Caffeine for Infants Born at 28 to 34 Weeks Receiving Respiratory Support (CARES-Pilot)

March 6, 2026 updated by: Eyad Bitar, Queen's University

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

62

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Ontario
      • Kingston, Ontario, Canada, K7L 2V7
        • Kingston Health Science Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Caffeine Citrate Group
Infants in this arm will receive a loading dose of caffeine base (10 mg/kg), followed by a daily maintenance dose (5 mg/kg). The study drug will be administered intravenously or enterally (once full oral feeds are established) until 24 hours after the successful weaning of respiratory support
Drug: Caffeine
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 Comparator: Placebo Group
Infants in this arm will receive an equivalent volume of 0.9% normal saline (placebo) instead of caffeine. The loading dose and daily maintenance doses will follow the same schedule and administration routes (intravenous or enteral) as the experimental arm. The placebo will be administered until 24 hours after the successful weaning of respiratory support.
Other: Placebo
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recruitment/Eligibility Proportion
Time Frame: Through study completion, up to 24 months
Ratio of enrolled/randomized infants to total eligible infants screened.
Through study completion, up to 24 months
Treatment Adherence Proportion
Time Frame: From randomization until 24 hours after weaning from respiratory support
Percentage of per-protocol doses (caffeine/placebo) successfully administered
From randomization until 24 hours after weaning from respiratory support
Retention Proportion
Time Frame: Through study completion, up to 24 months
Percentage of randomized infants who complete the study protocol until NICU discharge
Through study completion, up to 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
From the date of randomization until the date of discharge alive from NICU, assessed up to 24 months
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
Within 7 days prior to infant's NICU discharge
Healthcare Provider Acceptability
Time Frame: Through recruitment completion, an average of 24 months
Thematic analysis of healthcare provider focus group transcripts regarding protocol viability
Through recruitment completion, an average of 24 months
Data Completeness
Time Frame: At the end of the recruitment period, approximately 24 months
Proportion of missing data points across all secondary clinical outcomes.
At the end of the recruitment period, approximately 24 months
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)
From randomization until 24 hours after weaning from respiratory support
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
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
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)
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
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
From the date of first enteral feeding until the date when the targeted feeding volume is achieved, average of 14 days
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)
From the date of birth until the date of full oral feeding is achieved, an average of 6 weeks
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
At the time of weaning from respiratory support, an average of 4 to 6 weeks after birth
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.
At the time of NICU discharge, an average of 36 to 40 weeks post-menstrual age
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.
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
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.
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
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
At the time of NICU discharge, an average of 36 to 40 weeks post-menstrual age
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
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
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.
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
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.
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
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
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
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
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
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
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
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.
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
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)
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
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
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
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.
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
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
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
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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Queen's University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

March 31, 2028

Study Completion (Estimated)

March 31, 2028

Study Registration Dates

First Submitted

February 27, 2026

First Submitted That Met QC Criteria

March 3, 2026

First Posted (Actual)

March 6, 2026

Study Record Updates

Last Update Posted (Actual)

March 10, 2026

Last Update Submitted That Met QC Criteria

March 6, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TRAQ 73767

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Data sharing may be considered on a case-by-case basis upon reasonable request to the Principal Investigator, provided that the request does not conflict with the primary goals of the upcoming definitive trial or compromise participant privacy

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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