Automated Versus Manual Control Of Oxygen For Preterm Infants On Continuous Positive Airway Pressure In Nigeria

Study Overview
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Brief Summary
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One in ten babies are born preterm (<37 weeks gestation) globally. Complications of prematurity are the leading cause of death in children under 5 years, with the highest mortality rate in Sub-Saharan Africa (SSA). Low flow oxygen, and respiratory support - where an oxygen/air mixture is delivered under pressure - are life saving therapies for these babies. Bubble Continuous Positive Airway Pressure (bCPAP) is the mainstay of neonatal respiratory support in SSA. Oxygen in excess can damage the immature eyes (Retinopathy of Prematurity [ROP]) and lungs (Chronic Lung Disease) of preterm babies. Historically, in well-resourced settings, excessive oxygen administration to newborns has been associated with 'epidemics' of ROP associated blindness. Today, with increasing survival of preterm babies in SSA, and increasing access to oxygen and bCPAP, there are concerns about an emerging epidemic of ROP. Manually adjusting the amount of oxygen provided to an infant on bCPAP is difficult, and fearing the risks of hypoxaemia (low oxygen levels) busy health workers often accept hyperoxaemia (excessive oxygen levels). Some well resourced neonatal intensive care units globally have adopted Automated Oxygen Control (AOC), where a computer uses a baby's oxygen saturation by pulse oximetry (SpO2) to frequently adjust how much oxygen is provided, targetting a safe SpO2 range. This technology has never been tested in SSA, or partnered with bCPAP devices that would be more appropriate for SSA. This study aims to compare AOC coupled with a low cost and robust bCPAP device (Diamedica Baby CPAP) - OxyMate - with manual control of oxygen for preterm babies on bCPAP in two hospitals in south west Nigeria. The hypothesis is that OxyMate can significantly and safely increase the proportion of time preterm infants on bCPAP spend in safe oxygen saturation levels.

Detailed Description
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Trial description: A randomised cross-over trial of manual versus automated control of oxygen (OxyMate) for preterm infants on bCPAP. This trial will use an established technology (automated oxygen titration algorithm, VDL1.1) partnered with a low-cost bCPAP device in a low-resource setting. It will involve preterm infants requiring bCPAP respiratory support with allocation to OxyMate or manual oxygen control for consecutive 24 h periods in random sequence. Objectives: This trial seeks to examine safety and potential efficacy of our automated oxygen configuration (OxyMate) in preterm infants in a setting characterised by financial constraints, workforce limitations, and underdeveloped infrastructure, and assess contextual feasibility and appropriateness to inform future definitive clinical trials and product development.

Official Title
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Automated Oxygen Control for Preterm Infants On Continuous Positive Airway Pressure (CPAP): Phase 1/2 Trial In Southwest Nigeria

Conditions
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Neonatal Respiratory Distress Related Conditions, Neonatal Respiratory Failure, Prematurity, Oxygen Toxicity

Intervention / Treatment
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* Device: OxyMate
* Other: Manual oxygen control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: <34 weeks gestation (or birth weight < 2kg if gestation not known) ≥12 hours old Receiving CPAP support and supplemental oxygen (FiO2 >0.21) for respiratory insufficiency Projected requirement for CPAP and oxygen therapy for > 48 hours Exclusion Criteria: Deemed likely to fail CPAP in the next 48 hours Deemed clinically unstable or recommended for palliation by treating team Cause of hypoxaemia likely to be non-respiratory - e.g. cyanotic heart disease Informed consent from parent/guardians not obtained

Ages Eligible for Study
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Minimum Age: 12 Hours
Maximum Age: 1 Month

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
Interventional Model Description: Preterm infants on bCPAP are managed with each mode of oxygen control for 24 hours, prior to crossing over to the other mode of control. Change over simply involves flicking the computer switch from manual to automated control (or vice versa) and it is enacted immediately. It does not require any adjustment or interruption of the CPAP and it does not involve additional action from clinical staff. While the fraction of inspired oxygen (FiO2) adjustments have their effect relatively rapidly, we will apply a 1 h washout period (dropping this data from analysis) to avoid contamination between arms.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Manual oxygen control<br>Oxygen therapy delivered with bCPAP as per standard practice, except for the addition of continuous pulse oximetry. Nursing staff will make manual adjustments to Fraction of Inspired Oxygen (FiO2) provided to infants on bCPAP. Oxygen saturations (SpO2) will be monitored by continuous pulse oximetry, and nurses asked to target the range of SpO2 91-95%. Pulse oximeter alarms will be set to alert nurses to periods of hypoxaemia (SpO2<88%) and hyperoxaemia (SpO2>96%). | Other: Manual oxygen control<br>* Guidelines and training in FiO2 titration to achieve a target range of SpO2. Health workers instructed in responding to continuous pulse oximetry readings and alarms<br>|
| Experimental: OxyMate Automated Oxygen Control<br>Automated control of oxygen therapy partnered with bCPAP delivered as per standard practice. The automated oxygen control set-up (OxyMate) will consist of: continuous pulse oximetry input, a computer algorithm (VDL1.1) that calculates changes to delivered FiO2 based on the input SpO2, and a mechanism to automatically effect changes to delivered FiO2. The system will target an SpO2 of 93% (mid-point of the target range). There will be several embedded safety mechanisms, including the ability to manually over-ride OxyMate at any stage. Pulse oximeter alarms will be as for the manual control arm, with additional automated system alarms in place. | Device: OxyMate<br>* Automated Oxygen Control algorithm (VDL 1.1) coupled with Diamedica Baby CPAP device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of time in target SpO2 range | Proportion of time (over total recorded time) in the target SpO2 range (91-95%, or 91-100% when in room air). Measured as %time | Measured for each 24 hour study epoch | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of time in target SpO2 range when receiving supplemental oxygen | Proportion of time (over total recorded time) in SpO2 target range (91-95%) when receiving supplemental oxygen. Measured as %time when receiving oxygen | Measured for each 24 hour study epoch | 
| Proportion of time in hypoxaemia | Proportion of time (over total recorded time) with SpO2<90% (hypoxaemia). Measured as %time | Measured for each 24 hour study epoch | 
| Proportion of time in severe hypoxaemia | Proportion of time (over total recorded time) with SpO2 <80% (severe hypoxaemia). Measured as %time | Measured for each 24 hour study epoch | 
| Frequency of prolonged hypoxaemia episodes | Frequency of 30 seconds episodes with SpO2 continuously <80% (severe hypoxaemic episodes). Measured as episodes per hour | Measured for each 24 hour study epoch | 
| Proportion of time in hyperoxaemia | Proportion of time (over total recorded time) with SpO2 >96% when receiving supplemental oxygen (hyperoxaemia). Measured as %time when receiving oxygen | Measured for each 24 hour study epoch | 
| Proportion of time in severe hyperoxaemia | Proportion of time (over total recorded time) with SpO2 >98% when receiving supplemental oxygen (severe hyperoxaemia). Measured as %time when receiving oxygen | Measured for each 24 hour study epoch | 
| Frequency of prolonged hyperoxaemia episodes | Frequency of 30 seconds episodes with SpO2 continuously >96% (hyperoxaemic episodes). Measured as episodes per hour | Measured for each 24 hour study epoch | 
| Manual FiO2 adjustments | Frequency of manual FiO2 adjustments. Measured as FiO2 adjustments/hour | Measured for each 24 hour study epoch | 
| No response to prolonged severe hypoxaemia (frequency) | Number of periods of no FiO2 increment for ≥30 seconds with SpO2 <80% (i.e. failure to respond to severe hypoxaemia). Measured as episodes per hour | Measured for each 24 hour study epoch | 
| No response to prolonged severe hypoxaemia (duration) | Duration of periods of no FiO2 increment for ≥30 seconds with SpO2 <80% (i.e. failure to respond to severe hypoxaemia). Measured as mean duration per episode | Measured for each 24 hour study epoch | 
| Severe hypoxaemia with bradycardia (frequency) | Number of periods with SpO2 <80% for ≥30 seconds with any bradycardia (heart rate <100 bpm). Measured as episodes per hour | Measured for each 24 hour study epoch | 
| Severe hypoxaemia with bradycardia (duration) | Duration of periods with SpO2 <80% for ≥30 seconds with any bradycardia (heart rate <100 bpm). Measured as mean duration per episode | Measured for each 24 hour study epoch | 
| Device malfunction | Number of OxyMate malfunction events | Measured through to OxyMate study completion: estimated 20 weeks | 
| Acceptability and usability | Mean/median user acceptability score (total and per question) on Likert scale from structured questionnaire. Scores range from 1 (strongly disagree) to 5 (strongly agree) with posed statement or question | Completed for each participant (health workers) at end of an infant's study period (49 hours). Results recorded for unique health workers through to OxyMate study completion: estimated 20 weeks | 
| Costs | Total costs of prototype system (Diamedica +/- Automated Oxygen control - OxyMate) | Measured at completion of OxyMate study: an estimated 20 weeks | 
| Duration of CPAP and oxygen therapy | Duration of time on CPAP with supplemental oxygen. Measured in hours | Completed for each participant at end of their study period: 49 hours from study commencement | 
| CPAP in room air | Duration of time on CPAP in room air. Measured in hours | Completed for each participant at end of their study period: 49 hours from study commencement | 
| Time on low flow oxygen | Duration of time on low-flow oxygen therapy. Measured in hours | Completed for each participant at end of their study period: 49 hours from study commencement | 
| Final discharge outcome | Measured as categorical outcome (died in hospital, discharged well, discharged against medical advice, other) | Up to 4 weeks post enrollment | 
| Length of stay | Measured in days | Up to 4 weeks post enrollment |