Caffeine for Premature Birth

Overseen By Rosie Magallon

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Must be taking: Caffeine

Disqualifiers: Congenital heart disease, Neuromuscular conditions, Brain injury, Genetic disorders, Anatomic anomalies, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether extending caffeine therapy can help preterm infants learn to feed by mouth more quickly. The study involves two groups: one receiving caffeine and the other a placebo, both administered through a feeding tube or by mouth. It seeks infants born at or before 32 weeks who are no longer on breathing support and have been on caffeine therapy. Participants should have had no recent major heart or lung problems and are ready to stop caffeine. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in neonatal care.

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

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should already be on caffeine and meet criteria to discontinue it.

Is there any evidence suggesting that caffeine therapy is likely to be safe for preterm infants?

Research has shown that caffeine is generally safe for preterm infants. Studies have found that it can significantly improve their chances of survival without causing developmental problems up to 18-21 months of age. One study found that administering caffeine early to preterm babies is linked to fewer health issues after birth. However, monitoring for necrotizing enterocolitis, a serious intestinal condition, is important in preterm infants receiving caffeine.

While caffeine is safe at normal doses, high doses can be harmful. Therefore, healthcare providers carefully adjust the amount based on the baby's weight to prevent any negative effects. Overall, caffeine has been widely and safely used in preterm infants to aid their development. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for premature birth, which typically focus on respiratory support and nutritional management, caffeine offers a unique approach by stimulating the central nervous system. This helps improve breathing in premature infants by reducing apnea episodes, which are common in preterm babies. Researchers are excited about caffeine because it's a well-known substance with an established safety profile, and its use in this context could potentially reduce the need for more invasive interventions. By adjusting the dose based on the infant's weight, the treatment can be highly individualized, promising better outcomes for these vulnerable newborns.

What evidence suggests that caffeine might be an effective treatment for premature birth?

Research has shown that caffeine can benefit premature babies. In this trial, infants in the Caffeine Group will receive caffeine, which studies have linked to fewer health problems in newborns, such as improved breathing and higher survival rates. Caffeine also reduces the risk of developmental delays and other disabilities as babies grow. One study found that caffeine helps babies breathe independently sooner by reducing the need for prolonged use of breathing tubes. Overall, caffeine has proven effective in improving both short-term and long-term health outcomes for premature infants. ^{2 4 6 7 8}

Who Is on the Research Team?

Cherry Uy, MD

Principal Investigator

UC Irvine

Are You a Good Fit for This Trial?

This trial is for preterm infants born at or before 32 weeks, currently on caffeine treatment but ready to stop, and off respiratory support for a week. They should be at least 34 weeks corrected gestation without significant breathing problems in the past 5 days. Infants with neuromuscular issues, critical heart disease, severe brain injury, or who are already advancing in oral feeding protocols cannot participate.

Inclusion Criteria

On caffeine and meet criteria to discontinue caffeine

I haven't needed help breathing for at least a week.

My baby was born at or before 32 weeks but is now at least 34 weeks corrected age.

Exclusion Criteria

My infant has a condition that affects their breathing.

Failure to obtain consent or declined by parents

My infant has a physical condition that makes feeding by mouth difficult.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Infants receive either caffeine or placebo for up to four additional weeks after meeting clinical criteria to discontinue caffeine

4 weeks

Weekly weight adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including weight change and cardiopulmonary events

6 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Caffeine

Trial Overview The study is testing if continuing caffeine therapy longer than usual can help premature babies learn to eat by mouth quicker. Babies will either continue receiving caffeine or get a sterile water placebo to see which method leads to faster full oral feeding.

How Is the Trial Designed?

Group I: Caffeine Group Active Control 1 Intervention

Infants randomized to receive caffeine will continue to receive caffeine at standard of care maintenance dose of 10-15 mg/kg/day given every 24 hours. The dose will be weight adjusted every 7 days, starting on the day of enrollment. Caffeine will be given enterally, via nasogastric tube or by mouth.

Group II: Placebo Group Placebo Group 1 Intervention

Infants randomized to the placebo group will be given sterile water at an equivalent volume to the volume if caffeine were to be given, using the previous weight-based caffeine dose. The placebo will be given every 24 hours. The dose/volume will be weight adjusted every 7 days, starting on the day of enrollment. The placebo will be given enterally, via nasogastric tube or by mouth.

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 California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Published Research Related to This Trial

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]

In a study involving 1743 patients, the fixed combination of acetylsalicylic acid, paracetamol, and caffeine (Thomapyrin) provided significantly faster pain relief for tension-type headaches and migraines compared to other treatments, including placebo and individual components.

All treatments were well tolerated with a low incidence of adverse events, indicating that the combination therapy is not only effective but also safe for patients accustomed to using non-prescription analgesics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Diener, HC., Pfaffenrath, V., Pageler, L., et al.[2013]

Thomapyrin, a popular over-the-counter analgesic in Germany for 50 years, combines acetylsalicylic acid, paracetamol, and caffeine, demonstrating a 1.4-fold increase in analgesic effectiveness due to the synergistic effects of its ingredients.

The combination does not alter the side effect profile compared to individual components, indicating a favorable benefit/risk ratio, making it suitable for self-medication in managing various types of pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. Aicher, B., Kraupp, O.[2013]

In a double-blind, cross-over trial involving 216 patients (72 orthopedic inpatients and 144 outpatients with headaches), the combination of paracetamol and caffeine (Finimal) provided the greatest pain relief compared to paracetamol alone or aspirin.

This study supports previous findings that the paracetamol-caffeine combination is more effective for pain relief, highlighting its potential as a superior analgesic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind comparative evaluation of aspirin, paracetamol and paracetamol + caffeine (finimal) for their analgesic effectiveness. Wójcicki, J., Samochowiec, L., Lawczyński, L., et al.[2013]

The guideline recommends the fixed-dose combination of acetaminophen, acetylsalicylic acid, and caffeine, as well as monotherapies with ibuprofen or naratriptan, as effective first-line treatments for self-medication in migraine attacks.

For tension-type headaches, the same fixed-dose combination and monotherapies with ibuprofen, acetylsalicylic acid, or diclofenac are recommended as first-line therapies, highlighting the importance of self-medication strategies for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-medication of migraine and tension-type headache: summary of the evidence-based recommendations of the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG), the Deutsche Gesellschaft für Neurologie (DGN), the Österreichische Kopfschmerzgesellschaft (ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG). Haag, G., Diener, HC., May, A., et al.[2021]

The combination of indomethacin, caffeine, and prochlorperazine (IndoProCaf) effectively reverses hyperalgesia in mice, demonstrating a significant increase in pain threshold after treatment, even at doses much lower than typical analgesics.

IndoProCaf showed superior efficacy in reducing pain compared to the individual components, indicating that the combination therapy may be particularly effective for conditions like migraine, where hyperalgesia is present.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine. Galeotti, N., Ghelardini, C., Grazioli, I., et al.[2019]

Etodolac, a new NSAID, has an excellent safety profile, with gastrointestinal disturbances being the most common side effects, but the rates of serious issues like gastrointestinal ulceration are very low (less than 0.3%).

The review included data from 3,302 patients in clinical trials and 8,334 in post-marketing studies, showing that elderly patients do not have a higher risk of adverse effects compared to the general population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An updated safety profile of etodolac in several thousand patients. Schattenkirchner, M.[2013]

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]

The combination of indomethacin, prochlorperazine, and caffeine (IndoProCaf) effectively abolishes both peripheral and central sensitization in migraine models, suggesting its strong potential for treating migraines regardless of when it is administered.

In contrast, sumatriptan, a common migraine treatment, fails to reverse established sensitization, indicating that IndoProCaf may be more effective in managing migraine attacks that have already progressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indomethacin, alone and combined with prochlorperazine and caffeine, but not sumatriptan, abolishes peripheral and central sensitization in in vivo models of migraine. Ghelardini, C., Galeotti, N., Grazioli, I., et al.[2013]

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 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]

Citations

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Caffeine therapy in preterm infants - PMC - PubMed Central A recent study, demonstrated that early caffeine initiation is associated with reduced neonatal morbidity, including a decreased incidence of BPD and of patent ...

2. nature.com nature.com/articles/s41390-025-04066-1

Caffeine and preterm infants: multiorgan effects ... Prophylactic caffeine therapy was associated with a significant reduction in extubation failure within the first week, likely as a result of an ...

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Caffeine to prevent intermittent hypoxaemia in late preterm ... Caffeine reduces IH in late preterm infants at 2 weeks of age, with 20 mg/kg/day being the most effective dose.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9098661/

Five-year outcomes of premature infants randomized to ... At standard doses, caffeine citrate improves survival and lowers the risk of subsequent cerebral palsy, motor impairment, cognitive delays, and ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa073679

Long-Term Effects of Caffeine Therapy for Apnea ... Caffeine significantly improved the rate of survival without neurodevelopmental disability at a corrected age of 18 to 21 months. Of the 937 infants assigned to ...

6. fda.gov fda.gov/media/181638/download

Cafcit Pediatric Postmarketing Safety Review As with all preterm infants, patients being treated with CAFCIT should be carefully monitored for the development of necrotizing enterocolitis.

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

Safety and Efficacy of Caffeine Citrate in Premature Infants The authors concluded that caffeine citrate significantly improved survival without neurodevelopmental disability at a corrected age of 18-21 months, therefore ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01751724

Caffeine to Reduce Mechanical Ventilation in Preterm Infants The primary hypothesis of this study is that early use of caffeine in mechanically ventilated preterm infants will reduce the time to first elective extubation ...