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NCT Number: NCT07456670

Caffeine for Infants Born at 28 to 34 Weeks Receiving Respiratory Support

The goal of this pilot clinical trial is to test if it is possible to conduct a larger study on the use of caffeine in preterm infants who need help with their breathing. It will also look at whether caffeine helps these infants get healthy enough to leave the hospital sooner.

The main questions the researchers aim to answer are:

Can the investigators successfully recruit and keep enough participants in the study? Do the medical teams follow the study drug instructions correctly? Does caffeine reduce the total time infants spend in the Neonatal Intensive Care Unit (NICU)? Researchers will compare caffeine to a placebo (a look-alike substance with no active medicine) to see if caffeine is a helpful treatment for babies born between 28 and 34 weeks of gestation who are using a breathing machine or oxygen.

Participants will:

Be randomly assigned to receive either caffeine or a placebo through an IV or a feeding tube.

Receive the study treatment once a day as long as they require respiratory support (and for 24 hours after they stop).

Be monitored by the research team for clinical outcomes like feeding progress, breathing stability, and growth until they are discharged from the hospital.

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Key information

Conditions

Preterm Birth Caffeine Female Urogenital Diseases and Pregnancy Complications Neonatal Outcomes Obstetric Labor Complications Obstetric Labor, Premature Pregnancy Complications Premature Birth Urogenital Diseases

Age range

0 day–28 day

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Kingston Health Science Center

Kingston, Ontario, K7L 2V7, Canada

About this study

Despite the widespread use of caffeine for extremely preterm infants, a significant knowledge gap exists regarding its efficacy for infants (28+0 to 34+6 weeks' gestation) who require respiratory support. This patient population is at increased risk for respiratory morbidity and prolonged hospitalization, yet clinical practice regarding caffeine use remains highly variable.

The CARES-Pilot is a single-center, pilot randomized controlled trial (RCT) designed to assess the feasibility of a larger, definitive trial. The long-term goal of the definitive trial is to determine if routine caffeine administration reduces the time to discharge alive from the NICU.

This pilot study utilizes a double-blind, placebo-controlled, parallel-group design. Eligible infants are those born between 28+0 and 34+6 weeks of gestation who require invasive or non-invasive respiratory support within the first 72 hours of life. Participants are randomized to receive either caffeine base (10 mg/kg loading dose, followed by 5 mg/kg daily maintenance) or an equivalent volume of normal saline (placebo).

The primary focus of this pilot phase is to evaluate four key feasibility outcomes using a "traffic light" approach with pre-specified progression criteria:

Recruitment and Eligibility: Assessing the proportion of eligible infants whose parents provide consent and are successfully randomized.

Treatment Fidelity: Monitoring adherence to the blinded treatment protocol by the clinical and pharmacy teams.

Retention: Evaluating the number of participants who complete the study through to the primary clinical endpoint.

Data Completeness: Ensuring the reliability of data collection for secondary clinical outcomes.

Secondary clinical objectives include measuring the time to discharge alive from the NICU (the planned primary outcome for the definitive trial), duration of respiratory support, time to full enteral feeds, and neurodevelopmental status at discharge using the Test of Infant Motor Performance (TIMP). This pilot will also explore the acceptability of the trial protocol among healthcare providers and parents through surveys and focus groups.

The findings from this pilot study will be used to refine the protocol, calculate a precise sample size for the definitive multicenter RCT, and determine the viability of expanding the study to other sites.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Infant born at a gestational age between 28+0 and 34+6 weeks.
  • Admitted to the Neonatal Intensive Care Unit (NICU) within the first 72 hours of life.
  • Requiring either invasive respiratory support (mechanical ventilation) or non-invasive respiratory support (e.g., CPAP, High Flow Nasal Cannula) within the first 72 hours of life.
  • Informed consent obtained from parent(s) or legal guardian(s).

Exclusion criteria

  • Presence of dysmorphic features or major congenital malformations that adversely affect life expectancy.
  • Known or strongly suspected cyanotic heart disease.
  • Infants born at <28 weeks' gestational age (due to high risk of apnea requiring routine caffeine).
  • Late preterm infants born at ≥35+0 weeks' gestational age (due to short NICU stay not allowing for a safe caffeine-free period before discharge).

Treatment and study plan

Caffeine

Drug

Infants randomized to this arm will receive caffeine citrate administered as a 10 mg/kg loading dose (caffeine base equivalent), followed by a 5 mg/kg daily maintenance dose (caffeine base equivalent).

Other names: caffeine Base

Placebo

Other

Infants randomized to this arm will receive 0.9% normal saline administered in a volume equivalent to the caffeine citrate arm. The placebo will be administered as a loading dose followed by a daily maintenance dose matching the volume and timing of the experimental protocol

Primary outcomes

  1. Recruitment/Eligibility Proportion

    Time frame: Through study completion, up to 24 months

    Ratio of enrolled/randomized infants to total eligible infants screened.

  2. Treatment Adherence Proportion

    Time frame: From randomization until 24 hours after weaning from respiratory support

    Percentage of per-protocol doses (caffeine/placebo) successfully administered

  3. Retention Proportion

    Time frame: Through study completion, up to 24 months

    Percentage of randomized infants who complete the study protocol until NICU discharge

Secondary outcomes

  1. Time to Discharge Alive from the NICU

    Time frame: From the date of randomization until the date of discharge alive from NICU, assessed up to 24 months

    Hours from the time of randomization to the time of discharge alive from the NICU

  2. Parent/Guardian Acceptability

    Time frame: Within 7 days prior to infant's NICU discharge

    Frequency distribution of Likert-scale responses on the parent satisfaction survey

  3. Healthcare Provider Acceptability

    Time frame: Through recruitment completion, an average of 24 months

    Thematic analysis of healthcare provider focus group transcripts regarding protocol viability

  4. Data Completeness

    Time frame: At the end of the recruitment period, approximately 24 months

    Proportion of missing data points across all secondary clinical outcomes.

  5. Significant Apnea Frequency

    Time frame: From randomization until 24 hours after weaning from respiratory support

    Mean number of apneas per day requiring intervention (stimulation, or ventilation)

  6. Total Duration of Respiratory Support

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, assessed up to 24 months

    Total hours spent on invasive and non-invasive mechanical ventilation

  7. Duration of Invasive Support

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, assessed up to 24 months

    Total hours spent specifically on invasive mechanical ventilation (intubation)

  8. Time to Full Enteral Feeding

    Time frame: From the date of first enteral feeding until the date when the targeted feeding volume is achieved, average of 14 days

    Hours from the first feed until the infant reaches the protocol-defined "full" enteral volume

  9. Time to Full Oral Feeding

    Time frame: From the date of birth until the date of full oral feeding is achieved, an average of 6 weeks

    Hours from birth until the infant is successfully taking all feeds by mouth (no tube)

  10. Duration of Total Parenteral Nutrition (TPN)

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Total number of days during which the infant received any volume of parenteral nutrition

  11. PMA at Weaning

    Time frame: At the time of weaning from respiratory support, an average of 4 to 6 weeks after birth

    Mean post-menstrual age of the infant when respiratory support is successfully discontinued

  12. PMA at Discharge

    Time frame: At the time of NICU discharge, an average of 36 to 40 weeks post-menstrual age

    Mean post-menstrual age of the infant at the time of discharge alive from the NICU.

  13. Rate of New Invasive Ventilation

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, assessed up to 24 months

    Proportion of infants not intubated at enrollment who require intubation during the study.

  14. In-hospital Mortality

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, assessed up to 24 months

    Proportion of enrolled infants who die during their initial NICU stay.

  15. Test of Infant Motor Performance (TIMP) Score

    Time frame: At the time of NICU discharge, an average of 36 to 40 weeks post-menstrual age

    Mean score on the Test of Infant Motor Performance (TIMP). Scores range from 0 to 142, with higher scores indicating better motor maturity and performance

  16. Bronchopulmonary dysplasia (BPD)

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with BPD defined as: For infants born prior to 32 weeks of gestation, this will be defined as oxygen treatment for at least 28 days with oxygen need at 36 weeks' postmenstrual age or at discharge from the NICU, whichever occurs earlier. For infants born at 32 weeks or later, this will be defined as oxygen treatment at 56 days of life or at discharge from the NICU, whichever occurs earlier.

  17. Pulmonary Hemorrhage

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with pulmonary hemorrhage defined as the presence of sanguineous fluid in the trachea associated with clinical respiratory deterioration and new radiographic opacities.

  18. Pneumothorax

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with pneumothorax defined as accumulation of air in the pleural space, confirmed by chest radiograph, requires intervention such as needle aspiration or chest tube insertion

  19. Necrotizing Enterocolitis (NEC) Bell's Stage 2 or more

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with a diagnosis of NEC meeting at least Bell's Stage II criteria

  20. Gastrointestinal Surgery

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with any invasive surgical procedure related to the gastrointestinal tract, including laparotomy for NEC, intestinal resection, or the insertion of a peritoneal drain

  21. Intraventricular hemorrhage (IVH)

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with any grade of bleeding into the cerebral ventricular system of the brain. This will be graded according to the Papile classification (Grades I-IV) diagnosed by head imaging.

  22. Periventricular Leukomalacia (PVL)

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with localized areas of cystic necrosis in the periventricular white matter, diagnosed by serial cranial ultrasound or Magnetic Resonance Imaging (MRI)

  23. Seizure

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with clinical seizure identified by clinical observation

  24. Patent ductus arteriosus (PDA) Treatment

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants who received a pharmacological therapy or surgical ligation intended to close a hemodynamically significant PDA.

  25. Retinopathy of Prematurity (ROP) Stage

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Mean of the highest stage of RoP (Stages 1-5) recorded in either eye during the infant's hospital stay based on formal ophthalmological retinal examinations

  26. Late Onset Sepsis

    Time frame: From the date of randomization until the date of discharge alive from NICU or date of death from any cause, whichever came first, , an average of 36 to 40 weeks post-menstrual age

    Proportion of enrolled infants with a positive blood or cerebrospinal fluid culture obtained after day 3 (72 hours) of life in an infant with clinical signs of infection

Study contacts

Contact information is provided by the study sponsor or research team.

Eyad Bitar, MD

CONTACT

[email protected]

+1 (613) 548-6053

Sponsors and collaborators

Lead sponsor

Queen's University

Other

Registry information

Official study title

Caffeine Therapy in Preterm Infants Born at 28-34 Weeks: A Pilot Placebo-Controlled Randomized Controlled Trial

Acronym: CARES-Pilot

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Mar 6, 2026
Registry last updated
Mar 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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