The Effect of an Additional Pre-extubational Loading Dose of Caffeine-citrate (NEOKOFF22)

May 1, 2024 updated by: Dr. Gasparics Ákos, Semmelweis University

The goal of this clinical trial is to answer whether the use of a single loading dose (20 mg/kg) of caffeine citrate one hour before extubation has an impact on the success rate of extubation among preterm neonates. In addition, the investigators would like to assess the frequency of apneas and side effects of the intervention, as well as the development of NEC, BPD, IVH, PVL, and long-term neurodevelopmental outcomes in the investigated populations.

According to institutional protocol, preterm infants born before the 32nd week of gestation receive a standard dose of caffeine citrate therapy. This covers a maintenance dose of 5-10 mg/kg of caffeine citrate administered intravenously once or twice daily after a loading dose of 20 mg/kg on the first day of life. In this trial, preterm infants born before the 32nd gestational week and who had been mechanically ventilated for at least 48 hours before planned extubation are planned to be randomly allocated into intervention and control groups. The intervention group will receive an additional loading dose of caffeine citrate 60 minutes before extubation. The control group will receive standard dosing regimens.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The most common cause of the failure of non-invasive ventilatory support is poor spontaneous respiratory activity in preterm infants and recurrent respiratory arrest (apnea) due to the immature nervous system. The national and international literature has extensively studied apnea in preterm infants. Apnea is a respiratory failure of 15-20 seconds or shorter duration associated with bradycardia or desaturation. Apneas develop in preterm infants due to prematurity of the respiratory center and chemoreceptors and reduced patency of the upper airway. Apnea in preterm infants is the most common indication for intubation and reintubation.

The apnea-reducing effects of the respiratory center stimulant methylxanthines have been known for more than 40 years. Based on current knowledge, caffeine is the drug of choice for the medical treatment of apnea. Caffeine has the narrowest spectrum of side effects, the broadest therapeutic range, and the most prolonged half-life among methylxanthines.

Caffeine is currently one of the most commonly used drugs in premature neonatal intensive care units. The most common dosing recommendation is a maintenance dose of 5-10 mg/kg daily after a loading dose of 20 mg/kg of caffeine citrate. Higher saturating and maintenance doses have been used in some studies, with some reports suggesting that higher doses of caffeine increase the chance of successful extubation. However, other studies have reported more frequent adverse effects at higher doses. Conflicting literature suggests that caffeine dosing may vary between institutions. Further basic research and clinical studies are needed to determine the optimal dose.

The investigators seek to answer whether the use of a single loading dose of caffeine citrate one hour before extubation impacts the success rate of extubation. In addition, the investigators would like to assess the frequency and severity of side effects and the development of necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, and bronchopulmonary dysplasia.

To investigate the effect of a pre-extubational loading dose of caffeine-citrate, the investigators plan to carry out a two-armed randomized clinical trial, including preterm neonates being treated in one of the tertiary neonatal intensive care units of Semmelweis University. A total of 226 patients are planned to be enrolled. According to institutional protocol, preterm infants born before the 32nd week of gestation receive a standard dose of caffeine therapy. This covers a maintenance dose of 5-10 mg/kg of caffeine citrate administered intravenously once or twice daily after a loading dose of 20 mg/kg on the first day of life.

Preterm infants who have been on mechanical ventilation for at least 48 hours before planned extubation will be randomly allocated into intervention and control groups. Stratification of the randomization will be based on gestational age and antenatal steroid prophylaxis. Intervention is an additional loading dose (20 mg/kg) of intravenous caffeine citrate 60 minutes before extubation. The control group will receive routine dosing regimens as mentioned above. Before extubation, the parents will be informed and asked for consent. Pre-interventional, the investigators plan to collect baseline characteristics and oxygen requirements. After extubation, the need for reintubation within the next 48 hours will be assessed. This timeframe was chosen because most of reintubation due to respiratory reasons happens within the next 48 hours after extubation, and the caffeine half-life ranges from 40 to 230 hours.

The investigators will also assess the frequency of side effects such as gastric residuals, frequency of apneas, need for supplementary oxygen, elevated heart rate, or blood pressure. Data will be collected about adverse outcomes of prematurity, e.g., necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, and bronchopulmonary dysplasia.

Study Type

Interventional

Enrollment (Estimated)

226

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Hungary
      • Budapest, Hungary, 1083
        • Recruiting
        • Pediatric Center, Semmelweis University
        • Contact:
          • Leina Mahdi, MD
      • Budapest, Hungary, 1088
        • Recruiting
        • Department of Obstetrics and Gynecology, Semmelweis University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Premature infant born before 32nd week of gestation is completed;
  • Had been mechanically ventilated for at least 48 hours;
  • Before the first planned extubation.

Exclusion Criteria:

  • Lack of informed consent, refusal to participate in the study;
  • Major congenital anomaly;
  • Had not received surfactant treatment;
  • Hydrops foetalis;
  • Persistent tachycardia before extubation, fetal/neonatal arrhythmia;
  • Asphyxia.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Pre-extubational caffeine-citrate
Participants will receive 20 mg/kg loading dose of caffeine citrate on the first day of life and after that 5-10 mg/kg maintenance dose each day. On this arm, the participants will receive 20 mg/kg caffeine dose once again before the planned extubation.
Drug: Caffeine citrate
20 mg/kg caffeine-citrate before the planned extubation.
Other Names:
  • CITRATE DE CAFEINE COOPER 25 mg/ml Coopération Pharmaceutique Française, Melun, France
No Intervention: Routine care
Participants will receive 20 mg/kg loading dose of caffeine citrate on the first day of life and after that 5-10 mg/kg maintenance dose each day, also on the day of the extubation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of extubation failure
Time Frame: 48 hours
Reintubation. The discretion of the attending physician.
48 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency of apneas
Time Frame: 48 hours
Respiratory failure of 15-20 seconds or shorter duration associated with bradycardia or desaturation.
48 hours
Change in the mean heart rate
Time Frame: 72 hours
Mean heart rate measured 24 hours before and 48 hours after intervention.
72 hours
Tachycardia
Time Frame: 72 hours
The time interval when the heart rate >200 (min) during one day (1440 min) in percentage.
72 hours
Volume of gastric residuals
Time Frame: 72 hours
Gastric residuals measured 24 hours before and 48 hours after intervention.
72 hours
Reduction/Cessation of feeding
Time Frame: 48hours
48 hours after intervention.
48hours
Change in mean arterial blood pressure
Time Frame: 48 hours
Mean blood pressure measured 24 hours before and after intervention measured with non-invasive methods.
48 hours
Mechanical ventilation (MV) days
Time Frame: At discharge from participating centres, an average of one month.
MV days during the length of hospital stay
At discharge from participating centres, an average of one month.
Non-invasive ventilation (NIV) days
Time Frame: At discharge from participating centres, an average of one month.
NIV days during the length of hospital stay
At discharge from participating centres, an average of one month.
Rate of necrotizing enterocolitis
Time Frame: At discharge from participating centres, an average of one month.
Development of necrotizing enterocolitis according to Bell stages.
At discharge from participating centres, an average of one month.
Rate of Intraventricular hemorrhage
Time Frame: At discharge from participating centres, an average of one month.
Development or progression of intraventricular hemorrhage according to Papile stages diagnosed with cranial ultrasound.
At discharge from participating centres, an average of one month.
Rate of periventricular leukomalacia
Time Frame: At discharge from participating centres, an average of one month.
Development of periventricular leukomalacia, seen on cranial ultrasound.
At discharge from participating centres, an average of one month.
Rate of late-onset sepsis
Time Frame: At discharge from participating centres, an average of one month.
Culture proven sepsis after the first 72 hours of life.
At discharge from participating centres, an average of one month.
Rate of patent ductus arteriosus
Time Frame: At discharge from participating centres, an average of one month.
Pharmacological or surgical treatment was required.
At discharge from participating centres, an average of one month.
Rate of bronchopulmonary dysplasia
Time Frame: 36th postmenstrual age
Diagnosis of bronchopulmonary dysplasia.
36th postmenstrual age
Rate of death before discharge
Time Frame: At discharge from participating centres, an average of one month.
At discharge from participating centres, an average of one month.
Required oxygen concentration
Time Frame: 24 hours
Required oxygen concentration before and after the intervention.
24 hours
Long term neurodevelopmental outcome
Time Frame: At 2 years of corrected age
Measured by Bayley score. The standardized mean score is 100 (SD 15), with scores lower than 85 indicating mild impairment, and lower than 70 indicating moderate or severe impairment.
At 2 years of corrected age
Severity of sensoric or motoric impairment
Time Frame: At 2 years of corrected age
Hearing or visual impairment, and cerebral palsy
At 2 years of corrected age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Semmelweis University

Investigators

  • Principal Investigator: Ákos Gasparics, MD.PhD, Semmelweis University, Department of Obstetrics and Gynecology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 21, 2023

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

March 18, 2024

First Submitted That Met QC Criteria

May 1, 2024

First Posted (Actual)

May 6, 2024

Study Record Updates

Last Update Posted (Actual)

May 6, 2024

Last Update Submitted That Met QC Criteria

May 1, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NEOKOFF22
  • 2022-003202-77 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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