Indomethacin and Delayed Umbilical Cord Clamp for Preterm Infant IVH
Phase: PHASE1
Conditions: Intraventricular Hemorrhage, Periventricular Leukomalacia, Brain Injury, Renal Injury
Sponsor: Hong Huang

ICF, PROTOCOL, AND STATISTICAL ANALYSIS PLAN 
 Study Title: Effects of Delayed Cord Clamp and/or Indomethacin on Preterm Infant Brain Injury 
Institution/Site: 
University of Kentucky 
Document (Approval/Update) Date: 
05/15/2019 
NCT Number: 
NCT02221219 
IRB Number 
44507 
Coversheet created: 
10/30/2020 

Modified 6/26/15 
 
Page 1 of 8
Combined Consent and Authorization to 
Participate in a Research Study 
 
Delayed Umbilical Cord Clamping and Indomethacin in Preterm Infants
 
When we say “you/your” we are referring to you as an expecting mother and your baby.  
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH? 
You are being invited to take part in a research study about possible brain injury that often 
happens in babies that are born prematurely. You are being invited to participate because it is likely that 
your baby is going to be born early or prematurely.  
Infants born early, especially born at less than 29 weeks of gestational age, are at a high risk for 
various medical problems, including bleeding in the brain. It is possible, but unproven, that a short delay 
(of 45 seconds) in clamping the umbilical cord at the time a baby is born, may reduce the risks of this 
brain bleeding. It is also possible that a medicine called ‘indomethacin’ could be effective in reducing 
brain bleeding, either alone or in combination with a delayed umbilical cord clamp. This research study 
will investigate the potential benefits of delayed cord clamp, indomethacin, or their combined use to 
reduce how often or how severe brain bleeding occurs in babies born prematurely. 
If you volunteer to take part in this study, you will be one of more than 400 people to do so at 
the Kentucky Children’s Hospital, the University of Kentucky.  If you volunteer to take part in this study 
your baby may be enrolled in our research study, but only if it is born before 29 weeks gestational age. 
 
WHO IS DOING THE STUDY? 
The person in charge of this study is Peter J. Giannone, MD, Division of Neonatology, Department 
of Pediatrics, at Kentucky Children’s Hospital. Other members of the Neonatology Research Team will 
assist at different times during the study. 
WHAT IS THE PURPOSE OF THIS STUDY? 
Babies born prematurely are at risk of bleeding into the fluid spaces of the brain, called the 
ventricles and the tissue around the ventricles, known as the parenchymal white matter, in the first few 
days of life. If major bleeding in the brain occurs a baby may end up with long term problems like low IQ 
and cerebral palsy. Neonatologists, or doctors that take care of sick babies, have been trying to prevent 
the bleeding in the brain problem for many years, but so far there is no known way to prevent the 
bleeding.  This is a research study in which we are trying to find the best and safest way to prevent 
bleeding in premature babies’ brains to prevent brain damage.  
One possible way to reduce brain bleeding is to wait before cutting a premature baby’s umbilical 
cord after birth. Studies have shown that waiting 45 seconds to cut the umbilical cord may be helpful to 
prevent brain bleeds. No studies have shown that waiting to cut the umbilical cord has any negative 
effects on the baby. The obstetrician (doctor) delivering your baby will either: 1) cut the cord immediately 
following delivery and hand the baby over to the pediatricians to stabilize --- immediate cord clamping; or 
2) wait 45 seconds before cutting the cord, then hand the baby over to the pediatricians --- delayed cord 
clamping. 
Another possible way to reduce brain bleeding is by giving the baby a medicine called 
indomethacin. This medicine has been approved by the Food and Drug Administration and used for many 
years in premature babies for other reasons, but not to prevent brain bleeds. Studies have shown that this 
medicine can reduce the risk of premature babies bleeding in their brains but does have side effects and 
risks.  Most of these side effects are temporary, such as renal failure, but can be severe, such as a rupture 
of the intestine where a hole forms in the bowel.  By doing this study, we hope to learn if either delayed 
cord clamping by itself, indomethacin by itself or both together is the best and safest way to prevent 
bleeding in premature babies’ brains. 
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY? 
If you or your baby has one of the following situations, you should not take part in this study. 
 
Any congenital anomalies (or birth defects) of newborn;  

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You are not planning to have your baby resuscitated but have comfort care and hold your baby; 
Problems with the placenta that may cause bleeding  
If the obstetrician identifies complications in the mom (such as breathing problems, other); 
If the obstetrician identifies complications in the baby (such as decrease in heart rate, other)   
 
WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST? 
The research procedures will be conducted at the University of Kentucky Medical Center, 
Kentucky Children’s Hospital. Your baby will be admitted to the Neonatal Intensive Care Unit (NICU) 
right after delivery. The research procedures (blood draws, head ultrasounds, head MRI) will be 
conducted while your baby is in the NICU. After your baby goes home, you will need to bring your baby 
to the NICU Graduate Clinic at 3 different times (at about 3 months, 6-9 months, and 18-24 months of 
corrected gestational age) for neurodevelopmental assessments. Corrected gestational age means the 
age your baby would have been if he or she wasn’t early. This is a standard procedure for all premature 
babies at UK. Each of those visits will take about 2 hours. The total amount of time you will be asked to 
volunteer for this study is approximately 12hrs over the next two years.  
 
WHAT WILL YOU BE ASKED TO DO?
If you volunteer to participate in this research, the study will start when your baby is actually 
born.  The Labor Hall staff will record the number of seconds between the baby’s birth and the time till 
the umbilical cord is cut.  After that, the baby will receive normal resuscitation and be taken to the NICU.  
After being admitted to the NICU, your baby will be randomized to receive indomethacin or a 
placebo. Randomize means that your baby’s group will be picked by chance, like a coin toss.  The 
indomethacin and placebo will look alike, and the medical staff taking care of your baby won’t know if 
there is medicine or not.  You would have a 50% chance of being in any group.  Your baby will receive 
the same NICU care, no matter which treatment he or she receives. 
In the delivery room, 1 to 5 mL (1/5 - 1 teaspoon) of blood will be kept from the umbilical cord 
after the baby is born. This will be collected by the obstetrical nurse following the delivery of the infant, 
then immediately given to the study team (Dr. Giannone or other member of the study team).  The 
blood will be used for research tests. Once the baby is in the NICU, the medical team will place IV’s that 
will help give the baby nutrition and help with monitoring of various vital signs (heart rate, blood 
pressure). Special IV’s will also be placed which blood can be taken from.  These IV’s are standard or 
normal care in the NICU for premature babies because blood tests are done several times a day in the 
beginning, then weekly.  In this study, we will obtain half a milliliter (mL) or 1/10 of a teaspoon of blood 
from your baby at different times for research tests. The blood will be drawn from a special IV OR during 
a routine heel-stick. As premature babies get better, the special IV’s are removed and blood is drawn 
from the heel.  The study blood tests will occur at 7 times: 1) on admission, 2) 24 hours old, 3) 48 hours 
old, 4) 72 hours old, 5) 1 week old, 6) 1 month old, and 7) 2 months old. The total blood used for 
research is 3.7 mL, or less than 1 teaspoon.   
Head ultrasounds (HUS) are done in the NICU on every baby less than 29 weeks gestational age. 
Ultrasound is a type of x-ray using sound waves – a wand, or probe is used on the skin to see inside the 
body.  This test has been used for many years, safely, even used during pregnancy to see the baby.  The 
HUS is used to see if a baby has any bleeding in the brain, which occurs in about half of the babies less 
than 29 weeks. In a head ultrasound, the wand is put on the soft spot (top of a baby’s head), and can 
detect even a small amount of bleeding.  Usually babies have two or more HUS, (depending on how sick 
they are) which are normally done on day 7 and day 30.  In this study, your baby will have 4 ultrasounds, 
on days 3, 7, 14 and 30. By doing the ultrasound earlier (day 3), brain bleeds may be detected earlier. 
Your baby will also have a head MRI which will be performed at 38 weeks corrected gestational age.  
After a premature baby is taken to the NICU, he or she is watched very closely, and is attached to 
monitors.  One of the monitors is a pulse oximeter (attached by a soft sticky fabric is placed around the 
hand or foot of the baby, with a red light that shines).  This is used to measure oxygen in the body.  This 
monitor is used for most of every baby’s stay in the NICU.  For this study, it will be used until your baby 
goes home, and he or she may have 2 monitors.  Babies in this study will have a “sleep study” performed 
at 2 different times (one and two months old), if he or she is stable.  This will measure the oxygen levels 
and how well the baby is breathing at rest. 
All premature infants less than 29 weeks are routinely followed in the NICU Graduate Clinic after 
discharge. Your baby will receive the standard testing that is done for all babies in the Graduate Clinic. 
 
 
 
 

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Timeline
Procedure
Basic 
Care
Research
at delivery
umbilical cord blood collection (1-5mL)
X
1, 24, 48, & 72 hours,
7, 30 & 60days
blood draw (0.5mL) at each time point (total 
less than 1 tsp all together
X
X
72 hours or 3 days
head ultrasound
X
7 days, 14 days, & 30 days
head ultrasound
X
X
38 weeks of corrected GA
head MRI
X
30 & 60 days
Sleep Study
X
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS?
Most of your information is in the medical record (both you and your baby’s). If more 
information is needed, you may be asked questions about your pregnancy, and it is possible that you 
could feel upset. If you don’t want to answer a question, you don’t have to, and the study coordinator 
will be available to discuss this with you further.   
 
There have not been any studies to show that a delay of cutting the cord has hurt a baby in any 
way. One possible problem might be the baby could get cold.  Even without the delay, some babies get 
cold after being born because they’re so small.  The medical team at the delivery will use warm blankets, 
a plastic bag, and a warm bed to prevent your baby from getting cold.  Another potential risk is that the 
bilirubin levels (the chemical that makes babies turn yellow) is increased following a delay in cutting the 
umbilical cord due to increased number of red blood cells (about a 30% increased chance). Almost all 
premature babies get high bilirubin levels because of immature liver function.  Babies are treated with 
special lights – usually in the first week of life.  
 
Indomethacin is a drug approved by the FDA (Food and Drug Administration) and given to babies 
born prematurely to close PDA (a blood vessel in the heart) as well as other reasons. This medication has 
been shown to reduce brain bleeding in babies born very prematurely, but it has some side effects. The 
side effects including 1) the amount of urine (pee) becoming low, 2) damage to the intestine, 3) bleeding 
problems, 4) low blood sugar, and 5) low salt and potassium levels. These side effects happen only while 
the baby is receiving the indomethacin, and go away when the drug is done.  If the problems are serious, 
the medicine will be stopped.  There is no way to give absolute assurance either that your baby will or 
will not experience any of these or other side effects. Your doctors will watch all babies in the Neonatal 
Intensive Care Unit closely for all problems. 
Placing IV lines in a vein may cause soreness, bruising, pain, possible fainting, or bleeding at the 
puncture site. This is a routine requirement for babies in the NICU, for the purpose of collecting blood 
and making measurements that are used to make medical care decisions. Infection is a rare possibility. 
In this study, we will only obtain blood from an existing IV site or during a heel stick for routine labs.
 
Being in the group that does not get DCC or indomethacin may have higher risk of bleeding in the 
brain than the other groups. This, however, is currently the standard care of treating preterm babies and 
the reason this research is being done. 
 
There is always a chance that any medical treatment can harm you, and the investigational 
treatment in this study is no different. In addition to the risks listed above, you may experience a 
previously unknown risk or side effect. If you are worried about anything while in this study, please 
contact the Principal Investigators or the study coordinator.
 
WILL YOU OR YOUR BABY BENEFIT FROM TAKING PART IN THIS STUDY?
It is possible, but not guaranteed, that you or your baby will get benefit from taking part in this 
study. We hope to learn something that could help premature babies. At the present time, we do not 
know the best and safest way to prevent bleeding in the baby’s brain.  We are trying to figure out if the 
timing of the umbilical cord clamping is related to changes in blood cell levels in the babies, and if those 
changes help prevent bleeding in the brain that babies born too early are at risk for developing, if the 
medicine indomethacin is better at preventing brain bleeding or both together are the best and safest 
way to prevent brain bleeds in babies born early. The data collected from this study will be compared to 
see what might work best for reducing brain bleeding. Your willingness to take part may, in the future, 
help doctors better understand and/or treat others who have your condition. 
 
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to take part in the study, it should be because you really want to volunteer.  You 
will not lose any benefits or rights you would normally have if you choose not to volunteer.  You can stop 

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at any time during the study and still keep the benefits and rights you had before volunteering. If you 
decide not to take part in this study, your decision will have no effect on the quality of medical care you 
receive.
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES?
If you do not want to be in the study, there are no other choices except not to take part.
 
WHAT WILL IT COST YOU TO PARTICIPATE? 
You and/or your insurance company, Medicare or Medicaid will be responsible for the costs of all 
care and treatment you receive during this study that you would normally receive for your condition. 
These are costs that are considered medically reasonable and necessary and will be part of the care you 
receive if you do not take part in this study.  The tests and procedures that are done just for research 
purposes are paid by the study.   
 
WHO WILL SEE THE INFORMATION THAT YOU GIVE?
Only the Principal Investigators and the Neonatology Research Team will have access to the 
information provided and we will make every effort to prevent anyone who is not on the research team 
from knowing that you gave us information, or what that information is. You should know, however, 
that there are some circumstances in which we may have to show your information to other people. For 
example, the law may require us to show your information to a court or to tell authorities if you report 
information about a child being abused or if you pose a danger to yourself or someone else.  
In the event of any publication regarding this study, the identity of you or your baby will never be 
revealed. Your information will be combined with information from other people taking part in the 
study. When we write about the study to share it with other researchers, we will write about the 
combined information we have gathered from the many babies enrolled in the study. You will not be 
personally identified in these written materials. We may publish the results of this study; however, we 
will keep your name and other identifying information private. 
Reason(s) why the use or disclosure is being made: We will need to contact you in the future, 
need to locate medical records and lab values, and may need to contact your physician if there are 
dangerously abnormal results found in this study. You may decide not to authorize the use and 
disclosure of your PHI.  However, if it is needed for this study, you will not be able to be in this study. If 
you agree to be in this study and later decide to withdraw your participation, you may withdraw your 
authorization to use your PHI.  This request must be made in writing to Dr. Peter J. Giannone. If you 
withdraw your authorization, no new PHI may be collected and the PHI already collected may not be 
used unless it has already been used or is needed to complete the study analysis and reports. 
Dr. Giannone and the study team will keep a database of all subjects who participate in a 
research study. This database may be used to contact people about future studies. Only Dr. Giannone 
will have access to this database. The database will not be disclosed or sold to others outside UK. 
Officials at the Food and Drug Administration, the National Institutes of Health and the University 
of Kentucky may look at or copy pertinent portions of records that identify you. 
You will need to provide your social security number.   This is in order for you to be compensated 
for your time.    If you do not provide this number, you will not be compensated. If you earn $100 or 
more by participating in any research, it is potentially reportable for tax purposes.
 
CAN TAKING PART IN THE STUDY END EARLY? 
If you decide to take part in the study you still have the right to decide at any time that you no 
longer want to continue. You and your baby will not be treated differently if you decide to stop taking 
part in the study. However, if you decide to stop being in this study you must call the Principal 
Investigators or the study coordinator to see if there are any medical issues about stopping. 
The individuals conducting the study may need to withdraw you from the study if the principal 
investigators believe participating in this study is not the best choice of care. This may also occur if you 
are not able to follow the directions they give you, if they find that your being in the study is more risk 
than benefit to you, or if the agency funding the study decides to stop the study early for a variety of 
scientific reasons.  
 
ARE YOU PARTICIPATING OR CAN YOU PARTICIPATE IN ANOTHER RESEARCH STUDY AT THE SAME 
TIME AS PARTICIPATING IN THIS ONE? 

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You may take part in this study if you are currently involved in another research study. It is 
important to let the investigator/your doctor know if you are in another research study. You should also 
discuss with the investigators before you agree to participate in another research study while you are 
enrolled in this study.
It is important that health care providers know about all medicines that you are taking. This 
includes the medicine being tested in this research study. Because of this, we plan to tell your primary 
care doctor (if you have one) that you are in this research study. This is done so care can be taken in 
prescribing other medicines and looking at any unexplained symptoms that may occur. You cannot take 
part in this study if you do not want us to tell your primary care doctor.  
 
WHAT HAPPENS IF YOU OR YOUR BABY GETS HURT OR SICK DURING THE STUDY?
We believe that there is very little chance that injuries will happen as a result of being in this 
study. If you believe your baby is hurt or gets sick because of something that is due to the study, you 
should call Dr. Peter Giannone at 1-859-323-2662 immediately. Dr. Peter Giannone will determine what 
type of treatment, if any, that is best for your baby at that time. 
It is important for you to understand that the University of Kentucky does not have funds set 
aside to pay for the cost of any care or treatment that might be necessary because you get hurt or sick 
while taking part in this study. Also, the University of Kentucky will not pay for any wages you may lose if 
you are harmed by this study. In most cases, this care will be billed to your health insurance company or 
whoever usually pays for your health care at the usual charges, but some insurance companies will not 
pay for care related to a study. If the care is provided at Kentucky Children's Hospital, we make no 
commitment to pay for the medical care provided to you. If no one else pays for your care, you may 
have to pay for the cost of this care. This does not mean that you give up any of your legal rights to seek 
compensation for your injuries by signing this form. A co-payment/deductible from you may be required 
by your insurer or Medicare/Medicaid even if your insurer or Medicare/Medicaid has agreed to pay the 
costs).  The amount of this co-payment/deductible may be substantial. 
 
WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY? 
You will not be paid to be in this study at admission. However, we will provide $25 food and 
travel stipends at each post-discharge NICU Graduate Clinic visit (at 3-4, 6-9, and 18-24 months 
corrected age; these are the standard follow-up times in our hospital). In addition, your will receive gift 
certificates ($25) if you contact the study team with address or phone number change.
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS, CONCERNS, OR COMPLAINTS?
Before you decide whether to accept this invitation to take part in the study, please ask any 
questions that might come to mind now.  Later, if you have questions, suggestions, concerns, or 
complaints about the study, you can contact the investigators, Dr. Peter Giannone at 1-859-323-2662 or 
Ms. Vicki Whitehead at 1-859-323-5530. If you have any questions about your rights as a volunteer in 
this research, contact the staff in the Office of Research Integrity at the University of Kentucky between 
the business hours of 8am and 5pm EST, Mon-Fri at 1-859-257-9428 or toll free at 1-866-400-9428. We 
will give you a signed copy of this consent form to take with you.
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT AFFECT YOUR DECISION 
TO PARTICIPATE?
If the researcher learns of new information in regards to this study, and it might change your 
willingness to stay in this study, the information will be provided to you. You may be asked to sign a new 
informed consent form if the information is provided to you after you have joined the study. 
 
POTENTIAL FUTURE USE 
The Neonatology Research Team would like to keep the leftover blood collected during the main 
study participation but is not used for other tests for that study. No additional blood or tissue will be 
taken. If you agree, the blood samples may be used in future research, which could help other babies 
and their families in the future.  
 
Researchers may also need health information about the people who provide specimens. We are 
also asking for your consent to place information from your medical record and/or research record in a 
database to be used for research. Your name and address will not be placed in the database.  
Please read each sentence below and think about your choices. After reading each sentence, 
mark “yes” or “no.” If you have questions, please talk to the investigator or staff. Remember, no matter 

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what you decide to do about the storage, or banking, and future use of your blood samples, you may still 
take part in the main study.  If you answer yes to either choice below you also give your authorization 
for your accompanying health information to be used and disclosed along with the blood. The sample(s) 
(blood) that you or your baby are giving will no longer belong to you and might be used in studies that 
lead to new products for research, diagnosis or treatment.
 
1. Do you give permission for your blood samples to be kept by Dr. Peter Giannone’s study team 
in a central location/specimen bank at Kentucky Children’s Hospital (MS472) until they are 
used up but no longer than 10 years for use in future research to learn more about how to 
prevent, detect, or treat brain bleeding in babies?
 
   Yes 
   No
_________Initials
2. Do you give permission for your blood samples to be used for future research about other 
health problems, for example, causes of preterm delivery?
 
   Yes 
   No
_________Initials
 
Genetics research and banking:
In addition to the main study, you are being asked to volunteer in a genetic sub-study to study 
your genes, or DNA (deoxyribonucleic acid). Genes are made up of DNA. Your DNA is like a huge 
database of chemical bases that carry the “blue prints” or instructions to tell each and every cell in your 
body what they should do. Genes can influence the likelihood that you will get certain diseases. Your 
participation in this sub-study is optional. You can still be in the main study even if you do not wish to 
participate in this sub-study. 
Please read each sentence below and think about your choice. After reading each sentence, mark 
“yes” or “no.” If you have questions, please talk to the investigator or staff. Remember, no matter what 
you decide to do about the storage, or banking, and future use of your DNA samples, you may still take 
part in the main study.
You give your permission for your DNA to be stored in a central location/DNA bank at Kentucky 
Children’s Hospital for future use by the study investigators. We plan to store (or bank) the DNA samples 
until they are used up but they will not be kept longer than 7 years. You give authorization for your 
accompanying health information to be used and disclosed as marked below: 
 
1. Do you give permission for your DNA samples to be kept by Dr. Peter Giannone’s study 
team for use in future research to learn more about how to prevent, detect, or treat brain 
bleeding in babies? 
 
   Yes 
   No  
_________Initials 
 
2. Do you give permission for your DNA samples to be used for future research about other 
health problems, for example, causes of preterm delivery? 
 
   Yes 
   No  
_________Initials 
 
Contacting Research Subjects for Future Studies 
Do you give your permission to be contacted in the future by the Neonatology Research Team 
regarding your willingness to participate in future research studies about how to prevent, detect, or 
treat brain bleeding and related health issues?   
 
   Yes 
   No  
_________Initials
 
WHAT ELSE DO YOU NEED TO KNOW?
There is a possibility that the data/specimens collected from you and your baby may be shared 
with other investigators in the future. If that is the case the data/specimen will not contain information 
that can identify you unless you give your consent/authorization or the UK Institutional Review Board 
(IRB) approves the research. The IRB is a committee that reviews ethical issues, according to federal, 
state and local regulations on research with human subjects, to make sure the study complies with these 
before approval of a research study is issued. NIH is providing financial support and/or material for this 
study. 
 

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AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH INFORMATION 
Information collected for this study may include information that can identify you or your baby. 
This is called “protected health information” or PHI.  By agreeing to be in this study, you are giving 
permission to Dr. Peter J. Giannone and the study team to collect use and disclose your PHI for this 
research study unless otherwise allowed by applicable laws. Information collected is the property of the 
Principal Investigators and NIH (sponsor). The reason why this PHI is collected, and what information will 
be used is listed below. The PHI will only be shared with the groups listed, but if you have a bad outcome 
or adverse event from being in this study, the Principal Investigators and staff or other health care 
providers may need to look at your entire medical records. 
 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires 
researchers to protect your health information. The following sections of the form describe how 
researchers may use your health information.   
 
Your health information that may be accessed, used and/or released includes: 
 
Names (individual, relatives); Address (including city, state, zip code and county); 
Telephone/Fax Numbers; Birth Date; Admission Date; Discharge Date; Date of Death; E-mail 
Addresses/URLs; Medical Record Numbers; social security number and a unique study 
identifying code. 
Your age, how many pregnancies you’ve had, your race, treatments, medicines and tests 
during and after this pregnancy 
Your baby’s information which will include dates: birth data, results from tests, x-rays, 
ultrasounds, labs, treatments, complications and diagnoses  
 
The Researchers may use and share your health information with: 
 
The University of Kentucky’s Institutional Review Board/Office of Research Integrity. 
Law enforcement agencies when required by law. 
University of Kentucky representatives. 
UK Hospital  
Sponsor (NIH) 
Information Drug Services (IDS)  
Food and Drug Administration (FDA) 
Primary physician will be contacted if researcher in the course of the project learns of a 
medical condition that needs immediate attention. 
 
The researchers agree to only share your health information with the people listed in this 
document. Should your health information be released to anyone that is not regulated by the privacy 
law, your health information may be shared with others without your permission; however, the use of 
your health information would still be regulated by applicable federal and state laws.   
You will not be allowed to participate in the research study if you do not sign this form.   If you 
decide not to sign the form, it will not affect your: 
 
Current or future healthcare at the University of Kentucky 
Current or future payments to the University of Kentucky   
Ability to enroll in any health plans (if applicable) 
Eligibility for benefits (if applicable) 
 
After signing the form, you can change your mind and NOT let the researcher(s) release or use your 
health information (revoke the Authorization). If you revoke the authorization: 
 
You will send a written letter to: Dr. Peter Giannone at 800 Rose Street, MN470, Lexington, 
KY40536 to inform the study team of your decision. 
Researchers may use and release your health information already collected for this research 
study. 
Your protected health information may still be used and released should you have a bad reaction 
(adverse event). 
You may not be allowed to participate in the study. 
 

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You understand that you will not be allowed to review the information collected for this research study 
until after the study is completed.  When the study is over, you will have the right to access the 
information.
The use and sharing of your information has no time limit.  
If you have not already received a copy of the Privacy Notice, you may request one.  If you have any 
questions about your privacy rights, you should contact the University of Kentucky’s Privacy Officer 
between the business hours of 8am and 5pm EST, Mon-Fri at: (859) 323-1184.
 
You are the subject or are authorized to act on behalf of the subject.  You have read this information, 
and you will receive a copy of this form after it is signed. 
 
1-MOTHER’S CONSENT (REQUIRED): 
 
__________________________________                        ____________________________
Signature of research subject’s
Date
legal representative (Mother)
 
__________________________________
____________________________
Printed name of research subject’s
Representative’s relationship to 
legal representative (Mother) 
 
 
 
research subject 
 
MOTHER’S CURRENT AGE:
  
 
 
Note: Assent from legal guardian required if mother is 14-17 yrs of age
 
2-FATHER’S CONSENT (REQUIRED IF THIS PERSON IS REASONABLY AVAILABLE): 
 
__________________________________                        ____________________________ 
Signature of research subject’s Father 
 
 
Date 
 
IF THE FATHER’S SIGNATURE IS NOT INCLUDED AND HE IS ‘NOT REASONABLY AVAILABLE’
DEFINE THE REASON(S) BELOW:
Unknown
Incompetent
Deceased
Only the mother has legal responsibility for the care and custody of the child
Other reason (note provided here)
3-MOTHER’S LEGAL GUARDIAN (REQUIRED IF ENROLLED MOTHER IS 14-17 YRS OF AGE)
__________________________________
____________________________
Signature of mother’s legal guardian
Date
 
__________________________________                        ____________________________ 
Printed name of mother’s legal guardian 
 
 
Representative’s relationship to  
 
 
 
 
 
 
 
 
mother
 
4-AUTHORIZED STUDY REPRESENTATIVE (REQUIRED) 
 
__________________________________                        ____________________________ 
Name of [authorized] person obtaining    
 
 
Date 
Informed consent/HIPAA authorization 
 
__________________________________    
 
Signature of Investigator 
 
 
 

Study Protocol: 
1. Objectives:  
Primary GOAL: Compare efficacy and safety of prophylactic indomethacin, DCC, and their 
combination, in affecting the incidence and severity of IVH in infants less than 29wks GA at birth. 
• 
Aim 1A):  Test for differences in primary outcome measure: ‘fraction of survivors with no severe 
IVH or PVL’ among the 4 groups, using head ultrasound (1-30d), and head MRI at 38wks 
adjusted GA.  
• 
Aim 1B): Test the hypothesis that DCC improves effectiveness and/or decreases toxicities of 
indomethacin.  
• 
Aim 1C):  Test for treatment dependent differences in neurocognitive follow up evaluations and 
investigate relationships between short term brain imaging results and later neurocognitive 
performance across treatment groups. 
 
Secondary GOAL: Investigate mechanistic effects of prophylactic indomethacin, DCC, and their 
combination in infants less than 29wks GA.  
• 
Aim 2A): Test the hypotheses that blood volume status and/or hemodynamic stability are 
different between groups (at 0,1,2,3,7, 30, and 60 days of life).  
• 
Aim 2B): Test the hypothesis that biomarkers of inflammation and vascular endothelial stress 
are different between groups (at 0,1,2,3,7, 30, and 60 days of life).  
• 
Aim 2C): Test the hypothesis that numbers, or apoptotic frequency, of circulating progenitor cells 
with endothelial or neuronal phenotype capacity are different between groups (at 0,1,2,3,7, 30 
and 60 days of life). 
• 
Aim 3):   Determine relationships between clinical outcomes (Aim1) and blood measurements 
(Aim 2) among treatment groups.  
2. Study Design:   
 The study design of this research project is a randomized, blinded investigation of 4 treatment 
groups:  
1) Control (no intervention); 
2) DCC alone; 
3) Prophylactic indomethacin alone; 
4) Combination of DCC/indomethacin 
 
Infants randomized to block randomization with blocks of size 8 each to randomly assign the subjects into 
one of the 4 groups. The randomization table will be prepared in advance by the statistician and clinicians 
will be blinded to this choice prior to the delivery.  Investigational Drug Services will provide indomethacin 
dosing solutions and placebo dosing solutions that are matched in appearance and volume for each study 
participant. Please note that randomization will occur in all cases, but the attending Neonatologist at delivery 
and bedside will have authority to define care; if this physician has an objection to the randomization of 
indomethacin treatment for a specific patient that patient will be excluded from the study. Similar provisions 
are afforded to the delivering Obstetrician regarding delay of umbilical cord clamp randomization and 
treatment. 
3. 
Study Population:   
 
It is anticipated that this study will begin July, 2014 and will enroll subjects through June 31 of 2019.  
Follow-up in NICU Graduate Clinic will continue thru June 31, 2020.  We are going to enroll 400 infants 
during that time, male and female all inborn at the University of Kentucky.  The population is primarily 
Caucasian (80%), African American (15%), Asian (3%), and a Hispanic population of about 2%.  All races 
and ethnicities will be included if subjects parent(s) are able to understand English (spoken or written).  
Pregnant women are considered to also be research subjects in this trial.  When the pregnant mother is a 

legal adult (18yrs or older) their consent will include their participation as well as their infant.  Pregnant 
women whom are less than 18yrs and greater than 14yrs of age and qualify for enrollment criteria will also 
be invited to participate in this study. In these cases assent will be obtained from the pregnant mother (who 
is considered a legal minor), and consent will be obtained from the pregnant mother’s legal guardian. 
Inclusion criteria 
 
Neonates with a GA less than 29 6/7weeks (based on last menstrual period and/or early 
pregnancy ultrasound) 
 
Consent obtained prior to delivery 
Exclusion criteria 
 
neonates with congenital anomalies such as congenital heart disease 
 
a prenatal plan to withhold neonatal care 
 
maternal risks identified by obstetrician, including severe hemorrhage (placenta abruption or 
placental previa), hypertensive crisis 
 
if the attending obstetrician or neonatologist decides that infant requires immediate 
resuscitation for either maternal or newborn well-being 
 
any prenatal indocin use within 72 hours before birth 
 
4. 
Subject Recruitment Methods and Privacy: Recruitment:   
 
A total of 400 premature infants born <29 6/7weeks GA will be recruited from the obstetrics admission 
area and randomized to one of the 4 treatment groups; n=100 each will complete the study (control; DCC 
alone; Indomethacin alone; DCC + Indomethacin). This facility admits over 800 sick newborn infants/yr and 
sees a majority of the high-risk obstetrical patients in the Lexington area and beyond. Informed consent will 
be obtained prior to patient enrollment, by Dr. Giannone (PI) or another member of the research team 
experienced at consenting mothers for research studies. There will also be an on-call schedule at night to 
screen potentially eligible women, enroll them, and attend the births. Women enrolled will be assigned to 
either immediate or delayed cord clamping groups via a computer generated random number system to 
assure permuted block randomization. When notified of a subject’s impending birth, the research 
coordinator will open the randomization card, review the protocol with the attending/fellow/or resident 
obstetrician, and time the cord clamping.  
5. 
Informed Consent Process:   
 
We will consent mothers who are in preterm labor. After consent forms are reviewed, the families will 
be asked to participate in the study. Consent will be obtained from the parent/legal guardian by a research 
nurse or the PI/designee trained in the informed consent process. All conversations related to patient 
participation/research procedures will be performed in private locations. 
6. 
Research Procedures:   
 
Following enrollment and consent at time of delivery the infant will be placed in one of four groups (per 
the following algorithm)  
    RANDOMIZATION 
 
 
 
 
 
 
For the immediate cord clamping groups the obstetrician will clamp the umbilical cord immediately 
(<10sec) after birth, per standard procedure. For the delayed cord clamping groups the obstetrician will 
clamp the cord at 45 sec after delivery and hold the infant in a sterile bag (thermoregulatory bag) 10-15in 
below the mother’s introitus at vaginal delivery or at/below the level of incision if a cesarean section is 
performed. A stopwatch will identify the time when the infants’ buttocks are delivered from the vagina or the 
Group A 
Control (ICC)
Group B 
DCC
Group C 
DCC + Indocin
Group D 
ICC + Indocin

uterus (or head if breech); time elapsed will be counted in 10sec intervals for the OB by the investigator. 
Infants in the DCC group will be placed into a sterile bag to minimize heat loss at the sterile field by the 
delivery OB. Per standard NICU clinical protocol, infants in the ICC groups will be placed in the 
thermoregulatory bag once they are placed on the neonatal warming bed.  
 
Infants will be brought to NICU once the infant is determined stable by the neonatal resuscitation team. 
The enrolled infant will then be cared for in the NICU using standard practices and started on either Indocin 
0.1 mg/kg/day for 3 days (Groups C and D) or placebo (Groups A and B), depending on group assignment.  
Randomization of indomethacin is “blinded” to medical care team (physicians, nurses, clinic personnel).  
Maternal and infant clinical data and infant blood samples will be collected at specified times for 
measurement of mechanism-based endpoints. In addition to routine assessment of renal function via 
standard clinical meaures of BUN and creatinine, renal function status will also be monitored by serum 
Cystatin C levels (0.1mL) at 7 and 30 DOL (these will be considered research measures, since they are not 
routinely measured in NICU patients). Measurements will be done with ELISA (50uL serum required) at 
Bauer’s research lab. The oxygen saturation (SpO2) of all infants is continuously monitored upon admission 
to the NICU by a Masimo pulse-oximeter. Monitoring starts right after birth until discharge from the hospital. 
The SpO2 and heart rate waveforms stored in the Masimo pulse-oximeter will be downloaded for analysis. 
Some NICU beds have a different pulse oximeter (Nelcore) which does not allow for data downloads. If a 
patient is admitted to bedspace not equipped with a Masimo pulse oximeter, one will be placed but screen 
and alarms turned off.  This is a minimal risk procedure and of no additional cost to the patient for data 
consistency purposes.  A neonatal sleep study/pneumogram (respiratory inductance plethysmography, 
high-resolution pulse-oximetry and electrocardiography) will be performed on all subjects who are not 
intubated or on non-invasive ventilation at 30 and 60 days of life.  In case infants remain intubated or on 
non-invasive respiratory support at 60 (55 – 65) DOL, a pneumogram will be performed as soon as that 
level of respiratory support is weaned or discontinued. The pneumogram is non-invasive and is of minimal 
risk to patients. All data collected will be measured/recorded by persons who are essentially ‘blinded’ to the 
delivery/treatment at birth. 
 
If for any medical reason the bedside/attending Obstetrician or Neonatologist has concerns and 
wishes to become ‘unblinded’ to the infant’s enrollment, the study participant will be removed from the study. 
We expect that the only practitioner who is unblinded in the study is the specific Neonatologist at the 
particular infants’ delivery, who most likely is not performing the daily care for the newborn after admission 
based on the structure of our delivery room teams and NICU service teams. All study infants will routinely 
be followed-up at UK NICU Graduate Follow-up Clinic after discharge since these clinicians have the 
primary responsibilities for this standard clinical service in our institution. Research oversight for 
neurodevelopmental follow-up will be the responsibility of Dr. Sithisarn. The TIMP and Bayley Scales of 
Infant Development-III (BSID-III) will be administered at 3-4, 6-9, and 18-24 months corrected age; these 
are the standard follow-up times for collection of such data in our clinic, and the tests proposed has been 
optimized and defined for these age intervals. All exams will be performed by the same therapist trained in 
high-risk newborn neurodevelopmental exams to avoid performance biases, and will be blinded to the 
treatment group. Data will be reviewed quarterly by the research team. Money will be given to families ($25) 
for expenses (gas, parking, food) for each of the three follow-up evaluations. Frequent phone contact with 
project personnel has been another technique successfully used in past research by Dr. Giannone and 
colleagues. Project personnel will contact participants every 2 weeks until the first measurement (3-4 
months), and then monthly until all measurements are complete for the follow up groups (n=400 completed). 
Participants will be asked to give multiple phone numbers (work, family, and friends) to make contact more 
feasible; participants who move or change phone numbers will receive gift certificates ($25) if they contact 
research personnel with their new address or phone number. Some attrition (~5%) is anticipated and is 
built into the sample size calculation.  
 
In summary, a total of 3.7 ml of blood (7 time points during the 0-60 days of life, 0.5mL each, and 2 
time points with 0.1ml each), 4 head ultrasound measurements (day of life (DOL) three, first week of life, 
DOL fourteen and at 30 DOL or later), a head MRI at 38 weeks corrected GA will be obtained from each 
subject as well as 3 measurements of neurodevelopment (TIMP and Bayley III). Enrolled patients will 
receive a study number to protect confidentiality of demographic information. Data to be collected is shown 
on the attached data collection instrument. Only the Co-PIs and study coordinators will know the identities 

of the patients and be responsible for the storage of collected data. All data will be de-identified.   
 
Studies shown below are marked as part of standard care or research.  The 14 day ultrasound is 
variable, depending on findings on the 7 day ultrasound.  Our standard unit policy is to repeat at 14 days if 
our routine 7 day ultrasound shows a significant hemorrhage.   
 
Timeline 
Procedure 
Standard
Care 
Research
at delivery 
umbilical cord blood collection (1-5mL) 
X 
At admission, 24, 48, & 72hr,  
Days 7, 30, & 60 
blood draw (0.5mL) at each time point 
X 
72 hours 
head ultrasound 
X 
7 & 30 days 
head ultrasound 
X 
7 & 30 days 
Serum Cystatin C (0.1mL) 
X 
14 days  
head ultrasound 
X 
X 
Days 30 & 60 if not on vent, or as 
soon as possible when extubated 
neonatal sleep study/pneumogram 
X 
38 weeks of corrected GA* 
head MRI* 
X 
3-4 months of corrected GA 
Test of Infant Motor Performance (TIMP) 
X 
6-9 months of corrected GA  
Bayley III  
X 
18-24 months of corrected GA 
Bayley III; Brief infant Toddler Social Emotional 
Assessment (BITSEA), MCHAT(pass/fail) 
X 
 
*, Please note that at the initial start of this 5 year study our plan for head MRIs in all enrolled patients is 
considered a research effort. Note however that the use of head MRI in extremely premature infants that 
are known to or suspected to have brain lesions is currently common-place and at other institutions is 
standard care. Therefore it is possible (and perhaps likely) that the routine use of this imaging modality will 
in coming years become ‘standard care’ for all preterm infants that are at very high risk of cranial bleeds 
(e.g. the exact patient group in this study) at our institution. If this becomes the case we will provide 
amendments to the IRB to account for this issue. 
 

Statistical analysis plan 
 
All aspects of data analysis/statistics will be directed by Dr. Aric Schadler, the Director of 
Pediatric Data Analytics for the Kentucky Children’s Hospital-Office of Pediatric Research, 
and Dr. Arnold Stromberg, the Allen-Anderson Endowed Professor of Department of 
Statistics, University of Kentucky. 
 
Aim 1: Compare efficacy and safety of prophylactic indomethacin, DCC, and their 
combination, in affecting the incidence and severity of IVH in infants less than 28wks 
gestational age.  
• Aim 1A) Test for differences in primary outcome measure: ‘fraction of survivors with no severe 
IVH or PVL’ among the 4 treatment groups, using head ultrasound at1-30d and head MRI at 
38wks adjusted gestational age.  
• Aim 1B) Test the hypothesis that DCC improves effectiveness and/or decreases toxicities of 
indomethacin.  
• Aim 1C) Test for treatment dependent differences in neurocognitive follow up evaluations and 
investigate relationships between short term brain imaging results and later neurocognitive 
performance across treatment groups. 
 
Aim 1 Statistical analyses: [all analyses performed as ‘intention to treat’ where 
appropriate]: To investigate the primary hypothesis in Aim 1A (treatment-related outcome 
differences with respect to the primary endpoint fraction of cases surviving without severe IVH, 
grade 3 or 4) we will use head ultrasound data from day of life 0-30, and use two distinct 
approaches. First, based on the qualitative data used to compute the sample size, we will employ 
a bivariate analysis to identify the significant covariates, followed by a multiple logistic regression 
analysis to test for differences between the four groups in the presence of significant covariates. 
Secondly, we will develop severe IVH or PVL data and employ survival analysis statistics (log 
rank Mantel-Cox test). If the assumptions are validated, we will use the Cox proportional hazard 
model for this survival data. In addition we will compare head MRI results (measured at the single 
time point of 38wks adjusted gestational age using a multiple regression model that will 
incorporate significant covariates. Aim 1B is concerned with comparison of Groups 3 and 4 only 
(e.g. Indomethacin vs. Indo-DCC) and the procedures developed for the 4 group analysis are also 
applicable here. For Aim 1C we correlate later performance with the short term brain imaging 
results in the framework of a multiple regression model where the 4 groups will be used as 
predictors and will be compared. In all settings we will also perform separate analyses of IVH 
alone, and PVL alone.  
Aim 1 also involves comparisons of nominal/ordinal and continuous variables associated with 
neurodevelopment and toxicity where single or repeated measures on the response are available. 
Approaches similar to the one described above will be taken where we first build a statistically 
valid model that controls for all influential covariates and test the relevant hypotheses in the 
context of the model. Aim 1B corresponds to the testing of the interaction effect between the 
ICC/DCC effect and the use of prophylactic indomethacin. Other hypotheses correspond to the 
main effects. We will also compare the variables that reflect renal function/status (as assessments 
of potential indomethacin toxicities, other specific comorbidities and hospital stay related variables 
across the 4 groups. 
 
Aim 2: Investigate mechanistic effects of prophylactic indomethacin, DCC, and their 
combination in infants less than 28wks gestational age.  
• Aim 2A) Test the hypotheses that blood volume status and/or hemodynamic stability are 
different between groups (at 0,1,3,7,and 30 days of life).  

• Aim 2B) Test the hypothesis that biomarkers of inflammation and vascular endothelial stress 
are different between groups (at 0,1,3,7,and 30 days of life).  
• Aim 2C) Test the hypothesis that numbers, or apoptotic frequency, of circulating progenitor 
cells with endothelial or neuronal phenotype capacity are different between groups (at 
0,1,3,7,and 30 days of life). 
 
Aim 2 Statistical analyses: Comparisons of biochemical and hemodynamic variables 
across treatments: For Aim 2 we compare the blood sample variables (Hct, HB, Ferritin, CRP, 
IL6, TNF, s-ICAM, progenitor cell numbers, and apoptotic cell percentages) and summary 
measures of cardiovascular variables (blood pressure, pressor support and others) using a 
multivariate linear regression model (for continuous responses) and a multivariate logistic 
regression model (for nominal variables such as the need for inotropic/vasopressor support) 
regression analyses where influential demographic variables associated with mothers and infants 
will be used as covariates. The differences in the pattern of changes over time of the repeatedly 
measured cardiovascular status variables such as the blood pressure levels will be examined 
using repeated measures Analysis of Variance techniques and mixed effect ANOVA models. 
Influential covariates will be used for building a suitable predictive model using variable selection 
methods to identify the optimal variable set. Using this model, the hypotheses regarding the 
differences between the 4 groups and their interaction effect with time will be examined. 
 
 
Aim 3: Determine relationships between clinical outcome measures (Aim1) and blood 
measurements (Aim 2) among treatment groups. 
 
Aim 3 Statistical analyses: We will use our complete data set to investigate predictors of brain 
injury (IVH, or PVL), predictors of poor neurocognitive outcomes and the influence of treatment 
group on these predictive variables. Ultimately we will use the data collected in this project to 
identify which of our measured variables are the most ‘useful’ from a clinical perspective in 
forecasting outcomes in these high-risk patients.  Significant variables for prediction will be 
identified using bivariate methods. Correlations will be utilized for two continuous 
variables.  ANOVA, independent samples t-tests and independent samples nonparametric 
methods will be employed as appropriate for a nominal explanatory variable  and a continuous 
variable. Pearson’s chi-square and Fisher’s exact statistic will be used as appropriate when both 
variables are nominal. For each outcome variable, appropriate multivariate modeling will be 
constructed using the identified significant variables from the bivariate analysis along with the 
grouping variables to ascertain the best reduced models for prediction. An alpha level of 0.05 is 
used for inclusion into the models. Any non-normally distributed continuous data will be corrected 
through appropriate transformations. Statistical software SAS 9.4 (SAS Institute, Cary, NC) 
and  IBM SPSS Statistics (IBM Corp., Armonk, N.Y., USA) will be used for analyses. We have 
powered our study using chi-square tests for equality of proportions, but adopted analysis strategy 
that controls for influential covariates will generally improve the power. In all settings we will 
also perform separate analyses of IVH alone, and PVL alone.