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Late Hypothermia for Hypoxic-Ischemic Encephalopathy

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ClinicalTrials.gov Identifier: NCT00614744
Recruitment Status : Completed
First Posted : February 13, 2008
Results First Posted : August 7, 2017
Last Update Posted : March 9, 2021
Sponsor:
Collaborators:
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
NICHD Neonatal Research Network

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Infant, Newborn
Hypoxia, Brain
Hypoxia-Ischemia, Brain
Encephalopathy, Hypoxic-Ischemic
Hypoxic-Ischemic Encephalopathy
Ischemic-Hypoxic Encephalopathy
Interventions Procedure: Hypothermia
Procedure: Normothermic Control
Enrollment 168
Recruitment Details Multicenter randomized trial to evaluate whether induced hypothermia with body cooling initiated between 6-24 hours of age and continued for 96 hours in infants >= 36 weeks gestation with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18 months of age. Eligible infants were enrolled from 05/06/08 to 07/12/14.
Pre-assignment Details  
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Period Title: Overall Study
Started 83 85
Completed 78 79
Not Completed 5 6
Reason Not Completed
Lost to Follow-up             5             4
Incomplete for Behavior Issues             0             2
Arm/Group Title Whole-body Hypothermia Normothermia Total
Hide Arm/Group Description Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours Total of all reporting groups
Overall Number of Baseline Participants 83 85 168
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 83 participants 85 participants 168 participants
<= 12 Hours
26
  31.3%
28
  32.9%
54
  32.1%
> 12 Hours
57
  68.7%
57
  67.1%
114
  67.9%
[1]
Measure Description: Age at Randomization
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 83 participants 85 participants 168 participants
Female
47
  56.6%
55
  64.7%
102
  60.7%
Male
36
  43.4%
30
  35.3%
66
  39.3%
Level of Encephalopathy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 83 participants 85 participants 168 participants
Moderate
73
  88.0%
78
  91.8%
151
  89.9%
Severe
10
  12.0%
7
   8.2%
17
  10.1%
Birthweight  
Mean (Standard Deviation)
Unit of measure:  Grams
Number Analyzed 83 participants 85 participants 168 participants
3379  (528) 3303  (553) 3340  (541)
Length  
Mean (Standard Deviation)
Unit of measure:  Centimeters
Number Analyzed 83 participants 85 participants 168 participants
51  (3) 51  (3) 51  (3)
Gestational Age  
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 83 participants 85 participants 168 participants
39  (2) 39  (1) 39  (1)
1.Primary Outcome
Title Death or Moderate or Severe Disability
Hide Description Severe disability was defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit.
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
Does not include 9 lost to follow up and 2 infants without outcome for behavior issues
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 78 79
Measure Type: Count of Participants
Unit of Measure: Participants
19
  24.4%
22
  27.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Whole-body Hypothermia, Normothermia
Comments Whole-body Hypothermia vs. Normothermia (Normothermia is the comparison group)
Type of Statistical Test Superiority
Comments This trial estimated the probability that the intervention has no effect on the outcome (or conversely, the probability that it does), given the data obtained in the trial and any prior evidence.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Bayesian log binomial models
Comments Bayesian log binomial models were used to analyze the primary outcome of death or moderate/severe disability.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.59 to 1.29
Estimation Comments In log binomial models used Normal (0, sd=0.35) neutral prior in the log RR scale. Estimation used Normal weakly informative priors. Reported posterior medians & 95% credible intervals for the RR above instead of confidence intervals.
Other Statistical Analysis

We fitted all Bayesian models via Markov chain Monte Carlo methods (MCMC) using JAGS (version 3.4) and OpenBUGS (3.2.3) in R (version 3.2.5). For each analysis we ran 3 MCMC chains with starting values randomly drawn from the estimated parameters from a frequentist log binomial model. A burn-in of 1,000 iterations was used, with sampling from a further 10,000 iterations for each chain. To monitor convergence, trace plots and the Gelman-Rubin convergence diagnostic (Rhat) were used for all parameters.

For all analyses, the trace plots show good mixing of the 3 chains with Rhat < 1.01 for all parameters, indicating convergence.

2.Secondary Outcome
Title Number of Deaths in the NICU and Following Discharge
Hide Description [Not Specified]
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
Does not include 9 lost to follow up and 2 infants without outcome for behavior issues
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 78 79
Measure Type: Count of Participants
Unit of Measure: Participants
9
  11.5%
9
  11.4%
3.Secondary Outcome
Title Number of Infants With Moderate and Severe Disability
Hide Description Moderate disability will be defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 or blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
Does not include 9 lost to follow up and 2 infants without outcome for behavior issues
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 78 79
Measure Type: Count of Participants
Unit of Measure: Participants
10
  12.8%
13
  16.5%
4.Secondary Outcome
Title Number of Infants With Mild, Moderate and Severe Disability
Hide Description Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2 OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
Does not include 9 lost to follow up and 2 infants without outcome for behavior issues
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 78 79
Measure Type: Count of Participants
Unit of Measure: Participants
26
  33.3%
25
  31.6%
5.Secondary Outcome
Title Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization
Hide Description Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 69 70
Measure Type: Count of Participants
Unit of Measure: Participants
Moderate encephalopathy
24
  34.8%
25
  35.7%
Severe encephalopathy
2
   2.9%
0
   0.0%
Total
26
  37.7%
25
  35.7%
6.Secondary Outcome
Title Number of Infants With Non-CNS Organ System Dysfunction
Hide Description Based on observing presence of organ dysfunction on at least one of the following: Pulmonary (Meconium aspiration syndrome, PPHN, Pulmonary hemorrhage, Pneumonia, Chronic lung disease, ECMO, INO), Cardiovascular (Cardiomegaly, Cardiac failure, Cardiac dysfunction (by echo), Cardiac ischemia (by EKG and/or increased enzymes), Hypotension, Arrhythmia), Renal (Oliguria, Anuria, Dialysis), Gastrointestinal (NEC, Hepatic dysfunction), Hematologic (DIC) and Metabolic (Hypoglycemia, Hypocalcemia, Hypomagnesemia)
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 83 85
Measure Type: Count of Participants
Unit of Measure: Participants
63
  75.9%
59
  69.4%
7.Secondary Outcome
Title Number of Infants With a DNR Order
Hide Description [Not Specified]
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 83 85
Measure Type: Count of Participants
Unit of Measure: Participants
7
   8.4%
8
   9.4%
8.Secondary Outcome
Title Number of Infants With a DNR Order and Support is Withdrawn
Hide Description [Not Specified]
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 83 85
Measure Type: Count of Participants
Unit of Measure: Participants
6
   7.2%
8
   9.4%
9.Secondary Outcome
Title Number of Infants With a DNR Order That Died
Hide Description [Not Specified]
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
Only infants with DNR order
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 83 85
Measure Type: Count of Participants
Unit of Measure: Participants
5
   6.0%
7
   8.2%
10.Secondary Outcome
Title Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities
Hide Description [Not Specified]
Time Frame Birth to 18-22 months corrected gestational age
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description:
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Overall Number of Participants Analyzed 83 85
Measure Type: Count of Participants
Unit of Measure: Participants
63
  75.9%
56
  65.9%
Time Frame During study intervention period: 124 hours from baseline (time of insertion of esophageal probe).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Whole-body Hypothermia Normothermia
Hide Arm/Group Description Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
All-Cause Mortality
Whole-body Hypothermia Normothermia
Affected / at Risk (%) Affected / at Risk (%)
Total   6/83 (7.23%)      5/85 (5.88%)    
Hide Serious Adverse Events
Whole-body Hypothermia Normothermia
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/83 (6.02%)      1/85 (1.18%)    
Respiratory, thoracic and mediastinal disorders     
PPHN/Acidosis   2/83 (2.41%)  2 0/85 (0.00%)  0
Skin and subcutaneous tissue disorders     
Alteration of skin integrity   1/83 (1.20%)  1 0/85 (0.00%)  0
Vascular disorders     
Bleeding   4/83 (4.82%)  4 1/85 (1.18%)  1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Whole-body Hypothermia Normothermia
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/83 (0.00%)      0/85 (0.00%)    
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Investigators must adhere to the Neonatal Research Network Publication policies.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Abbot Laptook
Organization: Brown University, Women & Infants Hospital of Rhode Island
Phone: 401-274-1122 ext 47421
EMail: alaptook@wihri.org
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, Parikh NA, Ambalavanan N, Pedroza C, Pappas A, Das A, Chaudhary AS, Ehrenkranz RA, Hensman AM, Van Meurs KP, Chalak LF, Khan AM, Hamrick SEG, Sokol GM, Walsh MC, Poindexter BB, Faix RG, Watterberg KL, Frantz ID 3rd, Guillet R, Devaskar U, Truog WE, Chock VY, Wyckoff MH, McGowan EC, Carlton DP, Harmon HM, Brumbaugh JE, Cotten CM, Sánchez PJ, Hibbs AM, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017 Oct 24;318(16):1550-1560. doi: 10.1001/jama.2017.14972. Erratum in: JAMA. 2018 Mar 13;319(10 ):1051. Khan AM [added].
Layout table for additonal information
Responsible Party: NICHD Neonatal Research Network
ClinicalTrials.gov Identifier: NCT00614744    
Other Study ID Numbers: NICHD-NRN-0038
U10HD036790 ( U.S. NIH Grant/Contract )
U10HD021364 ( U.S. NIH Grant/Contract )
U10HD021373 ( U.S. NIH Grant/Contract )
U10HD021385 ( U.S. NIH Grant/Contract )
U10HD027851 ( U.S. NIH Grant/Contract )
U10HD027853 ( U.S. NIH Grant/Contract )
U10HD027856 ( U.S. NIH Grant/Contract )
U10HD027871 ( U.S. NIH Grant/Contract )
U10HD027880 ( U.S. NIH Grant/Contract )
U10HD027904 ( U.S. NIH Grant/Contract )
U10HD034216 ( U.S. NIH Grant/Contract )
U10HD040492 ( U.S. NIH Grant/Contract )
U10HD040689 ( U.S. NIH Grant/Contract )
U10HD053089 ( U.S. NIH Grant/Contract )
U10HD053109 ( U.S. NIH Grant/Contract )
U10HD053119 ( U.S. NIH Grant/Contract )
U10HD053124 ( U.S. NIH Grant/Contract )
UL1RR024139 ( U.S. NIH Grant/Contract )
UL1RR025744 ( U.S. NIH Grant/Contract )
UL1RR024979 ( U.S. NIH Grant/Contract )
U10HD068244 ( U.S. NIH Grant/Contract )
1U10HD068263-01 ( U.S. NIH Grant/Contract )
U10HD068270 ( U.S. NIH Grant/Contract )
U10HD068278 ( U.S. NIH Grant/Contract )
U10HD068284 ( U.S. NIH Grant/Contract )
First Submitted: February 11, 2008
First Posted: February 13, 2008
Results First Submitted: June 30, 2017
Results First Posted: August 7, 2017
Last Update Posted: March 9, 2021