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Trial registered on ANZCTR
Registration number
ACTRN12618001745235
Ethics application status
Approved
Date submitted
17/09/2018
Date registered
24/10/2018
Date last updated
11/02/2022
Date data sharing statement initially provided
9/04/2019
Date results information initially provided
15/02/2021
Type of registration
Prospectively registered
Titles & IDs
Public title
Caffeine to improve oxygen levels in mildly preterm babies (Latte Dosage Trial)
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Scientific title
Caffeine prophylaxis to improve intermittent hypoxaemia in infants born late preterm: a randomised controlled dosage trial (Latte Dosage Trial)
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Secondary ID [1]
295718
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None
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Universal Trial Number (UTN)
U1111-1218-4321
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Intermittent hypoxaemia
309114
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Condition category
Condition code
Reproductive Health and Childbirth
307990
307990
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0
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Complications of newborn
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Respiratory
307991
307991
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0
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Other respiratory disorders / diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Infants will be randomised to a caffeine citrate dose of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg or placebo (water), with 1:1:1:1:1 allocation. Infants will be randomised within 72 hours of birth. Infants from multiple births will be randomised to the same treatment group.
Randomised infants will receive a study allocation letter (A to E) that corresponds to pre-labelled study bottles containing either caffeine or placebo (identical appearanec). To maintain blinding all infants will receive the same dose volume (1ml/kg, once daily) of their allocated caffeine concentration.
Infants will be given a 2 ml/kg enteral loading dose of the study drug (10 mg/kg, 20 mg/kg, 30 mg/kg or 40 mg/kg of caffeine citrate or water) at 7-9 am on the first morning after the infant reaches 72 hours of age, followed by a daily dose of 1 ml/kg each morning (5 mg/kg, 10mg/kg, 15 mg/kg or 20 mg/kg of caffeine citrate or placebo) until term equivalent age (40 weeks’ post-menstrual age). The dose will be recalculated for the infants’ weight gain weekly after the infant has regained birth weight.
The study drug is given via a nasogastric tube for infants with a tube in situ, and orally for infants who do not require a nasogastric tube. Infants who are not able to tolerate enteral medications will have the study drug withheld.
Adherence will be assessed by a drug dairy which details the volume of the study drug that was given, the time of the dose, and any vomiting or reflux with the medication. This will be checked by the research nurse at the two weeks visit and collected at the last visit. At the two weeks visit the research nurse will give the parents a new bottle of the study drug and collect the current bottle to measure compliance. On the last visit (term equivalent age) the research nurse will ask what treatment they thought their infant received, to assess the adequacy of study blinding, and collect the remaining study drug for measurement to determine the remaining volume. Good compliance will be defined as <20% of the expected study drug volume remaining or missing <20% of daily doses by term equivalent age.
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Intervention code [1]
302041
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Treatment: Drugs
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Comparator / control treatment
Infants will be randomised to the placebo treatment using the same process described for the intervention. The placebo is water and of identical appearance to the intervention.
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Frequency of intermittent hypoxaemia (events/hour, defined as a brief transient fall in oxygen saturation concentration =10% below baseline) on overnight oximetry,
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Assessment method [1]
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Timepoint [1]
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Two weeks after randomisation
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Secondary outcome [1]
350272
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Frequency of intermittent hypoxaemia on overnight pulse oximetry
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Assessment method [1]
350272
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Timepoint [1]
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Term equivalent age (40 weeks’ post-menstrual age)
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Secondary outcome [2]
350273
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Mean overnight oxygen saturation measured using overnight pulse oximetry
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Assessment method [2]
350273
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Timepoint [2]
350273
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Two weeks after randomisation and at term equivalent age
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Secondary outcome [3]
350274
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Weight gain measured as growth velocity, g.kg-1.day- using baby scales
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Assessment method [3]
350274
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Timepoint [3]
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From birth to term equivalent age
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Secondary outcome [4]
350275
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Length measured as growth velocity, cm.kg-1.day-1 using a neonatometer
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Assessment method [4]
350275
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Timepoint [4]
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From birth to term equivalent age
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Secondary outcome [5]
350276
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Tachycardia, measured as percentage of time HR >180 beats/min on overnight pulse oximetry
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Assessment method [5]
350276
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Timepoint [5]
350276
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Two weeks after randomisation and at term equivalent age
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Secondary outcome [6]
350277
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Feed intolerance reported by parents using the Infant Gastroesophageal Reflux Questionnaire (I-GERQ-R)
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Assessment method [6]
350277
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Timepoint [6]
350277
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Two weeks after randomisation and at term equivalent age
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Secondary outcome [7]
350278
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Sleeping and arousal as measured by subscale 9 on the Infant Behaviour Questionnaire-Revised (IBQ-R), modified for neonates
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Assessment method [7]
350278
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Timepoint [7]
350278
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Two weeks after randomisation and at term equivalent age
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Secondary outcome [8]
350279
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Maternal salivary caffeine concentration collected by spitting into a tube
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Assessment method [8]
350279
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Timepoint [8]
350279
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Two weeks after randomisation
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Secondary outcome [9]
350280
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Maternal daily caffeine intake measured using a caffeine intake questionnaire
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Assessment method [9]
350280
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Timepoint [9]
350280
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Baseline, two weeks after randomisation and at term equivalent age
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Secondary outcome [10]
350281
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Maternal mental health (Edinburgh postnatal depression score)
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Assessment method [10]
350281
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Timepoint [10]
350281
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At baseline and term equivalent age
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Secondary outcome [11]
350282
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Duration of tube feeding in days, assessed using medical records
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Assessment method [11]
350282
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Timepoint [11]
350282
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From birth until 24 hours without a gastric tube in situ
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Secondary outcome [12]
350283
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Neonatal or infant death, assessed using clinical notes and reported to the DSMC within 24 hours
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Assessment method [12]
350283
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Timepoint [12]
350283
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From birth until 4 weeks of age (neonatal) or 1 year of age (infant)
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Secondary outcome [13]
350284
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Neonatal seizures requiring anti-convulsant treatment using medical records
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Assessment method [13]
350284
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Timepoint [13]
350284
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Before 44 weeks postmenstrual age
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Secondary outcome [14]
350286
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Study drug stopped due to presumed side effects (e.g. tachycardia, irritability, poor sleeping, feed intolerance), determined using clinical judgement or by parental request
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Assessment method [14]
350286
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Timepoint [14]
350286
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At time of event
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Secondary outcome [15]
351410
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Readmission to hospital, and reason(s) for admission (defined as admission to postnatal, medical or surgical ward, or emergency department stay) for >12 hours assessed using medical records
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Assessment method [15]
351410
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Timepoint [15]
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From initial discharge until 44 weeks postmenstrual age
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Secondary outcome [16]
351411
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Open label caffeine citrate use as determined when required from medical records for infants that have apnoea or intermittent hypoxaemia and require oxygen or positive pressure ventilation (high flow or CPAP)
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Assessment method [16]
351411
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Timepoint [16]
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At time of event
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Secondary outcome [17]
351412
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Use of respiratory support, including oxygen, determined using medical records
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Assessment method [17]
351412
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Timepoint [17]
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From birth until term equivalent age
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Secondary outcome [18]
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Head circumference growth velocity, cm.kg-1.day-1 measured using a tape measure
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Assessment method [18]
352235
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Timepoint [18]
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From birth to term equivalent age
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Secondary outcome [19]
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Infant salivary caffeine concentration collected using a mouth swab
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Assessment method [19]
352236
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Timepoint [19]
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Two weeks after randomisation
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Eligibility
Key inclusion criteria
Infants:
Infants born between 34+0 – 36+6 weeks’ GA without contradiction to caffeine treatment and are 72 hours of age or less.
Mothers:
Mother's who have given birth to an infant who is of 34+0 - 36+6 GA
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Minimum age
0
Hours
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Maximum age
50
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Infants:
• Major congenital abnormality
• Minor congenital abnormality likely to affect respiration, growth or development
• Previous caffeine treatment
• Renal or hepatic impairment
• Tachyarrhythmia
• Seizures
• Hypoxic ischaemic encephalopathy
• Residing outside of the Auckland DHB regions
Mothers:
Mother's who have given birth to an infant who has any of the exclusion criteria listed above
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed. Infants will be assigned randomly via an internet randomisation service to the placebo or one of four caffeine doses (5 mg/ml, 10 mg/ml, 15 mg/ml or 20 mg/ml) with equal allocation ratio.
During randomisation the infant will be allocated to a study group (A, B, C, D or E) that will correspond to a pre-labelled study drug bottle which contains either water or identical appearing caffeine citrate at one of four different concentrations. The infant’s hospital sticker will be applied to the bottle and the drug will only be dispensed to that infant.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation sequence will be generated by the study statistician, with variable block sizes and priority stratification for study site (ADHB or CMDHB) and gestational age at birth (34, 35 and 36 weeks’ GA). Multiples will be allocated to the same study group.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
If necessary (infant has apnoea or intermittent hypoxaemia), clinicians can give a loading dose of caffeine citrate as an open label medication . If a clinician decides to continue caffeine treatment, they can discuss the option of partially un-blinding the infant (caffeine or placebo) with the Site Principal Investigator.
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Phase
Phase 2
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
We estimate a mean (SD) frequency of 6.9 (3.4) episodes per hour of intermittent hypoxaemia greater than or equal to 10% below baseline at two weeks’ post randomisation. To detect a 50% reduction of 3.5 episodes per hour with 90% power, allowing for a 10% drop out rate and clustering of multiples with an ICC of 0.05, we will require 24 infants in each arm x 5 arms = 120 infants, with two-sided alpha of 0.05.
The primary analysis will compare primary and secondary outcomes between the placebo and each caffeine group using mixed generalised models with adjustment for gestational age at birth, multiple comparisons (Dunnett), and non-independence of multiples (random effect). Edinburgh Postnatal Depression Scale scores will be adjusted for baseline values. Treatment effects will be presented as odds ratio, count ratio, mean difference or ratio of geometric means (positively skewed data), as appropriate, with 95% confidence intervals. All tests will be two-tailed, with P<0.05 considered significant. The data will be analysed on an intention-to-treat basis.
Secondary analyses will be performed for compliance, open-label caffeine treatment and maternal caffeine intake.
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
1/11/2018
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Actual
27/02/2019
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Date of last participant enrolment
Anticipated
31/03/2020
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Actual
12/12/2020
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Date of last data collection
Anticipated
12/12/2021
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Actual
17/12/2021
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Sample size
Target
132
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Accrual to date
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Final
132
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Recruitment outside Australia
Country [1]
20730
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New Zealand
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State/province [1]
20730
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Auckland
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Funding & Sponsors
Funding source category [1]
300310
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Government body
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Name [1]
300310
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Health Research Council of New Zealand
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Address [1]
300310
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PO Box 5541
Wellesley Street
Auckland 1141
New Zealand
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Country [1]
300310
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New Zealand
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Primary sponsor type
University
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Name
The University of Auckland
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Address
Department of Paediatrics
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
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Country
New Zealand
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Secondary sponsor category [1]
299774
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None
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Name [1]
299774
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Address [1]
299774
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Country [1]
299774
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
301120
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Northern A Health and Disability Ethics Committee
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Ethics committee address [1]
301120
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Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
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Ethics committee country [1]
301120
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New Zealand
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Date submitted for ethics approval [1]
301120
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08/08/2018
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Approval date [1]
301120
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05/09/2018
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Ethics approval number [1]
301120
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18/NTA/129
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Summary
Brief 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.
We propose the Latte Dosage Trial, a randomised, placebo-controlled dosage trial of oral caffeine citrate from birth to term equivalent age to reduce intermittent hypoxaemia in late preterm infants.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
85926
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Dr Jane Alsweiler
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Address
85926
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Department of Paediatrics
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
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Country
85926
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New Zealand
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Phone
85926
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+64 21 526363
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Fax
85926
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Email
85926
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[email protected]
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Contact person for public queries
Name
85927
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Ms Elizabeth Oliphant
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Address
85927
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Department of Paediatrics, University of Auckland, Private Bag 92019, Auckland 1142
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Country
85927
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New Zealand
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Phone
85927
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+64 9 923 6342
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Fax
85927
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Email
85927
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[email protected]
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Contact person for scientific queries
Name
85928
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Dr Jane Alsweiler
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Address
85928
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Department of Paediatrics
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
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Country
85928
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New Zealand
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Phone
85928
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+64 21 526363
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Fax
85928
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Email
85928
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Published data are available to approved researchers under the data sharing arrangements provided by the Maternal and Perinatal Central Coordinating Research Hub (CCRH), Liggins Institute, University of Auckland (https://wiki.auckland.ac.nz/researchhub). Data access
requests are to be submitted to Data Access Committee via
[email protected]
.
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When will data be available (start and end dates)?
Data will be available after publication of the main trial data. No anticipated end date.
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Available to whom?
De-identified published data will be shared with researchers who provide a methodologically sound proposal and have appropriate ethical and institutional approval, to achieve the aims in the proposal, and approved by the Data Access Committee, Liggins Institute.
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Available for what types of analyses?
De-identified published data will be shared with researchers who provide a methodologically sound proposal and have appropriate ethical and institutional approval, to achieve the aims in the proposal, and approved by the Data Access Committee, Liggins Institute.
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How or where can data be obtained?
Researchers must sign and adhere to the Data Access Agreement that includes a commitment to using the data only for the specified proposal, to refrain from any attempt to identify individual participants, to store data securely and to destroy or return the data after completion of the project. Data will be made available electronically by a mechanism approved by the researcher.
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What supporting documents are/will be available?
No Supporting Document Provided
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
10672
Study protocol
The Study Protocol will be published in an academic journal
10673
Informed consent form
[email protected]
10674
Ethical approval
[email protected]
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
(Rad 8)Caffeine prophylaxis to improve intermittent hypoxaemia in infants born late preterm: a randomised controlled dosage trial (Latte Dosage Trial).
2020
https://dx.doi.org/10.1136/bmjopen-2020-038271
Embase
Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial.
2023
https://dx.doi.org/10.1136/archdischild-2022-324010
N.B. These documents automatically identified may not have been verified by the study sponsor.
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