Apnea, Apnea Neonatal, Prematurity
Conditions
Keywords
apnea following vaccination
Brief summary
A prospective, randomized open-label clinical trial will be conducted from July 2018 to October 2020. Approximately 300 preterm infants will be enrolled across three sites: Duke University Medical Center, the University of North Carolina, and Cincinnati Children's Hospital Medical Center. Eligible infants will be randomized 1:1 to receive either 2-month US licensed childhood vaccines (PCV13, DTaP, HBV, IPV an Hib) or no vaccines. After their participation in the study, healthcare providers of the infants in the unvaccinated group will make decision abut receipt of their 2-month childhood vaccines. The study will collect data from the continuous cardiorespiratory and pulse oximetry monitors from randomization to 48 hours after randomization for infants in the unvaccinated group, and from randomization to 48 hours after vaccination for infants in the vaccinated group. Infants in both groups will be monitored for up to 60 hours for the occurrence of apnea, bradycardia, and oxygen desaturation. For infants in the vaccinated group, the study will also collect adverse events of clinical interest and serious adverse events occurring between the end of the 48-hour monitoring period and 14 days after vaccination. This information will be collected through parental report and review of medical records.
Detailed description
Modified Intent-to-Treat (mITT) Analysis Population: Defined as any infant that was enrolled and randomized in the study For the mITT analysis, infants will be analyzed in their assigned treatment arms irrespective of receipt of vaccine. Study outcomes will be included in the analysis as follows: i) Vaccinated group: study outcomes in the 48-hour monitoring after vaccination. If vaccination does not occur by 12 hours after randomization, then study outcomes will be assessed between 12 and 60 hours after randomization. ii) Unvaccinated group: study outcomes in the 48-hour monitoring period after randomization.
Interventions
Sponsors
Centers for Disease Control and Prevention
Children's Hospital Medical Center, Cincinnati
University of North Carolina
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Weeks to No maximum
Healthy volunteers
No
Inclusion criteria
1. \<33 and 0 days weeks gestational age at birth 2. ≥6 weeks and 0 days and ≤12 weeks and 0 days postnatal age at randomization 3. Remains hospitalized after birth (has never been discharged home) 4. Treating clinician deems infant eligible to receive 2-month vaccines 5. English- or Spanish-speaking parent(s)/legally authorized representative(s) (LAR(s)) 6. Not planned for discharge within 60 hours of study entry 7. The parent/guardian must be willing and capable of providing permission for their child to participate through the written informed consent process
Exclusion criteria
1. Receipt of DTaP, IPV, PCV13, or Hib prior to enrollment. Previous administration of the first dose of HBV is permitted 2. Anticipated receipt of any vaccine other than DTaP, IPV, HBV, PCV13, or Hib during the first 60 hours after randomization 3. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose of any hepatitis B vaccine 4. History of a severe allergic reaction (e.g. anaphylaxis) to any component of the vaccines used in the study including neomycin, yeast and polymyxin B 5. History of latex allergy 6. Fever ≥38°C within 48 hours prior to randomization\* \*This may result in a temporary delay of randomization 7. Active known respiratory infection within 48 hours prior to randomization\* \*This may result in a temporary delay of randomization 8. Active infection being treated with systemic antimicrobials\* \*This may result in a temporary delay of randomization 9. Requiring mechanical ventilation or support with nasal intermittent positive pressure ventilation (NIPPV)\* \*This may result in a temporary delay of randomization 10. History of unstable progressive neurologic disorder of unknown cause 11. Known cause of apnea other than apnea of prematurity 12. Cyanotic heart disease (congenital or acquired) 13. Major invasive medical or surgical procedure (including circumcision) within 48 hours prior to randomization or anticipated to have major invasive medical or surgical procedure during the first 60 hours after randomization\* \*This may result in a temporary delay of randomization 14. Child or parent/LAR is an immediate relative of study staff or an employee who is supervised by study staff. 15. Any condition that would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Apnea | 48 hours | Number of infants with ≥ 1 apneic event in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group, mITT Population Apnea was defined as a pause in respirations of \>20 seconds, or a pause in respirations of \>15 seconds with associated bradycardia (heart rate \<80 beats per minute for any duration occurring within 1 minute of the apnea event). Potential apnea events triggered by the cardiorespiratory monitors were manually reviewed by 2 neonatologists to verify the event. In uncommon situations in which manual review of a triggered event was not possible due to missing data, the triggered event was considered to be apnea. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Apneic Episodes | 48 hours | Average number of apneic episodes in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. |
| Duration of Apneic Episodes | 48 hours | Average duration of apneic episodes in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. |
| Increase in Respiratory Support | 48 hours | Proportion of infants requiring any increase in respiratory support in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. |
| Severe Cardiorespiratory Events | 48 hours | Proportion of infants with severe ≥1 severe cardiorespiratory event in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. Only severe apnea events in the mITT analysis window and only the severe bradycardia events in the mITT analysis window from Duke University. The monitor data were not viable at UNC and Cincinnati Children's Hospital. Duke data were adjudicated by neonatologists. |
| Positive Pressure Ventilation | 48 hours | Proportion of Infants Requiring Positive Pressure Ventilation in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vaccinated In the study arm, infants will receive PCV13, DTaP, HBV, IPV, and Hib vaccines within 12 hours of randomization. Infants will be monitored from time of vaccination to 48 hours post-vaccination for the occurrence of apnea, bradycardia and desaturation.
PCV13: ACIP Recommended vaccine
DTaP: ACIP Recommended vaccine
HBV: ACIP Recommended vaccine
IPV: ACIP Recommended vaccine
Hib: ACIP Recommended vaccine | 107 |
| Unvaccinated In the study arm, infants will not receive PCV13, DTaP, HBV, IPV, and Hib vaccines during the study. Infants will be monitored from randomization to 48 hours post-randomization for the occurrence of apnea, bradycardia and desaturation. | 116 |
| Total | 223 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discharged prior to study completion | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Vaccinated | Total | Unvaccinated |
|---|---|---|---|
| Age, Continuous Gestational Age at Birth | 27.3 Gestational Age in Weeks | 27.6 Gestational Age in Weeks | 27.7 Gestational Age in Weeks |
| Age, Customized Age: <28 wks | 60 Participants | 121 Participants | 61 Participants |
| Age, Customized Age: >=28 wks | 47 Participants | 102 Participants | 55 Participants |
| Age, Customized Postmenstrual Age | 36.6 Postmenstrual Age in Weeks | 36.6 Postmenstrual Age in Weeks | 36.6 Postmenstrual Age in Weeks |
| Age, Customized Postnatal Age | 8.7 Postnatal Age in Weeks | 8.7 Postnatal Age in Weeks | 8.7 Postnatal Age in Weeks |
| Birth Weight | 940 Grams | 970 Grams | 1000 Grams |
| Combination Vaccine Brand Administered Pediarix | 100 Participants | 100 Participants | 0 Participants |
| Combination Vaccine Brand Administered Pentacel | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 26 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 192 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Haemophilus influenzae type b Vaccine Brand Administered ActHIB | 98 Participants | 98 Participants | 0 Participants |
| Haemophilus influenzae type b Vaccine Brand Administered Hiberix | 1 Participants | 1 Participants | 0 Participants |
| Haemophilus influenzae type b Vaccine Brand Administered PedvaxHIB | 1 Participants | 1 Participants | 0 Participants |
| Hepatitis B Vaccine Brand Administered - Engerix-B | 1 Participants | 1 Participants | 0 Participants |
| Insurance Any Private | 50 Participants | 99 Participants | 49 Participants |
| Insurance None | 2 Participants | 3 Participants | 1 Participants |
| Insurance Public | 55 Participants | 121 Participants | 66 Participants |
| Multiple Gestation Single | 73 Participants | 157 Participants | 84 Participants |
| Multiple Gestation Triplets | 0 Participants | 2 Participants | 2 Participants |
| Multiple Gestation Twins | 34 Participants | 64 Participants | 30 Participants |
| Race/Ethnicity, Customized Black Only | 33 Participants | 75 Participants | 42 Participants |
| Race/Ethnicity, Customized Other | 19 Participants | 27 Participants | 8 Participants |
| Race/Ethnicity, Customized White Only | 55 Participants | 121 Participants | 66 Participants |
| Reason for Preterm Delivery Fetal distress | 18 Participants | 40 Participants | 22 Participants |
| Reason for Preterm Delivery Hypertension/Preeclampsia/Hemolysis, Elevated Liver Enzymes, Low Platelet Count (HELLP) | 30 Participants | 55 Participants | 25 Participants |
| Reason for Preterm Delivery Other | 25 Participants | 54 Participants | 29 Participants |
| Reason for Preterm Delivery Placental Abruption | 12 Participants | 24 Participants | 12 Participants |
| Reason for Preterm Delivery Preterm Labor/Premature Rupture | 55 Participants | 124 Participants | 69 Participants |
| Received Caffeine No | 4 Participants | 12 Participants | 8 Participants |
| Received Caffeine Yes | 98 Participants | 205 Participants | 107 Participants |
| Received Synagis During Study Period No | 107 Participants | 222 Participants | 115 Participants |
| Received Synagis During Study Period Yes | 0 Participants | 1 Participants | 1 Participants |
| Respiratory Support at Randomization Continuous Positive Airway Pressure (CPAP) | 17 Participants | 33 Participants | 16 Participants |
| Respiratory Support at Randomization Nasal Cannula | 34 Participants | 80 Participants | 46 Participants |
| Respiratory Support at Randomization None | 55 Participants | 109 Participants | 54 Participants |
| Sex: Female, Male Female | 57 Participants | 117 Participants | 60 Participants |
| Sex: Female, Male Male | 50 Participants | 106 Participants | 56 Participants |
| Sibling Enrolled in Study No | 79 Participants | 171 Participants | 92 Participants |
| Sibling Enrolled in Study Yes | 28 Participants | 52 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 0 / 116 |
| other Total, other adverse events | 32 / 107 | 20 / 116 |
| serious Total, serious adverse events | 1 / 107 | 0 / 116 |
Outcome results
Primary
Occurrence of Apnea
Number of infants with ≥ 1 apneic event in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group, mITT Population Apnea was defined as a pause in respirations of \>20 seconds, or a pause in respirations of \>15 seconds with associated bradycardia (heart rate \<80 beats per minute for any duration occurring within 1 minute of the apnea event). Potential apnea events triggered by the cardiorespiratory monitors were manually reviewed by 2 neonatologists to verify the event. In uncommon situations in which manual review of a triggered event was not possible due to missing data, the triggered event was considered to be apnea.
Time frame: 48 hours
Population: The mITT population includes any infant that was enrolled and randomized in the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vaccinated | Occurrence of Apnea | Yes | 25 Participants |
| Vaccinated | Occurrence of Apnea | No | 80 Participants |
| Vaccinated | Occurrence of Apnea | Missing | 2 Participants |
| Unvaccinated | Occurrence of Apnea | Yes | 12 Participants |
| Unvaccinated | Occurrence of Apnea | No | 104 Participants |
| Unvaccinated | Occurrence of Apnea | Missing | 0 Participants |
p-value: 0.010495% CI: [1.27, 5.73]Mantel Haenszel
Secondary
Duration of Apneic Episodes
Average duration of apneic episodes in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group.
Time frame: 48 hours
Population: The mITT population includes any infant that was enrolled and randomized in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vaccinated | Duration of Apneic Episodes | 27.7 seconds | Standard Deviation 2.6 |
| Unvaccinated | Duration of Apneic Episodes | 32.3 seconds | Standard Deviation 4.7 |
p-value: 0.36Mixed Effects Model
Secondary
Increase in Respiratory Support
Proportion of infants requiring any increase in respiratory support in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group.
Time frame: 48 hours
Population: The mITT population includes any infant that was enrolled and randomized in the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vaccinated | Increase in Respiratory Support | Missing | 7 Participants |
| Vaccinated | Increase in Respiratory Support | Yes | 8 Participants |
| Vaccinated | Increase in Respiratory Support | No | 92 Participants |
| Unvaccinated | Increase in Respiratory Support | Yes | 4 Participants |
| Unvaccinated | Increase in Respiratory Support | No | 112 Participants |
| Unvaccinated | Increase in Respiratory Support | Missing | 0 Participants |
p-value: 0.355595% CI: [0.59, 7.23]Mantel Haenszel
Secondary
Number of Apneic Episodes
Average number of apneic episodes in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group.
Time frame: 48 hours
Population: The mITT population includes any infant that was enrolled and randomized in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vaccinated | Number of Apneic Episodes | 2.72 Apneic Episodes | Standard Deviation 2.76 |
| Unvaccinated | Number of Apneic Episodes | 2.00 Apneic Episodes | Standard Deviation 1.76 |
p-value: 0.11Regression, Linear
Secondary
Positive Pressure Ventilation
Proportion of Infants Requiring Positive Pressure Ventilation in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group.
Time frame: 48 hours
Population: The mITT population includes any infant that was enrolled and randomized in the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vaccinated | Positive Pressure Ventilation | Yes | 2 Participants |
| Vaccinated | Positive Pressure Ventilation | No | 104 Participants |
| Vaccinated | Positive Pressure Ventilation | Missing | 1 Participants |
| Unvaccinated | Positive Pressure Ventilation | Yes | 1 Participants |
| Unvaccinated | Positive Pressure Ventilation | No | 115 Participants |
| Unvaccinated | Positive Pressure Ventilation | Missing | 0 Participants |
Comparison: The proportion of infants requiring positive pressure ventilation for each group were compared using a Mantel-Haenszel statistic in a stratified analysis by study site and gestational age group to control for the randomization blocks at the two-sided alpha 0.05 level and corresponding 95% confidence interval for the occurrence of apnea during the 48-hour monitoring period.p-value: 195% CI: [0.17, 21.63]Mantel Haenszel
Secondary
Severe Cardiorespiratory Events
Proportion of infants with severe ≥1 severe cardiorespiratory event in a 48-hour monitoring period after vaccination in the vaccinated group and a 48-hour monitoring period after randomization in the unvaccinated group. Only severe apnea events in the mITT analysis window and only the severe bradycardia events in the mITT analysis window from Duke University. The monitor data were not viable at UNC and Cincinnati Children's Hospital. Duke data were adjudicated by neonatologists.
Time frame: 48 hours
Population: mITT Analysis Population: Duke Site Only
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vaccinated | Severe Cardiorespiratory Events | Yes | 7 Participants |
| Vaccinated | Severe Cardiorespiratory Events | No | 31 Participants |
| Vaccinated | Severe Cardiorespiratory Events | Missing | 1 Participants |
| Unvaccinated | Severe Cardiorespiratory Events | Yes | 8 Participants |
| Unvaccinated | Severe Cardiorespiratory Events | No | 34 Participants |
| Unvaccinated | Severe Cardiorespiratory Events | Missing | 0 Participants |
Comparison: Only Duke University had viable monitoring data to analyze this compound outcome objective.p-value: 195% CI: [0.29, 2.77]Mantel Haenszel