PROTOCOL Caffeine prophylaxis to improve intermittent hypoxaemia in infants born late preterm: a randomised controlled dosage trial (Latte Dosage Trial) Short Title: The Latte Dosage Trial Registration: The Latte Dosage Trial will be registered with ANZCTR (ACTRNXX) Protocol details: version 1.1, dated 28 September 2018 Funding: Health Research Council Sponsor: University of Auckland Principal Investigator: Dr Jane Alsweiler Department of Paediatrics: Child and Youth Health, University of Auckland and Newborn Services, Auckland City Hospital, Auckland District Health Board (ADHB) Address: Department of Paediatrics University of Auckland Private Bag 92019 Auckland 1142 New Zealand Email: [email protected] Phone: +64 21 526363 Investigators: Dr Chris McKinlay, Liggins Institute, University of Auckland and Kidz First Neonatal Care, Counties Manukau Health Dr David McNamara, Starship Hospital, Auckland District Health Board Ms Elizabeth Oliphant, Starship Hospital, Auckland District Health Board and School of Pharmacy, University of Auckland Study Sites: Newborn Services, Auckland City Hospital, Auckland District Health Board (ADHB) Kids First Neonatal Care, Counties Manukau District Health Board (CMDHB) This study protocol follows the SPIRIT checklist Latte Dosage Trial Protocol Version 1.1 28 September 2018 1 Version Record Date Version Updates to this version 13/07/2018 1.0 HDEC application Submitted to HDEC 28/09/2018 1.1 Modification of Adverse Events for reporting to DMC Latte Dosage Trial Protocol Version 1.1 28 September 2018 2 1. PROJECT SUMMARY Late preterm infants (34+0-36+6 weeks’ gestational age (GA)) are the most common of all preterm infants, constituting 6% of all births or 3,700 births annually in New Zealand. These infants have a 30% increased risk of severe long-term neurodevelopmental impairment compared to infants born at term. While there has been progress in improving neurodevelopmental outcomes for infants born more preterm, it is only recently that late preterm infants have been recognised as being at risk of significant problems. Remarkably, there has been very little research on how to improve the long term outcomes of infants born late preterm. In very preterm infants, both apnoea (pauses in breathing) and intermittent hypoxaemia (recurrent drops in oxygen saturation) are common and are associated with worse neurodevelopmental outcomes. Treatment with caffeine not only reduces apnoea and intermittent hypoxaemia in very preterm infants but also improves long-term neurodevelopment. While apnoea of prematurity is less common in late preterm infants, we have recently identified that infants born late preterm are also at increased risk of intermittent hypoxaemia. Caffeine has been shown to improve intermittent hypoxaemia in very preterm infants at 35 weeks’ and 36 weeks’ post-menstrual age, but there are no data to show if caffeine improves long-term neurodevelopmental outcomes in infants born late preterm. The most effective dose of caffeine at this gestational age is uncertain. Very preterm infants have limited ability to metabolise caffeine, but this increases with greater gestational age. Therefore, late preterm infants are likely to need a higher dose of caffeine than very preterm infants. However, if the dose is too high it may have increased side effects and will not be tolerated. This randomised, placebo-controlled, dosage trial of prophylactic caffeine treatment will determine the most effective and best tolerated dose of caffeine to reduce intermittent hypoxia in late preterm infants. Latte Dosage Trial Protocol Version 1.1 28 September 2018 3 Contents 1. PROJECT SUMMARY ........................................................................................................ 3 2. INTRODUCTION ................................................................................................................ 7 2.1 Background ..................................................................................................................... 7 2.2 Objective ......................................................................................................................... 8 2.3 Hypothesis ...................................................................................................................... 8 2.4 Study Design ................................................................................................................... 9 3. METHODS .......................................................................................................................... 9 3.1 Participants, Interventions and Outcomes ....................................................................... 9 3.1.1 Study Setting ............................................................................................................ 9 3.1.2 Eligibility Criteria ....................................................................................................... 9 3.1.3 Exclusion criteria ...................................................................................................... 9 3.1.4 Study Intervention .................................................................................................... 9 3.1.5 Open Label Caffeine Citrate ....................................................................................10 3.1.6 Compliance .............................................................................................................10 3.1.7 Primary Outcome ....................................................................................................11 3.1.8 Secondary Outcomes ..............................................................................................11 3.1.9 Participant Timeline .................................................................................................11 3.1.10 Sample Size ............................................................................................................12 3.1.11 Recruitment .............................................................................................................12 3.1.12 Discontinuation of Study Drug .................................................................................12 3.1.13 Withdrawal ..............................................................................................................12 3.1.14 Co-interventions ......................................................................................................13 3.1.15 Safe sleep ...............................................................................................................13 3.1.16 Re-admission ..........................................................................................................13 3.2 Assignment of interventions ............................................................................................13 3.2.1 Allocation sequence generation ...............................................................................13 3.2.2 Allocation concealment mechanism .........................................................................13 3.2.3 Implementation ........................................................................................................13 3.2.4 Blinding ...................................................................................................................13 3.2.5 Emergency unblinding .............................................................................................14 4. DATA COLLECTION, MANAGEMENT AND ANALYSIS ....................................................14 4.1 Data Collection Methods ................................................................................................14 4.1.1 Pulse Oximetry ........................................................................................................14 Latte Dosage Trial Protocol Version 1.1 28 September 2018 4 4.1.2 Anthropometry .........................................................................................................14 4.1.3 Neonatal Salivary Caffeine ......................................................................................14 4.1.4 Maternal Caffeine Consumption ..............................................................................15 4.1.5 Questionnaires ........................................................................................................15 4.1.6 Neonatal Morbidity ..................................................................................................16 4.2 Data Management ..........................................................................................................16 4.3 Statistical Methods .........................................................................................................16 4.3.1 Descriptive Statistics ...............................................................................................16 4.3.2 Treatment Effect ......................................................................................................16 4.3.3 Secondary Analysis .................................................................................................16 5. DATA MONITORING .........................................................................................................16 5.1.1 Interim Analysis .......................................................................................................17 5.1.2 Harms .....................................................................................................................17 6. ETHICS AND DISSEMINATION ........................................................................................17