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

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

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.

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.

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