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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Caffeine Citrate Group | Experimental | 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 |
|
| Placebo Group | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Recruitment/Eligibility Proportion | Ratio of enrolled/randomized infants to total eligible infants screened. | Through study completion, up to 24 months |
| Treatment Adherence Proportion | Percentage of per-protocol doses (caffeine/placebo) successfully administered | From randomization until 24 hours after weaning from respiratory support |
| Retention Proportion | Percentage of randomized infants who complete the study protocol until NICU discharge | Through study completion, up to 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Discharge Alive from the NICU | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Eyad Bitar, MD | Contact | +1 (613) 548-6053 | eyad.bitar@queensu.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kingston Health Science Center | Kingston | Ontario | K7L 2V7 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38553606 | Background | Oliphant EA, Hanning SM, McKinlay CJD, Alsweiler JM. Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis. J Perinatol. 2024 Jun;44(6):785-801. doi: 10.1038/s41372-024-01939-x. Epub 2024 Mar 29. | |
| 16707748 | Background | Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065. |
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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
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D002110 | Caffeine |
| ID | Term |
|---|---|
| D014970 | Xanthines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011688 | Purinones |
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A randomized, double-blind, 1:1 parallel-group allocation comparing a daily caffeine base to a matched saline placebo
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|
| 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 |
|
Frequency distribution of Likert-scale responses on the parent satisfaction survey |
| Within 7 days prior to infant's NICU discharge |
| Healthcare Provider Acceptability | Thematic analysis of healthcare provider focus group transcripts regarding protocol viability | Through recruitment completion, an average of 24 months |
| Data Completeness | Proportion of missing data points across all secondary clinical outcomes. | At the end of the recruitment period, approximately 24 months |
| Significant Apnea Frequency | 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 | 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 | 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 | 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 | 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 |
| Duration of Total Parenteral Nutrition (TPN) | 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 |
| PMA at Weaning | 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 | 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 | 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 | 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 | 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 |
| Bronchopulmonary dysplasia (BPD) | 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 | 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 | 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 | 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 | 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) | 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) | 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 | 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 | 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 | 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 | 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 |
| 35429946 | Background | Iranpour R, Armanian AM, Miladi N, Feizi A. Effect of Prophylactic Caffeine on Noninvasive Respiratory Support in Preterm Neonates Weighing 1250-2000 g: A Randomized Controlled Trial. Arch Iran Med. 2022 Feb 1;25(2):98-104. doi: 10.34172/aim.2022.16. |
| 28126032 | Background | Sekhon M, Cartwright M, Francis JJ. Acceptability of healthcare interventions: an overview of reviews and development of a theoretical framework. BMC Health Serv Res. 2017 Jan 26;17(1):88. doi: 10.1186/s12913-017-2031-8. |
| 33536076 | Background | Lewis M, Bromley K, Sutton CJ, McCray G, Myers HL, Lancaster GA. Determining sample size for progression criteria for pragmatic pilot RCTs: the hypothesis test strikes back! Pilot Feasibility Stud. 2021 Feb 3;7(1):40. doi: 10.1186/s40814-021-00770-x. |
| 33129702 | Background | Muehlbacher T, Gaertner VD, Bassler D. History of caffeine use in neonatal medicine and the role of the CAP trial. Semin Fetal Neonatal Med. 2020 Dec;25(6):101159. doi: 10.1016/j.siny.2020.101159. Epub 2020 Oct 21. No abstract available. |
| D000091642 | Urogenital Diseases |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |