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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to assess whether extending the duration of caffeine therapy will help preterm infants achieve full oral feeding faster.

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.

What evidence supports the effectiveness of caffeine as a drug for premature birth?

Research shows that caffeine, when combined with other pain relievers like acetylsalicylic acid and paracetamol, enhances their effectiveness in treating headaches and migraines. This suggests caffeine can boost the effects of other medications, which might be relevant for its use in treating premature birth. ^{1 2 3 4 5}

Is caffeine safe for use in humans?

Research shows that caffeine, when combined with other medications like paracetamol or ibuprofen, is generally safe for treating tension-type headaches. Studies have not found significant safety concerns, and caffeine may even enhance the pain-relieving effects of these medications. ^{1 3 6 7 8}

How does the drug caffeine differ from other treatments for premature birth?

Caffeine is unique in its use for premature birth as it is primarily known for its stimulating effects on the central nervous system, which can help improve breathing in premature infants. Unlike other treatments, caffeine is well-tolerated and has a well-established safety profile in neonatal care. ^{3 9 10 11 12}

Research Team

Cherry Uy, MD

Principal Investigator

UC Irvine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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 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]

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 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]

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]

References

1. England 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. [2013]

2. Austria pubmed.ncbi.nlm.nih.gov

[Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. [2013]

3. England 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. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Chlorpheniramine Potentiates the Analgesic Effect in Migraine of Usual Caffeine, Acetaminophen, and Acetylsalicylic Acid Combination. [2020]

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

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

7. Ireland pubmed.ncbi.nlm.nih.gov

Toxicological effect of Artemisinin-Based Combination Therapies plus Paracetamol in malaria patients. [2023]

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

The use of ibuprofen plus caffeine to treat tension-type headache. [2019]

9. England 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). [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

A double-blind comparative evaluation of aspirin, paracetamol and paracetamol + caffeine (finimal) for their analgesic effectiveness. [2013]

11. United States 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. [2013]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine. [2019]