Mild Encephalopathy in the Newborn Treated With Darbepoetin (MEND)
Phase: PHASE2
Conditions: Neonatal Encephalopathy, Hypoxic-Ischemic Encephalopathy Mild
Sponsor: University of New Mexico

MEND (Mild Encephalopathy in the Newborn treated with Darbepoetin) 
11.18.2020 
 
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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 
 

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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. 
 
 

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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) 

20 MEND 
 
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 
      
 
 
References:  
 
1. 
Fan X, van Bel F. Pharmacological neuroprotection after perinatal asphyxia. J Matern 
Fetal Neonatal Med.23 Suppl 3:17-9. 
2. 
Hasselblatt M, Ehrenreich H, Siren AL. The brain erythropoietin system and its potential 
for therapeutic exploitation in brain disease. J Neurosurg Anesthesiol. 2006;18(2):132-8. 

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3. 
Dame C, Bartmann P, Wolber E, Fahnenstich H, Hofmann D, Fandrey J. Erythropoietin 
gene expression in different areas of the developing human central nervous system. Brain Res 
Dev Brain Res. 2000;125(1-2):69-74. 
4. 
Banks WA, Jumbe NL, Farrell CL, Niehoff ML, Heatherington AC. Passage of 
erythropoietic agents across the blood-brain barrier: a comparison of human and murine 
erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol. 2004;505(1-3):93-101. 
5. 
Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, et al. 
Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc 
Natl Acad Sci U S A. 2001;98(7):4044-9. 
6. 
Grasso G, Buemi M, Alafaci C, Sfacteria A, Passalacqua M, Sturiale A, et al. Beneficial 
effects of systemic administration of recombinant human erythropoietin in rabbits subjected to 
subarachnoid hemorrhage. Proc Natl Acad Sci U S A. 2002;99(8):5627-31. 
7. 
Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E, et al. 
Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. 
Childs Nerv Syst. 2003;19(1):19-22. 
8. 
Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates 
angiogenesis in vitro. Kidney Int. 1995;47(3):740-5. 
9. 
Iwai M, Cao G, Yin W, Stetler RA, Liu J, Chen J. Erythropoietin promotes neuronal 
replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in 
rats. Stroke. 2007;38(10):2795-803. 
10. 
Iwai M, Stetler RA, Xing J, Hu X, Gao Y, Zhang W, et al. Enhanced oligodendrogenesis 
and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain 
injury. Stroke.41(5):1032-7. 
11. 
Matis GK, Birbilis TA. Erythropoietin in spinal cord injury. Eur Spine J. 2009;18(3):314-
23. 
12. 
Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin regulates the in vitro and in 
vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci. 
2001;21(24):9733-43. 
13. 
Kumral A, Ozer E, Yilmaz O, Akhisaroglu M, Gokmen N, Duman N, et al. 
Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol 
Neonate. 2003;83(3):224-8. 
14. 
Matsushita H, Johnston MV, Lange MS, Wilson MA. Protective effect of erythropoietin in 
neonatal hypoxic ischemia in mice. Neuroreport. 2003;14(13):1757-61. 
15. 
Spandou E, Soubasi V, Papoutsopoulou S, Karkavelas G, Simeonidou C, Kaiki-Astara 
A, et al. Erythropoietin prevents hypoxia/ischemia-induced DNA fragmentation in an 
experimental model of perinatal asphyxia. Neurosci Lett. 2004;366(1):24-8. 
16. 
Gonzalez FF, McQuillen P, Mu D, Chang Y, Wendland M, Vexler Z, et al. Erythropoietin 
enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci. 
2007;29(4-5):321-30. 
17. 
Traudt CM, McPherson RJ, Bauer LA, Richards TL, Burbacher TM, McAdams RM, et al. 
Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman 
primate model of perinatal asphyxia. Dev Neurosci. 2013;35(6):491-503. 

28 MEND 
 
18. 
Cherian L, Goodman JC, Robertson C. Improved cerebrovascular function and reduced 
histological damage with darbepoietin alfa administration after cortical impact injury in rats. J 
Pharmacol Exp Ther.337(2):451-6. 
19. 
Grasso G, Graziano F, Sfacteria A, Carletti F, Meli F, Maugeri R, et al. Neuroprotective 
effect of erythropoietin and darbepoetin alfa after experimental intracerebral hemorrhage. 
Neurosurgery. 2009;65(4):763-9; discussion 9-70. 
20. 
Belayev L, Khoutorova L, Zhao W, Vigdorchik A, Belayev A, Busto R, et al. 
Neuroprotective effect of darbepoetin alfa, a novel recombinant erythropoietic protein, in focal 
cerebral ischemia in rats. Stroke. 2005;36(5):1071-6. 
21. 
Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, et al. 
Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8(8):495-505. 
22. 
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