Doxapram for Breathing Problems in Preterm Infants

Recruiting at 28 trial locations

Overseen By Jeroen J Hutten, MD, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Erasmus Medical Center

Must be taking: Caffeine

Must not be taking: Theophylline

Disqualifiers: Chromosomal defects, Major congenital malformations, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 2

Duration: Variable, based on patient condition

396 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called doxapram to assist preterm infants with apnea of prematurity (AOP), a condition where they briefly stop breathing. AOP can lower oxygen levels, impacting heart and brain development. The trial compares doxapram to a placebo to determine if it can prevent the need for invasive breathing support, which may cause long-term lung and brain issues. Babies born before 29 weeks, already receiving caffeine and non-invasive breathing assistance, and still requiring medical intervention for apnea may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering a chance to contribute to a potentially groundbreaking treatment for AOP.

Will I have to stop taking my current medications?

The trial does not specify if participants must stop taking their current medications, but it does exclude those using theophylline. Participants must be on caffeine therapy.

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

A previous study used doxapram in an unofficial capacity to address breathing problems in premature babies, particularly when other treatments failed. Some babies who received doxapram experienced side effects such as high blood pressure, irritability, and jitteriness. While these side effects are important to consider, they do not occur in every baby.

Doxapram already aids adults with breathing issues, such as those with COPD, a lung disease, suggesting it can stimulate breathing. However, its safety for babies under 12 years old remains unproven. This trial aims to provide more information on the safety and effectiveness of doxapram for premature babies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breathing problems in preterm infants?

Unlike the standard treatments for breathing problems in preterm infants, which often involve mechanical ventilation or other respiratory stimulants like caffeine, doxapram offers a novel approach. Researchers are excited about doxapram because it works by stimulating the respiratory center in the brain, which may help improve breathing without the need for invasive procedures. Additionally, doxapram can be administered intravenously or switched to gastro-enteral delivery if needed, offering flexibility in treatment. This unique mechanism and delivery method could provide a promising alternative for managing respiratory issues in these vulnerable infants.

What evidence suggests that doxapram might be an effective treatment for apnea of prematurity?

This trial will compare doxapram with a placebo to treat apnea of prematurity (AOP) in premature babies. Research has shown that doxapram can reduce apnea episodes by more than half in most babies who receive it. Other studies have found that doxapram lowers the number of apnea episodes and decreases the frequency of low oxygen levels. Overall, doxapram is being considered because it might help avoid the need for machines to assist breathing, which can cause lung problems and affect brain development. ^{1 6 7 8 9}

Who Is on the Research Team?

Karel Allegaert, MD, PhD

Principal Investigator

Universitair Ziekenhuis Leuven

Anne Smits, MD, PhD

Principal Investigator

Universitair Ziekenhuis Leuven

Are You a Good Fit for This Trial?

The DOXA trial is for preterm infants born before 29 weeks who are in the NICU and still have breathing pauses despite caffeine treatment and non-invasive respiratory support. Parents must consent to participate. Infants not eligible include those with certain conditions that make them unsuitable for the study.

Inclusion Criteria

Admitted to the neonatal intensive care unit (NICU) of one of the participating centers

Written informed consent of both parents or legal representatives

Gestational age at birth < 29 weeks

Exclusion Criteria

I have a chromosomal defect like Down syndrome.

I am taking theophylline instead of doxapram.

I have previously used doxapram.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Blinded continuous doxapram or placebo infusion as long as needed, with therapy down titrated or stopped based on the patients' condition

Variable, based on patient condition

Continuous monitoring in NICU

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurodevelopmental assessments at 2 years corrected age

8 years

Follow-up visits at 2, 5.5, and 8 years

Long-term follow-up

Additional long-term outcomes including readmissions, growth metrics, and behavioral assessments

2 years corrected age

What Are the Treatments Tested in This Trial?

Interventions

• Doxapram
• Placebo

Trial Overview This study tests whether Doxapram, a drug that stimulates breathing, can help prevent severe apnea (breathing stops) and reduce the need for invasive mechanical ventilation which could lead to lung disease or poor brain development compared to a placebo.

How Is the Trial Designed?

Group I: Doxapram Experimental Treatment 1 Intervention

Blinded doxapram (2mg/ml, in glucose 5%) loading dose of 2.0 to 2.5 mg/kg administered in 5 to 10 minutes, followed by a continuous infusion of 0.5 - 1.0 mg/kg/hr ('www.kinderformularium.nl') as long as needed. Therapy is down titrated or stopped based on the patients' respiratory condition. If endotracheal intubation is needed study drug is stopped. After extubation study drug may be restarted. Switch to gastro-enteral administration is allowed if no iv-access is needed for other reasons.

Group II: Placebo Placebo Group 1 Intervention

Placebo (glucose 5%) will also be administered with a loading dose and continuous infusion (in equal amounts of fluid as in experimental arm) by intravenous or gastro-intestinal infusion. The treatment protocol will be equal to the protocol in the doxapram arm.

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

Approved in United States as Dopram for:

• Postanesthesia respiratory depression
• Drug-induced central nervous system depression
• Chronic pulmonary disease associated with acute hypercapnia

Approved in Canada as Doxapram for:

• Respiratory insufficiency due to drug overdose, surgery, or chronic pulmonary disease

Approved in European Union as Doxapram for:

• Acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease

Who Is Running the Clinical Trial?

Erasmus Medical Center

Lead Sponsor

Trials

742

Recruited

2,156,000+

Universitaire Ziekenhuizen Leuven

Collaborator

Trials

850

Recruited

1,233,000+

Nederlands Neonataal Netwerk (N3), the Netherlands

Collaborator

Trials

1

Recruited

400+

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborator

Trials

722

Recruited

2,726,000+

Maternal, Infant, Child and Youth Research Network (MICYRN)

Collaborator

Trials

1

Recruited

400+

Universitaire Ziekenhuizen KU Leuven

Collaborator

Trials

1,048

Recruited

1,658,000+

Published Research Related to This Trial

A single trial involving 21 preterm infants suggested that intravenous doxapram may reduce the incidence of apnea episodes within the first 48 hours compared to placebo, but the results were not statistically significant due to wide confidence intervals.

Despite some initial benefits, the long-term effectiveness of doxapram is unclear, as many infants who responded initially experienced treatment failures later, indicating a need for further research to assess its safety and efficacy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxapram treatment for apnea in preterm infants. Henderson-Smart, DJ., Steer, PA.[2020]

Doxapram, a respiratory stimulant used for treating apnea in premature infants, has minimal side effects but can cause significant heart issues, such as second-degree atrioventricular block due to QT interval prolongation.

In three reported cases, the heart rhythm returned to normal after stopping doxapram, indicating that while it can be effective, careful monitoring is necessary to avoid potential cardiac complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-degree atrioventricular heart block after doxapram administration. De Villiers, GS., Walele, A., Van der Merwe, PL., et al.[2019]

The DOXA-trial is a large, multicenter study involving 396 preterm infants under 29 weeks gestation, aiming to evaluate the safety and efficacy of doxapram compared to placebo in reducing the risk of death or severe disability due to apnoea of prematurity (AOP).

The primary outcome focuses on long-term effects at 18-24 months, assessing cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, which will provide crucial evidence on whether doxapram can improve neonatal outcomes and reduce the need for invasive mechanical ventilation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial). Poppe, JA., Flint, RB., Smits, A., et al.[2023]

Doxapram is commonly used in French neonatal intensive care units as a second-line treatment for apnea in preterm infants when methylxanthines are ineffective, with 64.1% of surveyed units reporting its use.

Despite its frequent use, there are concerns about doxapram's potential adverse effects and a lack of routine monitoring of drug plasma concentrations, highlighting the need for further studies to assess its safety in both the short and long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Determinants of doxapram utilization: a survey of practice in the French Neonatal and Intensive Care Units]. Bénard, M., Boutroy, MJ., Glorieux, I., et al.[2015]

Doxapram significantly improved breathing in 12 premature infants with apnea of prematurity who were already receiving aminophylline, leading to increased minute ventilation and reduced apnea attacks after just 6 hours of treatment.

The medication also resulted in a significant decrease in carbon dioxide levels and an increase in mean arterial blood pressure, suggesting it effectively stimulates the respiratory center.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologic effects of doxapram in idiopathic apnea of prematurity. Barrington, KJ., Finer, NN., Peters, KL., et al.[2019]

In a study of 85 preterm infants, dosing doxapram based on gender and postmenstrual age (PMA) led to better clinical outcomes, reducing significant apnea episodes in 76% of infants compared to 56% in those dosed by weight alone.

While the adjusted dosing did not significantly increase the number of infants achieving therapeutic plasma levels, it resulted in more stable plasma levels and showed no adverse effects, indicating a safer and more effective approach to treating apnea in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxapram Dosing for Apnea of Prematurity Based on Postmenstrual Age and Gender: A Randomized Controlled Trial. Greze, E., Benard, M., Hamon, I., et al.[2018]

In a study of 20 preterm infants treated with doxapram for apnea of prematurity, the drug significantly decreased levels of oxygenated hemoglobin and cerebral oxygenation, indicating a potential risk for reduced oxygen delivery to the brain.

Despite these changes in oxygen levels, doxapram did not affect cerebral blood volume or blood flow velocity, suggesting that while it stimulates respiration, it may also increase cerebral oxygen consumption without improving oxygen delivery, warranting caution in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain hemodynamic effects of doxapram in preterm infants. Dani, C., Bertini, G., Pezzati, M., et al.[2013]

In a study involving five preterm infants, doxapram infusion effectively controlled apnoea episodes that were not managed by therapeutic levels of theophylline.

The treatment led to a significant decrease in arterial blood PCO2 levels, and importantly, no side effects were reported, indicating a safe profile for doxapram in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idiopathic apnoea of prematurity treated with doxapram and aminophylline. Sagi, E., Eyal, F., Alpan, G., et al.[2019]

In a study of 203 preterm infants, doxapram treatment successfully prevented endotracheal intubation in 77% of cases during the first 48 hours, indicating its efficacy in managing apnoea of prematurity.

Key predictors of successful treatment included the infants' postnatal age and the fraction of inspired oxygen at the start of therapy, suggesting that earlier intervention and lower oxygen needs may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective study shows that doxapram therapy avoided the need for endotracheal intubation in most premature neonates. Flint, R., Halbmeijer, N., Meesters, N., et al.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8921943/

Doxapram for the prevention and treatment of apnea in ... To determine the effects of doxapram administration on the incidence of apnea and longer‐term clinical outcomes in preterm infants.

2. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07683-5

Doxapram versus placebo in preterm newborns - Trials Journal Several observational studies found that treatment with doxapram can be beneficial in reducing the apnoea rate and the number of hypoxemic ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5296887/

Doxapram Treatment for Apnea of Prematurity - PubMed Central [25] reported that doxapram was effective by reducing AOP with a reduction in apnea frequency by more than 50% in 9 out of 11 infants in the high-dose group and ...

4. clinicaltrials.eu clinicaltrials.eu/trial/study-on-doxapram-for-treating-apnea-in-preterm-newborns/

Study on Doxapram for Treating Apnea in Preterm Newborns This study evaluates the efficacy and safety of Doxapram in treating apnea in preterm newborns.

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1155/2013/251047

Doxapram Use for Apnoea of Prematurity in Neonatal ... However, retrospectively, we found positive results in almost 65% of infants treated with doxapram. Response to doxapram therapy seemed to be ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2004/14879slr040_dopram_lbl.pdf

Dopram Injection - accessdata.fda.gov Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric ...

7. go.drugbank.com go.drugbank.com/drugs/DB00561

Doxapram: Uses, Interactions, Mechanism of Action Doxapram is a short acting respiratory stimulant used to treat acute respiratory insufficiency in COPD patients.

8. publications.aap.org publications.aap.org/pediatriccare/drug-monograph/18/5662/Doxapram

Doxapram | Drug Lookup | Pediatric Care Online Apnea of prematurity, refractory: Limited data available: Note: Typically considered third-line agent. Preterm neonates: Loading dose: IV: 2.5 to 3 mg/kg (Bhatt ...

9. drugs.com drugs.com/monograph/doxapram.html

Doxapram Monograph for Professionals Safety and efficacy not established in children <12 years of age. Each mL of doxapram hydrochloride injection contains 9 mg of benzyl alcohol; ...