Moderately Preterm Infants With Caffeine at Home for Apnea (MoCHA) Trial

Study subjects will be patients in the NICU at one of the participating hospitals at a Neonatal Research Network site. Infants who meet the eligibility criteria will be randomized to either caffeine citrate at 10 mg/kg/dose or placebo (equal volume of all the excipients except for the active ingredient, caffeine citrate) to be given daily beginning within 72 hours of open label caffeine discontinuation. The infant may still require hospitalization for observation after discontinuation of open label caffeine or for other discharge issues such as temperature control or feeding tolerance.

Once deemed ready for discharge, infants will be continued at home on the same dose of caffeine citrate or placebo for the first 28 days after hospital discharge. On the day of discharge, the parent will be supplied with 28 numbered vials with oral caffeine citrate (intervention group) or placebo at an equivalent volume (placebo group).

The parents will be educated by the research nurse, discharge nurse, physician, or pharmacist on storage and administration of study medication. A member of the research team will contact the parents to obtain post-discharge information within 72 hours after discharge, once a week for the first 4 weeks, and biweekly during the weeks 5 to 8 after discharge.

• Caffeine Citrate (Drug): The study intervention is caffeine citrate given once daily at 10 mg/kg/day. It is given orally, before hospital discharge and 28 days after discharge.
• Placebo (Drug): The study intervention is placebo given once daily at a volume equivalent to 10 mg/kg of caffeine citrate. It is given orally, before hospital discharge and 28 days after discharge.

Primary outcomes

• Number of Days Between Randomization and Hospital Discharge [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days between randomization and hospital discharge. This outcome is censored at 48 weeks PMA and at time of transfer or death.
• Number of Sick Visits Related to Apneic or Apparent Life-threatening Events Within First 4 Weeks Post-discharge [Discharge through 4 weeks post-discharge]: Number of sick visits related to apneic or apparent life-threatening events within first 4 weeks post-discharge MEASTYPE=SEC

Secondary outcomes

• The Number of Days to Physiologic Maturity After Randomization [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days to physiologic maturity after randomization. Physiologic maturity is defined: 1. Temperature: out of the incubator for at least 48 hours with normal body temperature; 2. Feeding: oral feeding at a volume of at least 140 ml/kg for 48 hours or growing on less than 140 ml/kg/day for at least 48 hours; 3. Respiratory: apnea-free for at least 5 consecutive days. This outcome is censored at 48 weeks PMA
• The Number of Days to When Out of Incubator for 48 Hours: When Maintained Stable Temp for 48 Hrs [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days to when out of incubator for 48 hours: when maintained stable temp for 48 hrs. This outcome is censored at 48 weeks PMA
• The Number of Days to Apnea/ Bradycardia Free for 5 Consecutive Days [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days to apnea/ bradycardia free for 5 consecutive days. This outcome is censored at 48 weeks PMA
• The Number of Days to Oral Feeds >140 ml/kg/Day or Growing on Less Than 140 ml/kg/Day for at Least 48 Hours [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days oral feeds >140 ml/kg/day or growing on less than 140 ml/kg/day for at least 48 hours. This outcome is censored at 48 weeks PMA
• Post-menstrual Age at Discharge [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The post-menstrual age of the infant at discharge censored at 48 weeks PMA and at time of transfer or death
• Weight Gain From Randomization Until Status [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: Weight gain from randomization until status %(discharge up to 48 wks PMA, with censoring at time of transfer or death%).
• The Number of Days After Randomization Until Status That Infant Had at Least Two Consecutive Heart Rates >200 Documented at Least 3 Hours Apart [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days after randomization until status that infant had at least two consecutive heart rates >200 documented at least 3 hours apart
• Treatment for High Blood Pressure [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: Treatment for high blood pressure initiated after randomization until status.
• The Number of Episodes Between Randomization and Status That Infant Was Placed NPO for >= 24 Hours [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of episodes between randomization and status that infant was placed NPO for >= 24 hours
• Use of Anti-reflux Medications [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The use of anti-reflux medications started between randomization and status
• Number of Days That Significant Apnea/Bradycardia [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: The number of days that significant apnea/bradycardia, as defined by documentation of infant receiving any of the following between randomization and status: open label caffeine, other methylxanthines, doxapram, CPAP or ventilatory support for apnea/bradycardia.
• All-cause Mortality [Randomization through hospital discharge, censored at time of transfer, death, or 48 wks PMA]: All-cause mortality
• Number of All-cause Readmissions Within First 4 Weeks Post-discharge [Discharge through 4 weeks post-discharge]: Number of all-cause readmissions within first 4 weeks post-discharge
• Number of All-cause Readmissions Within Second 4 Weeks Post-discharge [4 weeks through 8 weeks post-discharge]: Number of all-cause readmissions within second 4 weeks post-discharge
• Number of All-cause Readmissions Within First 8 Weeks Post-discharge [Discharge through 8 weeks post-discharge]: Number of all-cause readmissions within first 8 weeks post-discharge
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within First 4 Weeks Post-discharge [Discharge through 4 weeks post-discharge]: Number of all-cause sick visits, urgent care, emergency rooms, or health care provider%'s office, within first 4 weeks post-discharge
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within Second 4 Weeks Post-discharge [4 weeks through 8 weeks post-discharge]: Number of all-cause sick visits, urgent care, emergency rooms, or health care provider%'s office, within second 4 weeks post-discharge
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within First 8 Weeks Post-discharge [Discharge through 8 weeks post-discharge]: Number of all-cause sick visits, urgent care, emergency rooms, or health care provider%'s office, within first 8 weeks post-discharge
• Number of Sick Visits Related to Apneic or Apparent Life-threatening Events Within Second 4 Weeks Post-discharge [4 weeks through 8 weeks post-discharge]: Number of sick visits related to apneic or apparent life-threatening events within second 4 weeks post-discharge
• Number of Sick Visits Related to Apneic or Apparent Life-threatening Events Within First 8 Weeks Post-discharge [Discharge through 8 weeks post-discharge]: Number of sick visits related to apneic or apparent life-threatening events within first 8 weeks post-discharge

Sex: All, ages: 29 Weeks to 33 Weeks

Inclusion Criteria:

* Inborn and outborn infants of 29 0/7 to 33 6/7 weeks gestational age at birth
* admitted to hospitals of the NICHD NRN who, are at time of enrollment:
* ≤35 6/7 weeks post-menstrual age at the time of randomization
* Receiving caffeine with plan to discontinue treatment or just discontinued caffeine treatment
* Receiving feeds at a volume of ≥120 ml/kg/day by oral and/or tube feeding
* Ability to start study medication within 72 hours after stopping caffeine

Exclusion Criteria:

* On respiratory therapy (oxygen more than room air equivalent for high altitude sites, nasal cannula, continuous positive pressure ventilation, and/or mechanical ventilation)
* Infants who would otherwise be discharged home on apnea monitor due to underlying disease or family history, including history of a sibling with sudden infant death syndrome
* Parental request for apnea monitor
* Congenital heart disease other than atrial septal defect, ventricular septal defect, or patent ductus arteriosus
* Neuromuscular conditions affecting respiration
* Major congenital malformation and/or genetic disorder
* Plans to transfer to a non-NRN site before discharge
* Unable to obtain parental or guardian consent

Participant flow

Outcome results

• Number of Days Between Randomization and Hospital Discharge (Primary), Median, days: Caffeine 18 (10 to 30); Placebo 16.5 (10 to 27)
• The Number of Days to Physiologic Maturity After Randomization (Secondary), Median, days: Caffeine 13 (7 to 23); Placebo 14 (8 to 23)
• The Number of Days to When Out of Incubator for 48 Hours: When Maintained Stable Temp for 48 Hrs (Secondary), Median, days: Caffeine 5 (2 to 9); Placebo 5 (1 to 9)
• The Number of Days to Apnea/ Bradycardia Free for 5 Consecutive Days (Secondary), Median, days: Caffeine 8 (5 to 16); Placebo 11 (5 to 18)
• The Number of Days to Oral Feeds >140 ml/kg/Day or Growing on Less Than 140 ml/kg/Day for at Least 48 Hours (Secondary), Median, days: Caffeine 14 (6 to 23); Placebo 12 (5 to 22)
• Post-menstrual Age at Discharge (Secondary), Mean, weeks: Caffeine 37.7 (37.5 to 37.9); Placebo 37.6 (37.4 to 37.8)
• Weight Gain From Randomization Until Status (Secondary), Mean, grams per day: Caffeine 28.9 (28.1 to 29.8); Placebo 32.2 (30.9 to 33.4)
• The Number of Days After Randomization Until Status That Infant Had at Least Two Consecutive Heart Rates >200 Documented at Least 3 Hours Apart (Secondary), Median, days: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Treatment for High Blood Pressure (Secondary), Count of participants, Participants: Caffeine 412; Placebo 410
• The Number of Episodes Between Randomization and Status That Infant Was Placed NPO for >= 24 Hours (Secondary), Median, episodes: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Use of Anti-reflux Medications (Secondary), Count of participants, Participants: Caffeine 384; Placebo 387
• Number of Days That Significant Apnea/Bradycardia (Secondary), Median, days: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• All-cause Mortality (Secondary), Count of participants, Participants: Caffeine 415; Placebo 411
• Number of All-cause Readmissions Within First 4 Weeks Post-discharge (Secondary), Median, count of readmissions: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of All-cause Readmissions Within Second 4 Weeks Post-discharge (Secondary), Median, count of readmissions: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of All-cause Readmissions Within First 8 Weeks Post-discharge (Secondary), Median, count of readmissions: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within First 4 Weeks Post-discharge (Secondary), Median, count of sick visits: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within Second 4 Weeks Post-discharge (Secondary), Median, count of sick visits: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of All-cause Sick Visits, Urgent Care, Emergency Rooms, or Health Care Provider%'s Office, Within First 8 Weeks Post-discharge (Secondary), Median, count of sick visits: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• Number of Sick Visits Related to Apneic or Apparent Life-threatening Events Within First 4 Weeks Post-discharge (Primary), Median, count of apnea visits: Caffeine 0 (0 to 0); Placebo 0 (0 to 0)
• 2 more outcome measures not shown.

Adverse events

Time frame: Randomization through 8-weeks post discharge, up to 48 weeks Post-Menstrual Age.

Serious adverse events by term

Other adverse events by term

• Results publication: Carlo WA, Eichenwald EC, Carper BA, Bell EF, Keszler M, Patel RM, Sanchez PJ, Goldberg RN, D'Angio CT, Van Meurs KP, Hibbs AM, Ambalavanan N, Cosby SS, Newman NS, Vohr BR, Walsh MC, Das A, Ohls RK, Fuller J, Rysavy MA, Ghavam S, Brion LP, Puopolo KM, Moore R, Baack ML, Colaizy TT, Baserga M, Osman AF, Merhar SL, Poindexter BB, DeMauro SB, Kumar V, Cotten CM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Extended Caffeine for Apnea in Moderately Preterm Infants: The MoCHA Randomized Clinical Trial. JAMA. 2025 Jun 24;333(24):2154-2163. doi: 10.1001/jama.2025.5791. PMID 40294395

• Study Protocol (PDF, 2021-12-16)
• Statistical Analysis Plan (PDF, 2022-12-12)
• Informed Consent Form (PDF, 2021-12-16)

• Waldemar Carlo, MD, Principal investigator, University of Alabama at Birmingham

NIH grants: UG1HD034216, UG1HD027904, UG1HD021364, UG1HD027853, UG1HD040689, UG1HD040492, UG1HD027851, UG1HD087229, UG1HD053109, UG1HD068278, UG1HD068244, UG1HD068263, UG1HD027880, UG1HD053089, UG1HD087226, U10HD036790