Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001073695
Ethics application status
Approved
Date submitted
16/08/2023
Date registered
6/10/2023
Date last updated
6/10/2023
Date data sharing statement initially provided
6/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of early Restoration of CIRCADian rhythms in very preterm Infants via Environmental Modification on Infection in Early Life: The CIRCA DIEM Infection and Immunology Substudy
Scientific title
Effect of early Restoration of CIRCADian rhythms in very preterm Infants via Environmental Modification on Infection in Early Life: The CIRCA DIEM Infection and Immunology Substudy
Secondary ID [1] 309803 0
Nil known
Universal Trial Number (UTN)
Trial acronym
CIRCA DIEM II
Linked study record
ACTRN12618000371291 is the parent study for the sub-study described in this record.

Health condition
Health condition(s) or problem(s) studied:
Infection 331109 0
Impaired immunity 331110 0
Prematurity 331111 0
Condition category
Condition code
Infection 327082 327082 0 0
Studies of infection and infectious agents
Inflammatory and Immune System 327895 327895 0 0
Normal development and function of the immune system
Reproductive Health and Childbirth 327896 327896 0 0
Complications of newborn

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
2
Target follow-up type
Years
Description of intervention(s) / exposure
Very preterm infants (<32 w gestation) will be eligible for the CIRCA DIEM Infection and Immunology Substudy if they are enrolled in the parent CIRCA DIEM study.

The parent CIRCA DIEM study involves randomisation of eligible enrolled infants to either standard environmental care (control) or a cycled environment (light and noise) from birth until discharge. The intervention group will receive cycled environmental light and noise to simulate day/night-time environments using a pragmatic 14 hour day (6 am – 8 pm), 10 hour night (8 pm – 6 am) cycle. Daytime intervention will include exposure to light including removal of cot-covers if present, to achieve lighting within the range of 300-600 lux, whilst avoiding direct bright light to the infant’s eyes. Nocturnal intervention will include repositioning of cot-covers, application of light-occlusive eye-masks; and silicone ear-plugs. Eye-masks and ear-plugs will remain in position during any medical procedures or overnight cares unless removal is necessary for medical reasons. Light meters positioned within the infant’s cot will be used to ensure daylight lux targets are achieved and maintained (intervention group) or level of ambient lighting recorded (control group). Lux/noise levels will be documented at 8 am, 4 pm and midnight, and audited frequently.

Eye masks will continue to be used for phototherapy and ear protection for high-frequency ventilation as per normal nursery protocols (normally short-term). Respiratory stimulants (e.g. caffeine) will be regulated to 8 am dosing for all infants, when prescribed, to avoid pharmacologic confounding on circadian rhythm development. Similarly, if postnatal glucocorticoids are prescribed for severe lung disease, they will be given at 6 am/6 pm to reduce nocturnal disruption.

Standardised eye masks and silicone earplugs will be supplied, and applied during each period by the nurse caring for the infant.

Protocol adherence to the intervention in the parent CIRCA DIEM study will be monitored by inspection of hospital and clinical record form logs, direct observation by trials staff, and auditing of downloaded electronic recordings of environmental noise exposure (from sound monitors)

Infants are eligible to be enrolled in the Infection and Immunology substudy if parental assent is provided for the collection of additional information and/or samples required. For most infants, involvement in the Infection and Immunology substudy involves provision of access to medical records detailing utilisation of health services (GP visits, hospitalisations for infections). For infants enrolled prospectively, parents will be invited to record their infant's general well-being on a custome designed mobile app (using the Vanderbuilt University MyCap platform) to facilitate recording of information pertaining to presence of symptoms of infection, visits to health care providers and hospitalisations. Parents will be prompted to enter this information at least weekly over the first 2 years of life. Reminders to complete the app will be sent if responses are not received within 24 hours of the due date for an entry.
Biological samples (placental epithelial cells, nasal epithelial and microbiome, buccal cells, faeces, blood) collected at around the time of study entry (~ 7d age), at 36 w postmenstrual age, and at 2 years corrected postnatal age will be obtained from a subset of participants who are recruited to the Infection and Immunology substudy, are born in Western Australia and whose parents provide informed consent to the collection of these biological samples. Participation in this substudy will require parental assent to collection of the biological samples. We will aim to collect samples from up to 120 infants at each time point.
Intervention code [1] 327164 0
Not applicable
Comparator / control treatment
The control treatment in the parent CIRCA DIEM study will be routine care with no individual environmental modification.
Control group
Active

Outcomes
Primary outcome [1] 335740 0
Number of hospitalisations for bacterial or viral infection (composite outcome). Data will be collected prospectively via study-specific survey and confirmed via data-linkage to medical records.
Timepoint [1] 335740 0
2 years corrected postnatal age
Secondary outcome [1] 425425 0
Number of febrile episodes (>38.5 C) in the first 2 years of life collected by parental self-report in study specific survey for prospective enrolled subjects.
Timepoint [1] 425425 0
at 0.5, 1, and 2 years corrected postnatal age
Secondary outcome [2] 425426 0
Number of courses of antibiotics after discharge from hospital collected by parental self-report in study specific survey for prospective enrolled subjects.
Timepoint [2] 425426 0
At 2 years corrected postnatal age
Secondary outcome [3] 425427 0
Number of hospitalisations for respiratory illnesses collected prospectively via study-specific survey and confirmed via data-linkage to medical records.
Timepoint [3] 425427 0
2 years corrected postnatal age
Secondary outcome [4] 425428 0
Number of hospitalisations for gastrointestinal infections collected prospectively via study-specific survey and confirmed via data-linkage to medical records.
Timepoint [4] 425428 0
2 years corrected postnatal age
Secondary outcome [5] 425429 0
Time to first rehospitalisation post initial discharge home collected prospectively via study-specific survey and confirmed via data-linkage to medical records.
Timepoint [5] 425429 0
2 years corrected postnatal age
Secondary outcome [6] 425430 0
Time to first febrile episode post initial discharge home from hospital collected by parental self-report in a study-specific survey for prospectively enrolled subjects.
Timepoint [6] 425430 0
2 years corrected postnatal age
Secondary outcome [7] 427216 0
Number of respiratory viral infections collected by parental self-report in a study-specific survey for prospectively enrolled subjects.and confirmed via data-linkage to medical records
Timepoint [7] 427216 0
2 years corrected postnatal age
Secondary outcome [8] 427217 0
Diagnosis of asthma or wheezy illness collected by parental self-report in a study-specific survey for prospectively enrolled subjects
Timepoint [8] 427217 0
2 years corrected postnatal age
Secondary outcome [9] 427218 0
Indices of neutrophil function assessed from blood samples
Timepoint [9] 427218 0
Study entry, 36 weeks postmenstrual age and at 2 years corrected postnatal age
Secondary outcome [10] 427227 0
Indices of airway epithelial cell function collected from nasal swabs
Timepoint [10] 427227 0
36 weeks postmenstrual age and at 2 years corrected postnatal age
Secondary outcome [11] 427673 0
Indices of immune function assessed from blood samples
Timepoint [11] 427673 0
Study entry, 36 weeks postmenstrual age and at 2 years corrected postnatal age

Eligibility
Key inclusion criteria
• Are born at < 32 weeks postmenstrual age by best obstetric estimate (inborn or outborn)
• Have initial care at a perinatal centre where routine care does not include individual environmental light/noise cycling
• Have informed parental consent to participation in the parent CIRCA DIEM trial (ANZCTRN12618000371291),
• Have consented to participate in the CIRCA DIEM Infection and Immunology substudy
Minimum age
0 Hours
Maximum age
2 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Have a congenital neurodevelopmental abnormality
• Are critically ill and not expected to survive to discharge
• Grade IV intracerebral haemorrhage prior to enrolment into study.
• Unlikely to return for a 2 year follow-up
• Intervention unable to be continued until discharge home (step-down discharge unit not participating as a sub-site in the trial)

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Convenience sample
Timing
Both
Statistical methods / analysis
Convenience cohort defined by written consent to participate from infants already enrolled in the parent CIRCA DIEM RCT. Sample size will be limited by the final sample size of the parent CIRCA DIEM study (target n=954), the number of participants who agree to participate in the Infection and Immunology Substudy, and the availability of data.
We project that a sample size of 636 infants will achieve 90 % power to identify a 15 % reduction in the proportion of premature infants hospitalised for an infection in the first 2 years of life from 63 % to 48 %. with an alpha 0.05 after accounting for 10 % loss to follow-up and 20 % multiple birth.
Data will be collected prospectively for infants still in hospital following birth or who are randomised to the parent CIRCA DIEM study after commencement of the Infection and Immunology substudy.
Data for the primary outcome and available secondary outcomes will be collected via data linkage for infants randomised to the parent CIRCA DIEM study and discharged from hospital prior to commencement of the Infection and Immunology substudy.
Data will be analysed in R on an intention to treat basis by biostatisticians blinded to study group assignment.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
9/10/2023
Actual
Date of last participant enrolment
Anticipated
9/04/2025
Actual
Date of last data collection
Anticipated
9/06/2027
Actual
Sample size
Target
636
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 25400 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [2] 25401 0
Monash Children’s Hospital - Clayton
Recruitment hospital [3] 25402 0
Westmead Hospital - Westmead
Recruitment hospital [4] 25403 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 25404 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [6] 25405 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [7] 25590 0
Gold Coast University Hospital - Southport
Recruitment hospital [8] 25591 0
Joan Kirner Women’s and Children’s Hospital - St Albans
Recruitment hospital [9] 25592 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 41143 0
2050 - Camperdown
Recruitment postcode(s) [2] 41141 0
2145 - Westmead
Recruitment postcode(s) [3] 41415 0
2747 - Kingswood
Recruitment postcode(s) [4] 41414 0
3021 - St Albans
Recruitment postcode(s) [5] 41140 0
3168 - Clayton
Recruitment postcode(s) [6] 41413 0
4215 - Southport
Recruitment postcode(s) [7] 41144 0
5006 - North Adelaide
Recruitment postcode(s) [8] 41139 0
6008 - Subiaco
Recruitment postcode(s) [9] 41142 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 25714 0
New Zealand
State/province [1] 25714 0
Country [2] 25715 0
United Kingdom
State/province [2] 25715 0
England

Funding & Sponsors
Funding source category [1] 313986 0
Government body
Name [1] 313986 0
National Health and Medical Research Council
Country [1] 313986 0
Australia
Funding source category [2] 314613 0
Other Collaborative groups
Name [2] 314613 0
Telethon Kids Institute
Country [2] 314613 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Telethon Kids Institute
Address
15 Hospital RdNedlandsWestern Australia, 6009
Country
Australia
Secondary sponsor category [1] 316575 0
None
Name [1] 316575 0
Address [1] 316575 0
Country [1] 316575 0
Other collaborator category [1] 282824 0
University
Name [1] 282824 0
The University of Western Australia
Address [1] 282824 0
35 Stirling Hwy, Crawley, 6009
Country [1] 282824 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313123 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 313123 0
15 Hospital RdNedlandsWestern Australia, 6009
Ethics committee country [1] 313123 0
Australia
Date submitted for ethics approval [1] 313123 0
17/01/2023
Approval date [1] 313123 0
28/04/2023
Ethics approval number [1] 313123 0
RGS0000000954

Summary
Brief summary
Recent research suggests that our circadian rhythm plays a very important role in how we develop and how our immune system works. The CIRCA DIEM Study (ACTRN12618000371291) is randomising hospitalised premature infants born before 32 weeks gestation to be standard routine care or to be cycled between an artificial night-time from 8 pm to 6 am (using eye masks to block out light and ear plugs to reduce noise) and then to be exposed to an artificial daytime from 6 am to 8 pm (removal of eye masks and ear plugs and light levels from 300-600 lux (similar to low-level office lighting). The intervention continues until babies are discharged home to a normal day/night environment.
As part of the CIRCA DIEM trial, we are inviting participating families to enrol their baby into an Infection and Immunology substudy. The main aim of the CIRCA DIEM Infection and Immunology Sub-Study is to find out whether the timing of the development of a circadian rhythm influences the likelihood of premature babies developing infections that require hospitalisation over the first 2 years of life. Babies enrolled in the CIRCA DIEM main study whose parents agree to their participation in the Infection and Immunology Substudy will be followed-up after discharge home using a mobile app to track infant well-being, presence of symptoms of infection, visits to health care providers and hospitalisations. Some infants will also have some biological samples collected to help us understand the mechanism of any differences that are evident between the intervention and control groups with respect to hospitalisations for infections and other secondary substudy outcomes.
Trial website
https://www.telethonkids.org.au/projects/the-circa-diem-study/sub-studies/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127078 0
Prof Jane Pillow
Address 127078 0
The Telethon Kids Institute, 15 Hospital Avenue, Nedlands, Western Australia, 6009
Country 127078 0
Australia
Phone 127078 0
+61482089854
Fax 127078 0
Email 127078 0
jane.pillow@telethonkids.org.au
Contact person for public queries
Name 127079 0
Prof Jane Pillow
Address 127079 0
The Telethon Kids Institute, 15 Hospital Avenue, Nedlands, Western Australia, 6009
Country 127079 0
Australia
Phone 127079 0
+61482089854
Fax 127079 0
Email 127079 0
jane.pillow@telethonkids.org.au
Contact person for scientific queries
Name 127080 0
Prof Jane Pillow
Address 127080 0
The Telethon Kids Institute, 15 Hospital Avenue, Nedlands, Western Australia, 6009
Country 127080 0
Australia
Phone 127080 0
+61482089854
Fax 127080 0
Email 127080 0
jane.pillow@telethonkids.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification;
When will data be available (start and end dates)?
Data will be available following the publication of study results, currently anticipated 31/3/2028
Study data will be available for approximately 25 years.
Available to whom?
Researchers who provide a methodologically sound proposal, at the discretion of the chief investigator and project sponsor
Available for what types of analyses?
For IPD meta-analysis, and potentially other analyses at the discretion of the chief investigator and project sponsor
How or where can data be obtained?
Access subject to approvals by Principal Investigator (PI) and requirement to sign a data access agreement.
Potentially subject to agreement from participating sites/subsites.
The PI may be contacted at the study email address: circadiem@telethonkids.org.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20046Study protocol  circadiem@telethonkids.org.au 386005-(Uploaded-16-08-2023-18-06-30)-Study-related document.pdf
20048Informed consent form    386005-(Uploaded-16-08-2023-18-07-47)-Study-related document.docx
20050Ethical approval    386005-(Uploaded-16-08-2023-18-08-55)-Study-related document.pdf
20486Ethical approval https://www.telethonkids.org.au/projects/the-circa-diem-study/circadiem@telethonkids.org.au Initial ethics approval for parent CIRCA DIEM Stud... [More Details] 386005-(Uploaded-26-09-2023-14-22-39)-Study-related document.pdf



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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