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Acute Kidney InjuryPhase 1NCT05295784

PK and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

A Phase 1 study testing Caffeine citrate in people with Acute Kidney Injury and Hypoxic-Ischemic Encephalopathy, run by University of Arkansas at 2 sites in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

A phase 1 study investigating the tolerability and pharmacokinetics of caffeine citrate in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns. Read more about this study

Who is it for?
Ages 0 to 24 hours
What is being tested?
Caffeine citrate
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
2 sitesUnited States
Study dates
8 May 2024to 8 May 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 0 to 24 hours
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Newborns ≥ 35 weeks GA
  • Admitted to the ACH NICU less than 24 hours of life
  • Receiving active or passive TH or whole-body cooling at 12 hours of life to treat hypoxic ischemic encephalopathy per institutional criteria based on National Institute of Child Health and Human Development criteria

Who cannot join

  • Genetic or congenital condition that affects renal function (e.g., congenital anomalies of the kidney and urinary tract (CAKUT), complex congenital heart disease)
  • Diminished capacity or autonomy of the neonate's parents that prevents their ability to give informed consent
  • Theophylline, aminophylline, or caffeine exposure prior to enrollment
  • Status epilepticus as defined by:
  • A seizure lasting longer than 30 minutes
  • Use of a continuous infusion of antiepileptic medication (i.e., midazolam)
  • The use of 3 or more antiepileptic medications for the indications of intractable seizures

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • Arkansas Children's Hospital

    Little Rock, Arkansas, 72202

  • University of Arkansas for Medical Sciences

    Little Rock, Arkansas, 72205

Other trials in United States

About this study

Official title: Pharmacokinetics (PK) and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

A phase 1 study investigating the tolerability and pharmacokinetics of caffeine citrate in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns.

Read the detailed description

Neonatal acute kidney injury (AKI) is an unfortunate comorbidity in neonates with hypoxic ischemic encephalopathy (HIE) which is brain injury due to a lack of blood flow and oxygen delivery to a neonate around the time of delivery. Neonatal AKI increases the risk of death by 4 fold. AKI in neonates with HIE is associated with brain injury on brain MRI and worse neurodevelopmental outcomes at 2 years. Despite the increases in death and morbidity associated with AKI, limited therapeutic interventions currently exist.

Caffeine is a promising medication for kidney protection in neonates at high risk for AKI. Three retrospective studies in premature neonates identified a reduction in AKI in neonates exposed to caffeine. Theophylline, which is in the same drug class as caffeine, has been shown to improve urine output and decrease AKI in neonates with HIE. Limited centers worldwide utilize theophylline in neonates with HIE due to its side effects. Caffeine is a well-tolerated and is extensively utilized in neonatal intensive care units (NICUs) in the premature population for prevention of chronic lung disease and for apnea of prematurity (or immature breathing patterns). Therefore, dosing guidelines are well established for preterm neonates and neonatologists are comfortable administering the drug.

Specific Aim 1: Determine the pharmacokinetics (how an organism affects a drug) of caffeine in neonates ≥ 35 weeks GA with HIE receiving therapeutic hypothermia.

Specific Aim 2: Assess the preliminary safety and tolerability of caffeine in neonates with HIE receiving hypothermia including any impact on seizure burden.

Specific Aim 1: Characterize acute kidney injury (AKI) in neonates with HIE receiving therapeutic hypothermia with caffeine exposure using serum creatinine (SCr), urine output, renal near infrared spectroscopy (NIRS), and urinary biomarkers.

General Experimental Approach:

A total of 18 neonates will be enrolled over approximately 18 months. Each neonate will receive a single dose of caffeine in the first 24 hours of life. The first six neonates will receive low dose (5 mg/kg), the next six neonates will receive a medium dose (15 mg/kg), and the next six neonates will receive high dose or (25 mg/kg).

Demographic data (birthdate, sex, ethnicity, race, gestational age) and clinical data (perinatal birth history, other diagnosis) will be collected from the electronic medical record input into a secure REDCap database created uniquely for this study. Laboratory (serum creatinine) and imaging (head ultrasound and brain MRIs) results will also be recorded.

Blood samples will be obtained from the newborns to monitor the caffeine blood levels. Urine samples will be analyzed for biomarkers that detect kidney damage. Data on seizures and medications will be monitored closely. Blood flow and oxygen levels in the kidney will be monitored with a non-invasive technology called near infrared spectroscopy or NIRS. Data will be collected on urine output and blood creatinine levels to determine which newborns have acute kidney injury.

In conclusion, this study will investigate the drug levels in the blood of caffeine in neonates with HIE receiving therapeutic hypothermia. Safety will also be monitored obtained. The investigators anticipate caffeine is a safe and effective therapy. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns.

Being tested
Caffeine citrate
Medical subject headings
Acute Kidney Injury, Hypoxia-Ischemia, Brain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Caffeine citrateDrug

    Also called Cafcit

    A single dose of intravenous caffeine citrate will be administered to neonates with hypoxic ischemic encephalopathy to determine the pharmacokinetics and tolerability.

Study groups in NCT05295784
Study groupRoleWhat they receive
Arm 1: Low dose caffeineActive comparatorEach neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 1 neonates will receive low dose intravenous caffeine citrate (5 mg/kg).
Receives: Drug: Caffeine citrate
Arm 2: Medium dose caffeineActive comparatorEach neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 2 neonates will receive medium dose intravenous caffeine citrate (15 mg/kg).
Receives: Drug: Caffeine citrate
Arm 3: High dose caffeineActive comparatorEach neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 3 neonates will receive high dose intravenous caffeine citrate (25 mg/kg).
Receives: Drug: Caffeine citrate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clearance of caffeine

    Clearance (mL h-1 kg-1)

    Measured: 1 week

  2. Volume of distribution of caffeine

    Volume of distribution (ml/kg)

    Measured: 1 week

  3. Peak plasma concentration (Cmax) of caffeine

    Peak plasma concentration (Cmax) (ng/mL)

    Measured: 1 week

  4. Area under the plasma concentration-time curve of caffeine

    Area under the plasma concentration-time curve from 0 to infinity (AUC0-INF) (mg*h/L)

    Measured: 1 week

  5. Seizure incidence

    Number of neonates who developed seizures based on continuous video electroencephalogram (VEEG) data

    Measured: 2 weeks

  6. Seizure burden

    Electrographic seizures (in minutes per hour) based on continuous video electroencephalogram (VEEG) data

    Measured: 2 weeks

Secondary outcomes (5)
  1. Acute kidney injury

    AKI incidence utilizing KDIGO criteria based on urine output and SCr.

    Measured: 10 days

  2. Renal near infrared spectroscopy (NIRS)

    Investigate changes in renal NIRS values during the therapeutic hypothermia and rewarming period.

    Measured: 5 days

  3. Urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL)

    Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for NGAL.

    Measured: 3 days

  4. Urine kidney injury molecule-1 (KIM-1) (pg/mL)

    Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for KIM-1.

    Measured: 3 days

  5. Urine interleukin-18 (IL-18) (pg/mL)

    Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for IL-18.

    Measured: 3 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Mar 2022
  2. Study start8 May 2024
  3. Primary completion8 May 2024
  4. Study completion8 May 2024

Why it stopped: Data no longer support this study

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
Each neonate will receive a single dose of caffeine citrate in the first 24 hours of life. The first six neonates will receive low dose (5 mg/kg), the next six neonates will receive a medium dose (15 mg/kg), and the next six neonates will receive high dose or (25 mg/kg).
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05295784
Sponsor's protocol ID
260845
Status last verified
Apr 2024
First submitted
21 Feb 2022
Last updated
10 May 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Rumpel J, Spray BJ, Chock VY, Kirkley MJ, Slagle CL, Frymoyer A, Cho SH, Gist KM, Blaszak R, Poindexter B, Courtney SE. Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia. J Pediatr. 2022 Feb;241:133-140.e3. doi: 10.1016/j.jpeds.2021.08.090. Epub 2021 Sep 20.

    PubMed 34547334
  • Selewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr. 2013 Apr;162(4):725-729.e1. doi: 10.1016/j.jpeds.2012.10.002. Epub 2012 Nov 10.

    PubMed 23149172
  • Kirkley MJ, Boohaker L, Griffin R, Soranno DE, Gien J, Askenazi D, Gist KM; Neonatal Kidney Collaborative (NKC). Acute kidney injury in neonatal encephalopathy: an evaluation of the AWAKEN database. Pediatr Nephrol. 2019 Jan;34(1):169-176. doi: 10.1007/s00467-018-4068-2. Epub 2018 Aug 28.

    PubMed 30155763
  • Jetton JG, Boohaker LJ, Sethi SK, Wazir S, Rohatgi S, Soranno DE, Chishti AS, Woroniecki R, Mammen C, Swanson JR, Sridhar S, Wong CS, Kupferman JC, Griffin RL, Askenazi DJ; Neonatal Kidney Collaborative (NKC). Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc Health. 2017 Nov;1(3):184-194. doi: 10.1016/S2352-4642(17)30069-X.

    PubMed 29732396
  • Cavallin F, Rubin G, Vidal E, Cainelli E, Bonadies L, Suppiej A, Trevisanuto D. Prognostic role of acute kidney injury on long-term outcome in infants with hypoxic-ischemic encephalopathy. Pediatr Nephrol. 2020 Mar;35(3):477-483. doi: 10.1007/s00467-019-04406-4. Epub 2019 Dec 11.

    PubMed 31828471
  • Bhatt GC, Gogia P, Bitzan M, Das RR. Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review. Arch Dis Child. 2019 Jul;104(7):670-679. doi: 10.1136/archdischild-2018-315805. Epub 2019 Feb 23.

    PubMed 30798259
  • Chock VY, Cho SH, Frymoyer A. Aminophylline for renal protection in neonatal hypoxic-ischemic encephalopathy in the era of therapeutic hypothermia. Pediatr Res. 2021 Mar;89(4):974-980. doi: 10.1038/s41390-020-0999-y. Epub 2020 Jun 5.

    PubMed 32503030
  • Harer MW, Askenazi DJ, Boohaker LJ, Carmody JB, Griffin RL, Guillet R, Selewski DT, Swanson JR, Charlton JR; Neonatal Kidney Collaborative (NKC). Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates: Results From the AWAKEN Study. JAMA Pediatr. 2018 Jun 4;172(6):e180322. doi: 10.1001/jamapediatrics.2018.0322. Epub 2018 Jun 4.

    PubMed 29610830
  • Aviles-Otero N, Kumar R, Khalsa DD, Green G, Carmody JB. Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation. Pediatr Nephrol. 2019 Apr;34(4):729-736. doi: 10.1007/s00467-018-4140-y. Epub 2018 Nov 10.

    PubMed 30415418
  • Carmody JB, Harer MW, Denotti AR, Swanson JR, Charlton JR. Caffeine Exposure and Risk of Acute Kidney Injury in a Retrospective Cohort of Very Low Birth Weight Neonates. J Pediatr. 2016 May;172:63-68.e1. doi: 10.1016/j.jpeds.2016.01.051. Epub 2016 Feb 18.

    PubMed 26898806
  • AlGadeeb K, Qaraqei M, Algadeeb R, Faqeehi H, Al-Matary A. Prediction of risk factors and outcomes of neonatal acute kidney injury. J Nephrol. 2021 Oct;34(5):1659-1668. doi: 10.1007/s40620-021-01130-x. Epub 2021 Sep 1.

    PubMed 34468977
  • Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, Herring A, Laughon MM, Carlton D, Hunt CE. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr. 2014 May;164(5):992-998.e3. doi: 10.1016/j.jpeds.2013.12.025. Epub 2014 Jan 23.

    PubMed 24461786
  • Lee TC, Charles B, Steer P, Flenady V, Shearman A. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther. 1997 Jun;61(6):628-40. doi: 10.1016/S0009-9236(97)90097-7.

    PubMed 9209245
  • Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit. 2008 Dec;30(6):709-16. doi: 10.1097/FTD.0b013e3181898b6f.

    PubMed 19057373
  • Falcao AC, Fernandez de Gatta MM, Delgado Iribarnegaray MF, Santos Buelga D, Garcia MJ, Dominguez-Gil A, Lanao JM. Population pharmacokinetics of caffeine in premature neonates. Eur J Clin Pharmacol. 1997;52(3):211-7. doi: 10.1007/s002280050276.

    PubMed 9218928

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Caffeine citrate in people with Acute Kidney Injury and Hypoxic-Ischemic Encephalopathy, run by University of Arkansas at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 10 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clearance of caffeine (time frame: 1 week). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05295784, which also lists 33 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2024.

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