Rhein 2014.

Study characteristics
Methods	Prospective, randomized controlled parallel‐group trial onducted in the USA
Participants	Inclusion criteria: Gestational age of 25 + 0 to 32 + 0 weeks PMA at birth, and 34 + 0 to 37 + 6 weeks PMA at randomization Prior treatment with caffeine based on routine clinical indications, and clinical caffeine now discontinued ≥ 5 days before randomization Previously tolerated clinical treatment with caffeine Breathing room air (no current supplemental O2 treatment; may have previously required respiratory support) Parental consent to enroll in pilot study Exclusion criteria: Congenital syndrome or other medical diagnosis associated with known risk for neurodevelopmental abnormality, including intraventricular hemorrhage Grade 3 or greater, cyanotic congenital heart disease, confirmed central nervous system infection, or fetal alcohol syndrome Currently receiving supplemental oxygen, ventilatory support, or nasal airflow therapy Clinical decision to restart caffeine prior to completing 5 days of continuous physiologic monitoring after clinical caffeine stopped Anticipated inability to meet protocol requirements Characteristics: Sample size: 105; randomized infants: 98; boys: 51 (group 1: 24; group 2: 27); girls: 44 (group 1: 18, group 2: 26) Number randomized: 98; number lost to follow‐up/withdrawn: 3; number analyzed: 95; Mean GA (w)*: group 1: 28.6 (1.7), group 2: 29.1 (1.7) Mean BW (g)*: group 1: 1262.1 (265.6), group 2: 1274.5 (270.3) PMA at randomization (w)*: group 1: 35.6 (1.1), group 2: 35.4 (1.1) PMA at discharge (w)*: group 1: 37 (1.6), group 2: 37.1 (1.8) Maternal age (y)*: group 1: 29.7 (6.5), group 2: 32.7 (6.9)
Interventions	As soon as clinical caffeine treatment had been discontinued for 5 days and their PMA was 34 to 37 weeks, infants were randomized to either receive the study caffeine protocol or to continue with usual care (controls). Group 1 ‐ late discontinuation: oral loading dose of caffeine citrate (20 mg/kg) at randomization followed by oral maintenance dosage (6mg/kg/die) until 40 weeks PMA Group 2 ‐ early discontinuation: no caffeine (usual care) until 40 weeks PMA
Outcomes	Primary outcomes: Episodes of IH per hour: number of episodes of IH per hour of pulse oximeter recording less than 90% oxygen saturation Number of seconds of IH per hour: number of seconds of IH per hour of pulse oximeter recording less than 90% oxygen saturation
Funding and declaration of interest	Funding: American SIDS Institute Declaration of interest: Dr McEntire reports being the executive director of the American SIDS Institute, and Dr Hunt reports being a member of the American SIDS Institute board of directors. No other disclosures were reported.
Notes	Mail from C. Hunt: Enrollment ended 31 July 2023, and the last subject will complete the study protocol this week. We will not be ready to unblind the study until late October at the earliest, but we nevertheless hope to submit a PAS abstract with our primary results for the Spring 2024 meeting in Toronto. We ended the study with 170 enrolled subjects.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Personal communication with study authors: computer generated random numbers, with blocks.
Allocation concealment (selection bias)	Low risk	Personal communication with study authors: sealed opaque envelopes provided by the Data Coordinating Center were used for each randomization to extend caffeine use or usual care
Blinding of participants and personnel (performance bias) All outcomes	High risk	The control group did not receive a placebo. The decision to discontinue routine caffeine treatment and the exact timing of discontinuation was completely at the discretion of the clinical team and not dictated by the study protocol.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All analyses of outcome measures were to be performed by persons masked to treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sample size: 98; intervention group: 45; control group: 53; analysed: 95. 3 infants in intervention group dropped out because of insufficient data analysed
Selective reporting (reporting bias)	Low risk	PICO of protocol and full text match
Other bias	Low risk	No comments

AED: antiepileptic drugs; AOP: apnea of prematurity; BPD: bronchopulmonary dysplasia; BW: birth weight; CPAP: continuous positive airway pressure; EUGR: Extrauterine growth restriction; GA: gestational age; HFNC: High flow nasal cannula; IH: intermittent hypoxia; MV: mechanical ventilation; NEC: necrotizing enterocolitis; PMA: postmenstrual age; PNA: Postnatal age; RAP: recurrence of apnea of prematurity; RDS: respiratory distress syndrome; ROP: retinopathy of prematurity; RS: respiratory support; SIDS: Sudden infant death syndrome

* Mean (SD); ° Median (interquartile range).