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Trial registered on ANZCTR


Registration number
ACTRN12619001708145
Ethics application status
Approved
Date submitted
30/06/2019
Date registered
4/12/2019
Date last updated
4/12/2019
Date data sharing statement initially provided
4/12/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Randomized controlled trial (RCT) comparing between High versus Standard dose caffeine citrate for apnoea in prematurity
Scientific title
Randomized controlled trial (RCT) comparing between High versus Standard dose caffeine citrate for apnoea in prematurity for premature baby with gestational age 28 to 32 weeks.
Secondary ID [1] 298211 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Apnoea of prematurity 312808 0
Condition category
Condition code
Reproductive Health and Childbirth 313050 313050 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Name : Comparing between High dose caffeine (Arm 1) and standard dose caffeine (Arm 2)
Why : Available literatures regarding high versus standard/low dose caffeine for Apnoea in prematurity is not conclusive due to heterogeneity of the doses, gestational age, indication of starting caffeine and sample size. However, some data suggest that the high dose caffeine is beneficial without causing adverse effects except for mild tachycardia. The reason of conducting the study is to determine the efficacy and safety of a high dose of caffeine compared to standard dose for the prevention of apnoea in prematurity

WHAT
Materials : All the research tools that will be used in the study is routinely used for premature babies in Neonatal Intensive Care Unit (NICU). All the research tools have been proved its safety and reliability. Infant’s oxygen saturation, heart rate, and respiratory rate are continuously monitored using monitor that is available in NICU. Blood pressure will be checked, indirectly by oscillometry or Intra-arterial blood pressure if patient is on arterial line.

Procedures :
Before premature delivery and subject recruitment, medical officer or specialist will be subjected to do prenatal counselling to the mothers in antenatal ward HUSM. During the counselling, the study will be briefly explained to the mother in order to give them an ample time to think whether wants to include in the study or not.
Premature babies who fulfill inclusion and exclusion criteria will be assigned randomly into either two groups (Group A: High dose group, Group B: Standard dose group). Infants in group A will receive high dose oral caffeine citrate (loading dose of 40 mg/kg/day equivalent to 20 mg /kg/day of caffeine base and maintenance dose of 20 mg/kg/day equivalent to 10 mg /kg/day of caffeine base). Maintenance dose will be given 24 hours after loading. Infants in group B will receive standard dose oral caffeine citrate (loading dose of 20 mg/kg/day equivalent to 10mg/kg/day of caffeine base and maintenance dose of 10mg/kg/day equivalent to 5 mg/kg/day of caffeine base)
Oral caffeine loading dose will be given to the allocation group (Group A and Group B) within 24 hours periextubation period. If the patient is not intubated, oral caffeine loading dose will be given immediately. If patient has failure extubation, caffeine will be off and continue ventilation. Sameh Mohammed et al defined failure extubation as requiring reintubation within 72 hours. If successful extubation, maintenance dose (MD) will be continued 24 hours after starting caffeine and continue on daily basis. If patient has feeding intolerance while the patient is on caffeine, the medication will be changed into intravenous aminophylline. Previous oral caffeine dose will be restarted once feeding intolerance resolved.

The duration of oral caffeine will be continued at least corrected gestational age is 34 weeks after been assessed by trained doctor. Oral caffeine will be continued beyond 34 weeks gestational age if indicated and assigned by doctor.

The study will be conducted in Neonatal Intensive Care Unit, Hospital USM, Kubang Kerian Kelantan,Malaysia. The hospital is a teaching hospital for University Sains Malaysia and this is where the Health Campus located. Kubang Kerian is one of the major towns of Kelantan, a state in Malaysia where majority of its population are Malays from different socio-economic background. The Neonatal Intensive Care Unit provides level 1 to level 4 intensive care to neonate patient and received referral from all parts of Kelantan and all over the country

The Primary Investigator will monitor the study monthly and fill the data in proforma.


Intervention code [1] 314470 0
Treatment: Drugs
Comparator / control treatment
Infants in group A / control group, received high dose oral caffeine citrate (loading dose of 40 mg/kg/day equivalent to 20 mg /kg/day of caffeine base and maintenance dose of 20 mg/kg/day equivalent to 10 mg /kg/day of caffeine base). Maintenance dose will be given 24 hours after loading
Control group
Dose comparison

Outcomes
Primary outcome [1] 320057 0
frequency of apnoea per duration of treatment in prematurity between high versus standard dose of caffeine as assessed by clinical examination

Participants will be examined by specialist and senior registrar every day during the duration of treatment

Equipment that will be used for clinical examination are stethoscope, BP oscillatory monitoring, intraarterial BP if participant is on arterial line, SPO2 monitoring. All equipment used is routinely available in NICU.

Timepoint [1] 320057 0
every day after starting on syrup caffeine until or beyond 34 weeks gestation as long as patient is on the treatment
Primary outcome [2] 321602 0
total number of days of apnoea in prematurity between high versus standard dose of caffeine as assessed by clinal examination

Participants will be examined by specialist and senior registrar every day during the duration of treatment

Equipment that will be used for clinical examination are stethoscope, BP oscillatory monitoring, intraarterial BP if participant is on arterial line, SPO2 monitoring. All equipment used is routinely available in NICU.

Timepoint [2] 321602 0
every day after starting on first dose of oral caffeine until or beyond 34 weeks gestational age as long as patient is on caffeine treatment
Secondary outcome [1] 370383 0
Extubation failure as assessed by clinical examination

Participants will be examined by specialist and senior registrar every day during the duration of treatment

Equipment that will be used for clinical examination are stethoscope, BP oscillatory monitoring, intraarterial BP if participant is on arterial line, SPO2 monitoring. All equipment used is routinely available in NICU.

Timepoint [1] 370383 0
assess after patient's extubation . Extubation failure defined as requiring reintubation within 72 hours extubation period

Participant will be closely monitored within 72 hours post extubation
Secondary outcome [2] 375553 0
Duration of Non Invasive ventilation. How many days / months the patient require on Non Invasive ventilation (e.g: Duopap, Cpap, optiflow). The outcome will be assessed by using data-linkage to medical records
Timepoint [2] 375553 0
assess after patient has successful extubation
Secondary outcome [3] 375554 0
Duration of Patient is on nasal prong oxygen as assessed by clinical examination

How many days/months the participant is on nasal prong oxygen
Timepoint [3] 375554 0
assess the duration while patient is on nasal prong oxygen
Secondary outcome [4] 375555 0
Chronic lung disease as assessed by clinical examination and chest x- ray
Timepoint [4] 375555 0
Assess once patient is at corrected gestational age 36 weeks or discharge , which one is earlier as long as patient is on oxygen usage at least 28 days.
Secondary outcome [5] 375556 0
Post natal steroid therapy for Chronic Lung Disease assessed by clinical examination

If participant fulfilled criteria of Bronchopulmonary Dysplasia according to the National Institute of Child Health and Human Development diagnostic criteria , The clinician will start on post natal steroid therapy
Timepoint [5] 375556 0
Assess by neonatologist on steroid requirement once patient use oxygen at least 28 days
Secondary outcome [6] 375558 0
Retinopathy of prematurity assessed by ophthalmologist
Timepoint [6] 375558 0
Formal eye assessment done by ophthalmologist at 34 weeks gestational age
Secondary outcome [7] 375559 0
Intraventricular Hemorrhage (IVH) as assessed by doing ultrasound of cranium
Timepoint [7] 375559 0
Ultrasound of cranium will be done to all premature baby based on the protocol timing

Protocol timing :
Ist ultrasond cranium: Day 3 to Day 7
Second ultrasound cranium : Day 7 or Day 14 if no IVH
Weekly monitor with ultrasound cranium if presence of IVH
Secondary outcome [8] 375560 0
Tachycardia will be continuously monitored by trained medical staff . It will be assessed by using bench-top sphygmomanometer or machine monitoring if patient is on intraarterial line
Timepoint [8] 375560 0
continuous monitoring will be done throughout the treatment
Secondary outcome [9] 375561 0
weight monitoring by weigh scale
Timepoint [9] 375561 0
weight monitoring will be done twice weekly until discharge
Secondary outcome [10] 375562 0
urine electrolytes (urine calcium, urine phosphate and urine creatinine). This is composite outcome
Timepoint [10] 375562 0
urine electrolytes will be done at Day seven of treatment
Secondary outcome [11] 377193 0
Periventricular malacia as assessed by doing ultrasound cranium
Timepoint [11] 377193 0
Ultrasound of cranium will be done to all premature baby based on the protocol timing

Protocol timing :
Ist ultrasond cranium: Day 3 to Day 7
Second ultrasound cranium : Day 7 or Day 14 if no IVH
Weekly monitor with
ultrasound cranium if presence
of IVH
Secondary outcome [12] 377194 0
Hypertension will be continuously monitored by trained medical staff . It will be assessed by using bench-top sphygmomanometer
Timepoint [12] 377194 0
continous monitoring will be done throughout the treatment

Eligibility
Key inclusion criteria
1. Prematurity 26 to 32 completed weeks admitted to Neonatal Intensive Care Unit Hospital
Universiti Sains Malaysia
2. 24 hours periextubation period if ventilated
Minimum age
1 Hours
Maximum age
34 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Hydrops fetalis
2. Major congenital anomaly (Major malformations causing significant functional or
cosmetic impairment or being life-limiting. ‘Examples of major malformations include
neural tube defect, hypoplastic left heart, ventral wall defect, and craniofacial cleft’)
3. Major neurological condition; examples Grade 3 or 4 intraventricular haemorrhage
4. Contraindication on starting oral medication (Examples Necrotising Enterocolitis,
bowel pathology like malrotation, Hirschprung disease)

Withdrawal criteria
1. Premature baby who developed Supraventricular tachycardia (SVT) or persistent
tachycardia during the course of treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
9/06/2019
Date of last participant enrolment
Anticipated
31/05/2020
Actual
Date of last data collection
Anticipated
14/06/2020
Actual
Sample size
Target
78
Accrual to date
3
Final
Recruitment outside Australia
Country [1] 21482 0
Malaysia
State/province [1] 21482 0
Kota Bharu, Kelantan

Funding & Sponsors
Funding source category [1] 302753 0
University
Name [1] 302753 0
Hospital Universiti Sains Malaysia
Country [1] 302753 0
Malaysia
Primary sponsor type
University
Name
Hospital Universiti Sains Malaysia
Address
Jalan Raja Perempuan Zainab II, Kubang Kerian, 16150 Kota Bharu, Kelantan
Country
Malaysia
Secondary sponsor category [1] 302689 0
None
Name [1] 302689 0
Address [1] 302689 0
Country [1] 302689 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303353 0
Jawatankuasa Etika Penyelidikan Manusia USM (JEPeM)
Ethics committee address [1] 303353 0
Ethics committee country [1] 303353 0
Malaysia
Date submitted for ethics approval [1] 303353 0
Approval date [1] 303353 0
24/03/2019
Ethics approval number [1] 303353 0

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

Contacts
Principal investigator
Name 93378 0
Dr Anis Munirah Mohd Kori
Address 93378 0
Lot 119 Kampung Sungai Baru, Pengkalan Chepa, 16100 Kota Bharu, Kelantan, Malaysia

Hospital Universiti Sains Malaysia,16150 Kubang Kerian, Kalantan,Malaysia
Country 93378 0
Malaysia
Phone 93378 0
+60132076730
Fax 93378 0
Email 93378 0
munirah_anis@student.usm.my
Contact person for public queries
Name 93379 0
Anis Munirah Mohd Kori
Address 93379 0
Lot 119 Kampung Sungai Baru, Pengkalan Chepa, 16100 Kota Bharu, Kelantan, Malaysia

Hospital Universiti Sains Malaysia,16150 Kubang Kerian, Kalantan,Malaysia
Country 93379 0
Malaysia
Phone 93379 0
+60132076730
Fax 93379 0
Email 93379 0
munirah_anis@student.usm.my
Contact person for scientific queries
Name 93380 0
Anis Munirah Mohd Kori
Address 93380 0
Lot 119 Kampung Sungai Baru, Pengkalan Chepa, 16100 Kota Bharu, Kelantan, Malaysia

Hospital Universiti Sains Malaysia,16150 Kubang Kerian, Kalantan,Malaysia
Country 93380 0
Malaysia
Phone 93380 0
+60132076730
Fax 93380 0
Email 93380 0
munirah_anis@student.usm.my

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
2667Study protocol    377580-(Uploaded-30-06-2019-23-49-23)-Study-related document.docx
2669Informed consent form    377580-(Uploaded-30-06-2019-23-50-24)-Study-related document.docx



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.