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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
15/02/2021
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)
Scientific title
Caffeine prophylaxis to improve intermittent hypoxaemia in infants born late preterm: a randomised controlled dosage trial (Latte Dosage Trial)
Secondary ID [1] 295718 0
None
Universal Trial Number (UTN)
U1111-1218-4321
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intermittent hypoxaemia 309114 0
Condition category
Condition code
Reproductive Health and Childbirth 307990 307990 0 0
Complications of newborn
Respiratory 307991 307991 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 302041 0
Treatment: Drugs
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.
Control group
Placebo

Outcomes
Primary outcome [1] 306967 0
Frequency of intermittent hypoxaemia (events/hour, defined as a brief transient fall in oxygen saturation concentration =10% below baseline) on overnight oximetry,
Timepoint [1] 306967 0
Two weeks after randomisation
Secondary outcome [1] 350272 0
Frequency of intermittent hypoxaemia on overnight pulse oximetry
Timepoint [1] 350272 0
Term equivalent age (40 weeks’ post-menstrual age)
Secondary outcome [2] 350273 0
Mean overnight oxygen saturation measured using overnight pulse oximetry
Timepoint [2] 350273 0
Two weeks after randomisation and at term equivalent age
Secondary outcome [3] 350274 0
Weight gain measured as growth velocity, g.kg-1.day- using baby scales
Timepoint [3] 350274 0
From birth to term equivalent age
Secondary outcome [4] 350275 0
Length measured as growth velocity, cm.kg-1.day-1 using a neonatometer
Timepoint [4] 350275 0
From birth to term equivalent age
Secondary outcome [5] 350276 0
Tachycardia, measured as percentage of time HR >180 beats/min on overnight pulse oximetry
Timepoint [5] 350276 0
Two weeks after randomisation and at term equivalent age
Secondary outcome [6] 350277 0
Feed intolerance reported by parents using the Infant Gastroesophageal Reflux Questionnaire (I-GERQ-R)
Timepoint [6] 350277 0
Two weeks after randomisation and at term equivalent age
Secondary outcome [7] 350278 0
Sleeping and arousal as measured by subscale 9 on the Infant Behaviour Questionnaire-Revised (IBQ-R), modified for neonates
Timepoint [7] 350278 0
Two weeks after randomisation and at term equivalent age
Secondary outcome [8] 350279 0
Maternal salivary caffeine concentration collected by spitting into a tube
Timepoint [8] 350279 0
Two weeks after randomisation
Secondary outcome [9] 350280 0
Maternal daily caffeine intake measured using a caffeine intake questionnaire
Timepoint [9] 350280 0
Baseline, two weeks after randomisation and at term equivalent age
Secondary outcome [10] 350281 0
Maternal mental health (Edinburgh postnatal depression score)
Timepoint [10] 350281 0
At baseline and term equivalent age
Secondary outcome [11] 350282 0
Duration of tube feeding in days, assessed using medical records
Timepoint [11] 350282 0
From birth until 24 hours without a gastric tube in situ
Secondary outcome [12] 350283 0
Neonatal or infant death, assessed using clinical notes and reported to the DSMC within 24 hours
Timepoint [12] 350283 0
From birth until 4 weeks of age (neonatal) or 1 year of age (infant)
Secondary outcome [13] 350284 0
Neonatal seizures requiring anti-convulsant treatment using medical records
Timepoint [13] 350284 0
Before 44 weeks postmenstrual age
Secondary outcome [14] 350286 0
Study drug stopped due to presumed side effects (e.g. tachycardia, irritability, poor sleeping, feed intolerance), determined using clinical judgement or by parental request
Timepoint [14] 350286 0
At time of event
Secondary outcome [15] 351410 0
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
Timepoint [15] 351410 0
From initial discharge until 44 weeks postmenstrual age
Secondary outcome [16] 351411 0
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)
Timepoint [16] 351411 0
At time of event
Secondary outcome [17] 351412 0
Use of respiratory support, including oxygen, determined using medical records
Timepoint [17] 351412 0
From birth until term equivalent age
Secondary outcome [18] 352235 0
Head circumference growth velocity, cm.kg-1.day-1 measured using a tape measure
Timepoint [18] 352235 0
From birth to term equivalent age
Secondary outcome [19] 352236 0
Infant salivary caffeine concentration collected using a mouth swab
Timepoint [19] 352236 0
Two weeks after randomisation

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
Minimum age
0 Hours
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
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.
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.
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
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.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
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.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 20730 0
New Zealand
State/province [1] 20730 0
Auckland

Funding & Sponsors
Funding source category [1] 300310 0
Government body
Name [1] 300310 0
Health Research Council of New Zealand
Address [1] 300310 0
PO Box 5541
Wellesley Street
Auckland 1141
New Zealand
Country [1] 300310 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Department of Paediatrics
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand

Country
New Zealand
Secondary sponsor category [1] 299774 0
None
Name [1] 299774 0
Address [1] 299774 0
Country [1] 299774 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301120 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 301120 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 301120 0
New Zealand
Date submitted for ethics approval [1] 301120 0
08/08/2018
Approval date [1] 301120 0
05/09/2018
Ethics approval number [1] 301120 0
18/NTA/129

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85926 0
Dr Jane Alsweiler
Address 85926 0
Department of Paediatrics
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country 85926 0
New Zealand
Phone 85926 0
+64 21 526363
Fax 85926 0
Email 85926 0
j.alsweiler@auckland.ac.nz
Contact person for public queries
Name 85927 0
Ms Elizabeth Oliphant
Address 85927 0
Department of Paediatrics, University of Auckland, Private Bag 92019, Auckland 1142
Country 85927 0
New Zealand
Phone 85927 0
+64 9 923 6342
Fax 85927 0
Email 85927 0
e.oliphant@auckland.ac.nz
Contact person for scientific queries
Name 85928 0
Dr Jane Alsweiler
Address 85928 0
Department of Paediatrics
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country 85928 0
New Zealand
Phone 85928 0
+64 21 526363
Fax 85928 0
Email 85928 0
j.alsweiler@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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 researchhub@auckland.ac.nz.
When will data be available (start and end dates)?
Data will be available after publication of the main trial data. No anticipated end date.
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.
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.
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.
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 10672 0
Study protocol
Citation [1] 10672 0
The Study Protocol will be published in an academic journal
Link [1] 10672 0
Email [1] 10672 0
Other [1] 10672 0
Attachment [1] 10672 0
Type [2] 10673 0
Informed consent form
Citation [2] 10673 0
Link [2] 10673 0
Email [2] 10673 0
s.philipsen@auckland.ac.nz
Other [2] 10673 0
Attachment [2] 10673 0
Type [3] 10674 0
Ethical approval
Citation [3] 10674 0
Link [3] 10674 0
Email [3] 10674 0
s.philipsen@auckland.ac.nz
Other [3] 10674 0
Attachment [3] 10674 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary