Improving Preterm Kidney Outcomes With Caffeine

Optimizing Caffeine Therapy for Hypoxia in Preterm Neonates: A Randomized Trial Assessing Efficacy, Acute Kidney and Brain Injury, Safety, and Pharmacokinetics

This study is being done to see if additional caffeine citrate (20 milligrams per kilogram IV bolus) helps babies with low kidney oxygenation already being treated with caffeine citrate (20 milligrams per kilogram IV bolus on day of life (DOL) 1 followed by 8 milligrams per kilogram daily maintenance). The investigators hypothesize that additional caffeine will improve kidney oxygen levels, while not causing any brain injury, and may reduce rates of acute kidney injury compared to placebo. This study will take place in preterm babies born less than 30 weeks gestational age, with the intervention occurring between greater than 48 hours of age until DOL 14 and outcomes tracked until neonatal intensive care unit (NICU) discharge.

Study Overview

• Status: Recruiting
• Conditions: Kidney Injury; Pre-Term
• Intervention / Treatment: Drug: Caffeine citrate; Drug: Placebo

Detailed Description

The study population will consist of 114 preterm neonates born less than 30 weeks gestational age who have an intravenous (IV) line for which IV medications can be administered and who can have brain and kidney Near Infrared Spectroscopy (NIRS) monitoring.

Eligible participants will be enrolled between 12-96 hours of life after preterm birth and admission to the Meriter NICU. Baseline data will be collected and NIRS monitoring will be started when appropriate as determined by the team based on clinical guidelines and standard of care.

Those participants having kidney oxygenation less than 50 percent (and troubleshooting procedures have occurred and while ensuring brain oxygenation is not below 55 percent) after 48 hours and within the first 14 DOL will be randomized in a 1:1 manner to one of two treatment arms (Arm 1 and Arm 2).

• Arm 1: IV caffeine citrate (20 mg/kg) (n = 51)
• Arm 2: Placebo - same volume of 0.9% Sodium Chloride United States Pharmacopeia (USP) (n=51)

Those participants who do not develop kidney hypoxia during the first 14 DOL will be the normal kidney oxygenation control group and receive no intervention (Arm 3).

• Arm 3: Normal Kidney oxygenation (no intervention) (Approximately n = 12)

Participant accrual will occur over 48 months. Participants will complete all study specific activities during the NICU hospitalization over the course of the first 28 DOL and clinical outcomes will be collected through NICU discharge or 6 months of age, whichever occurs first. Each participant will contribute blood specimens for creatinine and caffeine levels as well as approximately 20-40 urine samples for biomarker analysis.

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Elena Alfaro, CCRP; Phone Number: (608) 890-0584; Email: elalfaro@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • UW Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Gestational age at birth between 23 0/7 and 29 6/7 weeks.
• Able to have near-infrared spectroscopy (NIRS) monitoring of cerebral and kidney oxygenation.
• Able to receive IV medications.
• Indwelling umbilical arterial catheter (UAC), umbilical venous catheter (UVC), peripheral arterial line (PAL), or peripherally inserted central catheter (PICC) already in place that can draw blood.
• Receiving caffeine at the time of enrollment
• Have a birth parent who is at least 18 years old and have a parent or guardian who is able to provide parental permission in English or Spanish

Exclusion Criteria:

• Known or suspected major congenital anomaly of the brain, heart, lungs or kidney (excluding UTD A1 pyelectasis).
• Known or suspected chromosomal or genetic anomaly.
• Not suitable for study participation due to other reasons at the discretion of the investigators.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm 2: Placebo	Drug: Placebo; same volume of 0.9 percent Sodium Chloride United States Pharmacopeia (USP); Other Names: saline
Experimental: Arm 1: Caffeine	Drug: Caffeine citrate; intravenous (IV) caffeine citrate (20 milligrams per kilogram) followed by 8 milligrams per kilogram daily maintenance
No Intervention: Arm 3: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants with Improvement in Kidney Oxygenation	In the 3 hours after receiving the intervention or placebo, participants have kidney oxygenation monitored. Improvement in oxygenation is defined as having 30 minutes where at least 90 percent of measured values are at least 50 percent.	Up to 3 hours post-intervention (Between days 1 and 17)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Days of Acute Kidney Injury (AKI)	AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) foundation. Outcome is measured for the 14 days after intervention.	14 days after intervention
Proportion of Participants with a Sustained Decrease in Cerebral Oxygenation	In the 3 hours after receiving the intervention or placebo, participants have cerebral oxygenation monitored. A sustained decrease in cerebral oxygenation is defined as less than 60 percent oxygenation for at least 60 minutes.	up to 3 hours post-intervention (Between days 1 and 17)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Urinary Biomarker Concentrations		baseline, day 17
Rates of Brain Injury	Rates of Brain injury (Periventricular Leukomalacia (PVL) or Interventricular hemorrhage (IVH) on term corrected brain imaging prior to discharge in participants receiving additional caffeine compared to those receiving placebo.	up to 6 months
Rates of Abnormal General Movement Assessment (GMA)	Rates of abnormal GMA prior to discharge in participants receiving additional caffeine compared to those receiving placebo.	up to 6 months

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Matthew W Harer, MD, UW School of Medicine and Public Health

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2026
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: November 21, 2025
• First Posted (Actual): December 3, 2025

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: acute kidney injury; caffeine
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Renal Insufficiency; Premature Birth; Acute Kidney Injury; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Sodium Chloride; caffeine citrate
• Other Study ID Numbers: 2025-1079; SMPH\PEDIATRICS\NEONATO (Other Identifier: UW Madison); 1R01HD116793-01 (U.S. NIH Grant/Contract); Protocol Version 3/8/2026 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will submit data to the National Institute of Child Health and Human Development (NICHD) Data and Specimen Hub (DASH). NICHD DASH is a NICHD-funded controlled access data repository established to facilitate data sharing and access to biospecimens for all NICHD clinical research. This study will produce four data types: Clinical data, Urine proteomic biomarker, PK/PD data, and near infrared spectroscopy (NIRS) oxygenation data. The final clinical dataset will include demographic data and study-related tests obtained from the electronic medical record. The urine proteomic data will contain output from the biological urine samples from each research subject. The PK/PD data will contain caffeine serum concentration and renal oxygenation data at various timepoints, dose levels, and selected demographic and clinical data. The NIRS oxygenation dataset will include every 1 second kidney and cerebral oxygenation percentage generated/obtained from INVOS Medtronic NIRS 7100 devices.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No