Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration

Perinatal arterial ischemic stroke (PAIS) is an important perinatal cause of
long-lasting neurodevelopmental problems. Recent studies report an incidence of
PAIS of 1 per 2300 full-term infants born alive. Adverse consequences of PAIS
include hemiplegia, cognitive dysfunction, epilepsy and speech problems. In
50-75% of infants, neonatal stroke leads to abnormal neuromotor and
-developmental outcome or epilepsy. The estimated annual mortality rate of
neonatal stroke is 3.49/100,000 annually. Current treatment options for PAIS
mainly focus on controlling convulsions and associated infections. There is no
treatment available that leads to reduction of neonatal brain damage in this
severely affected group of infants. This leads to life-long consequences of
PAIS and forms a large burden for patients and society. The overall aim of this
project is to meet this need by developing a treatment strategy.
Erythropoiesis-stimulating agents (ESA), such as erythropoietin (EPO) and
darbepoetin, have been proven to exert neuroprotection as they can reduce
(neonatal) hypoxia-ischemia-induced free radical formation, inappropriate
pro-inflammatory and apoptotic activity. EPO also stimulates neuroregeneration
via a trophic effect. Several RCTs have been performed in preterm infants with
preliminary results showing a positive effect of EPO and darbepoetin on
cognitive outcome. Other RCTs are underway in full-term infants with
hypoxic-ischemic encephalopathy (HIE). In our centre we performed a pilot study
in 20 infants with PAIS, who had open label treatment with EPO showing
feasibility and safety. Two other trials with preterm infants and term borns
with HIE also showed safety of treatment with darbepoetin in the same dosage as
we propose. It has been shown that EPO and Darbepoetin have similar effects,
but Darbepoetin is more potent, requires less dosing and is more universally
available across countries. The proposed project will undertake an multicenter
RCT using Darbe versus a placebo. Successful completion of this project will
provide the first evidence of the potential to use ESAs to treat PAIS in
newborn infants.

This study has been transitioned to CTIS with ID 2024-513042-12-01 check the CTIS register for the current data.

To perform a double-blind randomized placebo controlled multicenter study with
darbepoetin in infants with MRI confirmed PAIS and to investigate whether
darbepoetin can reduce brain injury in neonates who suffered from perinatal
arterial ischemic stroke (PAIS). The ultimate goal of this study is therefore
to develop a therapy using ESAs such as darbepoetin to reduce or even prevent
lifelong consequences of PAIS-related brain injury in this group of term
newborns.

Multicenter, double-blind, randomized placebo controlled intervention study in
the NICU at the Wilhelmina children*s Hospital / University Medical Centre in
Utrecht of (near-)term newborns >=36 weeks of gestation with diagnosis of PAIS
(confirmed on MRI within one week of onset of presenting clinical symptoms).

One group will be treated with active study medication, darbepoetin (Aranesp),
and the other with placebo both consisting of 2 doses of 10microgram/kg/each of
intravenous darbepoetin (active treatment) or saline (placebo).

In more detail: After written informed consent, neonates with PAIS will be
randomized to two groups: One group will be treated with active study
medication, darbepoetin, and the other with placebo both consisting of 2 doses
of 10microgram/kg/each of intravenous darbepoetin (active treatment) or saline
(placebo). The initial dose will be administered as soon as possible after the
MRI diagnosis of PAIS, but within one week after presenting symptoms. The
second dose will administered 7 days after the first dose. Blood pressure and
heart rate will be monitored during infusion, baseline red and white blood cell
samples taken and coagulation status determined.The placebo group will receive
2 dosages of placebo dissolved in an equal amount of fluid as during
darbepoetin infusion with a similar infusion time. The infusion scheme is
identical as compared to the darbepoetin group (study group). The study and
placebo medication either darbepoetin or placebo will be produced and prepared
by the local pharmaceutical department. The study medication will be numbered
and will not be recognizable by the attending neonatologist (nor the
studyteam). In case of signs of suspected adverse reactions of the drug used,
the pharmacist of the hospital will have the key to detect whether darbepoetin
or a placebo has been administered.

Newborns from other participating centers will be transported to the NICU of
the University Medical Center Utrecht after suspicion of PAIS and/or MRI
confirmation of PAIS and will undergo the procedures as described above.

The extra burden of the present study for the included infants is considered to
be very limited to non-existent given the fact that besides the administration
of darbepoetin or the placebo, treatment is not different compared to the
standard acting treatment protocol for newborns with PAIS. The drug will be
administered through an intravenous line which is already in place and one
blood sample will be taken at a time when a blood sample will be carried out
for routine clinical care. With respect to possible risks of darbepoetin
treatment, the most important potential risk factor such as polycythaemia has
been investigated in our own pilot study and did not appear to be present.
Other studies with darbepoetin in preterm and term infants did not show any
safety risks. Darbepoetin showed similar effects in imporving
neurodevelopmental outcome in these infants.
From experimental research and from our own study, we have learned that the
complication risk is very low, whereas possibility for a substantial better
short- and long-term outcome after PAIS, induced by darbepoetin treatment,
seems very realistic on the basis of previous research data.