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

Trial Summary

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.

What data supports the effectiveness of the drug theophylline for hypoxic-ischemic encephalopathy?

Research suggests that theophylline, a drug that blocks certain receptors in the brain, can improve blood flow in cases of low oxygen and blood supply, potentially benefiting newborns with hypoxic-ischemic encephalopathy. Additionally, studies in animals have shown that theophylline can reduce brain damage when given before a lack of oxygen occurs. ^{1 2 3 4 5}

Is theophylline generally safe for humans?

Theophylline has been associated with side effects, particularly in children, and can cause serious toxicity if overdosed. It affects the gastrointestinal, nervous, cardiovascular, and urinary systems, and can lead to significant metabolic issues in severe cases. ^{1 2 6 7 8}

How is the drug theophylline unique in treating hypoxic-ischemic encephalopathy?

Theophylline is unique because it acts as a non-selective adenosine receptor antagonist, which can improve blood flow to the kidneys and potentially reduce brain damage in neonates with hypoxic-ischemic encephalopathy. This mechanism is different from other treatments like allopurinol, which targets a different enzyme for neuroprotection. ^{1 2 4 9 10}

What is the purpose of this trial?

Acute kidney injury is a significant complication for infants who experience hypoxic ischemic encephalopathy, being associated with increased rates of death and prolonged hospitalization. This pilot study of theophylline administration soon after birth for the prevention of kidney injury will lay the foundation for the conduct of a larger clinical trial that seeks to identify a theophylline as a novel therapy to prevent kidney injury in thousands of at-risk infants.

Research Team

Jeffrey Segar, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[Protective effect of aminophylline on cerebral injury during cardiopulmonary bypass in infants]. [2014]

6. England pubmed.ncbi.nlm.nih.gov

Once or twice daily theophylline in childhood asthma. [2019]

7. England 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. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Theophylline toxicity. [2019]

9. Switzerland 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Hippocampal injury and neurobehavioral deficits following hyperglycemic cerebral ischemia: effect of theophylline and ZM 241385. [2013]