Intermittent Hypoxia and Caffeine in Infants Born Preterm

NCT03321734 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: R01HD0892891R01HD089289-01A1
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 15

Brief Summary

Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF) Our proposal will address the critical question: is persisting intermittent hypoxia (IH) in preterm infants associated with biochemical, structural, or functional injury, and is this injury attenuated with extended caffeine treatment? The investigators will study the effects of caffeine on IH in 220 preterm infants born at ≤30 weeks + 6 days gestation. Infants who are currently being treated with routine caffeine, and who meet eligibility criteria, will be enrolled between 32 weeks + 0 days and 36 weeks + 6 days PMA. At enrollment, infants will be started on continuous pulse oximeter recording of O2 saturation and heart rate. If, based on standard clinical criteria, the last dose of routine caffeine is given on or before the day the infant is 36 weeks + 5 days PMA, then on the day following their last dose of routine caffeine treatment, infants will be randomized (110/group) to extended caffeine treatment or placebo. Randomized infants should begin receiving study drug (i.e. 5 mg/kg/of caffeine base, or equal volume of placebo) on the day of randomization, but no later than the third calendar day following the last dose of routine caffeine. Prior to 36 weeks + 0 days PMA, study drug will be given once daily (i.e. 5mg/kg/day) and beginning at 36 weeks + 0 days PMA, study drug will be given twice daily (i.e. 10 mg/kg/day). The last dose of study drug will be given at 42 weeks + 6 days PMA. Pulse oximeter recordings will continue 1 additional week after discontinuing study drug. Two caffeine levels will be obtained, the 1st at one week after beginning study drug, and the 2nd at a target date of 40 weeks + 0 days PMA, but no later than the last day of study drug, whether in hospital or at home. Inflammatory biomarkers will be measured at study enrollment and again at 38 weeks + 0 days PMA, or within 2 calendar days prior to hospital discharge, whichever comes first. Quantitative MRI/MRS should be obtained between study enrollment and 3 calendar days after starting study drug and again at a target date of 43 weeks + 0 days, but no later than 46 weeks + 6 days PMA.

Conditions

Intermittent Hypoxia

Keywords

Caffeine; Prematurity

Outcome Measures

Primary Outcomes (3)

• Compare the extent of IH exposure, from randomization through 42 weeks + 6 days PMA (within each gestational week and overall), in infants randomized to extended caffeine treatment to infants assigned to receive placebo.

  Extent of IH as measured by seconds below 90% saturation per 24 hours of recorded oximetry data within each week PMA

  Randomization to 42 weeks PMA (post menstrual age)

• Compare changes in a panel of inflammation-related cytokines and chemokines, from enrollment to the target age of 38 weeks + 0 days PMA, in infants randomized to extended caffeine treatment to infants assigned to receive placebo.

  Plasma concentration of each inflammatory biomarkers between baseline and 38 weeks + 0 days PMA in caffeine-treated compared to placebo-treated infants measured by blood sample. Bulk analyses of inflammatory biomarker plasma concentrations will be performed at Children's National Medical Center using a commercially available 40-plex V-Plex ELISA multi-spot assay (MesoScale Diagnostics, Rockville, MD) to measure inflammation-related proteins from different functional categories of cytokines and chemokines, including growth factors, and adhesion molecules, IFN-alpha, IL-6, Gro/CXCL1, IL-1β, IL-4-6, IL-6 receptor, IL-8, IL-10, IL-13, ICAM-1, myeloperoxidase, CRP, MCP, IGFBP-1, MIP-1a, RANTES, and TNFa. Analytes that show strong trends or significance with this assay may be further analyzed with individual ELISA assays, to confirm the original result.

  Inflammatory biomarkers will be measured at study enrollment and again at 38 weeks + 0 days PMA, or within 2 calendar days prior to hospital discharge, whichever comes first.

• Compare changes in quantitative MRI structural, microstructural from enrollment to 43-46 weeks PMA, in infants randomized to extended caffeine treatment to infants assigned to receive placebo.

  • MRI changes in microstructural measures between baseline and end of study (between 43 weeks + 0 days and 46 weeks + 6 days PMA). MRI acquisition protocols will be standardized and field-tested across all sites in Y1 Q1-3, and MRI calibration studies will be performed to ensure that the MRI scanner properties and parameter settings during the acquisition phase are correct. Conventional MRI studies will be reviewed in a standardized fashion by a pediatric neuroradiologist at each site blinded to study randomization. All MRI data sets will be processed at the Advanced Pediatric Brain Imaging Research Laboratory (DBRL) at Children's National Medical Center. All quantitative MRI outcome measures are continuous and will be performed by a single investigator masked to randomization. Abnormalities of brain development, maturation, the presence of focal destructive ischemic or hemorrhagic lesions, will be documented.

  Quantitative MRI/MRS should be obtained between study enrollment and 3 calendar days after starting study drug and again at a target date of 43 weeks + 0 days, but no later than 46 weeks + 6 days PMA.

Secondary Outcomes (2)

• Association between Salivary Caffeine concentration and IH outcomes

  One week post randomization and 40 weeks + 0 days PMA assessments.

• Determine whether caffeine effects on changes in inflammatory or MRI biomarkers from baseline to follow-up are mediated by caffeine-related reduced IH.

  Baseline to follow-up

Study Arms (2)

Extended Caffeine Treatment

EXPERIMENTAL

Infants in the extended caffeine treatment arm will, beginning the next day after stopping routine caffeine treatment, receive 5 mg/kg/day of caffeine base and increase to 5 mg/kg/twice-a-day (BID) of caffeine base beginning at 36 weeks + 0 days PMA and continuing the BID doses through 42 weeks + 6 days PMA.

Drug: Caffeine

Placebo

PLACEBO COMPARATOR

Infants in the placebo arm will, beginning the next day after stopping routine caffeine treatment, receive the equivalent (to study drug) volume of placebo daily and increase to the equivalent (to study drug) volume placebo BID through 42 weeks + 6 days PMA.

Drug: Placebos

Interventions

Caffeine DRUG

Infants will be started on oral caffeine base at 5 mg/kg/day. At 36 weeks + 0 days PMA drug dose will be increased to 5 mg/kg BID (total daily dose 10 mg/kg). Dose will be weight-adjusted weekly until NICU (neonatal intensive care unit) discharge. After discharge, all new doses will be calculated from the last weight recorded prior to discharge. The research pharmacy will prepare a bulk oral solution with active drug (caffeine base). While in the hospital, a daily 24-hour supply will be prepared and dispensed. For home administration of study drug, the research pharmacy at each clinical site will prepare and dispense a sufficient quantity of caffeine base solution for outpatient treatment up to 42 weeks + 6 days.

Extended Caffeine Treatment

Placebos DRUG

SyrSpend SF Unflavored will be used as the placebo for the control group infants. The volume of the placebo will match the volume of the study drug.

Placebo

Eligibility Criteria

• Age: 32 Weeks - 36 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female infants born preterm at ≤30 weeks + 6 days post menstrual age
• Current treatment with routine caffeine
• PMA 32 weeks + 0 days - 36 weeks + 6 days
• Anticipated last dose of routine caffeine will be by 36 weeks + 5 days
• At least 12 hours of breathing room air with no ventilatory support other than on room air nasal air flow therapy regardless of flow rate, or on room air and receiving nasal CPAP, and relapse not anticipated.
• Able to tolerate enteral medications
• It is feasible to administer the first dose of study drug no later than 36 weeks + 6 days PMA

You may not qualify if:

• Intraventricular hemorrhage Grade III-IV or cystic periventricular leukomalacia
• Current or prior treatment for seizures
• Current or prior treatment for cardiac arrhythmias
• Known renal or hepatic dysfunction that in the opinion of the investigator would have a clinically relevant impact on caffeine metabolism
• Major malformation, inborn error of metabolism, chromosomal abnormality
• Presence of a condition for which survival to discharge unlikely
• Social, mental health, logistical or other issues that, in the opinion of the investigator, would impact the ability of the family to complete the study

Sponsors & Collaborators

• Children's National Research Institute: lead
• Boston University: collaborator
• Beth Israel Medical Center: collaborator
• University of Massachusetts, Worcester: collaborator
• American SIDS Institute: collaborator
• Walter Reed National Military Medical Center: collaborator
• Dartmouth-Hitchcock Medical Center: collaborator
• Children's Hospital of Philadelphia: collaborator
• Johns Hopkins All Children's Hospital: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (15)

Loma Linda University Health System

Loma Linda, California, 92354, United States

Location

Children's National Medical Center/Children's Research Institute

Washington D.C., District of Columbia, 20010, United States

Location

AdventHealth Orlando

Orlando, Florida, 32803, United States

Location

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Kapiolani Medical Center

Honolulu, Hawaii, 96826, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

University of Massachusetss

Worcester, Massachusetts, 01605, United States

Location

University of Mississippi

Jackson, Mississippi, 39216, United States

Location

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014 Mar;168(3):250-7. doi: 10.1001/jamapediatrics.2013.4371.

  PMID: 24445955 RESULT

• Dobson NR, Rhein LM, Darnall RA, Corwin MJ, Heeren TC, Eichenwald E, James LP, McEntire BL, Hunt CE; Caffeine Study Group. Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age. J Perinatol. 2017 Oct;37(10):1135-1140. doi: 10.1038/jp.2017.82. Epub 2017 Jul 27.

  PMID: 28749480 RESULT

• Eichenwald E, Corwin M, McEntire B, Knoblach S, Limperopoulos C, Kapse K, Kerr S, Heeren TC, Ikponmwonba C, Hunt CE; ICAF Study Group. Intermittent hypoxia and caffeine in infants born preterm: the ICAF Randomized Clinical Trial. Arch Dis Child Fetal Neonatal Ed. 2025 Nov 24:fetalneonatal-2025-329230. doi: 10.1136/archdischild-2025-329230. Online ahead of print.

  PMID: 41285561 DERIVED

• Erickson G, McAnulty M, Powers C, Luong TL, Dobson NR, Hunt CE. Stability for 6 months and accuracy of a specific enteral caffeine base preparation for a multisite clinical trial. Br J Clin Pharmacol. 2023 Aug;89(8):2631-2635. doi: 10.1111/bcp.15739. Epub 2023 Apr 21.

  PMID: 37039338 DERIVED

MeSH Terms

Conditions

Premature Birth

Interventions

Caffeine

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Carl E. Hunt, M.D.

  Children's Reserach Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All clinical team personnel and all research staff (except research pharmacist) will remain blinded to study group until study completion.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, placebo-controlled, double-blinded clinical trial A site-stratified randomly-permuted blocked randomization design will be used to ensure balance at each site. Randomization will also be stratified into 2 birth gestational age categories of \<28 wks and 28 wks + 0 days to 30 wks + 6 days gestation to ensure balance. The randomization scheme will be developed by the DCC using specialized software, and clinical sites will be provided appropriate enrollment logs and randomization procedures from the research pharmacy.

Study Record Dates

• First Submitted: October 23, 2017
• First Posted: October 26, 2017
• Study Start: January 18, 2019
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: September 1, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Starting 6 months after publication
• Access Criteria: De-identified patient data will be made available to other investigators at their request providing written required IRB (institutional review board) approval in obtained.

Locations

US (15)