Doxapram for Breathing Problems in Preterm Infants

Recruiting at 26 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

Trial Summary

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.

What data supports the effectiveness of the drug doxapram for breathing problems in preterm infants?

Research shows that doxapram can effectively reduce apnea (pauses in breathing) in preterm infants when other treatments like theophylline and caffeine have not worked. It helps by increasing the output of the respiratory center, leading to better breathing patterns and reduced apnea episodes. ^{1 2 3 4 5}

Is doxapram safe for preterm infants?

Doxapram is used to help preterm infants with breathing problems, but it can cause some side effects. It may lead to a temporary decrease in blood flow to the brain and, in rare cases, heart rhythm issues. More research is needed to fully understand its safety. ^{1 2 5 6 7}

How is the drug doxapram different from other treatments for breathing problems in preterm infants?

Doxapram is unique because it can stimulate breathing in preterm infants who do not respond to other treatments like theophylline, potentially avoiding the need for invasive procedures like intubation. However, its use is controversial due to a narrow safety margin and possible short-term side effects. ^{1 2 5 8 9}

What is the purpose of this trial?

Preterm infants often suffer from apnea of prematurity (AOP; a cessation of breathing) due to immaturity of the respiratory system. AOP can lead to oxygen shortage and a low heart rate which might harm the development of the newborn, especially the central nervous system. In order to prevent oxygen shortage, infants are treated with non-invasive respiratory support and caffeine. Despite these treatments, many preterm newborns still suffer from AOP and need invasive mechanical ventilation. Although this will result in complete resolution of AOP, invasive mechanical ventilation has the disadvantage of being a major risk of chronic lung disease and impaired neurodevelopmental outcome. Restrictive invasive ventilation is therefore advocated nowadays in preterm infants. Doxapram is a respiratory stimulant that has been administered off-label to treat AOP. Doxapram, as add-on treatment, seems to be effective in treating AOP and to prevent invasive mechanical ventilation. It is unclear if a preterm infant benefit from doxapram treatment on the longer term. This study compares doxapram to placebo and hypothesizes that doxapram will protect preterm infants from both invasive ventilation (and related lung disease) and AOP related oxygen shortage (and related impaired brain development).

Research Team

Karel Allegaert, MD, PhD

Principal Investigator

Universitair Ziekenhuis Leuven

Anne Smits, MD, PhD

Principal Investigator

Universitair Ziekenhuis Leuven

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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, 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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Brain hemodynamic effects of doxapram in preterm infants. [2013]

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

Idiopathic apnoea of prematurity treated with doxapram and aminophylline. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Doxapram Dosing for Apnea of Prematurity Based on Postmenstrual Age and Gender: A Randomized Controlled Trial. [2018]

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

Physiologic effects of doxapram in idiopathic apnea of prematurity. [2019]

5. France pubmed.ncbi.nlm.nih.gov

[Determinants of doxapram utilization: a survey of practice in the French Neonatal and Intensive Care Units]. [2015]

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

Second-degree atrioventricular heart block after doxapram administration. [2019]

7. England 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). [2023]

8. Norway pubmed.ncbi.nlm.nih.gov

Retrospective study shows that doxapram therapy avoided the need for endotracheal intubation in most premature neonates. [2017]

9. England pubmed.ncbi.nlm.nih.gov

Doxapram treatment for apnea in preterm infants. [2020]