Closed-loop Automatic Oxygen Control (CLAC-4) in Preterm Infants

Study Overview
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Brief Summary
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Two-center, randomised controlled, cross-over clinical trial in preterm infants born at gestational age below 34+1/7 weeks receiving supplemental oxygen and respiratory support (Continous positive airway pressure (CPAP) or Non-invasive Ventilation (NIV) or Invasive Ventilation (IV)). Routine manual control (RMC) of the fraction of inspired oxygen (FiO2) will be tested against RMC supported by closed-loop automatic control (CLAC) with slow-algorithm and RMC supported by CLAC with fast-algorithm. The primary hypothesis is, that the use of the faster algorithm results in more time within arterial oxygen saturation (SpO2) target range compared to RMC only. The a-priori subordinate hypothesis is, that the faster algorithm is equally effective as the slower algorithm to maintain the SpO2 in the target range.

Detailed Description
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BACKGROUND AND OBJECTIVE In preterm infants receiving supplemental oxygen, routine manual control (RMC) of the fraction of inspired oxygen (FiO2) is often difficult and time consuming. The investigators developed a system for closed-loop automatic control (CLAC) of the FiO2 and demonstrated its safety and efficacy in a multi-center study. The objective of this study is to test a revised, faster algorithm with a shorter WAIT-interval of 30sec (= time between FiO2 changes) against the previously tested algorithm (WAIT of 180sec) and against RMC. The primary hypothesis is, that the application of CLAC with the faster algorithm in addition to RMC results in more time within arterial oxygen saturation (SpO2) target range compared to RMC only. The a-priori subordinate hypothesis is, that the faster algorithm is equally effective as the slower algorithm to maintain the SpO2 in the target range. Further hypotheses for exploratory testing are, that the fast algorithm will achieve a higher proportion of time with SpO2 within target range and an improved stability of cerebral oxygenation (measured as rcStO2 and rcFtO2E determined by Near-infrared spectroscopy) compared with the slow algorithm. STUDY DESIGN The Study is designed as a two-center, randomized controlled, cross-over clinical trial in preterm infants receiving mechanical ventilation or nasal continuous positive airway pressure or non-invasive ventilation and supplemental oxygen (FiO2 above 0.21). Within a twenty-four-hour period the investigators will compare 8 hours of RMC with 8-hour periods of RMC supported by CLAC slow algorithm or fast algorithm, respectively.

Official Title
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Closed-loop Automatic Oxygen Control (CLAC-4) in Preterm Infants: a Randomized Controlled Trial of a Revised Algorithm

Conditions
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Infant Respiratory Distress Syndrome, Ventilator Lung; Newborn

Intervention / Treatment
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* Device: Closed-loop automatic oxygen control (CLAC) fast in addition to RMC
* Device: Closed-loop automatic oxygen control (CLAC) slow in addition to RMC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gestational age at birth <34+1/7weeks invasive mechanical ventilation OR noninvasive ventilation OR continous positive airway pressure support Fraction of inspired oxygen above 0.21 before inclusion more than 2 hypoxaemic events (arterial oxygen saturation below 80%) within 8 hours before inclusion parental written informed consent Exclusion Criteria: congenital pulmonary anomalies diaphragmatic hernia or other diaphragmatic disorders
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: RMC only<br>routine manual control (RMC) of the fraction of inspired oxygen (FIO2) | |
| Active Comparator: CLAC slow<br>routine manual control (RMC) + Closed-loop automatic oxygen control (CLAC) with 180sec WAIT-Interval (slow algorithm) of the fraction of inspired oxygen (FIO2) | Device: Closed-loop automatic oxygen control (CLAC) slow in addition to RMC<br>* Closed-loop automatic oxygen control is an automated, algorithm based adjustment of the fraction of inspired oxygen in relation to arterial saturation (WAIT-interval 180s).<br>|
| Experimental: CLAC fast<br>routine manual control (RMC) + Closed-loop automatic oxygen control (CLAC) with 30sec WAIT-Interval (fast algorithm) of the fraction of inspired oxygen (FIO2) | Device: Closed-loop automatic oxygen control (CLAC) fast in addition to RMC<br>* Closed-loop automatic oxygen control is an automated, algorithm based adjustment of the fraction of inspired oxygen in relation to arterial saturation (WAIT-interval 30s).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of time with SpO2 within target range | Comparison of proportion of time with SpO2 within target range if the infant requires supplemental oxygen and time above target range if the infant requires no supplemental oxygen between CLAC-fast and RMC (superiority hypothesis). | 16 hours | 
| Proportion of Time with SpO2 within target range | Comparison of proportion of time with SpO2 within target range if the infant requires supplemental oxygen and time above target range if the infant requires no supplemental oxygen between CLAC-fast and CLAC-slow (subordinate, non inferiority hypothesis). | 16 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hyperoxaemia | Time with arterial oxygen saturation above 95% if the infant requires supplemental oxygen (hyperoxaemia). | 16 hours | 
| Duration of hypoxaemia | Time with arterial oxygen saturation below 80% (hypoxaemia) | 16 hours | 
| Duration of overshoot hyperoxaemia | Comparison of proportion of time with SpO2 higher than 95% after an automated increase of FiO2 between CLAC-fast and CLAC-slow. | 16 hours | 
| Number of overshoot hyperoxaemia | Comparison of number of events with SpO2 higher than 95% after an automated increase of FiO2 between CLAC-fast and CLAC-slow. | 16 hours | 
| Stability of cerebral oxygenation | Area under the curve of cerebral tissue saturation or fraction of tissue oxygen extraction outside of the infants Median +- 5% or outside of the save interval of 55-80% rcStO2. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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controller, hyperoxia, hypoxia, ventilation, cerebral oxygenation