Randomized Controlled Trial of Optimizing Cooling Strategies for Neonatal Hypoxic-Ischemic Encephalopathy

1
Randomized Controlled Trial of Optimizing Cooling
Strategies for Neonatal Hypoxic-Ischemic
Encephalopathy

• Seetha Shankaran, Abbot Laptook, Athina Pappas,
  Scott McDonald, Abhik Das, Jon Tyson, Kurt
  Schibler, Brenda Poindexter, Edward Bell, Roy
  Heyne, Claudia Pedroza, Rebecca Bara, Krisa Van
  Meurs, Cathy Grisby, Carolyn Huitema, Uday
  Devaskar and Rosemary Higgins
• for the NICHD Neonatal Research Network

2
Disclosures

• Speaker Seetha Shankaran
• Dr. Shankaran and co-investigators have no
  financial relationships to disclose or Conflicts
  of Interest to resolve
• This presentation will not involve discussion of
  unapproved or off-label, experimental or
  investigational use of a drug

3
Background

• Cooling to 33.0C to 34.0C for 72 hours for
  neonatal HIE has decreased death or disability at
  18 months in 5 major randomized controlled trials
  
• This neuroprotection continues to childhood
• However, the rate of death or disability in the
  cooled group remains high (up to 44-55)
• Jacobs SE, Cochrane Database review 2013, Guillet
  R, Pediatr Research 2012, Shankaran S, New Engl J
  Med 2012, Azzopardi D, New Engl J Med 2014

4
Background

• Preclinical studies have demonstrated that brain
  injury following hypoxia-ischemia continues and
  evolves over days and weeks
• Deeper cooling minimizes brain swelling,
  preserves energy and suppresses oxidative
  metabolism
• Longer cooling may protect against apoptosis and
  inflammation
• Busto R, J Cereb blood Flow Metab 1987, Thoresen
  M, Pediatr Res 1995, Williams JD, Pediatr Res
  1997, Iwata O, Ann Neurol 2005, Bennet L, J
  Physiol 2007, Perlman J, Pediatrics 2006,
  Johnston MV, Lancet Neurol 2011

5
Objective and Design

• To determine if longer duration cooling (120
  hours), deeper cooling (32.0C) or both is
  superior to cooling at 33.5C for 72 hours in
  term neonates with HIE
• A randomized 2 x 2 factorial design clinical
  trial performed in 18 US centers in the NICHD
  Neonatal Research Network between October 2010
  and November 2013

6
gt36 weeks, lt6 h
No Blood Gas or pH 7.01-7.15 or BD 10.0-15.9
Blood Gas
pH lt7.0 or BD gt16
Acute Event AND 10 min Apgar lt5 OR Ventilation
from birth
AND
SEIZURES OR MODERATE/SEVERE HIE
7
Design

• Randomly assigned to 4 hypothermia groups
  stratified by center and level of encephalopathy
• 33.5C for 72 hours
• 32.0C for 72 hours
• 33.5C for 120 hours
• 32.0C for 120 hours

Trial was powered for marginal comparisons of
33.5C vs. 32.0C and 72 hours vs.120 hours
8
Outcomes

• Primary outcome of death or moderate or severe
  disability at 18 to 22 months is still ongoing
• The independent data and safety monitoring
  committee paused the trial to evaluate safety
  after the first 50 neonates were enrolled
• Cardiac arrhythmia
• Persistent acidosis
• Major vessel thrombosis and bleeding
• Death in the NICU

9
Outcomes

• Data and safety and monitoring committee
  monitored safety after every subsequent 25
  neonates
• The trial was closed for emerging safety profile
  and futility analysis after the eighth review
  with 364 neonates enrolled of 726 planned
• This report focuses on safety and NICU deaths by
  marginal comparisons of 72 hours vs. 120 hours
  duration and 33.5C depth vs. 32.0C depth
  (predefined secondary outcomes)

10
Treatment Cooling protocol similar to first RCT
except

• Neonates assigned to 32.0C group had temperature
  initially lowered to 33.5C and when stable for
  15 minutes, lowered further to 32.0C
• Temperatures were monitored for the first 10 days
  and hyperthermia treated as per usual care

11
Analysis Plan

• Target sample size was 726 subjects (363 per
  marginal group comparison) based on 2-tailed type
  1 error of 0.05, 80 power, 5 loss to FU and a
  comparison of death or disability of 37.5 and
  27.5
• Intention-to-treat analysis
• Primary and secondary outcomes analyzed by robust
  Poisson regression models
• Adjust for center and level of HIE and assess
  treatment interactions

12
Results

Number screened 1261
Number eligible 514
Parents refused consent 100
Physician refused consent 5
Consent not requested 45
Number enrolled 364
13
Maternal and Neonatal Characteristics

Fetal decelerations 282 (78)
Cord mishap 49 (13)
Uterine rupture 22 (6)
Age at randomization h (meanSD) 4.92 1.23
Outborn 234 (64)
Apgar score lt 5 at 10 min 223 (69)
Cord blood pH (meanSD) 6.94 0.19
Birth weight g (meanSD) 3359 599
Severe HIE 84 (23)
14
Perinatal and Neonatal Characteristics

• Perinatal characteristics were similar between
  the 72 and the 120 h and the 33.5 and 32.0C
  groups
• Neonatal characteristics were similar between the
  72 and the 120 h groups. Among the 33.5 and
  32.0C groups, birth weight was higher in the
  32.0C group,
• 3432582g vs. 3292608g (P0.02)

15
Serious Adverse Events During Intervention 72
vs.120 h
72 h N 185 120 h N 179
Cardiac arrhythmia 2 (1) 8 (4)
Persistent acidosis 2 (1) 5 (3)
Major bleeding 5 (3) 2 (1)
Death within 72 h 5 (3) 9 (5)
Death within 120 h 11 (6) 16 (9)

Adjusted P values P0.04, other comparisons NS
16
Serious Adverse Events During Intervention 33.5
vs.32C
33.5C n191 32.0C n173
Cardiac Arrhythmia 2 (1) 8 (5)
Persistent acidosis 3 (2) 4 (2)
Major bleeding 4 (2) 3 (2)
Death within 72 h 4 (2) 10 (6)
Death within 120 h 10 (5) 17 (10)

Adjusted P values NS
17
Hospital Course 72 vs.120 h
72 h N185 120 h N179 Adj P-value
PPHN 47 (25) 60 (34) 0.13
INO 45 (24) 60 (34) 0.07
ECMO 10 (5) 12 (7) 0.52
Arrhythmia 2 (1) 12 (7) 0.02
Survivors LOS (d) 22 15 26 34 0.002
NICU mortality 20 (11) 29 (16) 0.12
Selected post-hoc by DSMC
18
Hospital Course 33.5 vs.32C
33.5C n191 32.0C n173 Adj P-value
PPHN 48 (25) 59 (34) 0.06
INO 46 (24) 59 (34) 0.03
ECMO 7 (4) 15 (9) 0.005
Arrhythmia 5 (3) 9 (5) 0.21
Survivors LOS (d) 22 16 26 34 0.21
NICU mortality 22 (12) 27 (16) 0.47
Selected post-hoc by DSMC
19
Mortality rate in 4 groups

• 33.5C for 72 h 7
• 32.0C for 72 h 14
• 33.5C for 120 h 16
• 32.0C for 120 h 17

20
(No Transcript)
21
Outcomes assessed for Safety Risk Ratio Adjusted
for HIE and Center
72 h 120 h 33.5C 32.0C
Death within 120 h 1.36 (0.75-2.48) 1.36 (0.75-2.48) 1.59 (0.77-3.30) 1.59 (0.77-3.30)
NICU mortality 1.37 (0.92-2.04) 1.37 (0.92-2.04) 1.24 (0.69-2.25) 1.24 (0.69-2.25)
NICU mortality or ECMO 1.33 (0.96-1.83) 1.33 (0.96-1.83) 1.35 (0.83-2.19) 1.35 (0.83-2.19)
Selected post-hoc by DSMC Selected post-hoc by DSMC Selected post-hoc by DSMC
22
Results

• Interaction between depth and duration for
  in-hospital mortality adjusted for level of HIE
  and center P0.20
• Futility analysis Probability of detecting
  statistically significant treatment benefit of
  longer or deeper cooling for in-hospital
  mortality lt2
• Follow-up of enrolled infants on-going

23
Conclusions

• Mortality in the longer or deeper cooling or both
  was lower than the cooled arm of our previous RCT
  (19) mortality in 33.5C for 72 hours was
  unexpectedly low
• Cooling at 32.0C was associated with more INO
  and ECMO therapy and cooling for 120 hr with more
  arrhythmia
• Need to adhere to established published protocols
  

24
Conclusions

• Among term neonates of at least 36 weeks
  gestation with moderate or severe HIE, deeper
  cooling or longer duration of cooling compared
  with hypothermia at 33.5C for 72 hours did not
  reduce NICU deaths
• These results have implications for patient care
  and design of future trials

25
Neonatal Research Network Centers

• Brown University
• Case Western Reserve University
• Childrens Mercy Hospitals and Clinics,
  University of Missouri-Kansas City
• Cincinnati Childrens Medical Center
• Duke University
• Emory University
• Indiana University
• Nationwide Childrens Hospital, Ohio State
  University
• RTI International
• Stanford University
• Tufts Medical Center

• University of Alabama at Birmingham
• University of California Los Angeles
• University of Iowa
• University of New Mexico
• University of Pennsylvania
• University of Rochester
• University of Texas Southwestern Dallas
• University of Texas Health Science Center Houston
• University of Utah
• Wayne State University
• Yale University

26

• Thank you
• Questions?
• sshankar_at_med.wayne.edu