Apnea in Hospitalized Preterm Infants Following the Administration of Routine Childhood Vaccines

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective, Randomized, Open-label Clinical Trial to Assess Apnea Following Administration of 13-valent Conjugate Pneumococcal Vaccine, Diphtheria Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine, Inactivated Polio Vaccine, Hepatitis B Vaccine, and Haemophilus Influenzae Type B Vaccine in Preterm Infants

Conditions
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Apnea, Apnea Neonatal, Prematurity

Intervention / Treatment
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* Biological: PCV13
* Biological: DTaP
* Biological: HBV
* Biological: IPV
* Biological: Hib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: <33 and 0 days weeks gestational age at birth ≥6 weeks and 0 days and ≤12 weeks and 0 days postnatal age at randomization Remains hospitalized after birth (has never been discharged home) Treating clinician deems infant eligible to receive 2-month vaccines English- or Spanish-speaking parent(s)/legally authorized representative(s) (LAR(s)) Not planned for discharge within 60 hours of study entry The parent/guardian must be willing and capable of providing permission for their child to participate through the written informed consent process Exclusion Criteria: Receipt of DTaP, IPV, PCV13, or Hib prior to enrollment. Previous administration of the first dose of HBV is permitted Anticipated receipt of any vaccine other than DTaP, IPV, HBV, PCV13, or Hib during the first 60 hours after randomization History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose of any hepatitis B vaccine 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 History of latex allergy Fever ≥38°C within 48 hours prior to randomization* *This may result in a temporary delay of randomization Active known respiratory infection within 48 hours prior to randomization* *This may result in a temporary delay of randomization Active infection being treated with systemic antimicrobials* *This may result in a temporary delay of randomization Requiring mechanical ventilation or support with nasal intermittent positive pressure ventilation (NIPPV)* *This may result in a temporary delay of randomization History of unstable progressive neurologic disorder of unknown cause Known cause of apnea other than apnea of prematurity Cyanotic heart disease (congenital or acquired) 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 Child or parent/LAR is an immediate relative of study staff or an employee who is supervised by study staff. 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

Ages Eligible for Study
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Minimum Age: 6 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Vaccinated<br>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. | Biological: PCV13<br>* Advisory Committee on Immunization Practices (ACIP) Recommended vaccine<br>* Other names: 13-valent Conjugate Pneumococcal Vaccine;Biological: DTaP<br>* ACIP Recommended vaccine<br>* Other names: Diphtheria, Tetanus, and Acellular Pertussis Vaccine;Biological: HBV<br>* ACIP Recommended vaccine<br>* Other names: Hepatitis B Vaccine;Biological: IPV<br>* ACIP Recommended vaccine<br>* Other names: Inactivated Polio Vaccine;Biological: Hib<br>* ACIP Recommended vaccine<br>* Other names: Haemophilus influenzae Type B Vaccine;|
| No Intervention: Unvaccinated<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 hours | 
| 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. | 48 hours | 
| 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. | 48 hours | 
| 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. | 48 hours | 
| 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. | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apnea following vaccination