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Trial registered on ANZCTR


Registration number
ACTRN12624000667516
Ethics application status
Approved
Date submitted
17/06/2023
Date registered
24/05/2024
Date last updated
24/05/2024
Date data sharing statement initially provided
24/05/2024
Type of registration
Retrospectively registered

Titles & IDs
Public title
Randomized Control Trial: Does oral paracetamol close a patent ductus arteriosus as effetively as intravenous paracetamol in premature infants?
Scientific title
Randomized Control Trial: Efficacy and safety of oral paracetamol versus intravenous paracetamol in premature neonates with patent ductus arteriosus
Secondary ID [1] 309918 0
none
Universal Trial Number (UTN)
nil
Trial acronym
PCM study
Linked study record
nil

Health condition
Health condition(s) or problem(s) studied:
patent ductus arteriosus 330391 0
Condition category
Condition code
Cardiovascular 327228 327228 0 0
Diseases of the vasculature and circulation including the lymphatic system
Reproductive Health and Childbirth 327229 327229 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Initial echocardiogram will be done by by the expert personnel (either medical officer or technician) - to assess the size of patent ductus arteriosus, left atrium / aortic ratio (LA/AO), and shunting direction of patent ductus arteriosus (PDA). If the patient fulfill the inclusion criteria and exclusion criteria and has hemodynamically significant PDA with echocardiography evidence, patient will be randomized for either treatment oral paracetamol or intravenous paracetamol.
Oral paracetamol will be administered orally either directly oral or through an orogastric tube at 15 mg/kg per dose in 6 hourly intervals for 3 consecutive days. The serving of medication will be signed and monitored on the patient’s medication chart.
Echocardiography assessment will be done after 24 hour post completion of each course of the investigational treatment (last dose of the course) by the expert personnel (either medical officer or technician), verified by paediatric cardiologist.
If echocardiography assessment showed PDA still open after first course of paracetamol treatment, patient will receive another course of similar route of paracetamol for 3 days and reassessment will be done after 24 hour complete treatment.
If PDA fails to close after second course, patient will be given the rescue therapy based on patient’s condition (ibuprofen/indomethacin) and they will be fully managed by the hospital neonatal team.
After they complete second course of investigational treatment, either PDA close or still open post second treatment, they are considered complete our trial and we will monitor the complication until 30 days post completion of treatment. Subsequently, if they fail the rescue therapy, patient will undergo surgical/medical intervention based on their suitable condition and this will be fully managed by the neonatal team
Intervention code [1] 326348 0
Treatment: Drugs
Comparator / control treatment
Initial echocardiogram will be done by by the expert personnel (either medical officer or technician) - to assess the size of patent ductus arteriosus, left atrium / aortic ratio (LA/AO), and shunting direction of patent ductus arteriosus (PDA). If the patient fulfill the inclusion criteria and exclusion criteria and has hemodynamically significant PDA with echocardiography evidence, patient will be randomized for either treatment oral paracetamol or intravenous paracetamol.
Intravenous paracetamol will be administered via any peripheral or central line at 15 mg/kg per dose in 6 hourly intervals for 3 consecutive days. The serving of medication will be signed and monitored on the patient’s medication chart.
Echocardiography assessment will be done after 24 hour post completion of each course of the investigational treatment (last dose of the course) by the expert personnel (either medical officer or technician), verified by paediatric cardiologist.
If echocardiography assessment showed PDA still open after first course of paracetamol treatment, patient will receive another course of similar route of paracetamol for 3 days and reassessment will be done after 24 hour complete treatment.
If PDA fails to close after second course, patient will be given the rescue therapy based on patient’s condition (ibuprofen/indomethacin) and they will be fully managed by the hospital neonatal team.
After they complete second course of investigational treatment, either PDA close or still open post second treatment, they are considered complete our trial and we will monitor the complication until 30 days post completion of treatment. Subsequently, if they fail the rescue therapy, patient will undergo surgical/medical intervention based on their suitable condition and this will be fully managed by the neonatal team
Control group
Active

Outcomes
Primary outcome [1] 335113 0
Closure of the PDA confirmed by echocardiography
Timepoint [1] 335113 0
Echocardiography assessment will be performed after 24 hour post commencement of each course of the investigational treatment
Secondary outcome [1] 423094 0
Urine output
- daily 24 hour urine collection, either by weighing pampers or urine catheter if patient's already on urine catheter prior to study
Timepoint [1] 423094 0
Early complication post commencement of treatment (within 7 days of starting treatment)
Secondary outcome [2] 433244 0
Renal function
- by monitoring blood urea and serum creatinine level
Timepoint [2] 433244 0
Early complication post commencement of treatment (any complication occur within 7 days of starting treatment)
Secondary outcome [3] 433245 0
liver function
- by monitoring patients blood for Aspartate Aminotransferase AST, Alanine Aminotransferase ALT, serum bilirubin
Timepoint [3] 433245 0
Early complication post commencement of treatment (any complication occur within 7 days of starting treatment)
Secondary outcome [4] 433262 0
Intraventricular hemorrhage
- screening done by ultrasound cranium
Timepoint [4] 433262 0
complication post commencement of treatment (all time since starting of treatment until 30 days of starting treatment) - assessment will be done within 7 days of starting of treatment. if there are intraventricular hemorrhage. the reassessment will be done every 2 weekly
Secondary outcome [5] 433263 0
Need of escalation of oxygen support
- monitor the oxygen support pre treatment, during and post treatment. this will be done by review medical record of the patient
Timepoint [5] 433263 0
Early complication post commencement of treatment (within 7 days of starting treatment)
Secondary outcome [6] 433264 0
Bronchopulmonary Dysplasia
-oxygen dependency that causes chronic lung disease
based on chest xray and duration of dependency to oxygen support
Timepoint [6] 433264 0
Late complication post commencement of treatment (daily from 8 days - 30 days of starting treatment)
Secondary outcome [7] 433265 0
Periventricular Leukomalacia
- based on ultrasound cranium
Timepoint [7] 433265 0
Late complication post commencement of treatment (daily 8 days - 30 days of starting treatment)
Secondary outcome [8] 433268 0
Necrotizing enterocollitis
- monitoring symptom and sign based on bell's criteria
Timepoint [8] 433268 0
Late complication post commencement of treatment (8 days - 30 days of starting treatment)
Secondary outcome [9] 433269 0
retinopathy of prematurity
- based on opthalmology assessment
Timepoint [9] 433269 0
Late complication post commencement of treatment (daily 8 days - 30 days of starting treatment)
Secondary outcome [10] 433270 0
Sepsis - this will be documented based on patients medical records and serum infection marker and positive cultures
Timepoint [10] 433270 0
complication post commencement of treatment (all time since starting of treatment until 30 days of starting treatment)
Secondary outcome [11] 433271 0
Death
Timepoint [11] 433271 0
complication post commencement of treatment (all time since starting of treatment until 30 days of starting treatment)

Eligibility
Key inclusion criteria
1. Patients born at between 26 to 33 weeks 6 days of gestation
2. Birth weight equal or more than 700g
3. Hemodynamically significant PDA (One of the clinical signs of PDA with one
echocardiographic evidence of significant PDA)
a. Clinical signs of PDA:
i. Respiratory signs, including tachypnea, chest retraction, increased respiratory support, unable to wean down respiratory support
ii. Physical signs, including tachycardia, murmur, hyperdynamic precordium, bounding pulse, wide pulse pressure (>25mmHg)
iii. Signs of congestive heart failure, including cardiomegaly, hepatomegaly or pulmonary congestion
b. Echocardiographic evidence:
Ductal left to right shunt with
i. ductal size > 1.5mm or
ii. left atrium to aortic root ratio > 1.4
Minimum age
No limit
Maximum age
2 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Major congenital malformation
2. Presence of any other structural abnormality of the heart
3. Echocardiographic evidence of pulmonary hypertension
4. Fetal hydrops
5. Life threatening infection
6. Grade 4 intraventricular haemorrhage
7. Severe liver failure
8. Previous treatment with paracetamol, ibuprofen, any COX inhibitor for any purpose

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)
At randomisation, 50% of the infants will be allocated to the active treatment of oral paracetamol, while the other 50% will have the intravenous paracetamol.
The enrolled patients will be allocated with the treatment arm using sequentially numbered, opaque, sealed and stapled envelopes. The parents, hospital staff, and medical personnel directly involves in the patient’s care are blinded to group allocation. Corresponding envelopes are opened only after the enrolled participants complete all baseline assessments and it is the time to allocate the intervention.
After acceptance of a patient by the panel, the appropriate numbered envelope is opened; the card inside will reveal the patient will to be an O or a I case, and this information is noted to the medical officer in charge to be endorsed. (O = Oral paracetamol, I = Intravenous paracetamol)
Oral paracetamol or intravenous paracetamol will then administer by the neonatal intensive care unit nurses based on the route stated in the envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The patient will be randomly assigned following simple randomization procedures (by computer-generated random numbers) to one of the 2 treatment groups (oral paracetamol or intravenous paracetamol) with 1:1 ratio.
The person who will generate the random sequence will not involve in any other aspect of the trial.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size is calculated using Arifin W.N. sample size calculator (version 2.0) 2017
Previous study by Rania A et al (2019) reported that the mean ductal diameter is significantly reduced after the first course of oral paracetamol with standard deviation of 1.06 and 0.4 after second course of oral paracetamol. Based on our clinical experience, 1 mm difference is significant for ductal diameter reduction after treatment with paracetamol.
Thus, this study will need 24 patients in each group to be able to reject the null hypothesis that the proportion between the groups are equal, with the power of study 0.90. The Type 1 error probability associated with the test of this null hypothesis is 0.05. Taking into accounts 10% drop rate, total sample size required is 27 in each group.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
27/01/2023
Date of last participant enrolment
Anticipated
30/10/2024
Actual
Date of last data collection
Anticipated
30/11/2024
Actual
Sample size
Target
54
Accrual to date
30
Final
Recruitment outside Australia
Country [1] 25599 0
Malaysia
State/province [1] 25599 0
Kelantan

Funding & Sponsors
Funding source category [1] 314101 0
University
Name [1] 314101 0
Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan
Country [1] 314101 0
Malaysia
Primary sponsor type
University
Name
Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan
Address
nil
Country
Malaysia
Secondary sponsor category [1] 316018 0
None
Name [1] 316018 0
Address [1] 316018 0
Country [1] 316018 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313239 0
JEPeM-USM (Human Research Ethic Committee Universiti Sains Malaysia)
Ethics committee address [1] 313239 0
Universiti Sains Malaysia Kampus Kesihatan,16150 Kubang Kerian, Kelantan
Ethics committee country [1] 313239 0
Malaysia
Date submitted for ethics approval [1] 313239 0
23/09/2022
Approval date [1] 313239 0
30/11/2022
Ethics approval number [1] 313239 0
USM/JEPeM/22050315

Summary
Brief summary
Background: Persistent patent ductus arteriosus (PDA) is diagnosed when the ductus arteriosus fails to close after 72 hour of life. The shunting of the circulating blood volume from the systemic to the pulmonary circulation may cause pulmonary overflow and impaired end organ perfusion. Therefore, treatment of PDA is important to prevent these complications.

Hypothesis: the oral paracetamol is better than the intravenous paracetamol in treatment of premature neonates with hemodynamically significant patent ductus arteriosus.

General Objective
To compare the efficacy and safety of intravenous paracetamol versus oral paracetamol in premature neonates with patent ductus arteriosus

Specific Objectives
1. To compare the number of complete closure of patent ductus arteriosus (Echo verified) in premature neonates following treatment with oral paracetamol versus intravenous paracetamol
2. To determine the safety profile of oral paracetamol and intravenous paracetamol in premature babies with patent ductus arteriosus

Trial Design
Single centre, randomized control trial (RCT) involving premature neonates with gestational age of 26 – 33 weeks 6 days who are admitted to Neonatal Intensive Care Unit (NICU) Hospital Universiti Sains Malaysia in Kelantan, Malaysia.

Patients who meet the inclusion criteria will be randomized and started on the 3 days course of investigational treatment. Parental consent will be taken before starting this study. Patients are randomly assigned to one of investigational treatment with allocation ratio of 1:1. Echocardiography assessment will be done after 24 hour complete treatment. If PDA remains open after first course, the patients will be treated with another course of similar route of investigational treatment.

If PDA fails to close after second course, patient will be given the rescue therapy based on patient’s condition (ibuprofen/indomethacin) and they will be fully managed by the hospital neonatal team. After they complete second course of investigational treatment, either PDA close or still open post second treatment, they are considered complete our trial and we will monitor the complication until 30 days post completion of treatment. Subsequently, if they fail the rescue therapy, patient will undergo surgical/medical intervention based on their suitable condition and this will be fully managed by the neonatal team.

Early complications during treatment and late complications during 30 days post completion treatment are observed to assess the safety of paracetamol in patent ductus arteriosus.
Trial website
nil
Trial related presentations / publications
nil
Public notes
nil

Contacts
Principal investigator
Name 127446 0
Dr Nurshafinaz Salmah Mohd Fezal
Address 127446 0
Paediatric DepartmentHospital Universiti Sains Malaysia,Jalan Raja Perempuan Zainab 2,16150 Kubang Kerian,Kelantan
Country 127446 0
Malaysia
Phone 127446 0
+60169214869
Fax 127446 0
Email 127446 0
nurshafinaz@usm.my
Contact person for public queries
Name 127447 0
Dr Mohd Rizal Mohd Zain
Address 127447 0
Paediatric DepartmentHospital Universiti Sains Malaysia,Jalan Raja Perempuan Zainab 2,16150 Kubang Kerian,Kelantan
Country 127447 0
Malaysia
Phone 127447 0
+60136846051
Fax 127447 0
Email 127447 0
drrizal@usm.my
Contact person for scientific queries
Name 127448 0
Dr Mohd Rizal Mohd Zain
Address 127448 0
Paediatric DepartmentHospital Universiti Sains Malaysia,Jalan Raja Perempuan Zainab 2,16150 Kubang Kerian,Kelantan
Country 127448 0
Malaysia
Phone 127448 0
+60136846051
Fax 127448 0
Email 127448 0
drrizal@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
19468Ethical approval    386097-(Uploaded-17-06-2023-23-06-11)-Study-related document.pdf



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.