other hand, improves metabolic 
profile by decreasing serum glucose, insulin, triglycerides and body weight, although it has modest effects on 
menstrual irregularity and hyperandrogenism.  These studies have several limitations including short study 
period, small numbers and the inclusion of Caucasian women only.  Moreover, none have evaluated the effect of 
interventions on the composite risk of MetS or examined underlying mechanisms leading to change in metabolic 
risk. It is clear that there are no evidence-based recommendations for the optimum and comprehensive medical 
management of overweight/obese women with PCOS.  The working hypothesis states that OCP, through lowering 
androgens, and metformin, through improvement in insulin sensitivity, will affect the prevalence of MetS thereby 
altering the risk profile for the development of diabetes and possible CVD in these young women. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.  Prevalence of MetS in women with PCOS, geographically matched controls 
and aged matched NHANES population 
 


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Metabolic Syndrome in PCOS 
In 2005, we reported that the age-adjusted prevalence of MetS was higher in women with PCOS (47.3%, 95% 
CI 35.3-56.9%) compared to geographically matched controls (4.3 %, 95% CI 1.9-7.6%, p < .001).  Even young 
women (< 30 years) had a high prevalence of MetS (Fig. 1).  PCOS phenotypes with hyperandrogenemia have a 
significantly higher prevalence or MetS compared to controls1,2,3. African Americans (AA) in the general 
population have less visceral adipose tissue (VAT) and lower TG levels compared to Caucasians4,5and our recent 
data shows significantly lower visceral fat measured in AA women compared to white women with PCOS. 
(Table1). 
 
Despite lower TG levels and less visceral adiposity, we found that AA women with PCOS ages 20-34 years have 
significantly increased risk of MetS compared to White women6 indicating racial disparity in cardiometabolic 
risk factors (Table 2). Inclusion of AA women in studies examining metabolic outcomes in PCOS is therefore 
critical and we will stratify our randomization by race. 
 
 
Table 2. Racial 
Disparity in MetS 
 
N 
Metaboli
c 
Syndrom
e 
BMI≥3
0 
kg/m2 
TG≥ 
150 
mg/dL 
HDL 
≤ 50 
mg/dL 
BP≥ 
130/85 
mmHg 
Glucos
e≥ 100 
mg/dL 
PCOS White 
2
22.6 % 
51.7
24.6
35.6% 
31.9% 
4.9% 
PCOS Black 
6
40 %** 
72.7
10.9
76.6% 
45.5% * 
18.8%
NHANES white 
2
14.9% 
66.1
15.5
39.9% 
3.3% 
9.0% 
NHANES black 
1
16.6% 
75.4
9.9% 
42.9% 
10.6%* 
8.3% 
 
 
Effect of OCP on MetS 
The OWL PCOS Study – We have recently completed an NIH funded study, OWL- PCOS at PENN and Hershey 
examining the effects of pretreatment with low dose OCP (20ug ethinyl estradiol) versus weight loss 
interventions for 16 weeks, on pregnancy rates in overweight/obese women with PCOS7. Surprisingly, the OCP 
arm showed a significant increase in MetS [OR=2.47; 95% CI 1.42, 4.27]; with no change in the intensive Lifestyle 
modification with pharmacotherapy arm [OR=1.18; 95% CI 0.63, 2.19)] or Combined arms [OR=0.72; 95% CI 0.44, 
1.17]. The conversion rate to MetS was 28% in the OCP arm with significant increase in TG levels, and trend 
towards increase in BP and fasting glucose levels. Interestingly, we noted a significant decrease in VAT after 
treatment with OCP (Table 3) but an increase in glucose AUC. Our study suggests early onset metabolic 
dysfunction only in the OCP group, and this was attenuated in the Combined group with the addition of lifestyle 
modification associated with weight loss.  We have previously shown that women with PCOS have a high risk for 
depressive disorders (OR 5.11 95% CI 1.26- 20.69; P<.03)8 and this risk persists over time9. In the OWL-PCOS study 
there was in fact an improvement in depressive symptoms and health related quality of life scores with OCP 
treatment7. These findings underscore the need for a clinical trial to comprehensively compare the effectiveness 
of therapeutic alternatives with specific focus on metabolic outcomes in addition to gynecological, 
dermatological and mood changes. Understanding the associated pathophysiological changes will add great 
value to this clinical trial. 
Table 1. Differences in BMI-matched AA and 
White women with PCOS  Mean (SD) 
AA 
N=48 
White 
N=48 
Difference of 
means 
P 
value 
Triglycerides mg/dl 
96 (66-120) 
117 (96.5-156.8) 
0.7 (0.6, 0.9) 
0.01 
% Fat in largest Visceral Fat region 
46.2 (5.4) 
48.7 (5.1) 
-2.5 (-4.3, -0.7) 
0.01 
% Fat in middle Visceral Fat region 
41.2 (5.1) 
44.4 (4.9) 
-3.2 (-4.8, -1.6) 
<.001 
% Fat in inner-most Visceral Fat region 
39.1 (4.9) 
43.0 (4.9) 
-3.9 (-5.5, -2.3) 
<.001 


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Table 3. Effect of OCP on Visceral  Adipose 
Tissue 
Mean Change from Baseline (95% 
CI) 
P-
valu
Fat Tissue in largest Visceral Fat region (g) 
-66.3 (-127.1, -5.5) 
0.03 
Fat Tissue in middle Visceral Fat region (g) 
-47.9 (-91.8, -4.1) 
0.03 
Fat Tissue in inner-most Visceral Fat region 
(g) 
-40.0 (-78.4, -1.5) 
0.04 
 
HDL-C function and lipoprotein analysis in PCOS 
There is increasing evidence showing measures of HDL-C function are more useful than HDL-C levels as 
predictors of CVD risk10,11. In collaboration with Dr. Nehal Mehta, Chief of Inflammation and CV Medicine at 
NIH/NHLBI, we reported no difference in HDL-C levels but a significant reduction in cholesterol efflux 
capacity in PCOS women12 (Table 4). We found a significant negative association between testosterone 
levels and ApoA1 and HDL-C efflux. Women with PCOS also had significant elevation in the atherogenic 
particles, large VLDL and small LDL, independent of obesity12. 
 
 
 
Table 4. Standard 
lipid and Lipoprotein 
PCOS n=124 
Controls n=67 
Difference of means 
P value 
Total Cholesterol 
192.5±37.9 
189.7±34.5 
-2.8(-13.9, 8.2) 
0.6 
HDL-C mg/dL 
54.7 ±16.1 
57.5± 17.9 
2.8 (-2.2, 7.9) 
0.2 
LDL-C mg/dl 
167.1 50.8 
154.9 43.9 
-12.7(-27.4,2.07) 
0.09 
Triglycerides mg/dl 
146.5 92.9 
112.2 69.9** 
-34.3 (-60.4,-8.2) 
0.01 
HDL-C function- 
Cholesterol efflux  
0.96 
(0.86-1.06) 
1.05 
(0.91-1.18)* 
0.07 (0.17, 0.12) 
0.005 
NMR spectroscopy 
Large VLDL nmol/L 
4.04±3.7 
2.37±1.73 
-1.6 (-2.7,-0.63) 
0.002 
VLDL particle size 
49.58±6.04 
46.78± 5.28 
-2.7(-4.7,-0.88) 
0.004 
Small LDL nmol/L 
652.91 ±367.95 
434.3± 280.7 
-218.57(-330,-106) 
0.0002 
 
 
Impact of OCP vs. metformin on HDL-C function and lipoprotein analysis in PCOS 
We have preliminary data using samples from the OWL PCOS study7 (OCP arm) and PPCOS1 study (metformin 
arm)111 showing significant increase in HDL-C efflux with both OCP and metformin treatments. (Table 5) However, 
this benefit is offset in the OCP group by a significant atherogenic effect, increased sLDL and VLDL particles. 
 
Table 5. Impact of 
OCP versus 
metformin on 
OWL PCOS-OCP arm n=34 
PPCOS1-Metformin arm n=98 
Mean Change from 
Baseline (95% CI) 
P-value 
Mean Change from 
Baseline (95% CI) 
P-value 
HDL-C efflux 
0.10 (0.05, 0.16) 
0.001 0.08 (0.04, 0.11) 
<.0001 
HDL-Cmg/dl 
3.6 (0.1, 7.1) 
0.04 2.2 (-0.2, 4.5) 
0.07 
HDL-Particles 
4.2 (1.9, 6.5) 
0.0004 0.9 (-0.6, 2.5) 
0.23 
LDL-Cmg/dl 
11.7 (0.6, 22.7) 
0.04 4.5 (-2.9, 11.8) 
0.23 
LDL-particles nmol/L 222.8 (98.6, 347.1) 
0.001 51.4 (-31.4, 134.2) 
0.22 
Small LDL nmol/L 
190.1 (113.1, 267.1) 
<.0001 13.3 (-38.4, 64.9) 
0.61 
Large VLDL nmol/L 
206.2 (90.5, 321.9) 
0.001 47.8 (-29.3, 125.0) 
0.22 


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PCOS and adipocyte dysfunction 
We have reported significantly lower serum adiponectin and higher leptin12, hsCRP13 and FFA levels12 in women 
with PCOS reflecting adipocyte dysfunction. Adipose tissue is a major source of FFA and inflammatory 
cytokines14,15which are drivers of CRP production in the liver 16,17. 
Polycystic ovary syndrome (PCOS), which affects 5-15% of reproductive age women, has been linked to a high 
prevalence of cardiometabolic risk factors, namely type 2 diabetes (DM), obesity, dyslipidemia and hypertension2. 
The co-occurrence of these risk factors suggests the existence of metabolic syndrome (MetS), a clinically validated 
marker for identifying high-risk subjects predisposed to cardiovascular disease (CVD)18,19. The CVD risks of Mets 
and DM have been shown to be higher in women20,21and more importantly the association between MetS and 
CVD is shown to be more pronounced in younger women warranting aggressive preventive therapy14 
. In our own studies, the prevalence of MetS in women with PCOS is significantly increased from a young age23 and 
is higher in the hyperandrogenic phenotype3. In a meta-analysis, including 2,256 PCOS women and 4,130 controls, 
the OR for MetS was 2.2 (95% CI 1.36-3.56) independent of obesity24.  
 
Longitudinal studies in this population demonstrate a persistent increase in risk of DM, dyslipidemia and 
hypertension over a twenty-year period10, an increase in serum markers of CVD25,26and evidence of subclinical 
atherosclerosis27. In addition, perimenopausal and post-menopausal women with symptoms suggestive of PCOS 
have a higher risk of CV events28,29further linking PCOS to CVD later in life. Finally, it should be highlighted that, in 
addition to health consequences, these metabolic comorbidities along with gynecological and dermatologic 
concerns, contribute significantly to the financial (~$4.36 billion annually) and emotional burden of PCOS30,31. 
Collectively, these data support the notion that PCOS is associated with significant CV risk starting in early 
reproductive life and possibly continuing through menopause. It is striking that evidence based data on treatments 
for overweight/obese women with PCOS not seeking pregnancy is descriptive, limited and mixed. In fact, there are 
conflicting clinical guidelines from several medical societies32,33,34for first line management recommending either 
oral contraceptive pills (OCP) or metformin (insulin sensitizer). Surprisingly, the increased risk of MetS in this ‘at 
risk’ population as a consequence of taking these medications was unknown till recently. In the OWL-PCOS study, 
an NIH funded RCT21 we recently reported an increased risk of MetS (OR=2.47; 95% CI 1.42, 4.27) in obese women 
treated with OCP for 16 weeks. It is clear that comprehensive treatments addressing common complaints such as 
menstrual irregularity and hirsutism whilst improving metabolic risk are urgently needed. It is therefore proposed 
COMET PCOS, a randomized clinical trial to compare the effects of OCP vs. metformin vs. OCP+metformin on the 
risk of MetS in young overweight/obese women with PCOS. 
 
 
OCP use in women with PCOS 
OCP are effective first line therapy as they regulate menses and improve acne and hirsutism by significantly 
lowering bioavailable androgens in PCOS35,36. Decreasing androgens with OCP may have additional but relatively 
unexplored benefits in PCOS as elevated androgens may adversely affect insulin sensitivity, adipocyte function and 
fat distribution37. Some studies in women without PCOS suggest that OCP use is associated with glucose 
intolerance38,39hypertension40, elevated CRP levels41,42and dyslipidemia (especially hypertriglyceridemia) 43,44. 
Therefore, it can be hypothesized that OCP use may increase CVD risk especially given the high prevalence of 
obesity (50-80%) and hypertriglyceridemia in PCOS2. However, in a meta-analysis, treatment with OCP was 
associated with paradoxical changes in lipids, increase in triglycerides (TG) and high-density lipoprotein (HDL-C) 
levels, with no significant change in fasting glucose, low density lipoprotein (LDL-C) and insulin resistance (IR) in 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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women with PCOS45. Further the impact of only one abnormal metabolic risk factor versus clustering of metabolic 
components on long term risk of DM and CVD in this population is unknown. None of these studies have examined 
MetS, a validated predictor of cardiometabolic risk, as a composite outcome. In the OWL-PCOS study pre-
conception treatment of obese women with OCP resulted in an increased risk of MetS7. 
 
Metformin as an alternative treatment for women with PCOS 
Women with PCOS have a greater degree of insulin resistance (IR) compared to age and weight matched controls46 
with defects in insulin-mediated glucose transport47,48 and GLUT4 production49,50. Given the role of 
hyperinsulinemia/IR in the development of hyperandrogenism and disordered folliculogenesis, metformin is the 
most extensively used insulin sensitizing drug and often first line treatment of PCOS51,52. In the general population, 
it decreases the risk of DM and CV events in adults53,54and in children and adolescents with IR or pre-diabetes 
metformin improves insulin sensitivity55 and may reduce BMI56. Metformin use in PCOS improves the frequency 
of menses and decreases androgens but less effectively compared to OCP making it less desirable as a first line 
agent57. However, metformin has a favorable impact on metabolic profile by decreasing fasting insulin and hsCRP 
levels, blood pressure53,58 and is associated with modest weight loss in women with PCOS 59,60,61,62. These studies, 
which are limited by size, randomization and short treatment duration, although suggestive of improvement in 
metabolic risk, are not conclusive. Lifestyle modification, another first line treatment in PCOS, is associated with 
poor adherence and sustainability. In a meta-analysis (608 women) use of metformin with lifestyle changes was 
associated with significantly lower BMI and improved menstruation compared to lifestyle changes alone63.  
 
OCP vs. metformin 
Very few RCTs have examined the effects of metformin versus OCP specifically in overweight/obese women with 
PCOS. A Cochrane systematic review (4 studies, 104 subjects) concluded that treatment with OCP is associated 
with improvement in menstrual pattern and serum androgen levels compared with metformin; but metformin use 
decreases fasting insulin and TG levels compared with OCP use64,65,66,67,68. All these studies were conducted in 
Europe using a progestin that is not available in the US (cyproterone acetate) limiting the generalizability of these 
findings. These studies do not provide evidence for any single treatment of choice and lack data on important 
clinical outcomes such as the development of MetS or DM69. 
 
OCP vs. metformin vs. OCP + metformin 
It is suspected that the combination of OCP+metformin may be an appropriate comparator to address 
gynecological, dermatologic and metabolic end points in PCOS. Only one clinical trial has included three arms 
namely OCP vs metformin vs OCP+metformin but included lean and obese women (n=65) with PCOS70 showing 
improvement in body fat distribution in the OCP+metformin arm71. 
 
This clinical trial examined traditional CV markers, lacked mechanistic data and most importantly was not powered 
to provide clear recommendations. Overall these limited data present a clinical conundrum and underscore the 
need to answer important clinical questions; do OCP increase the risk of MetS in overweight/obese women with 
PCOS, can metformin mitigate these effects and therefore will the combination of OCP+metformin offer the best 
outcomes for improving menstrual regularity, decreasing hyperandrogenism and improving CV risk? 
 
Further complicating matters, PCOS treatment practice patterns vary depending on the physician (i.e. pediatrician, 
gynecologist or endocrinologist) treating adolescent and adult women with PCOS not seeking fertility. In physician 
surveys metformin was noted to be preferentially used by Australian and European endocrinologists72,73while 
pediatricians and gynecologists practicing in the US frequently prescribed OCP as first line therapy74. Besides 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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competing guidelines from several international medical Societies, 32,33,34,75 there are no formal recommendations 
for CV risk stratification prior to prescribing these medications1. Although the best therapeutic approach for MetS 
is lifestyle modification, such programs alone have high dropout rates necessitating pharmacotherapy to achieve 
and maintain weight loss76. It is therefore critical to identify appropriate medical therapy whilst avoiding 
medications that might alter the risk of MetS in this young but high risk population. The overall goal of COMET-
PCOS is to provide practitioners with evidence for the selection of the most appropriate treatment for 
overweight/obese women with PCOS by carefully defining the clustering of metabolic risks and benefits associated 
with three interventions - OCP, metformin or OCP+metformin. 
 
Effects of OCP vs. metformin vs OCP + metformin on individual components of MetS 
There is some controversy regarding the predictive value of clustering of risk factors i.e. MetS versus the individual 
risk factors being independently associated with DM/CVD77. Therefore, evaluating the effects of OCP and/or 
metformin on each component of MetS can provide critical and novel mechanistic insights about the pathways 
altered by these treatments. 
 
Dyslipidemia 
Although PCOS is associated with low HDL-C levels and high TG1 and OCP use increases both HDL-C and TG levels, 
it is not clear how the interaction of these diametrically opposite alterations impacts the potential risk of coronary 
artery disease (CAD). While it may be beneficial that the estrogenic component of OCP increases HDL-C78,79, drugs 
such as the cholesterol ester transfer protein inhibitor torcetrapib and niacin that increase HDL-C, have failed to 
reduce CV events in clinical trials80,81. Two large studies recently indicated that HDL-C function may be a better 
marker of CVD outcomes independent of HDL-C levels10,11. We were the first to report significant reduction in 
cholesterol efflux capacity, a metric of HDL-C function, in PCOS12. While no gender differences have been described 
in HDL-C efflux82, it is unclear if hyperandrogenemia, IR or inflammation affects HDL-C function in PCOS83,84. Both 
hypertriglyceridemia, the commonest lipid abnormality in PCOS, and loss of function mutations of Apo C3 are also 
predictive of CHD85,86. In IR states, adipocytes increase free fatty acid (FFA) production14 and the liver subsequently 
increases TG and VLDL synthesis15 providing the substrate for increased atherogenic small (s)LDL particles87,88. 
Lipoprotein subclass profiles measured by nuclear magnetic resonance (NMR) spectroscopy are not fully apparent 
on a conventional lipid panel. sLDL and sHDL are associated with incident DM89 and IR90,91and are superior to 
standard LDL-C measurements in prediction of future CV events92. Of note, metformin therapy improved NMR 
measured lipoprotein profile in the Diabetes Prevention Study93. Therefore, as a secondary aim evaluating the 
effects of OCP, metformin and OCP+metformin on detailed lipid phenotyping will provide novel data to define the 
precise atherogenic impact of each study arm. 
 
Visceral adiposity 
Waist circumference is independently and strongly associated with DM, particularly in women94,95. Young women 
with PCOS have a twofold increased risk of DM9 independent of obesity96. It is however unclear if visceral adiposity 
in PCOS is similar97,98,99or increased 100,101,102 compared to controls. Studies examining change in body fat 
distribution after medical treatment in PCOS are also few and contradictory. While androgens may predispose to 
central body fat distribution103, OCP use, despite a decrease in androgens, has been associated in some studies 
with an increase in total and visceral fat mass104,105,106. On the contrary, metformin increases insulin-mediated 
glucose uptake in visceral adipose tissue, thereby increasing the re-esterification of FFA107,108. However, clinical 
studies in PCOS also show mixed results on the effects of metformin on visceral adiposity70,109,110. These 
controversies underscore the need to systematically evaluate change in visceral fat distribution with OCP and/or 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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metformin use in order to understand its contribution to risk factors such as dyslipidemia, inflammation and 
altered glucose tolerance. 
 
Adipokine and cytokine secretion 
Visceral adiposity is associated with adipocyte dysfunction, characterized by inflammation and impaired 
adipokine secretion. Leptin secretion rises in parallel with fat expansion in adipocytes111 and elevated leptin 
levels have been described in PCOS compared to weight matched controls112. Adiponectin, on the other hand, 
which has insulin-sensitizing, anti-atherogenic and anti-inflammatory properties, and is inversely associated with 
MetS and independently predicts DM113, has been shown in a meta-analysis to be significantly lower in PCOS114. 
This observation was independent of obesity and testosterone, but associated with IR. The impact of metformin 
or OCP therapy on changes in adiponectin are mixed67,68,69,115,116 possibly related to differential actions on the 
liver and adipose tissue. Adipocytes also secrete inflammatory cytokines and a meta-analysis confirmed 
significantly higher levels of hsCRP in PCOS25. Metformin treatment is associated with decreased hsCRP117 and IL-
6 levels in PCOS65,118. Precisely defining the effects of OCP and/or metformin use on adipokines and 
inflammatory cytokines will better assess the impact of these treatments on underlying pathophysiological 
processes associated with adipocyte dysfunction. 
 
In summary, evaluation of MetS risk modification associated with treatments such as OCP and/or metformin in a 
high risk PCOS population is urgently needed and will have a major impact on current clinical practice.  
 
 
 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Implications for the COMET-PCOS Trial  
This project brings together a multidisciplinary exceptionally well-qualified team with demonstrated expertise 
in reproductive endocrinology, cardiometabolic risk assessment and inflammation and clinical trials to study 
two major health issues namely, PCOS and MetS. Our study includes four highly innovative components: 
 
First Due to lack of evidence there is currently no consensus regarding the medical management of overweight/ 
obese women with PCOS. OCP and metformin, though currently in use, have differing treatment outcomes and 
safety profiles, resulting in conflicting guidelines for use in PCOS. COMET-PCOS will be the first 3 arm clinical trial 
to be adequately powered to provide evidence for single agent versus combination therapies for medical 
management of PCOS. It will have significant impact on current clinical practice paradigms much like the impact 
of the PPCOS1 trial (Clomid versus metformin versus clomid+metformin)111. 
 
Second Based on our recent findings from OWL-PCOS we have included MetS as a composite endpoint to provide 
comprehensive assessment of early CVD risk in this young population. 
 
Third We have included innovative mechanistic secondary aims and will apply novel concepts to the assessment 
of dyslipidemia, the commonest metabolic abnormality in PCOS. We will measure HDL-C function (cholesterol 
efflux capacity) and lipoprotein particle size and number using NMR spectroscopy to clearly define the 
atherogenic impact of the three therapeutic interventions. 
 
Fourth Recognizing that there are racial disparities in metabolic components in PCOS, we will stratify the 
randomization in our primary aim by race. This will provide unique observations of potential importance. 
 
 
 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Study Design 
 
Figure 2: COMET-PCOS Study Flowchart 
 
 
Overview 
The flowchart (Figure 2) summarizes this study which will consist of medical treatments commencing with 
randomization at equal allocation (1:1:1) to three interventions OCP, metformin and OCP+metformin for a 
duration of 6 months. The primary outcome will be change in prevalence of Mets in each group. The secondary 
outcomes include assessment of HDL-C efflux, lipoprotein particle size and number, glucose tolerance, body fat 
distribution and measurements of markers of inflammation. 
Treatment Design 
This will be a three-arm, multi-center, prospective randomized trial of three types of medication treatment in 
overweight/obese women with hyperandrogenic PCOS who will be randomized to either OCP + placebo, 
metformin + placebo or OCP + metformin.  All subjects will also receive lifestyle modification counseling regarding 
diet and exercise.  
The appropriate study candidates will be recruited from the University of Pennsylvania (Penn) or Pennsylvania 
State University, Hershey Medical Center (PSU).  Recruited subjects will meet the inclusion and exclusion criteria 
detailed below.  Monitoring of this trial at both sites will be conducted by the Penn designated monitor for the 
Women’s Health Clinical Research Center at the University of Pennsylvania, with progress reports provided to the 
Data and Safety Monitoring Board (DSMB) no less than every twelve months in order to review trial progress and 
subject safety.  
Study Population 
Two-hundred forty (240) overweight/obese women with hyperandrogenic PCOS not seeking pregnancy, age 18-
40 years, will be enrolled in the participating sites.  The overall goal of the inclusion/exclusion criteria is to identify 
a population of healthy women who are between 25-48 kg/m².  Subjects will have a history of androgen excess 
and chronic anovulation or PCO appearing ovaries.  If existing medical records are used to verify inclusion or 
exclusion criteria, the site should keep a copy of these in the source documents.  A one-month wash-out period (6 
month wash out in the case of injectable hormonal contraceptive) will be required for medications prior to 
screening (most common OCP and metformin).  Medications that subjects are required to wash-out are included 
in the MOP and questions can be directed to the Principal Investigator at each site. 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Selection and Enrollment of Subjects 
 
Inclusion Criteria 
 
1. Women ≥ 18 to ≤ 40 years of age (at the time of screening), with hyperandrogenic PCOS. 
2. Subjects will be diagnosed with PCOS defined by the most up to date Rotterdam criteria based on: 
a. Androgen excess  
And 
b.  polycystic ovaries. 
Or 
c. A history of chronic anovulation or spontaneous periods. 
 
3. BMI ≥ 25 kg/m² to ≤ 48 kg/m² obtained at screening visit. 
4. In good general health according to the investigators discretion 
5. Willing to avoid pregnancy for the duration of the study. 
 
Exclusion Criteria 
 
1. Current pregnancy or desire of pregnancy during course of study 
2. Currently breastfeeding 
3. Known 21 hydroxylase deficiency or any form of congential adrenal hyperplasia (CAH) 
4. Untreated thyroid disease (TSH ≤0.45 mlU/mL and ≥ 4.5 mlU/mL) 
5. Untreated hyperprolactinemia (2 Levels≥30 ng/ml at least one week apart) 
6. Type 1 or type 2 Diabetes Mellitus currently receiving anti-diabetic agents, (subjects may wash out from 
metformin if taking the drug for another indication.) 
7. Liver disease (AST/ALT≥2 times normal or a total bilirubin ≥2.5 mg/dL)  
8. Renal disease (BUN≥30 mg/dL or serum creatinine ≥1.4 mg/dL) 
9. Anemia (hemoglobin ≤10 mg/dL)  
10. current history of alcohol abuse (≥ 22 drinks/week in the past 3 months) 
11. Poorly controlled hypertension defined as average systolic blood pressure >= 150 mm Hg or average 
diastolic ≥100 mm Hg obtained on three measurements obtained 5 minutes apart. If treated, average 
systolic blood pressure ≥140 mm Hg or average diastolic ≥90 mm Hg 
12. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma 
13. TG≥250mg/dl  
14. Current Use of lipid lowering or weight loss agents  
15. Current use of hormonal contraceptives such as oral contraceptives, depo progestin, or hormonal implants  
16. Participation in any study of an investigational drug or device or biological agent within 30 days 
17. Suspected adrenal or ovarian tumor secreting androgens 
18. Suspected Cushing’s syndrome 
19. Bariatric surgery procedure in the recent past (≤12 months) 
20. Absolute contraindications to the use of hormonal contraceptives or metformin (details in MOP)  
22. subjects who are unable to comply with the study procedures, (In the opinion of the investigator, ) 
*Note: the study will allow rescreening of subjects. When subjects are re-screened a new consent form will be 
signed and a new study number will be assigned. 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Study Termination Criteria 
1. Development of diabetes as defined in the manual of procedures 
2. Development of hypertension as defined in the manual of procedures  
3. Unable to tolerate study medications due to side effects 
4. Pregnancy (women found to be pregnant will be referred to prenatal care) 
5. Miss more than 2 consecutive visits (unless excused by the PI) 
 
 
Study Enrollment Procedures 
Recruitment 
We do not anticipate difficulty with the completion of this trial as our study team has demonstrated the ability to 
recruit a similar population in several previous trials (PCOS studies completed by UPenn and PSU: OWL-
PCOS/PPCOS1 /PPCOS2). At both sites we have expert investigators in PCOS to improve external validity and to 
help overcome any possible recruitment barriers. Subjects recruited at UPenn are drawn from a four state area 
including Pennsylvania, New Jersey, Delaware, and Maryland. Dr. Dokras directs the Penn PCOS center which is 
located at 2 sites (Philadelphia city and in a suburban location - Radnor) and she sees approximately 1000 
visits/year exclusively for PCOS. UPenn also has a high patient volume in Reproductive Endocrinology with 
22,000 patient visits per year. Hershey Medical Center is the only academic medical center between Philadelphia 
and Pittsburgh with a large referral area. They have recruited subjects from areas as far away as Scranton/Wilkes 
Barre (90 miles) to the northeast, and Altoona (150 miles) to the West, Harrisburg (12 miles), York (30 miles), 
Lancaster (20 miles), State College (90 miles), Williamsport (90 miles), and Allentown (85 miles).   The location of 
the two sites, University of Pennsylvania (UPenn) in an urban setting, and Hershey Medical Center (PSU) in a 
rural/suburban setting will allow us to recruit from a representative sample of the population. 
 
Clinical Practices of Investigators 
Women presenting to the clinical practices of Dr. Dokras, Dr. Mainigi, and Dr. Legro for consultation for PCOS (after 
clinical confirmation of their potential eligibility for admission into the study based on inclusion and exclusion 
criteria) will be approached to participate by the research coordinator or non-care providing physician.  In the 
recruitment visit, study details including the intervention will be explained.  Risks and benefits will be thoroughly 
discussed and consents given to the patient prior to any study procedures being performed. The drugs being 
utilized in this study are commonly used in current practice and may be familiar to the women interested in 
participating in the study.  
 
Hospital/Local Health Care Referrals 
Subjects will be recruited at each site from individual practice(s) of the investigators as noted above as well as 
faculty/resident clinics.  Ongoing contact with practice and faculty members as well as with residents will be made 
by the investigators and coordinators, reminding them of the inclusion criteria, importance of the study, etc.  In 
addition, the investigators will describe the study to members of other departments in the hospital, primarily 
family practice, medical endocrinology, and gynecology who also see and treat these patients.  Contact with local 
physicians will be made and/or grand rounds will be given to disseminate information about the study. Letters will 
be mailed or emailed to potential subjects which provides details of the study and contact information of the study 
team (to allow for subject to reach out for more information). Penn Datastore as well as electronic medical record 
(EMR) recruitment tools such as SlicerDicer and best practice announcements (BPA) (and PSU, CHOP equivalents) 
may be utilized to provide a list of potential subjects based on clinical practice information.  


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
 
Referrals from Study Participants 
Study participants often refer friends, acquaintances and colleagues to be potential participants.  
A subject referral-based payment structure will be added to increase recruitment. Prior study participants who have given 
their permission for re-contact that are not Penn Employees will be contacted to give them the opportunity to refer 
individuals to our study. For each individual referred who qualifies as eligible, the prior participant will get $25. The referral 
period will last until the study team determines the budget to support this type of referral is no longer available. The study 
team will inform the prior participants at that time of the ending of the referral-based payment program. 
 
Previous Study Participants 
The trial will be offered to women who have previously participated in clinical trials offered by the study team, 
who have consented to be contacted for future participation via their preferred contact method (after 
confirmation of their potential eligibility for admission into the study based on inclusion and exclusion criteria). 
Local Advertisements 
Advertisements will be placed in local newspapers and run on local television networks / radio near Penn and 
PSU and will be continued on a regular basis if response is good. SEPTA advertising through regional rail, Market-
Frankford line and Broad Street Line has been a top source of recruitment in the pass and may be utilized again. 
 
Contact with PCOS support groups 
Contact will be made with both national and local support groups to spread information about the study through 
informational brochures and/or participation in local meetings if necessary.  
 
Web sites 
The study will be prominently displayed on the local (Penn, PSU, CHOP) web site.  Additionally, each center will 
have a web page devoted to this study with general as well as contact information. Information will also be 
available at clinicaltrials.gov. Social Media and Craigslist will also be utilized, as this has been a proven source of 
recruitment in the past. For ads placed on social media, specifically Facebook and Instagram, they will be one-way 
adds and the study team will not directly interact with subjects on social media.  The ad will highlight a contact 
number for the interested individual to call to discuss the study.  Social media ads will be monitored by the 
University of Pennsylvania study coordinator to ensure they are properly being featured and not causing 
inappropriate comments. This monitoring will occur bi-weekly.  If any problems arise with the social media ad they 
will be immediately removed however this is not anticipated as they are one-way ads. This type of advertising has 
been previously used for studies within the department and has been well received. 
 
IRB Approval  
It is expressly acknowledged that all informational material that could be construed to be advertising will be 
approved by the central IRB prior to dissemination.  
 
Procedures for Tracking Sources of Subjects and their Disposition 
We will track all contacts from subjects interested in the study.  We will develop a pre-screening list that 
documents date and point of contact, eligibility based on telephone screening or survey, and follow-up if subject 
meets prescreening and is interested in further participation.  The consent form may be mailed or emailed prior 
to the screening visit which is the next point of contact. 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
Obtaining Informed Consent 
Once potential women have been prescreened, they will be referred to the site clinical coordinator or his/her 
designee for a screening visit.  The consent process will be conducted according to each site’s standard operating 
procedures.   
Inclusion and exclusion criteria will be reviewed.  After the study has been completely explained to the woman, 
she 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 confirm the woman’s willingness to be contacted, and set up a 
tentative timeframe to be back in touch with the subjects.  The consent can be signed once all questions have been 
answered to the satisfaction of the potential subject.  A signed informed consent document, approved by the 
central IRB, will be confirmed on all subjects prior to the baseline evaluation.   
In order to be eligible for enrollment and randomization, the woman must be confirmed to meet all inclusion and 
exclusion criteria described above.   
 
Intervention Group Assignment 
After screening is completed the information will be uploaded in RedCAP electronically, and randomization will be 
performed by IDS at the time of the randomization visit.   Subjects and study coordinators will not be informed of 
their treatment assignment.    
Study Interventions 
 
Interventions, Administration and Duration 
Study Medication: All subjects will be randomized to receive either OCP + placebo, Metformin + placebo or OCP + 
Metformin for 24 weeks.  All medications will be self-administered.  Once eligibility has been confirmed and 
subjects have been randomized, the site staff will distribute appropriate medications during each visit. The subject 
will receive enough pills to last until the next visit (additional pills for each arm will be distributed at the start of 
the study for situations if/when the visit window must be utilized; subjects will receive appropriate instructions 
regarding the extra medication). Subjects will be required to wash out of any excluded medications prior to 
enrollment in the study. 
 
Medication Compliance: Medication bottles will be returned at visits 3 through 6 unless a remote visit is being 
conducted at the discretion of the PI. IDS will perform pill reconciliation during these visits to measure 
medication compliance. Medication compliance can also be assessed by reviewing the returned subject diaries. 
Compliance is assessed during the monthly visits on site or remote contact with the subject. Non-compliant 
subjects will be reminded of the importance of taking the medication properly. 
 
 
Life Style Modification (LSM): In addition to taking study medication, all subjects will receive counseling (through 
the use of handouts) about diet and exercise at the randomization and 16 week visit.  The diet is based on the 
lifestyle modification protocol of the look AHEAD study and POWER-UP trial. The study will follow the Diabetes 
Prevention Program recommendations for increasing physical activity.  A similar protocol was utilized in OWL-
PCOS and similar written materials will be provided to all subjects in the current trial.  Assessment of dietary intake 
will be based on NCI created automated self-administered 24-hour (ASA24) food recall tool.  This will allow us to 
access variability in dietary intakes in the 3 arms of the study.  


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Cognitive Testing: All subjects will undergo cognitive functioning testing via the NIH Toolbox, a comprehensive 
set of neuro-behavioral measurements that quickly assesses cognitive, emotional, sensory, and motor function. 
Audio-recording of cognitive testing is optional (all recordings will be deleted after transcription).  The NIH 
Toolbox is assessing cognition for subject (age3-85), thus eliminating a ceiling effect. Staff will be trained to 
administer the tests. Training is performed online via the NIH Toolbox website. Any additional training or 
oversite will be done by a Clinical Neuropsychologist. During testing staff will audio record cognitive testing with 
subjects to verify answers given in a timely matter. All audio recordings will be consented for by the subject prior 
to recording and will remain on file for less than 24 hours at which point they will be deleted. One patient 
recording from each certified staff member will go to the Clinical Neuropsychologist to verify standardization. A 
description of the neuropsychological assessments includes:  
Neuropsych assessments: 
• Controlled Oral Word Association (COWA): subjects must spontaneously name as many words as 
possible beginning with a given letter within a 60 second span. 
• Category fluency: subjects must spontaneously name as many objects as possible that fit a given 
category within a 60 second span. 
• Logical memory: subject is read the first story and recalls as many details as possible. The subject is then 
read a second story and must recall as many details as possible about that story; second story and recall 
is repeated. Following a delay of 25-35 minutes, the subject must again recall as many details of each 
story as possible.  
• Digit Span: subject is read a string of numbers and must repeat the numbers back to the examiner in 
either the exact same order (DS forward) or in reverse order (DS backward). Number strings increase in 
length by one number with each successful turn, and discontinued when patient makes an error. Score is 
the longest string a patient can successfully repeat back. 
• Digit symbol substation: Testing page shows a key at the top, which contains the numbers 1-9, each 
paired with a special symbol. Below the key, subjects must fill in the numbers that match a grid of special 
symbols as quickly as possible, based on the key above. 
• Rey-Osterreith Figure: subject copies the complex figure from the stimulus page. The stimulus is 
removed and the patient then immediately redraws as much of the figure as they can (immediate recall 
score).  
• Pegboard: subject is tested with both dominant and non-dominant hands on how quickly they can fill in 
a pegboard. Each peg has a groove, which must be perfectly matched with the groove of the hole in 
order to fit. Score based on time to complete. 
• Trail making: Numbers are scattered over a page and the subject must connect the numbers in 
numerical order; score derived from both number of errors and time to complete. Executive function 
can be tested by requiring patients to connect numbers in an alternating fashion between two colors, 
i.e. yellow 1-pink 2-yellow 3- pink 4, etc. Score still derived from both errors and time to complete. 
• Visual Puzzles: Subjects are shown a 2D item that they are to imagine as a puzzle made from 3 pieces. 
The subject indicates which 3 pieces fit next to each other without stacking to make the given item. Each 
item has a 30 second time limit, with a discontinuation rule of 3 errors in a row.  The score is based on 
time and errors. 
 
Urine Pregnancy Test: A urine pregnancy test will be performed for all subjects at every visit. If a positive result is 
found, the subject will be informed by site staff of positive result and offered resources regarding prenatal care 
or alternative options.  In the case of a positive pregnancy result, subjects will be withdrawn from the study. In 
the case of a subject becoming pregnant, the subject will have the choice to consent to allow the study team to 
track until outcome of the pregnancy. 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
 
Vital Signs and Biometrics: Vital signs and biometrics for this study include but are not limited to, measuring 
height and weight, blood pressure, pulse, waist and hip circumference. Vital signs and biometrics will be 
collected at every visit except height which will only be recorded at the screening visit.  
Blood pressure and pulse will be measured in sitting position at all visits after the subject has rested for at least 
five minutes. Three blood pressure measurements will be taken 5 minutes apart and then averaged. 
 
 
Laboratory Evaluations: Blood will be collected at Screening, Randomization, week 16 and week 24 visits (early 
termination visit). Subjects will be required to be fasting prior to Screening, Randomization, week 16 and week 24 
visit (nothing to eat or drink besides water for a minimum of 8 hours prior to blood draw). Subjects who have used 
hormonal contraception must wait at least 30 days prior to the collection of screening and fasting blood l tests. 
Screening blood tests that were completed within the last year can be substituted for laboratory tests collected at 
screening visit. 
 
Transvaginal Ultrasound: Transvaginal ultrasound examinations will be performed at screening if indicated, 
randomization and 24 week visit (or early termination visit). The transvaginal ultrasound examinations will be 
performed according to the standard procedure for the center and include finding regarding the uterus, the 
endometrium and the ovaries. If a transvaginal probe is not tolerated, then transabdominal ultrasound may be used. 
The same procedures were used in the OWL-PCOS study and are well known by the centers.  
 
F-G Score: The Ferriman-Gallwey score is a measure for quantifying hirsutism in women. The Primary 
Investigator (or designee, which may be the subject) will assess each subject’s hirsutism using the Ferriman-
Gallwey scale at Screening, Randomization (if applicable and/or necessary) and 24 week visit. During the 
assessment for hirsutism, the PI (or designee) will also assess the subject’s acne.  
 
DXA: DXA scans will be completed on each patient at Randomization Visit and 24 week visit. The scanning will 
include a whole body scan, the lumbar spine and both hips.   
Oral Glucose Test: OGTT will be performed at the randomization and at 24 week visit. Prior to the OGTT subject 
must fast overnight for minimum of 8 hours. If subject is not fasting, the blood work must be rescheduled. 
Patients will receive 75 g of an oral glucose solution at time zero (0) and blood will be sampled every 30 minutes 
for 2 hours for glucose, and insulin levels. 
 
PCOSQ: The PCOSQ is a self-administered questionnaire for measuring health-related quality of life in women 
with PCOS. The PCOSQ will be administered to subjects at Randomization and 24 week visit.     
 
STAI: The STAI (State-Trait Anxiety index) is a questionnaire for accessing trait anxiety and state anxiety.  The 
STAI will be administered to subjects at Randomization and 24 week visit. 
 
CES-D: The CES-D is a screening test for depressive symptoms. The CES-D will be administered to subjects at 
Randomization and 24 week visit. 
 
FSDS-R: The FSDS-R (The Female Sexual Distress Scale-Revised) is a screening questionnaire for measuring 
sexually related personal distress in women with Female Sexual Dysfunction (FSD) 
 
FSFI: The FSFI (Female Sexual Function Index) is a brief questionnaire measure of sexual function in women. It 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
was developed for the specific purpose of assessing domains of sexual function (e.g. sexual arousal, orgasm, 
satisfaction, pain) in clinical trials. 
 
ASA24: The Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24). This 24-hour dietary recall 
captures detailed information about all foods, drinks, and supplements (including vitamins, minerals, herbals, 
and other dietary supplements) you consumed from midnight to midnight. You will be asked to complete this at 
12 weeks and 24 weeks.  
 
Concomitant Interventions 
No other interventions, other than those specified in the protocol are allowed to treat PCOS or weight 
management during participation in the study.    
 
Adherence Assessment 
Adherence to the interventions will be monitored by the use of medication reconciliation, diary compliance and 
by monthly visits on site or contact with the subject.   
Clinical and Laboratory Evaluations 
 
Schedule of Evaluations 
 
The table below summarizes the clinical and laboratory evaluations during the trial.  A description of the visits 
follows. Note, prior to the screening visit, subjects may prescreen for potential eligibility. 
 
Table 6: Study Visits and Procedures 
Study Visit Schedule 
Screening 
(half of 
the visit 
as a 
remote 
option) 
Randomization 
Randomization 
Patient Contact 
(PC) 
4 Week 
Visit 
(remote 
option) 
8 Week 
Visit 
(remote 
option) 
12 
Week 
PC 
16 
Week 
Visit 
20 
Week 
PC 
24 
Week 
Visit 
Early 
Termination 
Visit (> or 
equal to 12 
weeks of 
medication) 
End 
of 
study 
PC 
Sign Informed Consent  
x 
  
  
  
  
  
  
  
  
  
  
Medical History 
Questionnaire 
x 
  
  
  
  
  
  
  
  
  
  
Screening labs 
x* 
  
  
  
  
  
  
  
  
  
  
DNA Sample 
  
x 
  
  
  
  
  
  
  
  
  
Safety Labs 
x* 
x  
  
  
  
  
x 
  
x 
x 
  
Menstrual History  
x 
x 
 
x 
x 
 
x 
 
x 
x 
 
Urine Pregnancy Test 
x 
x 
 
x 
x 
 
x 
 
x 
x 
 
Vitals and Biometrics 
x 
x 
  
x 
x 
  
x 
  
x 
x 
  
Hirsutism Assessment 
x 
x 
  
  
  
  
  
  
x 
x 
  
Transvaginal Ultrasound 
x* 
x 
  
  
  
  
  
  
x 
x 
  
Fasting labs 
  
x 
  
  
  
  
x 
  
x 
x 
  
OGTT labs 
  
x 
  
  
  
  
  
  
x 
x 
  
DXA Scan 
  
x 
  
  
  
  
  
  
x 
x 
  
Lifestyle Modification 
  
x 
  
  
  
  
x 
  
  
  
  
ASA 24 
  
  
  
  
  
x 
  
  
x 
x 
  
Acne Assessment 
  
x 
  
  
  
  
  
  
x 
x 
  
HRQOL – PCOS, STAI, 
CES-D, FSDS-R, FSFI & 
  
x 
  
  
  
  
  
  
x 
x 
  


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Cognitive testing 
Questionnaires 
Randomization 
  
x 
  
  
  
  
  
  
  
  
  
Dispense Medication/Log 
  
x 
  
x 
x 
  
x 
  
  
  
  
Collect 
Medication/Log 
  
  
  
x 
x 
  
x 
  
x 
x 
  
Review Concomitant 
Medications  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Review Adverse Events  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
*As Needed 
 
 
Timing of Evaluations 
 
7.2.1 Screening visit:  
1. Obtain informed, signed consent from subject. 
• Subject must specifically be made aware of potential drug side effects and adverse outcomes.  
* Remote option for e-consent via REDCap, utilization of this option at PI discretion 
2. Complete medical assessment. 
• At the Screening Visit, a detailed general medical history for the former 6 months (longer in case 
of gynecological relevance) and history of concomitant diseases or interventions is to be 
reviewed and to be documented.  
* Remote option for completion, utilization of this option at PI discretion 
 
3. Must obtain and record menstrual history. 
• Determine need for medroxyprogesterone acetate (if subject has had no menses in the last 3 
months) 
* Remote option for completion, utilization of this option at PI discretion 
 
4. Perform urine pregnancy test. 
 
5. Record vital signs and biometrics 
 
6. Blood draw for both screening labs (as needed) and safety labs (as needed) 
 
 
6. Review Hirsutism (F-G) Score 
* Remote option for completion, utilization of this option at PI discretion 
 
8. Transvaginal Ultrasound (if indicated) 
 
9. Review electronic Medical Record (if available) 
• If subjects are patients through the University of Pennsylvania Health System or Hershey Medical 
Center, electronic medical records will be reviewed to verify eligibility. Screening blood 
laboratory tests that were completed within the last year can be substituted for laboratory tests 
collected at screening and randomization visit. 
 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
 
Table 7: Screening Blood Tests 
 
Category 
Tests 
Safety Labs** 
Complete metabolic panel, lipid profile 
Screening Labs 
TSH*, Prolactin*, HbA1c*, CBC*, 17OH Progesterone^, DHEAS^, 
Total Testosterone#,  
 
*If drawn within 1 year of screening, eligible for use to determine eligibility criteria. 
^ If drawn within lifetime prior to screening, eligible for use to determine eligibility criteria.  
# If FG≥6 (≥2 for women of Asian descent) do not need to draw lab. Eligibility criteria can be determined without this lab value.   
** If drawn within 2 months of screening, eligible for use to determine eligibility criteria. These safety labs must be drawn at Randomization visit if not 
drawn at Screening visit.  
 
 
 
7.2.2 Randomization Visit:  
 
1. Review menstrual history 
 
2. Complete urine pregnancy test 
 
3. Record vital signs and biometrics 
 
4. Complete fasting blood draw and Safety labs (as needed) 
 
5. Optional whole blood draw for DNA testing 
 
6. Start the oral Glucose Tolerance Test (this may be first since the subjects are fasting) 
 
7. Review Lifestyle Modification Counseling 
 
8. Complete PCOSQ, CESD-R, STAI, FSDS-R & FSFI 
 
9. Cognitive testing 
 
10. Complete DXA scan 
 
11.  Transvaginal Ultrasound (if indicated) 
 
12. Randomize into study arm 
 
13. Dispense Logs/Medications 
• Review medication instructions 
 
 *For more detailed information regarding the order in which study procedures should occur, please refer to the 
Manual of procedures. 
 
  *Complete patient contact with subject two weeks after this visit. 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Table 1: Randomization Fasting Blood Tests 
 
Category 
Tests 
Fasting blood Labs 
Total and free T, Apo A, Apo B, Apo.C3, hsCRP, FFA, IL-1,IL-6,1L-
10, hsCRP, NMR lipoprotein analysis, HDL-C efflux, AMH, SHBG, 
TNF alpha, Estradiol 
 
7.2.3 Follow- Up Visits 
Follow up Visits will be scheduled as shown in Table 6. Initial visits are only one month apart to allow us to 
trouble shoot any side effects especially while increasing the metformin/placebo tablets to the full dose and 
ensure adherence with the protocol. Urine pregnancy test will be checked, adverse events assessed, study logs 
reviewed, and new medications and study logs will be dispensed at each visit.  After randomization and at 12 and 
20 weeks adverse events, menstrual history, medication compliance will be reviewed via patient contact. Patient 
contact has also been placed 2 weeks after randomization to ensure patients are taking the medication properly 
and have experienced no adverse side effects. 
 
 
Table 9: Follow- Up Visits  
 
Visit 
Ideal Date Lower Window 
(- 1 week) 
Upper Window  
(+ 1 week) 
Out of Window Limit 
(+/- weeks) 
2 Weeks* 
2 weeks 
1 week 
3 weeks 
0 / 4 weeks 
4 Weeks 
 4 weeks 
3 weeks 
5 weeks 
2 / 6 weeks 
8 Weeks 
 8 weeks 
7 weeks 
9 weeks 
6 / 10 weeks 
12 Weeks* 
12 weeks 
11 weeks 
13 weeks 
10 / 14 weeks 
16 Weeks 
16 weeks 
15 weeks 
17 weeks 
14 / 18 weeks 
20 Weeks* 
20 weeks 
19 weeks 
21 weeks 
18 / 22 weeks 
24 Weeks 
24 weeks 
23 weeks 
25 weeks 
22 / 26 weeks 
25 Weeks* 
25 weeks 
24 weeks 
26 weeks 
23 / 27 weeks 
* Patient contact 
 
7.2.4 Week 4 Follow- Up Visit  
* Remote option for completing visit, utilization of this option at PI discretion 
 
1. Collect menstrual log and review medical history 
 
2. Perform urine pregnancy test 
 
3. Record Vital signs and Biometrics 
 
4. Review Adverse Events 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
NOVEMBER 30, 2021 
 
5. Collect Logs/Medication 
 
6. Dispense Logs/Medications 
 
 
 7.2.5 Week 8 Follow- Up Visit 
* Remote option for completing visit, utilization of this option at PI discretion 
 
1. Collect menstrual log and review medical history 
 
2. Perform urine pregnancy test 
 
3. Record Vital signs and Biometrics 
 
4. Review Adverse Events 
 
5. Lifestyle Modification Assessment 
Instruction to subject that the ASA 24 (online diet diary recall assessment) to be completed prior to 
the 12-week patient contact. 
 
6. Collect Logs/Medication 
 
7. Dispense Logs/Medications 
 
 
7.2.6 Week 12 patient contact  
This contact will be made to ensure subject compliance with medications, keeping study logs and to review any 
side effects. 
 
7.2.7 Week 16 Follow- Up Visit 
1. Collect menstrual log and review medical history 
 
2. Perform urine pregnancy test 
 
3. Record Vital signs and Biometrics 
 
4. Fasting optional blood draw and safety labs 
 
5. Lifestyle Modification Counseling 
 
6. Review Adverse Events 
 
7. 
Collect Logs/Medication 
 
8. Dispense Logs/Medications 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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7.2.8 Week 20 patient contact 
This contact will be made to ensure subject compliance with medications, keeping study logs and to review 
any side effects. Instruction to subject that the ASA 24 (online diet diary recall assessment) to be completed 
prior to the 24-week visit 
 
 
7.2.9 Week 24 Final Follow- Up Visit or Early Termination Visit (≥ to 12 weeks of being on study medication) 
1. Collect menstrual log and review medical history 
 
2. Perform Urine pregnancy test 
 
3. Record vital signs and biometrics 
 
4. Review Hirsutism (F-G) Score/ Acne Assessment 
  
5. Fasting blood draw and safety labs 
 
6. Complete an oral Glucose Tolerance Test 
 
7. PCOSQ, CESD-R, STAI 
 
8. Review Hirsutism (F-G) Score/ Acne Assessment 
 
9. Complete DXA scan 
 
10. Obtain a Transvaginal Ultrasound (TVU) 
 
11. Review Adverse Events 
 
12. Collect Logs and medication 
 
13. Must obtain and record menstrual history 
 Determine need for medroxyprogesterone acetate (if subject has had no menses during 
the course of this study) 
 
 
7.2.10 Week 25 patient contact 
This contact will be made one week after patient has completed taking the medication to review any side effects 
and answer any patient questions. This patient contact will close out the study adverse events. 
 
 
Study Risk and Benefits 
 
Risk  
The risks of these studies include the risks of the study procedures, and the risk of the study interventions.  
These will be discussed separately below.  


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Risks of Study Procedures  
These risks include the risk of phlebotomy, oral glucose tolerance test and DXA. The risks of phlebotomy include 
pain at the phlebotomy site, bruising and rarely bleeding, and potentially iatrogenic anemia.  Risks of the oral 
glucose tolerance test include the risks of multiple phlebotomy or in some cases the risk of insertion of an IV. The 
risks of IV insertion include the risks of phlebotomy, and additionally the induction of anemia, and infection at 
the site. Glucose ingestion can cause nausea and in rare instances vomiting upon ingestion. We have never 
experienced an allergic reaction to the oral glucose solution, though this is possible. Some subjects also may 
experience an episode of hypoglycemia after the test which can present with increased heart rate and anxiety.  
In the most severe cases, fainting can occur. The DXA scan will involve exposure to radiation, on average 2-3 
milliroentgens of radiation during the procedure. The average amount of radiation that a person would receive 
from a DXA scan is less than 1% of the background radiation experienced from living in the Philadelphia area for 
one year, for example.  
 
Risks of Study Interventions   
Oral Contraceptive Pill - OCP used in this study is low dose (20micrograms ethinyl estradiol), which may cause 
bloating, nausea, breast tenderness, mood changes, weight change and headaches.  Common side effects 
include breakthrough bleeding and amenorrhea.  OCP are also associated with increased risk for cardiovascular 
disease, especially venous thromboembolism and stroke. OCP can also cause hypertension and alter blood lipid 
and glucose levels.  Interactions with drugs such as phenobarbital, phenytoin, and rifampin increase the 
metabolism of oral contraceptives, thus decreasing the effectiveness as a method of birth control. Table lists all 
side effects recorded in women in the OCP arm of the recently completed OWL-PCOS study (n=49). Roughly 
same numbers are expected in this current study. 
 
OWL-PCOS study 
OCP side effects 
Number of 
subjects (%) OCP side effects 
Number of  
subjects (%)
Headache 
14 (28.6) 
Dizziness/Vertigo 
2 (4.1) 
Upper Respiratory Infections 8 (16.3) 
Fatigue 
2 (4.1) 
OWL-PCOS 
N (%) 
Side effects 
N (%) 
Nausea/Vomiting 
7 (14.3) 
Back Pain 
1 (2.0) 
Breast Pain 
10 (20.4) 
Acne 
1 (2.0) 
Abdominal Pain 
1 (2.0) 
Chest pain 
1 (2.0) 
Dysmenorrhea 
8 (16.3) 
Dental abscess 
1 (2.0) 
Constipation 
1 (2.0) 
Hot flushes 
1 (2.0) 
Abnormal uterine bleeding 
4 (8.2) 
Elevated BP w/o hypertension 1 (2.0) 
Mood Swings 
3 (6.1) 
Gastroenteritis 
1 (2.0) 
Gas/Bloating 
2 (4.1) 
Otitis media 
1 (2.0) 
Musculoskeletal Pain 
3 (6.1) 
Anemia 
1 (2.0) 
Vaginitis/Vulvitis 
4 (8.2) 
Visual Changes 
1 (2.0) 
Pelvic Pain 
3 (6.1) 
Conjunctivitis 
1 (2.0) 
Bunion 
1 (2.0) 
Hemorrhoids 
1 (2.0) 
Myalgia/myositis 
1 (2.0) 
Bleeding, rectal 
1 (2.0) 
Fever 
1 (2.0) 
Cholelithiasis 
1 (2.0) 
Sweating excess 
1 (2.0) 
Galactorrhea 
1 (2.0) 
 
Treatment with metformin XR - Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, 
flatulence, metallic taste in the mouth and anorexia) are the most common reactions to metformin XR and 


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approximately 30% more frequent in women taking metformin XR compared to placebo.  These symptoms are 
generally transient and resolve shortly after initiation of treatment. These symptoms will be managed with a step 
down decrease in the daily metformin XR dose (1/2 to one tablet per day per week) until symptoms resolve.  
These symptoms alone will not be a reason for withdrawal from the study unless a patient is unable to tolerate 
any dose of the medication. There is a small risk of lactic acidosis among women taking this medication.  This 
most commonly occurs in patients with poorly controlled diabetes and impaired renal function. Vitamin B12 
deficiency has also been reported in metformin-treated adults with T2DM. Women with these pre-existing 
medical problems will be excluded from the study as per the exclusion criteria. The Table below shows adverse 
events from metformin use in women with PCOS in the PPCOS1 study and the same results are expected in this 
current study.  
 
PPCOS1 metformin Side effects 
Metformin(N=208)  
Blood and lymphatic system disorders  
1/208 (0.5%)  
Cardiac disorders  
1/208 (0.5%)  
Congenital, familial and genetic disorders  
0/208 (0.0%)  
Ear and labyrinth disorders  
3/208 (1.4%)  
Endocrine disorders  
2/208 (1.0%)  
Eye disorders  
3/208 (1.4%) 
Gastrointestinal disorders  
177/208 (85.1%)  
General disorders and administration site conditions  
61/208 (29.3%)  
Immune system disorders  
3/208 (1.4%)  
Infections and infestations  
43/208 (20.7%)  
Injury, poisoning and procedural complications  
3/208 (1.4%)  
Investigations  
6/208 (2.9%)  
Metabolism and nutrition disorders  
37/208 (17.8%)  
Musculoskeletal and connective tissue disorders  
29/208 (13.9%)  
Nervous system disorders  
108/208 (51.9%)  
Pregnancy, puerperium and perinatal conditions  
0/208 (0.0%)  
Psychiatric disorders  
41/208 (19.7%)  
Renal and urinary disorders  
7/208 (3.4%)  
Reproductive system and breast disorders  
84/208 (40.4%)  
Respiratory, thoracic and mediastinal disorders  
24/208 (11.5%)  
Skin and subcutaneous tissue disorders  
19/208 (9.1%)  
Surgical and medical procedures  
0/208 (0.0%)  
Vascular disorders  
33/208 (15.9%)  
 
 
Protection Against Risks 
Risks of adverse events will be reduced by the study personnel and the investigators regularly monitoring 
participants’ progress, by oversight of the local IRBs and the DSMB (see section below). 
 
Clinical staff at each site - Our reproductive endocrinology groups at UPenn and PSU staffs a daily infertility clinic 
that meets every day (365 days a year). The staffing doctor also covers inpatient responsibility and research 
aspects of our service. The subjects at UPenn will be seen in the WHCRC which is on the same floor and adjacent 
to the REI practice site. The daily clinic at PSU meets just below the GCRC where the subjects are studied. At both 
sites a physician is available at a moment’s notice to see a subject. Therefore, the patients participating in the 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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trials will have access to same day consult or visit with an investigator involved in the study, regardless of 
weekends and holidays, for any potential problem that arises in a study. We have utilized this system 
successfully for a wide variety of clinical studies for over 10 years.  
 
Review at research meetings - Both groups at UPenn and PSU currently hold weekly research meetings attended 
by all the research staff which allows for communication about study issues and problems with any subjects in 
the study.  In addition to the weekly site research meetings, the entire investigative team will meet by phone 
conference monthly, Face to face meetings will be held 2 times a year, to discuss the results of patients’ most 
recent study assessments as well as any adverse events. The research coordinators will inform the investigative 
team of any adverse medical events, or abnormal lab values, reported by study participants. All studies will be 
IRB approved and regular progress reports submitted to the IRB as well as adverse events (see below). 
 
Protection against Study Procedure Risks  
Phlebotomy - risks are reduced by the use of skilled nurses or study personnel who have had extensive 
experience with phlebotomy. The risks of an OGTT are minimized by utilizing trained nursing personnel with 
investigator back-up during the test. They are experienced in inserting IVs in study subjects.  When we know of 
prior difficulties with these procedures, we will consult with Anesthesia to insert the IV and minimize pain and 
psychological trauma. 
 
DXA - The whole body radiation dose to a female during a DXA is <1 mRem. The human race is continually being 
exposed to radiation from natural and man-made sources. The dose of background radiation to each person is 
300-400 mRem so the exposure for these measurements is a minimal increase in exposure. For comparison 
purposes, this is less radiation exposure than from a routine chest x-ray and it is comparable to the radiation 
exposure from cosmic ray exposure during an airplane flight across the United States.  The risk from this level of 
exposure is considered to be minimal. A negative pregnancy test will be obtained prior to these studies in all 
subjects. If an individual has participated in any other research study in the past 12 months that included 
exposure to ionizing radiation, we will assess overall exposure to radiation. If it exceeds 500 mrem for the 
calendar year by participating in this study, the potential participant will be excluded or moved to a later 
recruitment wave. Total ionizing radiation exposure will be evaluated with the help of the University of 
Pennsylvania and Penn State Radiation Protection Advisory Committees.  
 
 
8.2.1 Protection against Risk of Study Interventions 
Study subjects will be carefully screened for medical problems prior to randomization. The risks of the 
medications used in this study will be lowered through education and frequent follow-up. Study subjects will be 
monitored monthly in person or by telephone for adverse reactions.  Only a limited supply of medication will be 
dispensed at each visit to encourage compliance with the protocol and prevent a prolonged exposure of an early 
gestation to medication.  
 
Oral Contraceptive Pill -We will exclude subjects with all absolute contraindications to OCP including a history of 
thrombophlebitis, known or suspected clotting disorders, cerebrovascular or coronary artery disease or 
myocardial infarction, known or suspected uterine, cervical or breast neoplasia, history of a benign or malignant 
liver tumor that developed during the use of OCPs or other estrogen-containing products.  Additionally, we will 
exclude other relative contraindications as listed in the exclusion criteria.  Smoking will not be an absolute 
contraindication.  Subjects will be counseled about the risks of OCP, and warning signs for serious adverse events 
including leg swelling, redness, pain, shortness of breath, racing heart, chest pain, severe and unremitting 
headache, unilateral weakness or speech disturbance. Subjects will have a scheduled visit or receive 
communication from the study team monthly and symptoms elicited and recorded as part of the visit.  


COMET-PCOS PROTOCOL V10.1 
 
 
  
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Worrisome signs will be reported to study physicians immediately for evaluation and management.  We will have 
a low threshold of suspicion for discontinuing medication.  We should note that we had no serious adverse 
events among 49 obese women randomized to a low dose OCP in the OWL-PCOS study (see table 2 for side 
effects above). Although the OWL-PCOS study showed a significant increase in prevalence of MetS in the OCP 
arm, only a small proportion of subjects developed DM or hypertension (4.6% and 6.7% respectively after 16 
weeks). A fasting glucose level will be evaluated at the 16 week visit and a value >200mg/dl will prevent a subject 
from continuing in the study. BP will be measured at each visit and a subject with BP>150/100mmHg x2 will be 
unable to continue in the study. 
 
Metformin - There is a small risk of lactic acidosis among women taking this medication. This most commonly 
occurs in patients with poorly controlled diabetes and impaired renal function. Women with these pre-existing 
medical problems will be excluded from the protocol as per the exclusion criteria. There have been reports of 
lactic acidosis induced by exposure to iodine-containing radiocontrast agents, such as those used for an 
intravenous pyelogram.  Metformin XR will be stopped prior to procedures involving exposure to radiocontrast 
agents to reduce the chance of developing lactic acidosis (one week prior to medication and resume one week 
after the test). The development of lactic acidosis for any reason will be a reason for discontinuing participation 
in the study. Metformin XR is pregnancy category B with no known human teratogenic risk and no known 
embryonic lethality in humans.  Metformin XR has been used throughout pregnancy in a number of studies with 
no adverse maternal or fetal effects.  If a subject is pregnant during any part of the study, her participation will 
be stopped. 
 
Preventing Pregnancy - All subjects will be asked to use barrier contraception during this study. Pregnancy tests 
will be performed at each in person study visit. 
 
Menstrual irregularity - All subjects will be asked to keep detailed menstrual log and study coordinators and site 
PIs will review symptoms. Subjects may present with break through bleeding on the low dose OCP. Some 
subjects in the metformin arm may not have any menses during the study period. We will induce menses by 
administering medroxyprogesterone acetate at the screening visit if a subject has not had menses for 3 months. 
There is no data to suggest that lack of menses in the metformin arm for 6 months will increase risk of 
endometrial hyperplasia. In fact, several studies have described the biological plausibility of metformin having a 
protective effect on the endometrium. If a subject has not had menses during the study, we will administer 
medroxyprogesterone acetate after confirming a negative pregnancy test at the end of the study. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others 
The subjects in this study will not benefit directly. The results from the study can be applied in the future to 
patients who stand to benefit from this information.  
 
Importance of the Knowledge to be Gained    
The importance of this study is high for the following reasons:  
1. Both MetS and PCOS are major health problems and the risks of common treatments (OCP or metformin) 
on development of MetS are poorly understood.  
2. Knowledge gained from this investigation will identify optimal strategies for treatment of 
overweight/obese women with PCOS 
3. Understanding the underlying pathophysiology for alterations in metabolic risk with OCP or metformin 
use, will provide important information for future studies. 
 
 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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COMET-PCOS PROTOCOL V10.1 
 
 
  
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Statistical Considerations 
 
General Design Issues 
This will be a randomized, double-blind, double dummy clinical trial of three types of medication, OCP + placebo, 
metformin + placebo or OCP + metformin.  We will track all subjects to completion.  Subjects will be randomized 
1:1:1 to the three treatments.   
  
Randomization 
Randomization is a critical feature of a clinical trial because it prevents treatment-selection biases. The study 
statistician will develop the programs for the randomization; however, the final random seeds used to generate 
the randomization scheme will be prepared by a statistician in PSU’s Department of Public Health Sciences 
independent of the study in order to keep the study statistician blinded as well. The randomization scheme for this 
study will use variable-size, random permuted blocks to ensure that the number of participants in each treatment 
arm is balanced after each set of B randomized participants, where B is the block size. Furthermore, the 
randomization will be stratified by recruitment site (UPenn/PSU), race (AA/non-AA), and the presence of MetS at 
baseline (yes/no). Randomization to the metformin or OCP arms will use 1:1:1 allocation. 
 
Outcomes 
Primary Outcome Measurements 
The primary outcome for this trial is prevalence of MetS. 
Secondary Outcome Measurements 
We may assess change in HDL-C function, serum apolipoproteins, lipid particle size and number, body fat 
distribution, BMI, serum adipokines, HbA1c, glucose and insulin sensitivity, serum markers of inflammation, free 
fatty acids, androgens, quality of life parameters, cognitive testing and predictive factors for change in prevalence 
on MetS 
 
Sample Size and Accruals 
Sample Size and Power Calculations  
The primary outcome of the COMET-PCOS trial will be to assess a linear trend in prevalence of MetS after 6 
months’ treatment over the 3 arms assuming a 30% prevalence of MetS at baseline (derived from PENN data and 
OWL-PCOS). We anticipate a 15% subject drop-out over the course of the trial (in OWL-PCOS it was 8.1% over 16 
weeks). Based on these assumptions, a sample size of 240 (80 per arm) will provide 80% statistical power to 
detect a linear trend in the prevalence of MetS over the 3 arms at the end of 6 months of 26% in the metformin 
arm, 40% in the OCP+metformin arm and 50% in the OCP arm using a two-sided test for linear trend with a 
significance level of 0.05. 
 


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Table 10: Sample size scenarios based on varying assumptions 
 
Proportion 
with MetS at 
the End of the 
Trial in 
Metformin 
Arm 
Proportion with 
MetS at the End 
of the Trial in 
OCP+Metformin  
Arm 
Proportion 
with MetS 
at the End 
of the 
Trial in 
OCP Arm 
 
Total 
Sample 
Size (0% 
Drop-out) 
 
Total 
Sample 
Size (15% 
Drop-out) 
 
 
 
Power 
(%) 
 
 
Type I 
Error (α) 
0.25 
0.38 
0.50 
204 
240 
84 
0.05 
0.25 
0.38 
0.52 
204 
240 
89 
0.05 
0.26 
0.40 
0.50 
204 
240 
80 
0.05 
0.26 
0.40 
0.52 
204 
240 
86 
0.05 
0.28 
0.42 
0.52 
204 
240 
80 
0.05 
 
Statistical Analysis 
Primary analyses will invoke an intent-to-treat paradigm, wherein all randomized subjects are included according 
to their randomized treatment arm, regardless of actual treatment received, protocol violations, etc. Data will be 
summarized using descriptive statistics for continuous variables (mean, standard deviation, number of 
observations, and percentiles) and frequency statistics (frequencies and percentages) for categorical variables. 
The area under the curve (AUC) for glucose and insulin from the OGTT will be calculated using the trapezoidal 
rule. Univariate and bivariate distributions will be inspected in order to address any missing data, inconsistent 
responses, outliers, and data entry errors. The sample size estimates have taken into consideration a participant 
drop-out of 15%; however, every effort will be made during the studies to minimize any drop-out. If, however, 
study attrition appears to be an issue, we will use the observed data to determine if patients who completed the 
study differed from those who did not. To control for potential confounding factors for the association of the 
treatment effects with the metabolic syndrome, we have stratified the randomization by recruitment site, race, 
and the presence of metabolic syndrome at baseline. Although stratification may potentially yield unequal 
numbers between strata, within each individual stratum there will be approximately equal numbers and balance 
between treatment groups. All analyses will include these 3 randomization stratification factors as covariates in 
the statistical models. All hypothesis tests will be two-sided and all analyses will be performed using SAS 
software, version 9.4 (SAS Institute, Inc., Cary, NC), R software (open source), or Stata software, version 13 
(StataCorp LP, College Station, TX).   
 
For the primary outcome of the presence of the metabolic syndrome at the end of the 6-month trial, logistic 
regression will be used with independent variables that include terms for the treatment arm and the 3 
randomization stratification factors as covariates, with a contrast constructed to test for linear trend over the 
three treatment arms. 
 
A variety of secondary continuous outcomes will be collected during this longitudinal trial. These secondary 
outcomes include serum androgens, cholesterol efflux (HDL-C function) parameters, serum apolipoproteins, lipid 
particle size and number, anthropometric measures (BMI, adipokines, biomarkers of inflammation (e.g., hsCRP), 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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measures of adipose tissue, abdominal adiposity, and quality of life measures (PCOSQ). For these continuous 
outcomes, linear mixed-effects models will be fit to assess differences between the treatment arms with respect 
to changes in these outcomes over time. The independent variables in the model will be treatment arm, time, 
the interaction of treatment and time, and the 3 randomization stratification factors as covariates. From the 
mixed-effects models, contrasts will be constructed to test the hypotheses of interest with respect to changes 
over time in the outcomes. Linear mixed-effects models are an extension of ordinary regression models that 
account for the between- and within-subject correlation inherent in longitudinal trials. Further, linear mixed-
effects models do not drop patients with incomplete data and are easily extended to nonlinear mixed-effects 
models for ordinal data and count outcomes. Following our assessment of the initial fit of the models, we will 
add covariates to the models that correspond to other potential confounders (e.g., age) to assess their impact, if 
any, on the treatment effects. Residual diagnostics will be assessed to determine the appropriateness of the 
model fit and, if necessary, transformations of the response will be used to meet modeling assumptions. 
Differences in means and associated 95% confidence intervals (CIs) will be used to quantify the magnitude of the 
effects. 
 
For any binary outcomes collected at each visit, analyses will be based on generalized estimating equations (GEE) 
with a logit link, an extension of logistic regression that accounts for correlated data within-subjects inherent in 
longitudinal trials, with independent variables that include terms for the treatment arm, time, the interaction of 
treatment and time, and the 3 randomization stratification factors as covariates.  Following our assessment of 
the initial fit of the models, we will add covariates to the models that correspond to other potential confounders 
(e.g., age) to assess their impact, if any, on the treatment effects. The effect size will be quantified using the odds 
ratios (OR) and corresponding 95% CI.  
Accrual 
A total of 5 years will be required to complete the study after start up; 36-month enrollment period (based on 3 
subjects per site/month x 2 sites), 1-month screening/randomization period, 6-month treatment period and time 
built in for data analysis and interpretation.  
 
Data Collection, Monitoring and Adverse Experience Reporting 
 
Records to be kept 
Data will be collected prospectively by designated research personnel at each study site, supervised by the site PI. 
Original source documents will be kept in the study subject folder. Well-designed data collection forms will be 
developed to minimize data collection and recording errors. Administrative forms will be designed, such as visit 
procedure checklists, to assist the research staff in complying with protocol procedures. We will be collecting a 
medical history on each subject. We will also be obtaining biometric data, clinical data (hirsutism), imaging data 
from ultrasound, DXA scanning and biochemical data from blood. All data are being collected solely for the purpose 
of research and do not become part of the subject’s medical record.   
 
All tissue samples and images will be labeled with the code number assigned to each subject and only de-identified 
samples will be sent to laboratories for testing. Specimens will be stored in Women’s Health Clinic Research 
Center’s freezers at UPenn and banked for batched analysis. 
 
Study data will be managed using REDCap (Research Electronic Data Capture), a secure web application designed 
to support data capture for research studies, providing user-friendly web-based case report forms, real-time 
data entry validation (e.g., for data types and range checks), audit trails, a randomization module, and a de-


COMET-PCOS PROTOCOL V10.1 
 
 
  
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identified data export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). The database is 
hosted at the University of Pennsylvania, which will be used as a central location for data management. REDCap 
data collection projects rely on a thorough study-specific data dictionary defined in an iterative self-documenting 
process by all members of the research team. REDCap is flexible enough to be used for a variety of types of 
research and provides an intuitive user interface for database design and data entry. 
Database access for REDCap is granted on a study-by-study basis. At the start of the trial when the database is 
created all research personnel will be given defined user roles and assigned a unique username and password. 
There is a 90-day password update policy for all REDCap users.  The REDCap database sits behind an application 
firewall and the data is stored on a virtual machine at Penn which is backed-up nightly.  
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. Each clinical site will be responsible for 
ensuring study personal are trained and follow the data management guidelines of GCP and internal site policies. 
Data Security 
Study staff will make clear that subjects are not obligated to participate in the study and that their answers will 
be held strictly confidential. Questionnaires will not contain any identifying information, thus, ensuring the 
confidentiality of subjects’ responses. Code numbers will be assigned to each subject to maximize anonymity 
when entering and analyzing data. Any linking list of patient names and codes will be maintained separately, and 
destroyed at the earliest possible time. Only the investigators and research staff at each individual study center 
will have access to this information for patients recruited at that center. The second site and the research 
coordinator will not have access to the linking list. The security of the research project data will be maintained 
through network hardware and user authentication (usernames and passwords). Back-ups of the project data 
files will occur every night, with user data backed-up incrementally Monday through Thursday and complete 
back-ups every Friday. Archival back-ups, stored indefinitely, are cut on the last weekend of every month. All 
back-up data are stored in a secure off-site location. The number and variety of back-ups ensure ample data 
redundancy and protection. In addition, each participant will be assigned a unique subject identification number. 
Only the study coordinators will have the log linking this identification number with the participant’s personal 
information. 
 
Adverse Event Reporting 
Serious Adverse Events 
All serious adverse events (SAEs) that occur from randomization through thirty days after the last dose of study 
medication must be reported.  A serious adverse event is defined as: fatal or immediately life-threatening; severely 
or permanently disabling; requiring or prolonging inpatient hospitalization; overdose (intentional or accidental); ; 
or, any event adversely affecting the study’s risk/benefit ratio. Additionally, any event that, based on appropriate 
medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent 
one of the outcomes listed above is considered an SAE. 
 
If an SAE occurs and is thought to be related to the study medication, the study medication will be discontinued.   
 
The site PI will report the SAE by completing and signing the Serious Adverse Event Report Form Subjects will be 
identified by subject identification number only.  No other identifying information will be included on the form. 


COMET-PCOS PROTOCOL V10.1 
 
 
  
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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 DSMB and FDA (as applicable) will be notified and provide a determination regarding the SAE. 
 
These determinations will dictate timeframes for sites’ submission to the DSMB (Table 12): 
 
Table 11: Types of Serious Adverse Events and their reporting requirements 
TYPE 
SITE 
Unanticipated and related/possibly 
related SAE, fatal or life-
threatening 
Report to DSMB within 1 business 
day of discovery 
 
Other unanticipated and 
related/possibly related SAE 
Report to DSMB within 1 business 
day of discovery 
Anticipated and related/possibly 
related SAE 
Report to DSMB within 5 business 
days of discovery 
Unrelated SAE (anticipated or 
unanticipated 
Report to DSMB within 10 business 
days (no more than 3 weeks) of 
discovery 
 
 
Upon receiving notification of an SAE, the DSMB will review it via a closed-session email or conference-call 
discussion.   
The 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.  
 
Adverse events deemed non-serious will also be recorded throughout study participation from the start of study 
drug through one week after the last dose of study medication.  If an anticipated serious adverse event occurs at 
a frequency greater than expected, the DSMB will be notify the PI by the end of the next business day of discovery 
and follow the procedures for reporting serious and unanticipated and related adverse events.   If an adverse event 
not initially determined to be reportable to the FDA under 21CFR312.32 is so reportable, the PI will report the 
adverse event to the FDA within 15 calendar days after the determination is made.  
 
Data Monitoring 
There will be no pre-determined stopping rules and no interim analysis. 
 
Study Monitoring 
A monitoring plan that satisfies the ICH/GCP guidelines for clinical monitoring will be used. The Penn designated 
monitor at the Women’s Health Clinical Research Center, will lead this effort, and report findings to the PI of both 
sites and the DSMB when necessary. The Penn designated monitor  will have full knowledge of the study protocol, 
Manuals of Procedures, and is familiar with the database system redcap and is trained to review patient charts. 
The Penn designated monitor  along with the Project Manager/Lead Study Coordinator at each site will be 
responsible for training and supervising other personnel.  
Once personnel at participating site are trained to recruit patients, the Penn designated monitor 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 Penn designated monitor will review all signed 
and dated forms (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.   


COMET-PCOS PROTOCOL V10.1 
 
 
  
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The Penn designated monitor will return to the clinical site after a defined number of patients are recruited 
(recruitment of the first 5 patients) and yearly thereafter.  
During the site visit, the clinical sites should provide to the monitor(s) 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 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 study 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 PI, and DSMB 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. The monitor will be 
responsible for maintaining regular contacts 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. 
 
 
Human Subjects Protection 
 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent modifications will be reviewed and 
approved by the IRB responsible for oversight of the study.  A signed consent form will be obtained from the 
subject. The consent form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation.  A copy of the consent form will be given to the subject, and this fact will be 
documented in the subject’s record. 
 
Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified only 
by the Study Identification Number (SID) to maintain subject confidentiality.  All records will be kept in a locked 
file cabinet.  All computer entry and networking programs will be done using SIDs only to prevent the loss of 
confidentiality.  Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by IRB, the OHRP, the sponsor, or the sponsor’s designee. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e. that the subject is alive) at the end of their scheduled study period 
 
 
Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the IRB, the NIH, the OHRP, or other government 
agencies as part of their duties to ensure that research subjects are protected. 
 


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Data and Safety Monitoring Board 
 
Kathy Hoeger from the University of Rochester Medical Center will chair the DSMB for this clinical trial.  The 
DSMB will review safety information, especially SAEs that may occur, on a quarterly basis while the study is 
active and ongoing.  Kathy will be consulted for any safety questions that may arise during the trail.  
 
 
 


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