Transcript NEATO Trial - Stanford Neonatology

Causes of neonatal mortality
Congenital
7%
Other
7%
Sepsis/pneumon
ia
26%
Asphyxia
23%
Tetanus
7%
Diarrhea
3%
Preterm
27%
Lawn JE, et al. Intl J Epidemiol (2006)
Processes involved in HI Brain Injury
1o energy failure
↑ Excitatory amino acids
Loss of ionic balance
↑ Intracellular Ca++
↑ Lipases, proteases
↑ Free radicals
2o energy failure
 Activated microglia





Apoptosis
↓ Growth factors
↓ Protein synthesis
Oxidative injury
↑ Excitatory amino acids
NICHD Trial: Primary Outcome
Percent
Death or Disability
100
90
80
70
60
50
40
30
20
10
0
RR: O.72
95% CI 0.54-0.95
P value= 0.01
Disability defined as:
62%
Bayley MDI <70
GMFCS ≥ level 2
Hearing impairment
Seizure disorder
Blindness
44%
Hypothermia
n = 102
Control Group
n = 106
Shankaran S, et al. NEJM (2005)
Shankaran S et al., N Engl J Med (2005)
Erythropoietin (Epo)
 Generally used for erythropoiesis, may also provide neuroprotection
 Mechanisms include:
decreased apoptosis
enhanced neurogenesis
decreased inflammation
decreased susceptibility to glutamate toxicity
 Preterm infants treated with Epo for anemia have demonstrated improved
neurodevelopmental outcomes Neubauer AP, et al. Ann Neurol 2010
 Term infants treated with Epo have decreased seizures, improved EEG, and
better neurologic outcome Zhu C, et al. Pediatrics 2009, Elmahdy H, et al.
Pediatrics 2010
Erythropoietin improves neurologic outcome in
newborns with HIE: Primary outcomes
Epo
(N=73)
Control
(n=80)
RR (95% CI)
P value
24.6
4.1
21.4
43.8
5.0
40.8
0.62 (0.41-0.94)
0.89 (0.37-2.13)
0.59 (0.38-0.93)
.017
.999
.013
Primary outcome
Death
Disability
Conclusion: Low dose Epo given for 2 weeks reduced the risk of disability for
infants with moderate HIE without apparent side effects.
Zhu C et al. Pediatrics (2009)
Zhu C, et al. Pediatrics (2009)
Erythropoietin Improves neurologic outcome in
HIE : Secondary outcomes
Epo
(n=73)
Control
(n=80)
RR
(95% CI)
P value
Death or disability
Moderate HIE
Severe HIE
Male
Female
6.4
57.7
29.8
6.3
32.2
76.2
45.5
40.0
0.26 (0.48-2.47)
0.70 (0.43-1.15)
0.71 (0.47-1.08)
0.18 (0.03-1.22)
.001
.227
.118
.029
MDI <70
Moderate HIE
Severe HIE
10.0
4.3
21.7
22.4
15.8
42.1
0.56 (0.30-1.08)
0.38 (0.11-1.34)
0.62 (0.29-1.30)
.048
.106
.193
Cerebral palsy
Moderate HIE
Severe HIE
6.8
2.1
17.4
18.4
14.0
31.6
0.51 (0.23-1.11)
0.23 (0.04-1.47)
0.67 (0.30-1.52)
.051
.039
.468
Zhu C et al. Pediatrics (2009)
Zhu C, et al. Pediatrics (2009)
NEATO: A Phase II trial
 Objective: To determine if Epo administered for 7 days
improves neuroradiographic and short term outcomes for
moderate to severe HIE
 Intervention: Epo 1000 units/kg IV or placebo at 1, 2, 3, 5 and
7 days of age
 Outcome measures: MRI brain injury score and
neurodevelopmental outcome at 12-14 months using Warner
Initial Developmental Evaluations (WIDEA) and Alberta Infant
Motor Scale (AIMS)
Brain MRI Injury Score
Outcome
Epo (n=23)
Placebo (n=25)
P value
Age at MRI (days)
5.6
4.9
0.28
Global brain injury score
None
Mild
Moderate
Severe
0.01
35%
61%
0%
4%
12%
44%
24%
20%
Presence of brain injury by region
Subcortical
Cortical
White matter
Brainstem
Cerebellar
2 or more regions
30%
17%
52%
4%
0%
30%
68%
36%
60%
16%
20%
56%
0.02
0.26
0.80
0.35
0.05
0.14
Wu Y, et al. WSPR 2016
Neurodevelopmental Outcomes
Outcome
Epo (n=21)
Placebo (n=21)
P value
WIDEA at 6 months
Total score
75.3
68.8
0.04
WIDEA at 12 months
Total score
122
110
0.15
Alberta Infant Motor Score
(AMIS)
53.3
42.8
0.03
Moderate to severe NDI
8%
19%
0.42
Wu Y, et al. WSPR 2016
NEATO Phase II trial: Results
 Neonatal deaths did not differ between Epo and placebo
groups (8% versus 19%, p=0.42)
 Brain MRI at mean 5 days showed a lower global brain injury
score in Epo treated (2 versus 11, p=0.01)
 Moderate/severe brain injury, subcortical and cerebellar injury
were less frequent.
 At 1 year, infant motor scores were higher among Epo treated
based on WIDEA (p=0.05) and AIMS (p=0.03).
NEATO Phase II Trial: Conclusions
 High doses of Epo, in conjunction with hypothermia, resulted
in less MRI brain injury and in improved short-term motor
outcomes following moderate to severe hypoxic ischemic
encephalopathy
 A phase III trial has been designed and a grant application has
been submitted to NINDS.