Caffeine for Newborn Brain Injury

Overseen By Wesley Jackson, MD

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Anti-epileptic drugs

Disqualifiers: Congenital anomaly, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: Up to 72 hours

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how caffeine can aid newborns with hypoxic-ischemic encephalopathy (HIE), a brain injury that occurs when a baby's brain lacks oxygen. Researchers are testing two different caffeine doses to determine their safety and effectiveness alongside cooling therapy, which already treats HIE. Babies born at or after 36 weeks, less than 24 hours old, and undergoing cooling therapy for HIE might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on more than one anti-seizure medication.

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

Research has shown that caffeine citrate is usually safe for infants. One study found that caffeine reduced the risk of cerebral palsy in premature babies compared to those who did not receive it, suggesting it might help protect the brain. Another study found that caffeine improved brain development in preterm infants with a common breathing issue. These findings support the idea that caffeine is likely safe for newborns. However, since this trial is in an early stage, it primarily focuses on assessing safety. Caffeine remains a common and well-studied treatment for infants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Most treatments for newborn brain injury focus on managing symptoms and supportive care, rather than directly targeting the brain injury itself. Unlike these standard approaches, caffeine is being explored because it could help protect the brain and improve outcomes by enhancing alertness and stimulating breathing in newborns. Researchers are excited about caffeine's potential because it is already widely used in neonatal care for other purposes, like treating apnea of prematurity, and it could offer a new way to directly address brain injury in newborns. The trial is investigating different dosages to find the optimal amount for achieving the best results, which could lead to a straightforward, cost-effective treatment option.

What evidence suggests that caffeine might be an effective treatment for newborn brain injury?

Research has shown that caffeine might help protect newborns' brains after experiencing hypoxic-ischemic encephalopathy (HIE), a condition caused by a lack of oxygen. Caffeine is already used safely in premature babies to address breathing issues and is associated with improved brain development. In one study of 566 premature infants, caffeine reduced the need for high oxygen levels. Although caffeine is commonly used and considered safe, its specific effects on newborn brain injury from oxygen loss remain under investigation. In this trial, participants will receive either a lower loading dose (20 mg/kg) or a higher loading dose (30 mg/kg) of caffeine citrate. Early results suggest caffeine might offer brain protection in these situations. ^{1 4 5 6 7}

Who Is on the Research Team?

Wesley Jackson, MD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for newborns born at or after 36 weeks of pregnancy with brain injuries due to lack of oxygen (HIE) who are being treated with therapeutic cooling. They must be less than 24 hours old and have IV access. Babies with very fast heart rates, major birth defects, or on multiple seizure medications cannot join.

Inclusion Criteria

I was born at or after 36 weeks of pregnancy.

Intravenous (IV) access

I am undergoing cooling treatment for brain injury due to lack of oxygen.

Exclusion Criteria

Sustained (>4 hours) heart rate > 180 beats per minute

Known major congenital anomaly

I am taking more than one medication for seizures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a loading dose of caffeine citrate (20 mg/kg or 30 mg/kg) within 24 hours after delivery

Up to 72 hours

7 samples collected

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRI assessments and adverse event monitoring

7 days following the final dose

Long-term follow-up

Participants are assessed for neurodevelopmental outcomes and adverse events

18-24 months

What Are the Treatments Tested in This Trial?

Interventions

• Caffeine

Trial Overview The study tests two different doses of caffeine citrate (20 mg/kg and 30 mg/kg) in these babies to find the best dose and check for safety. It's an early-phase trial where all participants receive the drug openly without a comparison group.

How Is the Trial Designed?

Group I: Lower loading dose (20 mg/kg) Active Control 1 Intervention

Within 24 hours after delivery, participants will receive a loading dose of 20 mg/kg caffeine citrate IV.

Group II: Higher loading dose (30 mg/kg) Active Control 1 Intervention

Within 24 hours after delivery, participants will receive a loading dose of 30 mg/kg caffeine citrate IV.

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

Approved in United States as Caffeine for:

• Restoring mental alertness or wakefulness during fatigue or drowsiness
• Short-term treatment of neonatal apnea (breathing problems)
• Headache and migraine relief
• Weight loss

Approved in Canada as Caffeine for:

• Restoring mental alertness or wakefulness during fatigue or drowsiness
• Short-term treatment of neonatal apnea (breathing problems)
• Headache and migraine relief

Approved in European Union as Caffeine for:

• Restoring mental alertness or wakefulness during fatigue or drowsiness
• Short-term treatment of neonatal apnea (breathing problems)
• Headache and migraine relief

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

CGRP receptor monoclonal antibodies (CGRP/rec mAbs) have been shown to be significantly more effective than placebo in reducing migraine frequency, with responder rates of 21.4% for episodic migraine and 17.4% for chronic migraine, based on several randomized controlled trials involving thousands of patients.

These treatments have a favorable safety profile, with adverse effects similar to placebo, and they provide long-lasting relief, starting to take effect within a week and potentially lasting for months after treatment ends.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention. Schoenen, J., Manise, M., Nonis, R., et al.[2021]

In a randomized, double-blind, placebo-controlled study involving 113 elderly patients with painful osteoarthritis, the combination of tramadol 37.5 mg and acetaminophen 325 mg significantly reduced average daily pain intensity and improved pain relief compared to placebo over a 10-day period.

The tramadol/APAP combination was well tolerated, with common side effects like nausea and dizziness occurring at rates similar to those in the overall study population, indicating a favorable safety profile for managing osteoarthritis flare-ups in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. Rosenthal, NR., Silverfield, JC., Wu, SC., et al.[2019]

CGRP antagonists are a promising new class of medications for migraine prevention, with three already approved for use and four others in advanced clinical trials, showing positive efficacy and safety results.

Current preventive migraine treatments often have variable effectiveness and side effects, highlighting the potential of CGRP antagonists to provide a more effective and tolerable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Calcitonin Gene-Related Peptide (CGRP) Antagonists and Their Use in Migraines. Henson, B., Hollingsworth, H., Nevois, E., et al.[2020]

In a study of 57 malaria patients, the combination of Artemisinin-Based Combination Therapies (ACTs) with paracetamol significantly altered 24 out of 37 evaluated toxicity markers, indicating potential safety concerns with this treatment regimen.

The findings suggest that careful selection of ACTs plus paracetamol is crucial, especially for patients with existing health conditions, due to the observed changes in various biochemical and haematological indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicological effect of Artemisinin-Based Combination Therapies plus Paracetamol in malaria patients. Aghahowa, SE., Ozolua, RI., Bafor, EE., et al.[2023]

In a multi-center randomized controlled trial involving migraine patients, the combination of paracetamol (1,000 mg) and caffeine (130 mg) was found to be as effective as sumatriptan (50 mg) in relieving migraine pain.

Both treatments showed similar tolerability, with no significant differences in adverse events reported, confirming that the combination of paracetamol and caffeine is a safe alternative for migraine relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of migraine attack: a randomized, double-blind, double-dummy, cross-over study. Pini, LA., Guerzoni, S., Cainazzo, M., et al.[2021]

The 22nd French pharmacovigilance meeting revealed 315 notifications of severe adverse effects linked to non-specific 'immunostimulants', with 68% of cases considered likely attributable to the drugs, including three fatalities.

The meeting highlighted that many adverse effects, both known and rare, continue to occur with various medications, emphasizing the need for better documentation and monitoring of drug safety, as well as the potential for immediate market withdrawal of drugs with poor risk-benefit ratios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highlights of the 22nd French pharmacovigilance meeting. [2007]

The combination of paracetamol (1,000 mg) and caffeine (130 mg) (PCF) was found to be well-tolerated and effective for treating tension-type headache (TTH) in an Italian population, based on a multicenter, randomized, double-blind, placebo-controlled trial.

Both PCF and naproxen sodium (550 mg) showed significant efficacy compared to placebo, but there was no significant difference in effectiveness between PCF and naproxen, indicating that PCF is a viable alternative for acute TTH treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium. Pini, LA., Del Bene, E., Zanchin, G., et al.[2018]

Anti-CGRP monoclonal antibodies have shown good effectiveness and tolerability in preventing migraines, confirming their role as a viable treatment option.

When considering cost-effectiveness, it is important to prescribe anti-CGRP mAbs based on negotiated prices while ensuring that patients receive effective treatment without overburdening the national healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-CGRP monoclonal antibodies for the preventive treatment of migraine: a cost-effectiveness analysis in the Italian scenario.] Zovi, A., Vitiello, A., Langella, R., et al.[2023]

In a study of 61 migraine patients, discontinuing CGRP(-receptor) monoclonal antibody treatment led to a significant increase in headache impact and a decline in health-related quality of life (HRQoL) over three months, indicating that stopping treatment can negatively affect patients' well-being.

The decline in HRQoL was clinically meaningful, with significant changes observed in headache impact and both physical and mental health scores within the first month after discontinuation, suggesting that careful monitoring is essential when considering treatment resumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deterioration of headache impact and health-related quality of life in migraine patients after cessation of preventive treatment with CGRP(-receptor) antibodies. Terhart, M., Mecklenburg, J., Neeb, L., et al.[2022]

A multicenter, double-blind, placebo-controlled trial was conducted to evaluate the effectiveness and safety of combining ibuprofen with caffeine for treating tension-type headaches, building on previous evidence of caffeine's analgesic properties.

The study aims to confirm the pain-relieving effects of caffeine and explore how tension-type headaches can serve as a useful model for pain research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of ibuprofen plus caffeine to treat tension-type headache. Diamond, S., Freitag, FG.[2019]

The study found that Algopirin®, which includes chlorpheniramine, was more effective in reducing migraine pain compared to a standard combination of acetylsalicylic acid, acetaminophen, and caffeine, despite using lower doses of the latter three medications.

The addition of chlorpheniramine not only enhanced the analgesic effect but also allowed for reduced doses of acetylsalicylic acid, acetaminophen, and caffeine, potentially minimizing side effects without compromising pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chlorpheniramine Potentiates the Analgesic Effect in Migraine of Usual Caffeine, Acetaminophen, and Acetylsalicylic Acid Combination. Voicu, VA., Mircioiu, I., Sandulovici, R., et al.[2020]

In a study involving 60 young, healthy volunteers, tramadol, dextropropoxyphene, and a commercial drug mixture all significantly increased pain thresholds in dental pulp, indicating their analgesic efficacy.

There was no significant difference in the pain-relieving effects among the three drugs, suggesting that they may be equally effective for managing pain in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of tramadol and other analgesics on the pain threshold in human dental pulp (author's transl)]. Rost, A., Schenck, EG.[2006]

In a 91-day study involving 307 participants with osteoarthritis pain inadequately controlled by COX-2 NSAIDs, the combination of tramadol 37.5 mg and acetaminophen 325 mg significantly reduced pain compared to placebo, with a final VAS score of 41.5 versus 48.3 (p = 0.025).

The tramadol/APAP combination also improved overall medication assessments and quality of life measures, while the most common side effects were mild, including somnolence (6.5%) and nausea (4.6%), indicating it is a safe and effective add-on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. Emkey, R., Rosenthal, N., Wu, SC., et al.[2015]

A systematic review and network meta-analysis of 38 studies involving 5164 chronic migraine patients found that high doses of fremanezumab and eptinezumab were numerically more effective in reducing migraine days, although these results were not statistically significant.

All anti-CGRP monoclonal antibodies showed comparable safety and tolerability, indicating that they are generally safe options for the short-term prevention of chronic migraines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of anti-calcitonin gene-related peptide monoclonal antibodies for treatment of chronic migraine: A systematic review and network meta-analysis. Soni, P., Chawla, E.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10869636/

A phase I trial of caffeine to evaluate safety in infants with ... A promising, safe, and commonly used drug, caffeine, may reduce hypoxic injury to the brain and thus offer neuroprotection for infants with HIE.

2. nature.com nature.com/articles/s41390-025-04387-1

Cumulative caffeine exposure predicts ... Preterm infants who receive caffeine for apnea of prematurity have improved neurodevelopmental outcomes compared to untreated infants.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06972849

NCT06972849 | Caffeine Citrate to Improve Neonatal ... The goal of this clinical trial to learn what dose/s of caffeine citrate works to treat preterm born babies who have episodes where they stop breathing.

4. withpower.com withpower.com/trial/phase-1-hypoxia-ischemia-brain-3-2022-c6a81

Caffeine Citrate for Newborn Brain Injury A study of 566 preterm infants showed that a high maintenance dose of caffeine citrate (10 mg/kg per day) significantly reduced the need for high-concentration ...

5. karger.com karger.com/dne/article/doi/10.1159/000545126/923429/Caffeine-as-a-Treatment-for-Perinatal-Hypoxic

Caffeine as a Treatment for Perinatal Hypoxic-Ischemic ... It has been investigated as a potential neuroprotective treatment for perinatal hypoxic-ischemic (HI) brain injury, but the preclinical evidence so far has ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK564965/

Safety and Efficacy of Caffeine Citrate in Premature Infants For the individual outcomes, caffeine citrate compared to placebo significantly reduced the incidence of cerebral palsy (4.4% vs. 7.3%, P=0.009) and cognitive ...

7. fda.gov fda.gov/media/181638/download

Cafcit Pediatric Postmarketing Safety Review Six cases described fatal outcomes in patients who were not exposed to caffeine citrate injection. Five cases described neonatal and infant.