Conditions: Neonatal Encephalopathy Hypoxic-Ischemic Encephalopathy Mild
Keywords: darbepoetin Brain Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
This is a Phase II multicenter placebo-controlled randomized, feasibility/safety trial. Infants \>34 week gestational age with perinatal acidemia and mild neonatal encephalopathy on the modified Sarnat neurologic examination at less than six hours of age. Participants will be randomized to receive either one dose of Darbepoetin, or placebo within 24 hours of birth. Neurodevelopmental testing (Bayley (III or IV) and Gross Motor Function Assessment) will be performed at 24 months of age. Pharmacokinetics will be assessed on those infants that received Darbe.

Detailed description:
Therapeutic hypothermia (TH) is the standard of care for newborns diagnosed with moderate to severe neonatal encephalopathy (NE) presumably due to hypoxic ischemia. In order to be eligible for TH an infant must have perinatal acidemia and evidence of moderate or severe encephalopathy on a standardized neurologic examination (Sarnat). However, the majority of newborns with perinatal acidemia do not have a neurologic examination abnormal enough to be classified as moderate or severe NE. In a retrospective review, DuPont et al. found that as many as 20% of newborns with perinatal academia and mild NE have abnormal short-term outcomes such as seizures, death from progressive asphyxia insult, brain MRI findings consistent with NE, abnormal neurologic examination at discharge, gastrostomy tube feeding, or feeding difficulties. Preliminary data from a prospective trial investigating mild NE (PRIME study, NCT01747863) found that 39% had either abnormal electroencephalography at \< 9h of age, an abnormal brain MRI finding, or abnormal neurological exam at discharge. Murray et al. recently reported on 5-year outcomes of infants with mild encephalopathy and showed that 25% had neurodevelopmental disability. These data suggest that mild NE likely carries a higher risk of impaired neurological outcome then reported previously. Thus it would appear that neuroprotective strategies would be beneficial in this group of infants. Preliminary data suggest that erythropoiesis stimulating agents (ESA) provide neuroprotection, and improve short and long-term neurologic outcome in neonatal brain injury. ESA may work through several mechanisms including reduced inflammation, limited oxidative stress, decreased apoptosis and white matter injury, as well as via pro-angiogenic and neurogenic properties. Darbepoetin alfa (Darbe), a recombinant human erythropoietin (EPO)-derived molecule has established safety and pharmacokinetics in newborns. Because Darbe has an extended circulating half-life with comparable biological activity to EPO, it has the advantage of requiring less frequent administration

Arms:
arm 1: IV,10 mcg/kg/dose, Darbepoetin Alpha, one dose at \<24 hours of age arm 2: IV, Normal saline (placebo dose), one dose at \<24 hours of age

Interventions: intervention 1: Darbepoetin Alfa intervention 2: Normal Saline
Intervention descriptions: intervention 1: Single dose of 10 mcg/kg Darbepoetin Alpha given IV at less than 24 hours of age intervention 2: Single dose of normal saline, IV, given at less than 24 hours of age

Protocol document:
ICF_008.pdf: 
 
 
 
version: 12.4.18 
1 
University of New Mexico Health Sciences Center 
Consent to Participate In Research 
 
Mild Encephalopathy in the Newborn treated with Darbepoetin 
The MEND Study 
Version 12/4/2018 
 
PURPOSE AND BACKGROUND 
You are being asked to consider whether you would like your infant to participate in a research 
study.  The following information describes the study and your infant's role as a possible 
participant.  This consent form may contain words that you do not understand.  Please ask the 
study doctor or the study staff to explain any words or information that you do not clearly 
understand.  The study is being conducted by Dr. Tara Zamora, as principal investigator at the 
University of New Mexico, in conjunction with investigators at the University of Utah, 
University of Texas Southwestern, and by those assistants as she may need.  Approximately 15-
20 infants will take part in this study at the University of New Mexico, and a total of 80 infants 
will take part at all the sites combined.  The study will take approximately 2 years to complete 
enrollment and analysis.  Please read this information carefully and do not hesitate to ask any 
questions about the study information provided below. 
 
Your infant qualifies to be in this research study because he/she has been diagnosed to have a 
condition called neonatal encephalopathy (NE).  Neonatal encephalopathy results from decreased 
blood flow and oxygen to all the organs in the body, including the brain.  Your infant’s history 
and physical examination shows that he/she has a mild form of NE. In this hospital and in many 
others, infants with this condition are monitored for several days, often in a Neonatal Intensive 
Care Unit. There is currently no medical therapy available to infants with mild NE. However, 
some babies with mild NE go on to develop problems with their development, as they grow 
older.  Development refers to how well babies learn move their bodies, handle their 
emotions, learning ability, self-control, and memory. These skills usually grow as a child grows, 
but sometimes they develop more slowly or don’t fully develop.  In cases where these skills 
develop more slowly, or don’t develop, we refer to that as developmental disability.   
 
We are researching a medication called ‘Darbepoetin’ that may help to improve developmental 
outcomes by protecting the brain. The use of Darbepoetin in this study is investigational, 
meaning it has not been approved by the Food and Drug Administration (FDA) to be used this 
way. Darbepoetin (Darbe) helps the body to produce more red blood cells, which are the cells 
that carry oxygen around the body. In addition to increasing red cell growth, Darbe has been 
shown to provide brain protection and to improve developmental outcomes following brain 
injury in small clinical trials for babies with more severe forms of encephalopathy.  
 
This study will help us to learn if Darbe will help improve developmental outcomes in infants 
with mild NE. We hope that in the future the use of this medication may improve the 
developmental outcomes of babies with mild NE, and also lessen the risk of long-term 
disabilities. 
 
The study will be carried out at the University of New Mexico Hospital newborn intensive care 
unit (NICU) and other sites as listed above. 


2 
MEND Study 
 
 
 
version 5.25.18 
In this study, infants with mild NE will be placed in one of two study groups before 24 hours of 
age: Darbe group, or placebo group (placebo means no actual medicine will be given, only the 
fluid the medicine is mixed in will be given). The doctors and nurses will not know if your baby 
received Darbe or placebo.  All infants will be monitored very closely and will receive all the 
usual care of the Newborn Intensive Care Unit (NICU) for this condition. Your infant’s 
participation in the study will last for 12 months.  The medication will be given, one time, within 
24 hours of birth and you will then receive a phone call at 4 months of age asking you about your 
child’s development, and a formal in person developmental assessment will be done when your 
baby is 8-12 months old. After all the infants have been tested we will check to see which babies 
received Darbe and which ones received the placebo, this will take about 4 years.  
 
STUDY PROCEDURES 
What will happen if I decide to let me infant participate? 
If you agree to have your infant take part in this research study, he/she will be randomly assigned 
to one of two study groups. Random assignment (like a flip of a coin) means your infant has a 
one in two chance of being placed in any of the following treatment groups:  
 
1.Receive one dose of the study drug, (10 μg/kg) Darbe through an IV that your baby 
already has, within 24 hours of birth. 
 
2.Receive placebo (salt water) as an IV within 24 hours of birth. 
 
Your infant will be followed closely and important clinical information will be collected for the 
study such as blood tests, breathing support, infections, nutrition, as well as the results of any 
tests such as head ultrasounds and magnetic resonance imaging (MRI) that are ordered by your 
infant’s doctor as part of your infant’s NICU care.  We will also collect information from your 
baby’s chart about his or her family, specifically: mom’s age, mom’s education level, race, and 
ethnicity.  
 
If your baby has blood tests done as part of his or her normal care then we will save the leftover 
blood of all of those samples for up to 3 years. These samples will be used to check how much of 
the study drug is in your baby’s blood and may be used to check how your baby’s blood reacted 
to the study drug.   
 
Optional Baseline Sample for Drug level testing:  
Additionally, we would like to take an additional four drops of blood (less than 1/10th of a 
teaspoon or 0.3 mL) from a blood sample obtained before the study drug is given. This will 
ensure that we have enough blood to test for the change in drug level before and after the 
medication is given. We will try to draw this blood sample with one that is being drawn for your 
baby’s routine care, such as checking his or her sugar (glucose) level, but we may need to poke 
your baby to obtain this sample, if there is not a scheduled lab prior to administration of the 
study drug.  
 
______Yes, I agree to allow an extra sample of blood (less than 1/10th of a teaspoon) to be taken from my baby  
INITIALS 
 
______No, I do not agree to allow an extra two drops of blood to be taken from my baby’s blood sample 
INITIALS 


 
 
 
version: 12.4.18 
3 
 
No head ultrasounds or MRIs will be done just for the study, but your doctor may order these test 
so that he/she can better care for your baby.  
 
After you go home, you will receive one phone call at 4 months of age asking you important 
questions about your child’s development. 
 
At 8-12 months of age, research data will be collected at your normally scheduled clinic visit at 
UNM which will include a formal developmental test and brief medical exam.   
 
We will give your primary care doctor a letter stating that your baby is participating in this study 
and provide them with our contact information.  If your baby has had his/her blood levels 
checked (hematocrit), we will contact your baby’s primary care provider and ask your baby’s 
medical history We will ask your doctor to allow us to document these results.   
 
We will keep all data for up to 10 years.  
 
RISKS 
Darbe is currently approved for use in adults and children, but is considered an investigational 
drug in neonates.  Repeated use of Darbe in adults can increase the risk of abnormal blood clot 
formation, convulsions (seizures), hypersensitivity (allergic reactions), increase red blood cell 
number, decrease white blood cell number (white blood cells help fight infections), increase 
blood pressure, heart attack, stroke, and death.  Studies of Darbe use in adult cancer patients have 
shown increased cancer growth that rarely can result in death.   To date, there is no information 
that these drugs would increase any such complications in infants. Infants are at a lower risk for 
these complications than adults.  There may also be side effects and discomforts that are not yet 
known.   
 
This study was evaluated by the FDA as an investigational new drug.  They approved the study 
and would like us to monitor for a disease called Pure Red Blood Cell Aplasia (PRCA).  This is a 
very rare (less than 1 per 10,000 people treated with Darbe) disease that causes low blood levels 
(anemia) in adults who use frequent injections of Darbe.  None of these side effects have been 
documented in infants or children.  If your baby has low blood levels (anemia), and we have 
appropriate samples of blood stored (from the leftover blood from the NICU), we will ask to get 
a blood sample at the follow up visit and we will send your baby’s blood to a special lab to see if 
it is related to the Darbe that he/she was given, at no cost to you.  
 
Your infant will be assigned to a treatment group by chance (similar to flipping a coin).  The 
treatment your infant receives might be less effective, not effective, or have more side effects 
than another study treatment. 
 
BENEFITS 
There may or may not be a direct benefit to your infant being in the study. One possible benefit 
to your infant is that Darbe may help the brain recover from injury to a greater extent. Your baby 
will also receive extra developmental tests to see how they are developing. Additionally, the 
benefits seen in taking part in this study may help future infants with this condition.  
 
ALTERNATIVES TO PARTICIPATION 


4 
MEND Study 
 
 
 
version 5.25.18 
Your infant will continue to receive the same standard of intensive care whether or not you 
decide to allow him or her to participate in this study.  Currently, there is no FDA-approved drug 
in infants that is used to prevent brain injury.   
 
CONFIDENTIALITY 
Your infant’s participation in research will involve a loss of privacy, but information about your 
infant will be handled as confidentially as possible. Representatives of the University of New 
Mexico Health Sciences Center (UNMHSC) Human Research Review Committee (HRRC) that 
oversees human research, the FDA, and study auditors will be permitted access to your infant’s 
records.  Also, your infant’s participation in the study and information in your infant’s study 
records may be disclosed to your infant’s doctors and nurses, and may be disclosed as otherwise 
provided by law. Your infant’s name will not be used in any published reports about this study. 
All information about your infant taking part in this research will be kept confidential, in a 
locked file inside a locked office at the hospital.  A copy of this consent form will be placed in 
your infant’s medical record. 
 
COST OF STUDY 
The study drug will be given to your infant at no charge and you will not be required to pay for 
any study procedures.  The cost of the developmental assessments will be done at no charge to 
you but may be billed to a third party payer since it is part of standard care. The costs of your 
infant’s NICU clinical care will not be covered by the study, and will be billed to you or a third 
party payer. Examples of third party payer’s are insurance companies or Medicaid.  
 
EMERGENCY TREATMENT AND COMPENSATION 
If your infant is injured as a result of this study, the University of New Mexico Health Sciences 
Center (UNMHSC) will provide your infant with emergency treatment, at usual charge to you or 
a third-party payer.  No commitment is made by the UNMHSC to provide free medical care or 
money for injuries to participants in this study.  If you have any questions about these issues, or 
believe that you or your infant have been treated carelessly in the study, please contact the 
HRRC Office at the University of New Mexico Health Sciences Center, Albuquerque, New 
Mexico 87131, (505) 272-1129 for more information. 
 
PAYMENT FOR PARTICIPATION 
You will not receive payment for your infant's participation in this study. 
 
NEW FINDINGS 
You will be informed of any significant new findings that become available during the course of 
the study, such as changes in the risks or benefits resulting from your infant’s participation in the 
research, or new alternatives to participation that might change your mind about your infant 
participating.  Your contact information (phone, address) will be kept in a locked file so that we 
can inform you which treatment your child received when the study is fully completed, if you 
choose. 
 
WITHDRAWAL 
Your permission for your infant to participate in this study is voluntary.  You may refuse this 
permission or may stop your infant's participation at any time during the study without penalty or 
loss of benefits to which you are otherwise entitled.  If you end your infant's participation, he or 
she will continue to receive standard treatment and will be able to receive medical care as usual 


 
 
 
version: 12.4.18 
5 
or participate in future research studies.  In addition, your infant's participation may be stopped 
by the neonatology attending physician or the study doctor without regard to your consent if your 
infant has a study-related injury, or if there are administrative reasons.  If you withdraw 
permission for your infant to participate, we would like to perform a final examination of your 
infant for safety purposes, and to collect clinical information from any follow up visits scheduled 
to monitor your infant’s recovery.  If you would like to withdraw your permission for your infant 
to participate and have all of his or her data removed from our database please inform the study 
team. You will be given a copy of this signed and dated information sheet. 
 
A description of this study clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of results. You can search this website at any time.”  
 
HIPAA Authorization for Use of Your Protected Health Information (HIPAA) 
As part of this study, we will be collecting health information about you and your child. This 
information is “protected” because it is identifiable or “linked” to your child. 
 
Protected Health Information (PHI) 
By signing this Consent Document, you are allowing the investigators and other authorized 
personnel to use your protected health information for the purposes of this study.  This 
information may include: your education level, medical history, and growth parameters.  We will 
be contacting your primary care provider and asking them about information from your child’s 
appointment, such as weight, height, and head size.  
 
In addition to researchers and staff at UNMHSC and other groups listed in this form, there is a 
chance that your health information may be shared (re-disclosed) outside of the research study 
and no longer be protected by federal privacy laws.  Examples of this include disclosures for law 
enforcement, judicial proceeding, health oversight activities and public health measures.  
 
Right to Withdraw Your Authorization 
Your authorization for the use of your health information for this study shall not expire unless 
you cancel this authorization.  Your health information will be used as long as it is needed for 
this study, up to 10 years.  However, you may withdraw your authorization at any time provided 
you notify the UNM investigators in writing.  To do this, please send a letter notifying them of 
your withdrawal to: 
 
Tara G. Zamora 
MSC10 5590  
1 University of New Mexico 
Albuquerque New Mexico 87131 
 
Please be aware that the research team will not be required to destroy or retrieve any of your 
health information that has already been used or shared before your withdrawal is received. 
 
Refusal to Sign 
If you choose not to sign this consent form and HIPAA Authorization, then your child will not be 
allowed to take part in this study.  This will not affect the care your baby receives in the NICU. 
 


6 
MEND Study 
 
 
 
version 5.25.18 
What if I have questions or complaints about this study? 
If you have any questions, concerns or complaints at any time about the research study, Tara 
Zamora, MD, or her associates will be glad to answer them at 505-272-0180, Monday – Friday, 
8am-5pm.  If you would like to speak with someone other than the research team, you may call 
the Human Research Review Committee (HRRC) at (505) 272-1129.  The HRRC is a group of 
people from UNMHSC and the community who provide independent oversight of safety and 
ethical issues related to research involving human participants. 
 
What are my and my child’s rights as a research participant? 
If you have questions regarding your rights as a research participant, you may call the Human 
Research Protection Office (HRPO) at (505) 272-1129 or visit the HRPO website at 
http://hsc.unm.edu/research/hrpo/  
 


 
 
 
version: 12.4.18 
7 
 
Consent and Authorization 
You are making a decision whether to allow your baby to participate in this study.  Your 
signature below indicates that you read the information provided (or the information was read to 
you).  By signing this Consent Form, you are not waiving any of you or your child’s legal rights 
as research participants. 
I have had an opportunity to ask questions and all questions have been answered to my 
satisfaction.  By signing this Consent Form, I agree to have my child participate in this study.  A 
copy of this Consent Form will be provided to me. 
 
 
 
I have explained the research to the participant’s legal guardian/parent and answered all of 
his/her questions.  I believe that he/she understands the information in this consent form and 
freely consents to participate. 
 
 
 
 
 
 
X
Name of legal guardian/parent (print)
X
Signature of Legal Guardian/Parent  Date
X
Name of Research Team Member
X
Signature of Research Team Member  Date
X
Child's Name

Prot_SAP_007.pdf: 
MEND (Mild Encephalopathy in the Newborn treated with Darbepoetin) 
11.18.2020 
 
Page 1 of 30 
Version Date: 11.18.20 
PROTOCOL TITLE: 
 
Mild Encephalopathy in the Newborn treated with Darbepoetin (MEND) 
 
PRINCIPAL INVESTIGATOR: 
Jean Lowe, PhD 
Professor of Pediatrics 
University of New Mexico School of Medicine 
MSC 10 5590, 1 University of New Mexico 
Albuquerque, NM 87131-0001 
(505) 269-2538 
 
JLowe@salud.unm.edu 
 
VERSION NUMBER: 
10 
DATE: 
11.18.2020 
REGULATORY FRAMEWORK: 
Please indicate all that apply: 
 
DOD (Department of Defense) 
 
DOE (Department of Energy) 
 
DOJ (Department of Justice) 
 
ED (Department of Education) 
 
EPA (Environmental Protection Agency) 
 
FDA (Food and Drug Administration) 
 
HHS (Department of Health and Human Services) 
 
Other:       
 
Is this a clinical trial under ICH-GCP E6?   
 Yes   
 No 
If yes, please confirm that the research team is familiar with and agrees to 
comply with the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No  
ICH-GCP E6 can be accessed by copying and pasting this URL into your 
browser: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf 
 
 
 


2 MEND 
 
Table of Contents 
1. 
Objectives .................................................................................................................. 3 
2. 
Background ................................................................................................................ 3 
3. 
Study Design ............................................................................................................ 10 
4. 
Prior Approvals ........................................................................................................ 16 
5. 
Data Analysis ........................................................................................................... 17 
6. 
Provisions to Monitor the Data to Ensure the Safety of Subjects ............................ 17 
7. 
Withdrawal of Subjects ............................................................................................ 18 
8. 
Risks to Subjects ..................................................................................................... 18 
9. 
Potential Benefits to Subjects .................................................................................. 18 
10. Recruitment Methods ............................................................................................... 18 
11. Other Sites ............................................................................................................... 19 
12. Economic Burden to Subjects .................................................................................. 20 
13. Compensation .......................................................................................................... 20 
14. Compensation for Research-Related Injury ............................................................. 21 
15. Consent Process ...................................................................................................... 21 
16. Study Test Results/Incidental Findings .................................................................... 22 
17. Checklist Section ..................................................................................................... 23 
 


MEND (Mild Encephalopathy in the Newborn treated with Darbepoetin) 
11.18.2020 
 
Page 3 of 30 
Version Date: 11.18.20 
1. Objectives 
Primary Hypothesis: Darbe will improve neurodevelopmental outcomes in infants >34 
week gestational age with mild encephalopathy who do not qualify for therapeutic 
hypothermia  
Specific Aims: 
• 
To assess the feasibility of administering one dose of Darbe in late pre-term (≥34 
week) and term infants with mild encephalopathy, who do not qualify for TH 
• 
Establish population pharmacokinetics of Darbe in late pre-term (≥34 week) 
and term infants with mild encephalopathy, who do not qualify TH 
• 
To determine if Darbe improves neurodevelopemental outcomes in late pre-
term (≥34 week) and term infants who do not qualify for TH  
 
2. Background 
 
Therapeutic hypothermia (TH) has become the standard of care for newborns diagnosed 
with moderate to severe neonatal encephalopathy (NE) at <6 hours of age. However, in 
current practice TH is not indicated in newborns who are NOT classified as moderate to 
severe NE on a <6 hours standardized neurological examination. Although perinatal 
acidemia is the initial screening component in the decision to treat the newborn with TH, 
the majority of newborns with perinatal acidemia do not receive TH because their 
neurologic examination is not abnormal enough to be classified as having moderate or 
severe NE. A retrospective review of infants found that as many as 20% of newborns 
who do not do qualify for TH encephalopathy will have abnormal short-term outcomes 
such as seizures, death from progressive asphyxia insult, abnormal brain MRI consistent 
with NE, abnormal neurologic examination at discharge, gastrostomy tube feeding, or 
feeding difficulties in the NICU. Preliminary data from a multicenter, prospective study 
(PRIME study) show 36% of infants with mild HIE had either abnormal neurological 
exam, aEEG or MRI; only 2% (1infant) had abnormalities in all 3 parameters. There are 
currently no therapies offered to infants with mild NE. Although, outcomes are thought to 
be better in infants with mild NE there is still a significant risk of neuronal injury in infants 
born with perinatal/fetal acidemia who are diagnosed with mild encephalopathy. 
Neuroprotective strategies aimed at improving early childhood outcomes are needed.  
Erythropoiesis stimulating agents (ESA) have been shown to provide neuroprotection, 
improving short and long-term neurologic outcome in brain injury and NE in neonates. 
ESA may work through several important mechanisms including reduced inflammation, 
limited oxidative stress, decreased apoptosis and white matter injury, as well as via pro-
angiogenic and neurogenic properties. Darbepoetin alfa (Darbe), a recombinant human 
erythropoietin (EPO)–derived molecule, has an extended circulating half-life and 
comparable biological activity to EPO.  The proposed study is a Phase II trial of early 
Darbe administered to infants with mild NE.  The long-term objective of the proposed 
research is to decrease the risk of long-term disabilities in infants with mild NE who do 
not qualify for hypothermia therapy. 
 


4 MEND 
 
Preclinical Trials 
In recent years, ESA have been studied extensively in preclinical trials of 
neuroprotection prompted by the finding that EPO receptor is expressed in the human 
brain (in cultured neurons, astrocytes, oligodendrocytes, microglia, and endothelial 
cells)(1-3).  Importantly, both EPO and Darbe administered peripherally can cross the 
blood-brain barrier by way of extracellular pathways in amounts that can account for 
their neuroprotective actions.(4)  Animal models have shown EPO to activate cellular 
mechanisms that promote cellular maturation, inhibition of apoptosis, neurovascular 
remodeling, revascularization and neurogenesis. (5-9) Exogenously administered EPO 
also enhances endothelial progenitor cell mobilization from the bone marrow, amplifies 
the production of neural progenitor cells, and stimulates oligodendrogenesis. (10-12) 
 
With respect to the treatment of ischemic brain injury in experimental animal models of 
perinatal brain injury, systemic administration of EPO improves functional and 
histological recovery.  EPO reduced infarct volume and improved functional and 
neurobehavioral performance when given immediately prior to or after neonatal brain 
injury using the Vannucci-Rice model for neonatal HI (13-16).  Neurobehavioral testing 
revealed significant enhancement of muscle strength, limb placing reflexes, motor 
coordination and neurosensory skills. Recently, Traudt et al showed, in a non-human 
primate model of HIE, that EPO combined with hypothermia decreased death and 
moderate/severe cerebral palsy in comparison to placebo or hypothermia only. 
Additionally, neuroimaging studies were improved with combined EPO/hypothermia 
treatment. (17) 
 
Similarly, Darbe administration following cortical impact injury in adult rats improved 
cerebrovascular function and reduced histological damage in a dose and time 
dependent manner(18). Weekly administration of Darbe conferred histological and 
behavioral neuroprotection after intracerebral hemorrhage in rats similar to that of EPO 
administration.(7, 19, 20) 
Finally, following focal cerebral ischemia in rats (middle cerebral artery suture-
occlusion), Darbe-treated rats showed decreased infarct volume and total infarct areas 
as well as improved neurologic scores relative to vehicle-treated animals. (20)  
In summary, there is convincing data in a variety of animal models that ESA can 
cross the blood-brain barrier and enhance neurological recovery following stroke, 
NE, and trauma. This is accomplished through several important mechanisms 
such as inhibition of apoptosis and enhanced neurogenesis. 
 
 


MEND (Mild Encephalopathy in the Newborn treated with Darbepoetin) 
11.18.2020 
 
Page 5 of 30 
Version Date: 11.18.20 
Previous Human Experience 
 
Adult Clinical Trials 
ESA use in critically ill adult patients 
In recent years, EPO clinical trials have been designed to assess neuroprotection in a 
variety of conditions including stroke, subarachnoid hemorrhage, out-of-hospital cardiac 
arrest, and cardiac surgery(21-26).  In these settings, the dose of EPO ranged from 
30,000 U/dose X3 doses every 48 hours(26); 40,000 IU of IV EPO within 6hrs of 
symptoms, at 24h and at 48h(22); 40,000U IV q12h for the first 48h after ICU 
admission(23); or 375-1500 U/Kg x 3 daily doses(24).  
 
The overall outcomes have been quite variable, ranging from favorable to no difference 
in the outcomes measured between treatment groups. Among favorable outcomes, 
Tseng observed  that in those patients  <60 years old and non-septic, the EPO group 
developed significantly less cerebral vasospasm, impairment in cerebral autoregulation 
and neurological deficits (as measured by the National Institutes of Health Stroke 
Scale)(26). Haljan et al. observed a trend in reduction of neurocognitive dysfunction in 
patients undergoing coronary artery bypass surgery who received increasing doses of 
EPO divided in 3 daily doses, starting the day before surgery(24). In a recent 
retrospective matched case control study of EPO and Darbe, Talving et al observed that 
ESA administration following severe traumatic brain injury in adult patients was 
associated with a significantly improved in-hospital survival rate without increase in 
morbidities in comparison to matched controls(25).  
 
In some, but not all of these studies, EPO administration was associated with a higher 
rate of death, intracranial hemorrhage, thromboembolic events and brain edema (22) 
(23). These results are in contrast to a smaller trial in critically ill patients that were also 
treated with EPO but who did not receive thrombolytic therapy, as was the case in 
patients with the complications described above(21).  
 
A 2016 analysis of ESAs in critically Ill trauma patients found a significant improvement 
in mortality without an increase in the rate of proximal deep vein thrombosis(27).  
In conclusion, further studies of the potential therapeutic effects of ESA are 
warranted in select populations, such as newborns with hypoxic-ischemic injury 
at birth, with close monitoring of outcomes and adverse effects. 
 
Studies of ESA in Premature Infants 
The administration of human recombinant EPO in preterm infants has been studied as 
an alternative to red blood cell transfusion in the treatment of anemia since the late 
1980s.  Between 1991 and 2009, 2,723 preterm infants were enrolled in 33 randomized 
controlled trials to evaluate the safety and efficacy of EPO as a treatment for anemia of 
prematurity. Treatment regimens varied widely, ranging from 70 to 5000 U/kg/week, with 
duration of therapy ranging from 2 weeks to several months. Halperin et al reported data 
from the first pilot study on the treatment of anemia of prematurity in 1990(28).  Since 


6 MEND 
 
then, a multitude of studies have been performed examining a variety of EPO doses 
from low <500 U/kg/week to high >500 U/kg/week and treatment periods from early 
(started before 8 days of age) versus late (between 8 - 28 days after birth).(29-31).  The 
NICHD NRN study of early erythropoietin therapy for anemia of prematurity examined 
the effects of EPO treatment (400 U/kg 3 X/ week) initiated by 4 days after birth and 
continued through 35 weeks postmenstrual age in preterm infants < 1250g birth weight.  
This study revealed no impact in transfusion requirement, but was important in that it 
demonstrated no increase in adverse events with similar rates of hospital morbidities, 
mortality, length of hospital stay, neutropenia, hypertension and seizures in the EPO 
treated and placebo/control infants.  Follow-up at 18-22 months’ corrected age revealed 
similar rates of neurodevelopmental impairment and need for rehospitalization between 
groups(32).  Gumy-Pause et al studied higher doses (up to 5000 U/kg/week) of EPO and 
once again demonstrated no impact on episodes of infection, NEC, sepsis and 
neutropenia between low (1250 U/kg/wk) and “high-dose” (up to 5000U/kg/wk) EPO(33).  
In a small ancillary study to the NRN trial, 16 premature infants were treated with EPO or 
placebo for anemia of prematurity, and Bierer et al reported an association between 
higher EPO levels (> 500 mU/mL) and higher Mental Developmental Index scores 
on the Bayley Scales of Infant Development II at 18-22 months’ corrected age(34).  
Similarly, Brown et al reported improved neurodevelopmental outcomes in a secondary 
analysis of 82 preterm infants born <1500g and < 30 weeks’ gestational age treated with 
erythropoietin for anemia.  Increasing cumulative EPO exposure was associated 
with higher BSID II Mental Developmental Index scores (35).  Neubauer et al 
reported a similar beneficial effect on 10-13y outcome of 148 preterm infants 
treated with EPO under a variety of dosing regimens:  the EPO group scored 
significantly better than untreated children in the overall developmental assessment 
(55% vs. 39% normally developed, p<0.05) as well as in the psychological examination 
(mean composite HAWIK-III IQ score, 90.8 vs. 81.3, p < 0.005)(36). Over this wide 
range of dosing and duration of therapy, EPO and Darbe has been quite safe in 
neonatal populations. No study of EPO treated newborns has reported an increase 
in thrombotic complications similar to those observed in adults. 
 
Several recent single-center trials reported on the safety and pharmacokinetics of 
“neuroprotective” doses of erythropoietin in premature infants using doses that are 
approximately 10 fold higher than those used for anemia of prematurity.  Juul and 
colleagues performed a prospective, open-label dose-escalation trial in which 30 infants 
were treated with high dose recombinant human erythropoietin (Epoetin Alfa 
Recombinant) and compared with 30 concurrent control infants(37).  Infants received 
doses of 500U/kg/dose, 1000U/kg/dose or 2500U/kg/dose for three doses at 24 hour 
intervals starting on day 1, with ten infants in each group.  The researchers found that 
both the 1000U/kg/dose and 2500U/kg/dose produced peak serum EPO concentrations 
that were analogous to neuroprotective concentrations seen in animal and adult studies.  
High dose EPO followed nonlinear pharmacokinetics as decreased clearance was 
observed with the highest dosing regimens.  No increase in adverse events was 
reported for the EPO treated infants when compared with the control infants(37).  


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Fauchère and colleagues performed a randomized, double-masked trial in which 
preterm infants between 24 and 31 weeks GA were given recombinant human EPO 
(Epoietin Beta in doses of 3000U/kg birth weight) or placebo at 3, 12-18, and 36-42 
hours after birth. A multicenter trial looked at preterm infants (26-32 weeks gestation) 
and found no improvement in neurodevelopmental outcome at 2 years corrected age, 
and no adverse effects using rhEPO 3000 U/kg.  
Once again, administration of high dose EPO resulted in no significant adverse 
events(38).   
 
Regarding the administration of Darbe in preterm infants, Warwood el al showed that a 
single dose of Darbe accelerated effective erythropoiesis in a pilot study of 12 preterm 
infants(39). The same group of investigators reported that IV administration to neonates 
resulted in a shorter half-life, a larger volume of distribution and more rapid 
clearance(40).  
 
Ohls et al. performed a randomized, placebo controlled study to assess the safety 
and efficacy of Darbe administered to preterm infants (500-1250 grams birth weight). 
In this study they reported preterm infants who received ESAs (Darbe 10µg/kg or EPO 
400 U/kg) had significantly better cognitive outcomes at 18-22 months and at preschool 
testing compared with placebo recipients, with no adverse events reported.(41) 
Natalucci et al. recently published a study using prophylactic early high-dose 
recombinant human erythropoietin in preterm infants (26-31 weeks gestation).  228 
participants were randomized to receive either erythropoietin 3000 IU/kg and 220 
received the placebo. Erythropoietin was given IV at 3 hours, 12-18 hours, and at 36-42 
hours after birth.  They found that among infants who received prophylactic 
erythropoietin there was no significant difference in neurodevelopmental outcome 
between the groups.  No adverse events were reported(42).  
 
Trials of EPO in term infants with NE  
Recent studies have evaluated the use of EPO in term infants with NE not treated with 
hypothermia.  The first was a randomized prospective study of 167 term infants with 
moderate/severe NE conducted by Zhu et al(43).  Infants were randomly assigned to 
receive either EPO (N=83) or conventional treatment (N=84). EPO treated infants 
received either 300U/kg of rhEPO (N=52) or 500U/kg of rhEPO every other day for 2 
weeks starting within 48 hours of birth. Study participants were followed to 18 months of 
age and underwent detailed neurodevelopmental assessment.  Primary outcome was 
death or moderate/severe disability defined as CP, severe hearing loss, blindness, gross 
motor function classification levels 3 through 5, and a MDI <70 on the Bayley Scales of 
Infant Development II.  Complete outcome data were available for 91.6% of participants.  
EPO treated infants had significantly lower rates for death or moderate to severe 
disability (24.6% [18/73] infants versus 43.8% [35/80]) in control infants; P=0.017).  
Subgroup analyses revealed benefit from EPO treatment only in babies with moderate 
NE. No differences in primary outcomes or side effect profiles were noted for the two 
studied EPO doses (43). 


8 MEND 
 
 
A study conducted by Elmahdy et al, was a pilot study that examined the safety and 
efficacy of much higher doses of EPO administration upon generation of nitric oxide 
(NO), a mediator of hypoxic injury.  This was a case-control study with 3 groups of 
infants (15 infants per group).  The first group was comprised of normal healthy term 
infants; the second was comprised of term infants with mild/moderate NE who were 
administered 2500U/kg of subcutaneous EPO daily for 5 days; and the third group was 
an NE control group that received no EPO.  Baseline serum concentrations of NO were 
measured in the normal healthy neonates, and at baseline and 2 weeks for the two NE 
groups.  In addition, the two NE groups underwent encephalography at baseline and 2-3 
weeks and MRI at 3 weeks of age.  Neurological assessment and neurodevelopmental 
screening (Denver Developmental Screening Test II) were performed at 6 months of 
age.  Compared with the healthy term infants, the NE groups had higher serum NO 
levels.  Though the two NE groups did not differ in severity of illness, NO levels, seizure 
burden or EEG background activity at baseline, the EPO treated group had statistically 
lower serum NO levels, fewer neurodevelopmental deficits and improved EEG 
background at follow-up.  MRI findings did not differ between groups.  No side effects 
related to EPO administration were identified despite close monitoring for allergic 
reactions, venous thrombosis, renal/hepatic effects, hypertension or electrolyte 
disturbances(44). 
 
In 2012, an open label, dose-escalation, phase I study, enrolled 24 term infants 
undergoing TH for moderate/severe NE. Patients received 1 of 4 Epo doses 
intravenously: 250 (N=3), 500 (N=6), 1000 (N=7), or 2500 U/kg per dose (N=8).  They 
gave up to 6 doses every 48 hours beginning at <24 hours of age.  Epo did not follow 
linear pharmacokinetics, but excessive accumulation did not occur.  At 500, 1000, and 
2500 U/kg Epo, t1/2 was 7.2, 15.0, and 18.7, and the area under the curve was 50,306, 
131,054, and 328,002 U*h/L, respectively.  They noted drug clearance at a given dose 
was slower than reported in uncooled preterm infants.  No deaths or serious adverse 
events were seen. They found that Epo at 1000 U/kg given intravenously in conjunction 
with hypothermia is well tolerated and produces plasma concentrations that are 
neuroprotective in animals (45).   
 
In 2016 a phase II double-blinded, placebo-controlled trial randomized newborns with 
moderate/severe NE to treatment with hypothermia alone or high-dose erythropoietin in 
addition to hypothermia.  50 infants were enrolled. They found that high-dose 
erythropoietin and hypothermia resulted in less MRI injury and improved 
neurodevelopmental outcomes at 12 months of age. There were no safety issues 
reported(45).  
 
The therapeutic potential of EPO and its chemical analog Darbe for NE brain injury 
in the newborn appears to be safe. 
 
 


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Low Dose vs. High Dose Darbepoetin   
In 2015 a multi-center study was published to assess safety and pharmacokinetics of 
Darbe in infants undergoing TH for NE.  It evaluated 30 term infants with moderate to 
severe NE who were undergoing hypothermia therapy and randomized to standard of 
care TH or TH and Darbe low dose (2 µg/kg) or TH and Darbe high dose (10 µg/kg) 
given intravenously within 12h of birth and at 7 days. Adverse events were documented 
for 1 month and pharmacokinetics were evaluated. Adverse events were similar to 
placebo and historical controls.  Following the first dose (hypothermia conditions) at 2 
and 10 µg/kg, t1/2 was 24 and 32 hours, and the area under the curve was 26,555 and 
180,886 h*mU/ml*, respectively.  The clearance of the drug was not noted to be different 
between the doses.  At 7 days (normothermia conditions), t1/2 was 26 and 35 hours, and 
the area under the curve was 10,790 and 56,233 h*mU/ml*, respectively(46).  
 
This study showed that the 10 µg/kg dose produced a median AUCinf  of 180,886 
h*mU/ml after the first dose, which is comparable to previous report of neuroprotection in 
animal studies. (47)  
 
In summary, despite more than 20 years of use, few safety concerns have been 
identified with the use of ESAs in preterm and term infants. Furthermore, there is 
emerging evidence that early use of EPO or Darbe in extremely low birth weight 
infants can improve neurological outcomes. Additionally, recent research has 
given guidance as to the pharmokinetics of Darbe in neonates with 
moderate/severe encephalopathy.  
 
 
 


10 MEND 
 
 
3. Study Design 
Eligible patients will be identified by the admitting neonatologist or by the research 
nurses based on admission diagnosis (perinatal depression, perinatal acidemia, HIE or 
NE, encephalopathy, clinical assessment for the need for therapeutic hypothermia).  
 
Inclusion Criteria: Infants will be eligible for the MEND trial if they have a gestational age > 34 
weeks by best obstetric estimate, are <24 hours old and have evidence of mild encephalopathy 
and DO NOT have moderate-severe acute NE as defined by Shankaran et al based on a 
modified Sarnat examination performed at <6 hours of age (48).  
Eligibility will include criteria presently used in the NICU to initiate therapeutic hypothermia and 
used in the NICHD NRN hypothermia trial: 
1) History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart rate 
abnormality, or meconium staining) 
2) Infant is evaluated for hypothermia therapy and DOES NOT meet clinical criteria for TH. 
3)  Infant has an IV for clinical treatment 
 
 
Exclusion Criteria 
1) Moderate/Severe encephalopathy on modified Sarnat examination at < 6 hours 
of age 
2) Major congenital and/or chromosomal abnormalities 
3) Prenatal diagnosis of brain abnormality or hydrocephalus 
4) Severe growth restriction (< 3% for gestational age) 
5) Central venous hematocrit >65%, platelet count >600,000/dL, and/or neutropenia 
(ANC<500 µL) 
6) ECMO 
7) Infant judged critically ill and unlikely to benefit from neonatal intensive care by 
the attending neonatologist 
 
After eligibility is confirmed, with approval from the Attending Care Provider, the parent 
or legal guardian will be approached for consent (as noted below under consent 
process). All patients eligible for this study will be managed in the NICU.  
 
Drug administration: Each center will obtain their own Darbe through their research 
pharmacies. Randomization will take place at each site using a provided block-design 
randomization table created by UNM research pharmacy.  The site pharmacy will then 
dispense the study drug to the research nurse in a closed container. Darbe and vehicle 
are the same in appearance, and will be labeled “study drug”.  
 
DESIGN:  
This is a Phase II placebo-controlled randomized, blinded, feasibility trial. 
The multisite study will consist of 80 infants (n=40 in each arm) >34 week GA infants with NE 
who DO NOT qualify for hypothermia therapy, that will be randomized to receive either Darbe, 


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(10 μg/kg IV), or placebo. We plan to enroll 20 participants at the University of New Mexico. 
A total of 80 infants at all sites (see table below) will be enrolled.  
 
Dr. DuPont (PI) Holds the IND for Darbepoetin and mild NE (IND 132207) and will remain as a 
study team member and overall PI of this multi-center study. Treatment will be randomized by 
the pharmacy and blinded to the caregivers. All groups will receive the dose within 24 hours of 
birth.  
√ 
                               Intervention 
Experimental groups 
Darbe  
N=40 
10 mcg/kg/dose Darbe IV <24 hours of age 
Control group 
Placebo  
N=40 
 
Normal saline placebo dose IV at <24 hours of age     
 
 
STUDY PROCEDURES:  
Timeline for the study: 
Anticipated time to recruit 80 patients will be 2 years.  Centers that will participate in this 
Phase II study will include University of New Mexico Children’s Hospital, University of 
Utah Medical Center, Intermountain Medical Center, Primary Children’s Medical Center, 
The University of South Florida, Stanford University, and University of Texas 
Southwestern.  
 
Once the infant meets eligibility criteria and consent has been obtained from the 
parent(s), the infant is a study participant.  
 
Data collection 
At study entry maternal demographics, specifically: age, education, race, ethnicity will be 
collected.  A modified Sarnat exam will be repeated at discharge, transfer, or 96 hours of 
age (which ever occurs first) and documented. We will collect vital signs, MRI, 
hemoglobin/hematocrit, CBC with differential, liver function tests, and complete physical 
exam if they are done as indicated by clinical care.  MRIs done for clinical indication will 
be de-identified and sent to a pediatric neuroradiologist for a centralized read.  Once de-
identified, these will be sent via CD or LifeImages to UT Southwestern where they will be 
read by the neuroradiologist.     We are requesting waiver of consent to send de-
identified MRIs to UT Southwestern for an additional reading.  All MRIs have been and 
will be ordered per clinical indication and are not required under the study protocol. 
 
 
Immunogenicity Testing 
The vast majority of babies admitted to the NICU have a CBC with diff drawn on 
admission.  If there is at least 0.5mL of blood remaining (scavenged blood) after 
analysis, we will collect that blood and use as our baseline sample for potential 
immunogenicity testing. If the baby remains in the NICU for 2 weeks and has a blood 
test done for clinical reasons, we will attempt to keep 0.5mL (scavenged blood). 
Additionally, a letter (attached) will be given to the PCP stating that the patient is 


12 MEND 
 
enrolled in a research study.  If there are concerns for anemia and the PCP orders a 
CBC within the first year of life we will ask for 0.5mL of blood (scavenged blood). We will 
ask the lab to hold “scavenged” blood and store for up to 6 months beyond enrollment of 
the last patient.  
 
PK Sampling 
Blood samples will be used to establish population pharmacokinetics. Scavenged blood 
samples of 0.05 mL of blood will be collected from all clinical blood draws throughout the 
infant’s hospitalization and sent to the University of Iowa for population pharmacokinetics 
using meso-scale discovery assay to detect Epo levels. Since a baseline sample is also 
required for immunogenicity testing we will collect an extra 0.3 mL of blood with the “pre-
drug” blood work drawn in the NICU. Study participants will have the option of opting in 
for this additional blood draw. This will ensure that there is enough blood for potential 
immunogenicity testing and pK analysis. Every effort will be made to obtain this sample 
with a blood draw that is needed for clinical purposes (such as a glucose check). All 
other pk samples will be off of scavenged blood. Parents will be given the option to opt 
into this part of the study on the consent form.   
  
Parents of participants will be contacted by phone call at 4 months of age which will 
include developmental screening via a modified Ages and Stages questionnaire 
(attached), number of hospitalizations, seizures, need for assisted respiratory support, 
failure to thrive, medication use, use of early intervention services, hearing impairment, 
any concern with vision.  
 
Participants will have neurodevelopmental testing (Bayley III and Gross Motor Function 
Assessment) performed at 8-12 months of age. We will also conduct a brief medical 
exam including weight, length, head circumference, blood pressure, and heart rate.  
 
In addition, we may contact the child’s primary care provider and ask for the baby’s most 
recent medical history and the result of the most recent hematocrit.   
 
Data will be kept for analysis for up to 10 years.  
 
Standard of Care vs. Research-Related Procedures:   
Research-Related procedures: 
1. Study drug can be given as soon as the infant is found to NOT qualify for TH but 
before 24 hours of age. 
2. Extra 0.3 mL of blood drawn prior to drug administration (optional) 
3. Neurological examination at discharge, transfer, or 96 hours of age (which ever 
occurs first) 
4. Follow up phone calls at 4 months of age 
5. Bayley Scales of Infant Development examination at 8-12 months corrected age. 
6.   


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7. Weight, length, head circumference, heart rate, and blood pressure at 8-12 
months. 
8. Medical records from primary care provider including hemoglobin and hematocrit  
if available when indicated.  
 
Standard of Care: 
1. Monitoring and routine supportive care.   
  
Safety 
For the purpose of this study, an adverse event (AE) will be defined as any adverse 
change from the patient’s baseline condition that occurred following the administration of 
the study drug through the end of the study period. Safety will be evaluated during the 
first 7 days of life or until hospital discharge (whichever comes first) by documenting 
potential adverse events such as (but not limited to) alterations in blood pressure, 
secondary infections, neutropenia, thrombotic/vascular events, hematologic events 
(platelets, Hct level, polycythemia), and hepatic/renal function that are outside of normal 
range for the study population.   
 
We will assess for the rare complication (1 in 10,000 in adults with renal failure) of pure 
red blood cell aplasia. The vast majority of babies admitted to the NICU have a CBC with 
diff drawn on admission.  If there is at least 0.5mL of blood remaining (scavenged blood) 
after analysis, we will collect that blood and use as our baseline sample. Similarly, most 
babies admitted to the NICU have electrolytes or bilirubin levels drawn at 24-72 hours of 
age, if there is at least 0.5mL of blood remaining (scavenged blood) after analysis, we 
will collect that blood and use as our second sample.  If the baby remains in the NICU 
for 2 weeks (uncommon) and has a blood test done for clinical reasons, we will attempt 
to keep 0.5mL (scavenged blood) to assess for pure blood cell aplasia. Additionally, a 
letter (attached) will be given to the PCP stating that the patient is enrolled in a research 
study.  If there are concerns for anemia and the PCP orders a CBC within the first year 
of life we will ask for 0.5mL of blood (scavenged blood). We will ask the lab to hold 
“scavenged” blood and store for up to 6 months beyond enrollment of the last patient.   
 
We will also ask for the medical records from the child’s primary care provider and their 
most recent hematocrit/hemoglobin.   
 
Long Term Safety will involve phone calls at 4 months of age which will include 
developmental screening via Ages and Stages questionnaire, hospitalizations, seizures, 
need for assisted respiratory support, failure to thrive, medication use, use of early 
intervention services, hearing impairment, any concern with vision.  In addition we will 
contact the child’s primary care provider and ask for the child’s medical records and 
most recent hematocrit/hemoglobin to assess for safety.  
Serious adverse events (SAE) will be defined as any event that results in: death, a life 
threatening event (major venous thrombosis, stroke, and/or severe hypertension), 
persistent or significant disability/ incapacity, and/or prolongs inpatient hospitalization. 


14 MEND 
 
SAEs will be reported until 30 days following final cessation of therapy or until hospital 
discharge, whichever comes first. 
 
 


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Evaluation 
Screening 
Pre-Entry 
(Prior to 24 hrs) 
Entry (<24 hr of age) 
discharge, transfer, or 
96 hours of age (which 
ever occurs first) 
3-10 days 
Discharge 
4 months corrected age 
8-12 months corrected 
age 
Screen admissions to NICU 
X 
X 
 
 
 
 
 
 
Documentation of Gestational Age 
 
X 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Maternal Demographics and History 
 
 
X 
 
 
X 
 
 
Blood Pressure  
 
 
X 
 
X 
X 
 
X 
Modified Sarnat Exam 
 
 
 
X 
 
 
 
 
MRI as available from clinical care 
 
 
 
 
X 
X 
 
 
Hematology 
(CBC/transfusions/phlebotomy loss) 
as available from clinical care 
 
 
X 
 
 
X 
 
X 
Administration of study drug IV 
 
 
X 
 
 
 
 
 
Liver/kidney Function Tests (as 
clinically available) 
 
 
 
 
X 
 
 
 
Complete Physical Exam including 
weight, head circumference and 
length 
 
 
X 
 
 
X 
 
 
Telephone contact to review current 
status 
 
 
 
 
 
 
X 
 
Ages and Stages phone 
questionnaire 
 
 
 
 
 
 
X 
 
Phone/in person survey on 
hospitalizations, seizures, need for 
respiratory support, failure to thrive, 
medication use, use of early 
intervention, hearing impairment, 
concerns with vision 
 
 
 
 
 
 
X 
X 
Neurodevelopmental assessment 
Bayley III & 
Standardized Neurologic exam 
 
 
 
 
 
 
 
X 
Weight, length, head circumference, 
blood Blood pressure, and heart rate 
 
 
 
 
 
 
 
X 
 
 
 


16 MEND 
 
4. Prior Approvals 
• 
Tara DuPont, MD holds the IND (IND 132207) for this trial.  
• 
See the attached departmental review form. 
 
Study Resources: Trained NICU research nurses are available at the University of New 
Mexico, the University of Utah, and Primary Children’s Medical Center NICU’s. All sites 
have a locked office with locking cabinets in which study data will be kept. All 
participating infants will be assigned a study number and identified for study purposes by 
that number only. 
• 
All sites have the most current version of the protocol, consent document, 
and HIPAA authorization. 
• 
We are seeking approval from the IRB’s at each site, when obtained they will 
be added to this document as a modification. 
• 
All modifications will be communicated to sites, and approved (including 
approval by the site’s IRB of record) before the modification is implemented. 
• 
All engaged participating sites will safeguard data as required by local 
information security policies as they are all actively involved in neonatal 
clinical trials. 
• 
All local site investigators will conduct the study appropriately. 
• 
All non-compliance with the study protocol or applicable requirements will 
reported in accordance with local policy. 
Control of Investigational Devices/Drugs: The study drug will be stored in, controlled 
and dispensed by, the Investigational Research Pharmacy. Labeling for the study drug will 
be done per standard investigational drug guidelines employed by the research pharmacy 
 
Dr. Tara DuPont, the sponsor-investigator, will maintain complete and accurate records 
showing any financial interest in 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of the 
CFR paid to clinical investigators by the sponsor of the covered study. Dr Tara DuPont, 
the sponsor-investigator, will also maintain complete and accurate records concerning all 
other financial interests of investigators subject to part 54 of the CFR. 
 
Jean Lowe and qualified study team members will prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each participant who is given darbepoetin or employed as a control in 
the study. Jean Lowe and the Clinical Research manager, will be responsible for 
preparing and maintaining these case history reports at the University of New Mexico.  
 
 Jean Lowe or her designee will retain the records and reports required by 21 CFR 
312.57 (c) for two years after a marketing application is approved for the drug; or if the 
application is not approved for the drug, until 2 years after shipment and delivery of the 
drug for investigational use is discontinued and FDA has been so notified. 


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Jean Lowe will ensure that reserve samples and/or lot numbers of the study drug, darbe 
will be maintained at the University of New Mexico and released to the FDA upon 
request, in accordance with, and for the period specified in section 320.38.  These study 
drug samples will be maintained in a -80 freezer at the University of New Mexico for later 
testing for pK analysis. 
 
Assurance of IRB Review: 
Jean Lowe and participating clinical investigators will promptly report to reviewing IRBs 
all unanticipated problems involving risk to human participants or others according to 
IRB policy. Jean Lowe and/or study staff will be responsible for preparing and submitting 
these reports to the University of New Mexico IRB and maintaining files of IRB 
approvals/acknowledgements.  
 
5. Data Analysis 
This will be a multicenter pilot/feasibility trial to assess Darbe for infants who do not 
qualify for TH. Data from this trial will be used to power a large multicenter RCT. 
Primary outcome variable will be the incidence of abnormal neurodevelopmental 
score by Bayley III <85 or GMFS of >1 at 8-12 months of age. Chi-square or Fisher 
exact statistical tests will be performed for all categorical values. For continuous 
variables, t tests will be performed. All outcomes will be analyzed based on intention 
to treat inclusion of all randomized patients. We estimate infants who received Darbe 
will experience an estimated 30% decrease in neurodevelopmental impairment, 
defined as BSID III cognitive score or motor score <85, or a Gross Motor Function 
Classification Scale score >1.  A total of 40 infants per group will be required to 
identify a 30% difference between groups.  
 
6. Provisions to Monitor the Data to Ensure the Safety of Subjects 
The data and safety monitoring board (DSMB) is composed of members qualified by 
training and experience to monitor the progress of the investigation: 
1) John Philips, MD Professor of Neurology, University of New Mexico. Dr. Philips 
will be the DSMB Chair for this project. 
2) Kristi Watterberg, MD. Professor of Pediatrics, University of New Mexico. Dr. 
Watterberg has led and conducted multiple multicenter clinical studies .  
3) Lauren Jantzie, PhD. Division of Neuroscience, Department of Pediatrics, 
University of New Mexico 
4)  Pablo J. Sanchez, MD.  Professor of Pediatrics, Nationwide Children’s Hospital, 
Columbus, Ohio.  
 
Monitoring plan will include: 
1) The DSMB will review the study data for non-compliance and participant safety  
(adverse events, unanticipated problems, etc.) after the first 20 patients have 
been enrolled and every 6 months until study completion 


18 MEND 
 
2) The DSMB will report their findings to the sponsor-investigator after each 
meeting 
3) The sponsor-investigator will report DSMB findings to all participating clinical 
investigators after each meeting. Each participating investigator will submit the 
DSMB review to their IRB with corresponding documentation of the submission 
sent to Dr. Tara DuPont  
4) All SAEs will be reported to Dr. DuPont within 24 hours of the site learning of the 
event.  Each site PI will be responsible for reporting the serious or unexpected 
adverse events to their local IRB in accordance with the local IRB policies. Dr. 
DuPont will be responsible for notifying the DSMB chair within 24 hours of 
receiving the report and notifying the FDA in an IND safety report in accordance 
with FDA regulations. The DSMB will determine if the adverse event changes the 
risk to study subjects. If the information changes the known risk to subjects, the 
DSMB report of this event will be released to all participating investigators by Dr. 
DuPont. 
5) Criteria for Withholding Study Drug: Neutropenia (ANC <500/µL), hematocrit of 
>65%, stroke, symptomatic clot, or hypertension (blood pressure 2 SD greater 
than the mean for age).     
 
7. Withdrawal of Subjects 
This is a single intervention study.  If the infant is eligible and consented then the study 
drug will be given.  After the delivery of the drug the intervention is complete.  The family 
may choose to withdraw from the study at any time.  Follow-up phone calls and 
neurodevelopmental testing will occur between 4-12 months of age. 
8. Risks to Subjects 
Darbe use in adults can increase the risk of abnormal blood clot formation, increase red 
blood cell number, decrease white blood cell number, increase blood pressure, serious 
cardiovascular risks, including stroke, venous thrombus, and death.  Studies of Darbe 
use in adult cancer patients have shown increased cancer growth.  To date there is no 
information that these drugs would increase any such complications in infants.  There 
may also be side effects and discomforts that are not yet known.     
 
The infant will be assigned to a treatment group by randomization.  The treatment the 
infant receives might be less effective, not effective, or have more side effects than 
another study treatment. 
 
9. Potential Benefits to Subjects 
A potential benefit maybe improved neurodevelopmental outcome due to improved 
neuronal recovery from the administration of Darbe.  In addition, subjects will receive 
close developmental follow-up via phone calls and exam at 8-12 months of age. 
10. Recruitment Methods 


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Infants will be recruited for the study by the research nurses, investigator and co-
investigators during hospitalization in the NICU at each medical center following 
protocol criteria. 
 
 
 
 
11. Other Sites may include: 
University of Utah Hospital 
50 N Medical Drive 
Salt Lake City, UT 84132 
 
Intermountain Medical Center (Affiliated with University of Utah) 
5121 Cottonwood Street 
Murray, UT 84107 
 
Primary Children’s Hospital (Affiliated with University of Utah) 
100 North Mario Capecchi Drive 
Salt Lake City, UT 84113 
 
UTSW Sites (DUA attached.  This site will not be enrolling patients but will be sent 
MRIs of enrolled infants)  
Lina Chalak, MD 
University of Texas Southwestern Medical Center 
5323 Harry Hines BLVD, Dallas, TX 75390-9063 
Lina.Chalak@UTSouthwestern.edu 
 
 
Parkland Hospital 
5200 Harry Hines BLVD. 
Dallas, TX 75235 
 
Children’s Health Dallas 
1935 Medical District Dr. 
Dallas, TX 75235 
 
University of South Florida Site: (No data will be transferred until DUA has been 
obtained) 
Jaime Flores-Torres, MD 
5 Tampa General Cir, Suite HMT 450.19  
Tampa, FL 33606-3601 
jflorest@health.usf.edu 
 
University of South Florida/ Tampa General Hospital 
1 Tampa General Circle 
1st floor TGH F170 
Tampa, GL 33606 
 
Stanford Site: (No data will be transferred until DUA has been obtained) 


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Krisa Van Meurs, MD 
Stanford University/ Lucile Packard Children’s Hospital 
725 Welch Rd. 
Palo Alto, CA 94304 
vanmeurs@stanford.edu 
 
Each site will be responsible for screening, recruitment, and consent process for study 
subjects. Data collected at each site will be de-identified prior to transferring to the 
University of New Mexico, where it will be analyzed on an intention to treat basis. All 
participating infants will be assigned a study number and identified for study purposes by 
that number only. The University of New Mexico has a locked office with locking cabinets 
in which study data will be kept. No data will be transferred until DUA has been 
obtained. 
 
12. Economic Burden to Subjects 
Research Procedures 
Number of 
Samples/ 
Procedures 
Responsible Party 
Study 
3rd Party 
Payer or 
Participant 
Darbepoetin 10 micrograms/kg 
1 
 
 
Neurodevelopmental Testing 
1 
 
 
Follow up phone calls 
2 
 
 
Antibody testing 
2 
 
 
Pk Testing (non scavenged blood) 
1 
 
 
Pk Testing (scavenged blood) 
2-10 
 
 
      
      
 
 
      
      
 
 
Standard of Care Procedures 
Number of 
Samples/ 
Procedures 
Responsible Party 
Study 
3rd Party 
Payer or 
Participant 
Routine neonatal care 
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
 
13. Compensation 
At this time there are no plans for compensation.  With further funding for this project 
then a modification will be submitted.  


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14. Compensation for Research-Related Injury 
If the infant is injured as a result of this study, the University of New Mexico Health 
Sciences Center (UNMHSC) will provide the infant with emergency treatment, at usual 
charge.  No commitment is made by the UNMHSC to provide free medical care or 
money for injuries to participants in this study.   
 
 
15. Consent Process 
 
Consent  
The study and its options will be explained to the parent(s) ensuring that they know this 
is a voluntary study and they are in no way obligated to participate. Consent will be 
obtained by one of the study team members. Parents will be allowed time to ask 
questions and will be able to read the consent document as it is discussed. Consent 
should be obtained by the mother, if the mother is unable to sign and she is married to 
the father then the father may sign consent. If consent is given, a second clinical person 
will verify that they have understood all that has been explained to them and they will be 
asked to confirm that they are allowing their child to participate in this research study. In 
rare instance, if a baby is transported then consent will be obtained over the phone and 
signed consent faxed to UNMH.  Study procedures will begin only after signed consent 
has been received.  
 
 
Subjects not fluent in English 
After the English consent has been approved by the IRB we will obtain 
translation services in Spanish and submit at modification to the study 
including the Spanish consent.  
Subjects who are not yet adults (infants, children, teenagers) 
This study involves children from age 0 to 12 months.  
Written consent will be obtained by an investigator in a room which ensures the privacy 
of the family, and which is free of potential coercive influences. Consent for participation 
must be obtained by the time the baby is 24 hours of age.  
 
If a family has limited or no English speaking abilities, a certified interpreter will be 
provided. They will review the consent form with the family, and interpret the verbal 
explanation of the study during the discussion between the investigator and the family 
members. If individual sites have a large population of non-English speakers, consent 
forms will be translated into the appropriate languages. If an interpreter is not available 
in a timely manner, the family will not be approached. 
 


22 MEND 
 
The parents of the research participants will be given opportunity to review the study 
both verbally and in writing. The will be given opportunity to ask questions of the 
investigator prior to giving consent. 
 
If there are changes in the protocol or safety information that require consent forms to be 
updated, they will be sent through the IRB process for approval. The study entry form 
has a space for documentation of a signed consent form as well as a signed HIPAA 
form.  
 
16. Study Test Results/Incidental Findings 
Individual Results: Families will have access to neurodevelopmental results 
which will be delivered at the conclusion of testing and in a formal report 
delivered by mail.  The formal report will have a way to contact the 
investigators should the family have questions about the results.  In addition, if 
the child is found to be delayed, we will facilitate the child’s enrollment in 
therapy services.   
Incidental Findings: Given that only one dose of medication is being given it  
is unlikely to generate any incidental findings. We will facilitate finding 
resources for any child that is found to have a delay 
 
17. Data Management/Confidentiality 
The data will be stored electronically, stripped of any subject identifiers. The e-data will 
be stored for at least 10 years after the study closes. All data is coded with a unique 
identifying number, different from the patient’s medical record number or social security 
number, to maintain confidentiality. The link between identifiers and study ID will be 
destroyed upon closure of this study protocol with the HRRC. While identifiers are not 
needed in the participant data, we will have access to the patient’s electronic medical 
record in order to retrieve study data. This means that the patients’ medical record 
number is required to be able to locate the medical record and conduct follow-up 
activities. The medical record number will not be used in data analysis and all identifiers 
on participant data will be removed and coded with study ID.  Data will be stored in 
RedCap which is HIPAA secure. No data will be transferred until DUA has been 
obtained 
 
18.    Data and Specimen Banking 
 
Blood specimens will be banked for up to 3 years (approximately 6 months after the 
last patient is enrolled). 
At the completion of the study, University of Utah will send study samples to University 
of New Mexico for immunogenicity and/or pK testing.  Samples will be submitted per the 
attached Material Transfer Agreement.


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Checklist Section 
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research. 
 
I. 
Waivers or Alterations of Consent, Assent, and HIPAA Authorization 
A. Partial Waiver of Consent for Screening/Recruitment 
Complete this checklist if you are requesting a partial waiver of consent so that you 
can review private information to identify potential subjects and/or determine 
eligibility prior to approaching potential subjects for consent or parental permission. 
1. Describe the data source that you need to review (e.g., medical records): 
Eligible patients will be identified by the admitting neonatologist or by the research nurses based 
on admission diagnosis (perinatal depression, mild NE or NE, encephalopathy, clinical 
assessment for the need for cooling).  
 
2. Describe the purpose for the review (e.g., screening): 
Medical charts will not be reviewed for recruitment or screening. Instead, eligible patients will be 
identified by the admitting neonatologist or by the research nurses based on admission 
diagnosis (perinatal depression, mild NE or NE, encephalopathy, clinical assessment for the 
need for cooling).  
 
3. Describe who will conducting the reviews (e.g., investigators, research staff): 
The admitting neonatologist or by the research nurses based on admission diagnosis (perinatal 
depression, mild NE or NE, encephalopathy, clinical assessment for the need for cooling) 
 
4. Do all persons who will be conducting the reviews already have permitted 
access to the data source? 
 Yes 
 No. Explain:       
5. Verify that each of the following are true or provide an alternate justification 
for the underlined regulatory criteria: 
a) The activity involves no more than minimal risk to the subjects 
because the records review itself is non-invasive and the results of the 
records review will not be used for any purposes other than those 
described above. 
 True 


24 MEND 
 
 Other justification:       
b) The waiver or alteration will not adversely affect the rights and welfare 
of the subjects because eligible subjects will be approached for 
consent to participate in the research and are free to decline.  Further, 
the information accessed during the records review will not be 
disclosed to anyone without a legitimate purpose (e.g., verification of 
eligibility). 
 True 
 Other justification:       
c) The research could not practicably be carried out without the waiver 
or alteration because there is no other reasonably efficient and 
effective way to identify who to approach for possible participation in 
the research.   
 True 
 Other justification:       
d) Whenever appropriate, potentially eligible subjects will be presented 
with information about the research and asked to consider 
participation.  (Regulatory criteria: Whenever appropriate, the subjects 
will be provided with additional pertinent information after 
participation.) 
 True 
 Other justification:       
Partial Waiver of HIPAA Authorization for Screening/Recruitment 
Complete the following additional questions/attestations if the records you will review 
to identify potential subjects and/or determine eligibility include Protected Health 
Information (PHI). 
6. Will you be recording any PHI when conducting the records review to identify 
potential subjects and/or determine eligibility? 
 Yes. Describe:       
 No 
7. If you answered “Yes” to question 6 above, please describe when you will 
destroy identifiers (must be the earliest opportunity consistent with the 
conduct of the research) or provide justification for why they must be 
retained: 
      


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8. The PHI accessed or recorded for identification/screening purposes will not 
be reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule. 
 True 
 False 
 
II. Vulnerable Populations 
A. Children 
Complete this checklist if the subject population will include children. 
1. Select the category of research that you believe this research falls within and 
provide justification for any associated criteria.  If there are different 
assessments for different groups of children or arms (e.g., placebo vs. drug), 
include a memo to provide an assessment for each group.   
 Research not involving greater than minimal risk. (Minimal risk means 
that the probability and magnitude of harm or discomfort anticipated in 
the research are not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of routine 
physical or psychological examinations or tests.) 
 Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual subjects. 
Provide justification for each of the following criteria: 
(1) The risk is justified by the anticipated benefit to the subjects: 
Darbe has the potential to improve neurodevelopmental 
outcomes in a group of infants with no therapeutic options at this 
time.  Over the last decade, EPO (and its analogue darbepoetin) 
neuroprotective actions and underlying mechanisms in terms of 
signal transduction pathways have been studied in great of detail. 
Over 3000 infants have been treated with Erythopoesis Stimulatin 
Agents (ESA).  The side effect profile of infants treated with ESAs 
is similar to those infants who received placebo.    
 
(2) The relation of the anticipated benefit to the risk is at least as 
favorable to the subjects as that presented by available 
alternative approaches: 


26 MEND 
 
 
The pharmacokinetics of ESAs in neonatal brains are now 
better understood, and the safety of routine administration of 
ESAs to treat neonates with moderate/severe NE has been shown 
to be beneficial. 
 
In the present multicenter randomized study, we anticipate 
that Darbe administered to neonates with mild NE who do not 
qualify for hypothermia will be safe and reduce long-term 
neurodevelopmental impairments. 
 
 Research involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but likely to yield generalizable knowledge 
about the subject's disorder or condition. 
Provide justification for each of the following criteria: 
(1) The risk represents a minor increase over minimal risk: 
      
(2) The intervention or procedure presents experiences to 
subjects that are reasonably commensurate with those 
inherent in their actual or expected medical, dental, 
psychological, social, or educational situations: 
      
(3) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition which is of 
vital importance for the understanding or amelioration of the 
subjects' disorder or condition 
      
 
 
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28 MEND 
 
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30 MEND 
 
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