Theophylline for Hypoxic-Ischemic Encephalopathy

(TheoPHyLNNe Trial)

Overseen By Elizabeth Awe, BA

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Medical College of Wisconsin

Disqualifiers: Renal abnormalities, Brain abnormalities, Heart abnormalities, Lung abnormalities, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 48 hours

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether theophylline can protect infants with hypoxic-ischemic encephalopathy (HIE) from developing kidney problems. Researchers are testing two methods of administering theophylline: a single dose soon after birth or a series of doses over a day. The study seeks infants born after 35 weeks of pregnancy, weighing more than 1800 grams, and already receiving cooling therapy for HIE. The goal is to discover a new treatment to prevent kidney issues in these vulnerable infants. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works and measure its effectiveness in an initial group, offering a chance to contribute to significant medical advancements.

Do I need to stop my current medications for the trial?

The trial information does not specify whether participants need to stop taking their current medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that theophylline has been studied in babies with hypoxic-ischemic encephalopathy (HIE). One study found that when given to newborns with HIE who were also receiving cooling treatment, theophylline remained in their bodies longer than in other newborns. This finding suggests it might affect the dosage or frequency of administration.

A review of 119 patients revealed that a similar drug, aminophylline, did not significantly reduce the risk of early death or disability in individuals with sudden health problems. This indicates that while theophylline might not cause major immediate issues, further research is necessary to confirm its effectiveness in preventing serious outcomes.

Since this study is in its early stages, it aims to gather more safety information. Treatments in early-phase trials have usually undergone human testing before, but monitoring for safety and side effects remains crucial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for hypoxic-ischemic encephalopathy?

Researchers are excited about using theophylline for hypoxic-ischemic encephalopathy (HIE) because it offers a potentially quicker and more targeted approach to treating this condition. Unlike the traditional method of therapeutic hypothermia, which involves cooling the body to slow brain damage, theophylline is administered intravenously and works by blocking adenosine receptors to reduce brain injury. This approach could provide faster relief and be more accessible, especially in settings where cooling equipment is unavailable or impractical. Additionally, there are variations in dosing strategies, with single and repeat doses being tested, which might offer more flexible treatment options depending on the severity of the condition.

What evidence suggests that theophylline might be an effective treatment for hypoxic-ischemic encephalopathy?

Research has shown that theophylline, a drug that blocks certain signals in cells, might improve blood flow to the kidneys when oxygen is low, such as in hypoxic-ischemic encephalopathy (HIE). Studies on newborns with HIE suggest that theophylline could protect the kidneys by enhancing blood circulation. In this trial, participants may receive either a single dose or repeat doses of theophylline to assess its effectiveness. However, a review of two studies involving 119 patients found that aminophylline, a type of theophylline, did not significantly reduce the risk of early death or disability in this condition. This indicates that while theophylline has potential, further research is needed to confirm its effectiveness in preventing kidney injury in infants with HIE. ^{1 2 3 5 6}

Who Is on the Research Team?

Jeffrey Segar, MD

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

This trial is for newborns born at or after 35 weeks of gestation, weighing over 1800 grams, who can receive theophylline within 12 hours of birth and are starting hypothermia treatment for HIE within six hours. Infants with major organ abnormalities or those whose doctors don't agree to participate are excluded.

Inclusion Criteria

My baby started cooling treatment within 6 hours of birth for brain injury.

The baby was born at 35 weeks of pregnancy or later based on the best estimate of the due date.

I can receive theophylline intravenously within 12 hours of birth.

Exclusion Criteria

I was unable to give consent within 12 hours of birth.

My infant has a significant condition affecting the kidneys, urinary tract, brain, heart, or lungs.

Attending physician unwilling to have infant participate in the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Single or repeat doses of theophylline or aminophylline administered within 18 hours after birth

48 hours

Continuous monitoring during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Data Collection and Analysis

Collection and analysis of biospecimens and data to evaluate pharmacokinetic and safety profiles

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Theophylline

Trial Overview The study tests whether giving theophylline soon after birth can prevent kidney damage in infants with hypoxic ischemic encephalopathy undergoing hypothermia treatment. It compares repeated doses versus a single dose to lay groundwork for future larger trials.

How Is the Trial Designed?

Group I: Single Dose Theophylline Experimental Treatment 1 Intervention

Single dose of theophylline or aminophylline (5mg/kg IV) given within 18 hours after birth

Group II: Repeat Dose Theophylline Experimental Treatment 1 Intervention

Loading dose of theophylline or aminophylline (5mg/kg IV) given within 18 hours of birth, with two subsequent doses (1.2 mg/kg IV) given at 12 and 24 hours after the loading dose

Group III: Standard treatment Active Control 1 Intervention

Infants cared for according to standard practice.

Theophylline is already approved in United States, European Union for the following indications:

Approved in United States as Theophylline for:

• Asthma
• Bronchitis
• Emphysema
• Apnea of Prematurity

Approved in European Union as Theophylline for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

University of Oklahoma

Collaborator

Trials

484

Recruited

95,900+

Published Research Related to This Trial

Aminophylline appears to protect against cerebral injury during cardiopulmonary bypass (CPB) in infants, as evidenced by lower levels of S-100 beta protein and NSE, which are markers of brain damage, compared to a control group.

The study, involving 40 infants undergoing surgery for ventricular septal defect, suggests that aminophylline helps modulate the inflammatory response during CPB by reducing pro-inflammatory factors like TNF-alpha and IL-8 while increasing the anti-inflammatory factor IL-10.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Protective effect of aminophylline on cerebral injury during cardiopulmonary bypass in infants]. Pan, S., Lin, G., Jiang, H., et al.[2014]

Theophylline, an adenosine receptor antagonist, worsened hippocampal injury and impaired learning in the Morris water maze (MWM) tests in rats after both normoglycemic and hyperglycemic ischemia, indicating potential safety concerns when using this drug in such conditions.

In contrast, ZM 241385 showed protective effects against hippocampal injury and improved MWM performance in hyperglycemic ischemia, suggesting it may be a more effective treatment option for mitigating ischemic damage in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hippocampal injury and neurobehavioral deficits following hyperglycemic cerebral ischemia: effect of theophylline and ZM 241385. Higashi, H., Meno, JR., Marwaha, AS., et al.[2013]

A review of two trials involving 119 patients found that aminophylline did not significantly reduce early death or disability in individuals with acute ischaemic stroke compared to placebo.

The evidence is insufficient to determine the safety or efficacy of theophylline and its analogues in treating acute ischaemic stroke, indicating a need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke. Mohiuddin, AA., Bath, FJ., Bath, PM.[2018]

Allopurinol, an xanthine oxidase inhibitor, shows promise for neuroprotection in neonates with hypoxic-ischemic encephalopathy (HIE), with pharmacokinetics established in a study involving 46 neonates.

The dosing regimen used in the ALBINO trial effectively achieves targeted inhibition of xanthine oxidase, regardless of whether the neonates are undergoing therapeutic hypothermia, indicating its potential efficacy in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates. Chu, WY., Annink, KV., Nijstad, AL., et al.[2022]

In a study involving six healthy adult volunteers, four sustained-release formulations of theophylline were compared, revealing that Theo-Dur had a slower absorption rate and lower peak concentration compared to Nuelin SA, Phyllocontin, and Slo-phyllin after a single dose.

At steady-state dosing, Phyllocontin showed greater fluctuations in theophylline concentration compared to Theo-Dur, indicating that while all formulations had complete systemic availability, their pharmacokinetic profiles differ significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The rise and fall of serum theophylline concentration: a comparison of sustained-release formulations in volunteers with rapid theophylline clearance. Mucklow, JC., Kuhn, S.[2019]

In a study involving 59 children with chronic asthma, two theophylline preparations were compared, revealing that Uniphyllin (UP) resulted in significantly higher blood levels of theophylline and morning peak flow rates compared to Slophyllin (SP).

While UP may be beneficial for managing early morning asthma symptoms, it was associated with a higher frequency of severe side effects, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once or twice daily theophylline in childhood asthma. Barry, W., Loftus, BG., Price, JF.[2019]

Theophylline shows promise as a renal-protective therapy for neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia, with a significant pharmacokinetic analysis conducted on 22 neonates.

The study found that theophylline clearance is low in this population, with a median half-life of 39.5 hours, suggesting that dosing strategies must be adjusted to meet the unique needs of these neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Frymoyer, A., Van Meurs, KP., Drover, DR., et al.[2021]

Theophylline, a nonselective adenosine receptor antagonist, significantly reduced brain damage in 7-day-old rats by up to 48% when administered before hypoxia-ischemia, indicating its potential efficacy in protecting the brain during such injuries.

A2A-selective antagonist SCH 58261 also showed a reduction in brain injury by 19% when given post-treatment, while the A1-selective antagonist DPCPX had no effect, suggesting that targeting specific adenosine receptors can influence outcomes in neonatal brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. Bona, E., Adén, U., Gilland, E., et al.[2022]

A study of 82 premature neonates using NONMEM revealed that theophylline clearance is influenced by body weight and postnatal age, with specific population pharmacokinetic models developed for this group.

The study provided validated maintenance dosage recommendations for theophylline in infants aged 2 to 50 days and weighing between 700 to 2000 g, ensuring safer and more effective treatment for apnoea of prematurity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea. Lee, TC., Charles, BG., Steer, PA., et al.[2019]

Theophylline, once widely used, has been associated with significant adverse effects, particularly in children, leading to a decline in its use and a shift towards homeopathic dosing that proved ineffective.

Recent trends show that most serious cases of theophylline toxicity are now due to intentional overdoses, often in suicide attempts, and treatment focuses on managing fluid and electrolyte balance while employing methods to remove the drug from the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theophylline toxicity. Ellis, EF.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7704857/

Theophylline Dosing and Pharmacokinetics for Renal ... In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05853601

Theophylline Prophylaxis During Hypothermia to Limit ... Acute kidney injury is a significant complication for infants who experience hypoxic ischemic encephalopathy, being associated with increased rates of death ...

3. withpower.com withpower.com/trial/phase-2-acute-kidney-injury-5-2023-3e5c3

Theophylline for Hypoxic-Ischemic Encephalopathy A review of two trials involving 119 patients found that aminophylline did not significantly reduce early death or disability in individuals with acute ...

4. trialx.com trialx.com/clinical-trials/listings/219731/theophylline-prophylaxis-during-hypothermia-to-limit-neonatal-nephron-damage/

Theophylline Prophylaxis During Hypothermia to Limit ... ... hypoxic ischemic encephalopathy, being associated with increased rates of death and prolonged hospitalization. This pilot study of theophylline ...

5. researchgate.net researchgate.net/publication/344241555_Theophylline_dosing_and_pharmacokinetics_for_renal_protection_in_neonates_with_hypoxic-ischemic_encephalopathy_undergoing_therapeutic_hypothermia

(PDF) Theophylline dosing and pharmacokinetics for renal ... Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia–ischemia and may offer ...

6. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/539656

Theophylline Prophylaxis During Hypothermia to Limit ... Acute kidney injury is a significant complication for infants who experience hypoxic ischemic encephalopathy, being associated with increased rates of death ...