Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001344785
Ethics application status
Approved
Date submitted
11/10/2022
Date registered
19/10/2022
Date last updated
29/05/2024
Date data sharing statement initially provided
19/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of caffeine to improve neurodevelopmental outcomes in babies born late preterm: a randomised controlled trial
Scientific title
Investigating the effect of caffeine to improve neurodevelopmental outcomes in babies born late preterm: a randomised controlled trial
Secondary ID [1] 308144 0
HRC 22/305
Universal Trial Number (UTN)
U1111-1282-8881
Trial acronym
The LATTE Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Late preterm birth 327861 0
Neurodevelopmental impairment 327862 0
Condition category
Condition code
Reproductive Health and Childbirth 324945 324945 0 0
Complications of newborn
Neurological 324946 324946 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase III trial
Caffeine citrate, as an oral cherry flavoured syrup, 20 mg/kg once daily from Day 3 after birth until term corrected age.
Dose can be reduced to 10 mg/kg if the baby is tachycardic (heart rate greater than 180 beats per min at rest 1 week after randomisation) or if the parents or clinicians believe the infant is having side effects.
Adherence will be assessed by a research nurse measuring the remaining syrup in the bottle after 3 weeks of intervention.
Intervention code [1] 324598 0
Prevention
Comparator / control treatment
Equivolume of oral cherry flavoured syrup once daily from Day 3 after birth until term corrected age.
Control group
Placebo

Outcomes
Primary outcome [1] 332756 0
Bayley Scale of Infant Development 4th Edition (BSID IV) cognitive score
Timepoint [1] 332756 0
Two and a half years corrected age
Secondary outcome [1] 414612 0
Weight reported by parents during telephone follow up
Timepoint [1] 414612 0
term corrected age (40+0 weeks’ gestational age)
Secondary outcome [2] 414613 0
Length of stay in hospital, by review of medical records
Timepoint [2] 414613 0
From birth until discharge from primary neonatal admission
Secondary outcome [3] 414614 0
Study drug dose reduced due to side effects or poor tolerance from follow up phone-call with parents
Timepoint [3] 414614 0
Prior to term corrected age
Secondary outcome [4] 414615 0
Fully breastfeeding (the baby has taken breast milk only, no other liquids or solids except a minimal amount of water or prescribed medicines, in the past 48 hours) as reported by telephone follow up with parents.
Timepoint [4] 414615 0
Term corrected age (40+0 weeks’ gestational age).
Secondary outcome [5] 414616 0
Cognitive impairment, (BSID IV cognitive score more than one standard deviation (SD) below the test mean (<85, categorical))
Timepoint [5] 414616 0
Two and a half years corrected age
Secondary outcome [6] 414617 0
BSID IV language score (continuous)
Timepoint [6] 414617 0
Two and a half years corrected age
Secondary outcome [7] 414618 0
BSID IV motor score (continuous)
Timepoint [7] 414618 0
Two and a half years corrected age
Secondary outcome [8] 414619 0
Predicating Asthma Risk in Childhood (PARC) score greater than or equal to 5 (high risk of school-age asthma)
Timepoint [8] 414619 0
Two and a half years corrected age
Secondary outcome [9] 414620 0
Weight z score assessed using digital scales,
Timepoint [9] 414620 0
Two and a half years corrected age
Secondary outcome [10] 414621 0
Infant and Toddler quality of life score
Timepoint [10] 414621 0
Two and a half years corrected age
Secondary outcome [11] 414623 0
Moderate-Severe cognitive impairment (BSID IV cognitive score more than two SD below the test mean, <70, categorical)
Timepoint [11] 414623 0
2.5 years corrected age
Secondary outcome [12] 414624 0
Language delay (BSID IV language score more than one SD below the test mean, <85, categorical)
Timepoint [12] 414624 0
2.5 years corrected age
Secondary outcome [13] 414625 0
Moderate-Severe language delay (BSID IV language score more than two SD below the test mean, <70, categorical)
Timepoint [13] 414625 0
2.5 years corrected age
Secondary outcome [14] 414626 0
Motor delay (BSID IV motor score more than one SD below the mean, <85, categorical)
Timepoint [14] 414626 0
2.5 years corrected age
Secondary outcome [15] 414627 0
Moderate-Severe motor delay (BSID IV motor score more than two SD below the test mean, <70, categorical)
Timepoint [15] 414627 0
2.5 years corrected age
Secondary outcome [16] 414628 0
Social-emotional/behavioural delay (BSID IV Social-Emotional score or BSID IV Adaptive Behaviour score more than one SD below the mean, <85, categorical)
Timepoint [16] 414628 0
2.5 years corrected age
Secondary outcome [17] 414629 0
Developmental delay (BSID IV cognitive or language score more than one SD below the test mean, <85, categorical)
Timepoint [17] 414629 0
2.5 years corrected age
Secondary outcome [18] 414630 0
Asthma/wheeze defined as wheeze or whistling in the chest in the past 12 months or doctor diagnosed asthma (yes to PARC #1/International Study of Asthma and Allergies in Childhood (ISAAC) #3 or ISAAC #7-8 questions) by parental questionnaire
Timepoint [18] 414630 0
2.5 years corrected age
Secondary outcome [19] 414631 0
Death
Timepoint [19] 414631 0
assessed continuously from birth up to 2.5 years’ corrected age
Secondary outcome [20] 414632 0
Healthcare utilisation after primary hospital discharge from ministry of health records of hospitalization, outpatient visits and emergency department visits
Timepoint [20] 414632 0
Assessed continuously from primary hospital discharge until 2.5 years corrected age
Secondary outcome [21] 414828 0
Weight z score based on weight reported by parents during telephone follow up
Timepoint [21] 414828 0
Term corrected age (40+0 weeks’ gestational age)
Secondary outcome [22] 414830 0
Study drug dose discontinued due to side effects or poor tolerance from follow up phone-call with parents
Timepoint [22] 414830 0
term corrected age (40+0 weeks’ gestational age)
Secondary outcome [23] 414831 0
height z score assessed using stadiometer
Timepoint [23] 414831 0
two and half years corrected age
Secondary outcome [24] 414832 0
Head circumference z score assessed using tape measure
Timepoint [24] 414832 0
Two and half years corrected age
Secondary outcome [25] 414833 0
body mass index (BMI) z scores using data from secondary outcomes 9 and 23
Timepoint [25] 414833 0
two and half years corrected age

Eligibility
Key inclusion criteria
Babies born between 34+0 and 36+6 weeks’ gestational age without contra-indication to caffeine treatment.
Minimum age
No limit
Maximum age
72 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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
• Maternal age less than 16 years
• More than 72 hours after birth
• Multiple births of triplets or higher

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Variable block sizes with priority stratification for groups of collaborating centres, gestational age at birth (34, 35 and 36 weeks’ gestational age) and ethnicity (Maori or non-Maori).
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
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size
To detect a difference between caffeine and placebo groups of at least 5 points with 90% power (two-sided a=0.05) requires 191 babies in each arm (total 382). Allowing for a conservative 20% drop-out rate (withdrawal and loss to follow-up), we will recruit a total of 478 babies (239 in each arm). Babies from multiple pregnancy may be recruited and will be allocated to the same intervention to avoid accidental cross-over. Only one baby from a multiple pregnancy will be counted in the sample size but all enrolled babies will be included in the intention-to-treat analysis. Assuming a similar rate of multiple births to that seen in the Latte dosage study (ACTRN12618001745235 average number of babies per mother = 1.065), we will expect to include a total of 510 babies if we achieve our target sample size of 478.
We will place an emphasis on recruiting Maori whanau in this study to assist Mana Whakamarama (equal explanatory power) to occur. To incorporate this principle, we will aim to recruit equal numbers of Maori and non-Maori pepi (239 Maori, 239 non-Maori).
Statistical Methods
The primary analysis will compare primary and secondary outcomes between the placebo and caffeine group using generalised mixed models with adjustment for the stratification variables of groups of collaborating centres, gestational age at birth and ethnicity (Maori or non-Maori); potential confounding by socio-economic status (NZ Deprivation Index) and sex; and non-independence of multiples (random effect). Treatment effects will be presented as mean difference, ratio of geometric means (positively skewed data) or risk difference with 95% confidence interval. For categorical data, an estimate of relative effect will also be given (odds ratio, 95% confidence interval). A hypothesis test will be conducted for the primary outcome (two-tailed a=0.05). The data will be analysed on an intention-to-treat basis. Missing data will not be imputed in the primary analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/01/2023
Actual
22/05/2023
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/08/2027
Actual
Sample size
Target
478
Accrual to date
167
Final
Recruitment outside Australia
Country [1] 25052 0
New Zealand
State/province [1] 25052 0

Funding & Sponsors
Funding source category [1] 312407 0
Government body
Name [1] 312407 0
Health Research Council
Country [1] 312407 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
507-1046
Building 507,
Grafton Road
University of Auckland
Private Bag 92019
Auckland 1010
Country
New Zealand
Secondary sponsor category [1] 313979 0
None
Name [1] 313979 0
Address [1] 313979 0
Country [1] 313979 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311756 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 311756 0
Ethics committee country [1] 311756 0
New Zealand
Date submitted for ethics approval [1] 311756 0
25/09/2022
Approval date [1] 311756 0
10/10/2022
Ethics approval number [1] 311756 0
2022 FULL 13147

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122254 0
A/Prof Jane Alsweiler
Address 122254 0
507-1046
Department of Paediatrics: Child and Youth Health
University of Auckland
Private Bag 92019
Auckland 1010
Country 122254 0
New Zealand
Phone 122254 0
+6421526363
Fax 122254 0
Email 122254 0
[email protected]
Contact person for public queries
Name 122255 0
Jane Alsweiler
Address 122255 0
507-1046
Department of Paediatrics: Child and Youth Health
University of Auckland
Private Bag 92019
Auckland 1010
Country 122255 0
New Zealand
Phone 122255 0
+6421526363
Fax 122255 0
Email 122255 0
[email protected]
Contact person for scientific queries
Name 122256 0
Jane Alsweiler
Address 122256 0
507-1046
Department of Paediatrics: Child and Youth Health
University of Auckland
Private Bag 92019
Auckland 1010
Country 122256 0
New Zealand
Phone 122256 0
+6421526363
Fax 122256 0
Email 122256 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised study data from participants who have agreed for their data to be shared with other researchers.
When will data be available (start and end dates)?
Following publication of the main trial findings (estimated January 2028), no end date
Available to whom?
Only researchers who provide a methodologically sound proposal, have appropriate ethics approval and agree to the data sharing terms in the Latte Trial Data management plan, which include aligning with Maori data sovereignty frameworks and a Latte Trial Maori investigator directly overseeing use of the data to ensure it is respected as taonga (treasure).
Available for what types of analyses?
Analyses that meet the criteria of the Latte Trial Data Management Plan:
- The use of study data upholds and is respectful of Maori knowledge, worldviews and self-determination.
• Patients are likely to derive benefit from the use of study data, including promotion of equitable outcomes.
How or where can data be obtained?
Access subject to approvals by the Latte Trial Steering Group, contacted through the Principal Investigator (A/Prof Jane Alsweiler, [email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17335Study protocol    Not yet available, but will be published.



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
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