PAIR (Paracetamol and Ibuprofen Research) Study: A Randomised Controlled Trial Comparing IV Paracetamol With IV Ibuprofen in the Management of Haemodynamically Significant Patent Ductus Arteriosus
Phase: PHASE2
Conditions: Patent Ductus Arteriosus
Sponsor: Manchester University NHS Foundation Trust

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 1 of 24 
IRAS ID: 1003574 
 
PAIR (Paracetamol and Ibuprofen Research) Pilot Trial 
 
Full Title 
PAIR (Paracetamol and Ibuprofen Research) Study: 
A randomised controlled trial comparing IV 
paracetamol with IV ibuprofen in the management of 
haemodynamically significant patent ductus 
arteriosus 
Sponsor 
Sponsor reference 
Manchester University Foundation NHS Trust 
B01039 
IRAS Number 
1003574 
EudraCT number 
2020-003863-25 
Clinical trials.gov number: 
TBC 
Sponsor reference 
B01039 
 
 
 
This protocol has regard for the HRA guidance and order of content 
 
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 2 of 24 
IRAS ID: 1003574 
 
SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief Investigator 
agrees to conduct the trial in compliance with the approved protocol and will adhere to the principles outlined in 
the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 
2006/1928) and any subsequent amendments of the clinical trial regulations, the Sponsor’s (and any other relevant) 
SOPs, and other regulatory requirements as amended. 
This project will be conducted in accordance with the study protocol, Trust SOPs and the ethical principles 
outlined by Good Clinical Practice (GCP) and the Declaration of Helsinki. All individuals will be considered for 
inclusion in this study regardless of age, disability, race, religion and belief, except where the study inclusion and 
exclusion criteria EXPLICITLY state otherwise. 
 
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of the 
Sponsor. 
I also confirm that I will make the findings of the trial publicly available through publication in medical journals or 
other dissemination tools without any unnecessary delay and that an honest accurate and transparent account of the 
trial will be given; and that any discrepancies and serious breaches of GCP from the trial as planned in this 
protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
 
Date: ....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: ...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
......................... 
 
Date: 16 / 06 / 2021. 
Name: (please print): 
........(Dr Arindam Mukherjee) ........ 
 
 
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 3 of 24 
IRAS ID: 1003574 
 
KEY TRIAL CONTACTS 
 
Chief Investigator 
Dr Arindam Mukherjee 
Saint Mary’s Hospital 
Manchester University NHS Foundation Trust 
Principal investigator 
Dr Anupam Gupta 
Saint Mary’s Hospital 
Manchester University NHS Foundation Trust 
Co-investigator 
Dr Ruth Gottstein 
St Mary’s Hospital 
Manchester University NHS Foundation Trust 
 
Trial Coordinator 
 
Karen Dockery  
Neonatal Intensive Care Unit, St Mary’s Hospital 
Oxford Road, Manchester, M13 9WL 
 
Sponsor 
Manchester University NHS Foundation Trust 
The Research Office  
1st Floor, Nowgen Building, 29 Grafton Street 
Manchester  
M13 9WU 
Funder 
Department of Neonatology, St Mary’s Hospital, 
Oxford Road, Manchester M13 9WL 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 4 of 24 
IRAS ID: 1003574 
 
Key Protocol Contributors 
Dr Arindam Mukherjee 
Dr Anupam Gupta 
Dr Ruth Gottstein 
 
Statistician 
    Dr Catherine Fullwood 
    Senior Medical Statistician, Research and Innovation 
    Manchester University NHS Foundation Trust 
    Nowgen Building, 29 Grafton St, Manchester  
    M13 9WU 
Trials Pharmacist 
Sophia Burgess 
Lead R&I Clinical Trials Pharmacist 
Committees 
  Trial Steering Committee Members:  
1. Dr Abhijeet Godhamgaonkar, Clinical lead, 
Department of Neonatology, Wythenshawe Hospital, 
Southmoor Road, M23 9LT 
 
2. Dr Gopi Vemuri, Consultant Neonatologist, 
Department of Neonatology, Wythenshawe Hospital, 
Southmoor Road, M23 9LT 
 
Data Monitoring Committee Members: 
 
1. Dr Ahmed Elazabi, Consultant Neonatologist, 
Department of Neonatology, Wythenshawe Hospital, 
Southmoor Road, M23 9LT 
 
2. Dr Kuldip Bakaya, Consultant Neonatologist, 
Department of Neonatology, Wythenshawe Hospital, 
Southmoor Road, M23 9LT 
 
 
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 5 of 24 
IRAS ID: 1003574 
 
CONTENTS  
 
 
 
 
 
 
 
 
Page number 
1. 
General Information .......................................................................................................... 7 
1.1 Trial Summary ................................................................................................................ 7 
1.2 
Trial Flow Chart ......................................................................................................... 8 
1.3 
List of Abbreviations .................................................................................................. 9 
2. 
Roles and Responsibilities .............................................................................................. 10 
3.    Background ..................................................................................................................... 10 
4.  Study Objectives and Endpoints: ....................................................................................... 11 
5.  Study Design: .................................................................................................................... 11 
5.1 Selection of Study Participants ...................................................................................... 11 
5.1.1 
Inclusion Criteria: ............................................................................................. 11 
5.1.2 
Exclusion Criteria: ............................................................................................ 12 
5.2      Recruitment of Participants ...................................................................................... 12 
5.2.1 
Initial Contact ................................................................................................... 12 
5.2.2 
Recruitment ..................................................................................................... 12 
5.2.3 
Randomisation Procedure ............................................................................... 12 
5.2.4 
Sample Size Calculation .................................................................................. 13 
5.2.5 
Withdrawal from Study Treatment ................................................................... 13 
5.2.6 
Exit criteria ....................................................................................................... 13 
5.3 
Treatment details .................................................................................................... 13 
5.3.1 
Group A (Ibuprofen group) ............................................................................... 13 
5.3.2 
Group B (Paracetamol group) .......................................................................... 14 
5.3.3 
Concomitant medication .................................................................................. 14 
6.  Study methodology ............................................................................................................ 14 
6.1 
Standard monitoring during administration of Trial medications ............................... 14 
6.2 
Additional investigations and care following completion of Trial medications ........... 14 
7.     Safety Reporting: Definitions ........................................................................................... 15 
7.1.  Adverse Event (AE) ................................................................................................. 15 
7.1.1.  Serious Adverse Event (SAE) .............................................................................. 15 
7.1.2 Foreseeable Serious Adverse Events .................................................................... 15 
7.1.3 Unforeseeable Serious Adverse Events ................................................................. 16 
7.2    Adverse Reaction (AR)........................................................................................... 16 
7.2.1 Serious Adverse Reaction (SAR) ........................................................................... 16 
7.2.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................. 16 
7.3 Serious adverse events (SAE) and Serious adverse reaction (SAR) reporting .............. 16 
7.4 Assessment of causality ................................................................................................ 17 
7.5 Assessment of expectedness........................................................................................ 17 
7.6 Follow up procedures .................................................................................................... 17 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 6 of 24 
IRAS ID: 1003574 
 
7.7 Criteria for premature termination of study .................................................................... 17 
7.8 Regulatory reporting requirements ................................................................................ 18 
7.9 Safety reports / Development Safety Update Report (DSUR)........................................ 18 
7.10 Potential serious breach .............................................................................................. 18 
7.11 Urgent safety measures .............................................................................................. 18 
7.12 Accountability .............................................................................................................. 19 
8     Outcomes ........................................................................................................................ 19 
8.1 
Primary Outcome .................................................................................................... 19 
8.2 
Secondary Outcomes and Follow-up duration ......................................................... 19 
8.3 
Other recorded study parameters ............................................................................ 20 
8.4 
Definition of Hemodynamically significant PDA (hsPDA) ......................................... 20 
8.5 
Definition of non-hsPDA following treatment............................................................ 20 
9 
Study Monitoring ............................................................................................................. 21 
9.1 Data Collection ............................................................................................................. 21 
9.2 
Direct access to data ............................................................................................... 21 
9.3 
Site monitoring ........................................................................................................ 21 
10 
Confidentiality and data protection .............................................................................. 22 
10.1 
Confidentiality .......................................................................................................... 22 
10.2 
Data protection ........................................................................................................ 22 
11 
Study conduct ............................................................................................................. 22 
12 
Study record retention ................................................................................................. 22 
13 
End of study ................................................................................................................ 22 
14 
Peer review ................................................................................................................. 23 
15 
Indemnity .................................................................................................................... 23 
16 
Statistical Analysis ...................................................................................................... 23 
17 
Ethics and dissemination ............................................................................................. 24 
18 
Publication Plan .......................................................................................................... 24 
19 
References.................................................................................................................. 24 
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 7 of 24 
IRAS ID: 1003574 
 
1. General Information 
 
1.1 Trial Summary 
Trial Title 
PAIR (Paracetamol and Ibuprofen Research) Study: A randomised controlled trial 
comparing intravenous (IV) Paracetamol with IV Ibuprofen in the management of 
haemodynamically significant patent ductus arteriosus 
Short Title 
The PAIR study 
Clinical Phase  
Phase II/III 
Trial Design 
Randomised controlled trial 
Trial Participants 
Preterm infants (born at <32 weeks gestational age or birth weight < 1500 
grams) with haemodynamically significant patent ductus arteriosus (hsPDA) 
who are ≤ 28 days old 
Planned Sample Size 
32 babies 
Treatment duration 
3 days 
Follow up duration 
Till 36 weeks corrected postnatal age  
Planned Trial Period 
Two years 
 
Objectives 
Outcome Measures 
Primary 
 
To study the efficacy of Paracetamol 
(proposed new treatment) in treating 
hsPDA in comparison to Ibuprofen 
(current standard treatment) in preterm 
infants 
Conversion of hsPDA (defined in 
section 8.4) to non-hsPDA (defined 
in section 8.5) 
 
Secondary 
 
1. To compare BPD free survival at 36 
weeks post menstrual age (PMA)  
 
 
2.To compare the incidence of 
complications of prematurity in each group 
 
3.To record any evidence of adverse 
effects with Paracetamol or Ibuprofen 
1. BPD free survival at 36 weeks PMA 
 
2. a) NEC (Bell stage ≥IIa) 
    b)  Significant IVH (grade 3/4) 
    c) ROP requiring treatment 
 
3. a) Renal impairment (elevated urea 
and creatinine > upper limit of normal 
range)  
    b) Hepatic impairment (elevated 
liver enzymes ALT or AST > upper 
limit of normal) 
    c) Significant gastrointestinal or 
non-gastrointestinal bleeding requiring 
intervention 
 
 
Investigational Medicinal Product 
Dose, Route of Administration 
Group A (Ibuprofen group) 
Intravenous Ibuprofen loading dose at 10mg/kg, followed by 5mg/kg IV once daily 
for two more doses each given at 24-hour intervals.  
Group B (Paracetamol group) 
Intravenous Paracetamol at a loading dose of 20mg/kg/dose followed by 
10mg/kg/dose will be given four times daily for three days (total daily dose of 40-
50mg/kg).  
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 8 of 24 
IRAS ID: 1003574 
 
1.2 Trial Flow Chart  
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 9 of 24 
IRAS ID: 1003574 
 
1.3 List of Abbreviations 
 
AE  
Adverse Event 
AR  
Adverse Reaction 
BPD.          Bronchopulmonary Dysplasia  
CI  
Chief Investigator 
CRF 
Case Report Form 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EudraCT 
European Clinical Trials Database 
GCP           Good Clinical Practice 
hsPDA        Haemodynamically significant Patent Ductus Arteriosus 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 
IMP             Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NICU 
Neonatal Intensive Care Unit 
NEC           Necrotising Enterocolitis 
PDA 
Patent Ductus Arteriosus 
PI  
Principal Investigator 
PMA           Post menstrual age 
PIS  
Participant Information Sheet 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 10 of 24 
IRAS ID: 1003574 
 
2. Roles and Responsibilities 
 
a) Trial Steering Committee Members:  
 
1. Dr Abhijeet Godhamgaonkar, Clinical lead, Consultant Neonatologist, Department of 
Neonatology, Wythenshawe Hospital, Southmoor Road, M23 9LT 
 
2. Dr Gopi Venmuri, Consultant Neonatologist, Department of Neonatology, Wythenshawe 
Hospital, Southmoor Road, M23 9LT 
 
b) Data Monitoring Committee Members: 
 
1. Dr Ahmed Elazabi, Consultant Neonatologist, Department of Neonatology, 
Wythenshawe Hospital, Southmoor Road, M23 9LT 
 
2. Dr Kuldip Bakaya, Consultant Neonatologist, Department of Neonatology, Wythenshawe 
Hospital, Southmoor Road, M23 9LT 
 
3.    Background 
 
Patent Ductus Arteriosus (PDA) is present in 40-60 percent of preterm infants. While Ductus 
arteriosus is important for foetal circulation, it is undesirable postnatally and is expected to close 
spontaneously as part of normal postnatal adaptation in term infants. However, prolonged ductal 
patency is often seen as a complication of extreme preterm birth1. A persistent PDA with a large 
left to right ductal shunt may be 'haemodynamically significant' (hsPDA) resulting in pulmonary 
hyper-perfusion and systemic hypo-perfusion2. The association of a PDA with an increased 
incidence of pulmonary haemorrhage, bronchopulmonary dysplasia and prolonged need for 
ventilatory support is ascribed to pulmonary hyper-perfusion, whereas necrotising enterocolitis, 
renal failure, cerebral haemorrhage, and periventricular leukomalacia are consequences of 
systemic hypo-perfusion.  
 
In the UK, Ibuprofen (a non-steroidal anti-inflammatory drug, NSAID) is used to treat hsPDA in 
preterm babies. Though it is preferred over other NSAIDs like Indomethacin in view of less 
potential to cause intraventricular haemorrhage (IVH) or nephrotoxicity3, it is not without its own 
side effects4. Recently, Paracetamol has been suggested as a safe alternative medication to 
Ibuprofen particularly in situations where Ibuprofen fails to influence the PDA or is 
contraindicated. There is some evidence suggesting that while Paracetamol may confer 
comparable treatment efficacy similar to Ibuprofen for PDA closure3,6, it has a lower risk of 
adverse events in comparison to NSAIDs like Ibuprofen4,5,6,7 particularly in relation to renal 
toxicity and gastrointestinal bleeding5,6. 
 
While Ibuprofen has been primarily associated with adverse effects like nephrotoxicity, 
gastrointestinal bleeding and perforation, use of Paracetamol has been associated to adverse 
effects like hepatic toxicity with elevated liver enzymes and hyperbilirubinemia. 
 
Paracetamol is a medication that is recommended as a first-line antipyretic and analgesic in 
infants and has an excellent safety profile and track record for such use in the infant population. 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 11 of 24 
IRAS ID: 1003574 
 
While Paracetamol is licensed for use by BNFc (British National Formulary for Children) as an 
antipyretic in preterm infants more than 28 weeks’ gestation, it is not yet licensed for use in PDA 
treatment in preterm infants12. Recently it has been used in the management of PDA with 
promising results 5,8,9,10.  However, the current available body of evidence is considered to be of 
moderate to low quality and hence its effectiveness and safety profile is not fully established in 
this patient population10.  
 
We have conducted a national survey15 across 63 neonatal intensive care units (NICUs) in the 
United Kingdom between February and April 2020. The response rate was 95% (60/63). The 
survey disclosed widespread use of paracetamol while identifying that the practice remains 
variable, in absence of robust evidence. Strikingly, 95% of the respondents felt the need for a 
randomised controlled trial (RCT) to guide their practice. In keeping with an overwhelming 
interest across NICUs in UK, we propose this pilot study to address the safety and efficacy of 
paracetamol against ibuprofen using vigorous research methodology. The results of this study 
will inform a larger multi-centre trial, which will improve the ability of clinicians to make better 
evidence based clinical decisions and establish uniform practice recommendations. 
 
 
4.  Study Objectives and Endpoints: 
 
The primary objective is to study the efficacy of IV paracetamol in treating hsPDA in comparison 
to IV ibuprofen in preterm infants born at less than 32 weeks' gestation OR less than 1500 grams 
birth weight. 
Following the completion of the third day of trial medication administration, the end point for the 
primary outcome will be achieved. 
 
 
5.  Study Design:  
 
This is a single centre prospective randomised pilot study which will be conducted at St Mary’s 
Hospital NICU in Manchester. It is a level 3 neonatal intensive care unit. We aim to enrol 32 
eligible preterm babies for the trial. Recruitment duration will be 2 years. All infants who are 
symptomatic clinically and suspected of having PDA will have an echocardiogram to confirm 
presence and size of PDA. Decision to treat infants with hsPDA (defined in section 8.4) will lie 
with the Clinician. Once a decision is made to treat, parents would be approached, the study 
introduced, a parent information leaflet given and if they consent to enrol their baby (ies) in the 
trial. Once consented, infants will be randomly allocated to receive either IV Ibuprofen for 3 days 
or IV Paracetamol for 3 days. Following the completion of the treatment course, the 
echocardiogram will be repeated within 72 hours to re-assess the Ductus Arteriosus (DA). If the 
DA converts to non-hsPDA (defined in section 8.5), this will be regarded as the trial end point 
for primary outcome. 
 
5.1 Selection of Study Participants Inclusion Criteria:  
 
 
Gestational age - <32 weeks OR birth weight < 1500 grams  
 
Postnatal age ≤ 28 days 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 12 of 24 
IRAS ID: 1003574 
 
 
Meets criteria for hsPDA  
 
Clinician’s decision to treat PDA 
 
5.1.2 Exclusion Criteria: 
 
• 
Contraindication for administration of Ibuprofen (cyclooxygenase-inhibitors) or 
Paracetamol, such as: active bleeding (e.g. intracranial or gastrointestinal 
haemorrhage), thrombocytopenia (<50x109/L), renal failure (raised creatinine (>100 
micromole/l) or oliguria (<0.5 mL/kg/hour), known or suspected necrotising enterocolitis, 
any gastric or intestinal perforation, pre-treatment abnormal liver function tests (ALT > 
upper normal limit of the reference range, Bilirubin > NICE exchange phototherapy 
level13). 
• 
Previous use of Ibuprofen or Paracetamol prior to randomisation. 
• 
Persistent pulmonary hypertension (ductal right-to-left shunt ≧33% of cardiac cycle). 
• 
Congenital heart defect, other than PDA or PFO. 
• 
Life-threatening congenital birth defects. 
• 
Chromosomal abnormalities and/or congenital anomalies associated with abnormal 
neurodevelopment. 
 
5.2      Recruitment of Participants 
5.2.1 Initial Contact  
 
All infants admitted in our neonatal unit, who are symptomatic and clinically suspected of 
having PDA will have an echocardiogram to confirm presence, size and characteristics 
of the PDA. This is in keeping with current routine standard of care. Decision to treat 
infants with hsPDA will lie with the clinician. Once a decision is made to treat PDA, the 
clinical care team will discuss with the clinical research team to check whether the baby 
meets the eligibility criteria and to ensure that it is appropriate to approach parents to 
discuss the study. If baby meets eligibility criteria, the clinical research team will introduce 
the study to parents.  
 
5.2.2 Recruitment 
A Patient Information Sheet will be provided to the parents to provide information 
regarding the trial. Parents will be given sufficient time (ideally 24 hours) to read the 
leaflet and ask any questions. A written informed consent will be obtained from a person 
with parental responsibility prior to participation in the trial. 
 
5.2.3 Randomisation Procedure 
 
Computerised randomisation through sealedenvelope.com website will assign the neonate to 
medical treatment with either IV Ibuprofen or IV Paracetamol, both of which will be intended to 
close the PDA. There will be no allocation concealment during the trial. This trial will be single 
blinded and assessors (clinicians interpreting the echocardiogram) will also be blinded to the 
treatment arm.  

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 13 of 24 
IRAS ID: 1003574 
 
 
5.2.4 Sample Size Calculation 
 
This is a pilot study designed to assess whether it is possible to run a trial to assess the efficacy 
of using Paracetamol compared to Ibuprofen.  The study will aim to recruit 32 patients which will 
allow estimation of the sample size and power calculation for the larger multicentre RCT14  
 
 
5.2.5 Withdrawal from Study Treatment  
 
        The right of a participant to refuse participation after initial consent without giving reasons 
will be respected and parents will be assured that this decision will not impact on their baby’s 
clinical care. In the event of parental desire to withdraw from the study, the participants will not 
be receiving any further intervention. However, the data will be included on any participant who 
has received the trial medications on intention to treat basis.  
 
5.2.6 Exit criteria  
 
Following observations will be considered as exit criteria:  
         a) Ibuprofen associated: active gastro-intestinal bleeding and/or perforation, evidence of 
renal dysfunction e.g. oliguria <0.1 ml/kg/hour and/or raised Creatinine >200 micromol/l; 
evidence of platelet dysfunction (may manifest with petechiae) with absolute platelet count < 25 
x 109. 
         b) Paracetamol associated: Signs/evidence of liver dysfunction i.e., raised liver 
transaminases ALT/AST > ten times above upper reference range, unexpected jaundice with 
bilirubin above NICE exchange transfusion threshold13.  
          c) Significant gastrointestinal or non-gastrointestinal bleeding requiring resuscitation. 
 
5.3 Treatment details  
 Ibuprofen:       
 
IV preparation 20 mg/2 ml solution for infusion ampoules 
 
Marketed and packaged by Recordati Rare Diseases UK Ltd 
 
Labelled as Ibuprofen (Pedea) and kept in IV drug cupboard in NICU 
 
Intravenous infusion administered over 15 minutes (section 5.3.1) 
 
Accountability: Section 7.12 
Paracetamol:  
 
IV preparation 100mg/10 ml solution for infusion ampoules 
 
Marketing authorisation by several companies in UK and procured in keeping with 
local practice 
 
Labelled with active ingredient Paracetamol and kept in IV drug cupboard in NICU 
 
Intravenous infusion administered over 15 minutes (section 5.3.2) 
 
Accountability: Section 7.12 
                                            
5.3.1 Group A (Ibuprofen group) 
IV Ibuprofen loading dose at 10mg/kg, followed by 5mg/kg IV once daily for two more 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 14 of 24 
IRAS ID: 1003574 
 
doses each given at 24-hour intervals.  
 
5.3.2  Group B (Paracetamol group) 
IV Paracetamol at a loading dose of 20mg/kg/dose followed by 10mg/kg/dose will be 
given four times daily for three days6,8 (total daily dose of 40-50mg/kg). There is some 
evidence in the literature that doses of up to 60mg/kg/day are tolerated safely in extreme 
preterm babies6,8. 
 
5.3.3 Concomitant medication 
 
Paracetamol: Use of blood thinners like Warfarin or Heparin should be cautiously administered 
in conjunction with Ibuprofen because of theoretical possibility of bleeding. Any infants on 
enzyme-inducing antiepileptic drugs like Phenobarbitone, Rifampicin or Phenytoin will be 
monitored closely with caution due to its potential interaction with Paracetamol.  
 
Ibuprofen: Steroid use is not recommended in conjunction with Ibuprofen and any such use in 
special situations will be very closely monitored owing to its potential to cause gastro-intestinal 
haemorrhage. Ibuprofen may decrease the clearance of aminoglycosides such as gentamicin 
and strict surveillance of antibiotic levels will be done during coadministration with ibuprofen. 
Ibuprofen may also reduce the effect of diuretics, so should be used cautiously. 
 
6.  Study methodology 
Following informed consent in eligible babies (diagnosis of hsPDA confirmed with baseline 
echocardiogram) and electronic randomisation, allocation of babies in Paracetamol group (group 
A) and Ibuprofen group (group B) will be done. A 3-day treatment will be initiated with the trial 
medications.  
 
6.1 Standard monitoring during administration of Trial medications 
All infants on trial medications will be monitored as part of standard care. Their vital parameters 
would be recorded and analysed as per the unit policy. Blood tests like full blood count (FBC), 
neonatal profile and liver function tests (liver enzymes and Bilirubin) would be performed as per 
the unit policy. No additional blood test samples will be required. 
IV Paracetamol may be associated with raised liver enzymes and hyperbilirubinemia. IV 
Ibuprofen may be associated with renal impairment, bleeding and gastro-intestinal 
complications. The clinical team will be alert for any side effects being displayed in infants 
participating in either arm during the trial.  
 
6.2 Additional investigations and care following completion of Trial medications 
An echocardiogram will be performed by designated neonatologists (on the delegation log) 
within 72 hours after the last dose of trial medications on day 3, to assess the Ductus Arteriosus 
(DA). Echocardiograms will be reported by the Paediatric cardiologists in keeping with the routine 
standard of care.  
Following completion of the trial medications, if hsPDA persists, participating infants will return 
to routine standard of care and clinicians will be able to decide on further management of the 
PDA in keeping with the unit policy.   

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 15 of 24 
IRAS ID: 1003574 
 
 
7.     Safety Reporting: Definitions 
 
7.1.  Adverse Event (AE)  
 
An adverse event is any untoward medical occurrence in a participant administered a medicinal 
product, which does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of the trial medication, whether 
or not considered related to the trial medication.  
 
 
7.1.1.  Serious Adverse Event (SAE)  
 
A serious adverse event is any untoward medical occurrence that:   
• 
Results in death  
• 
Is life-threatening  
• 
Requires participant hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect  
• 
Is an important medical event  
 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance. This is not the same as ‘serious’, 
which is based on participant/event outcome or action criteria usually associated with events 
that pose a threat to a participant’s life or functioning.  
 
The term ‘life-threatening’ in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. Medical and scientific judgement should be exercised 
in deciding whether an adverse event is serious in other situations.  
 
7.1.2 Foreseeable Serious Adverse Events  
 
Foreseeable SAEs are those events which are foreseen in the patient population or as a result 
of the routine care/treatment of a patient. The following serious adverse events are a foreseeable 
occurrence in this population of preterm babies and as such do not require reporting as SAEs:  
 
Anaemia requiring transfusion  
 
Clinically significant intracranial abnormality on cranial ultrasound scan – intracranial 
haemorrhage or white matter injury  
 
Coagulopathy requiring treatment  
 
Culture proven sepsis  
 
Death (unless unforeseeable in this population)  
 
Fluid retention  
 
Gastrointestinal bleeding  
 
Haematuria  

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 16 of 24 
IRAS ID: 1003574 
 
 
Haemothorax  
 
High blood creatinine level (defined as >100 µmol/L)  
 
Hyperbilirubinemia necessitating exchange transfusion  
 
Hyperglycaemia  
 
Hypoglycaemia  
 
Hypotension treated with inotropes  
 
Impaired renal function (urine output 100 µmol/L)  
 
Raised liver enzymes (ALT>100) 
 
Raised serum bilirubin (Serum bilirubin above the exchange line ) 
 
Low serum sodium level/hyponatremia (defined as sodium <130 mmol/L)  
 
Necrotising enterocolitis  
 
Neutropenia (defined as <1.0 mmol/L)  
 
Pneumothorax requiring treatment  
 
Pulmonary hypertension requiring treatment with pulmonary vasodilator  
 
Respiratory failure  
 
Seizures requiring treatment  
 
Significant pulmonary haemorrhage  
 
Spontaneous intestinal perforation  
 
Thrombocytopenia (Platelet count <150 x109/L) 
 
7.1.3 Unforeseeable Serious Adverse Events  
 
An unforeseeable SAE is any event that meets the definition of a SAE and is not detailed in the 
list above as foreseeable. These events should be reported on the trial SAE form provided 
following the procedures detailed in Section 7.2. 
 
7.2    Adverse Reaction (AR)  
 
All untoward and unintended responses to a medicinal product related to any dose. The phrase 
“response to a medicinal product” means that a causal relationship between trial medication and 
an AE is at least a reasonable possibility, i.e. the relationship cannot be ruled out.  
 
7.2.1 Serious Adverse Reaction (SAR)  
 
A serious adverse reaction is a SAE which is considered to have been caused by the 
administration of trial medication. For a SAE to be considered as a reaction there must be a 
reasonable probability that it was related to the administration of IMP.  
 
7.2.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
 
This is a SAR, the nature or severity of which is not consistent with the known safety profile of 
the trial medication (e.g. Investigator’s Brochure for an unapproved IMP or Summary of Product 
Characteristics for an approved product). The Reference Safety Information for Sodium Chloride 
of ibuprofen and paracetamol is contained within section 4.8 of the SmPCs.   
 
7.3 Serious adverse events (SAE) and Serious adverse reaction (SAR) reporting 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 17 of 24 
IRAS ID: 1003574 
 
All SARs and SAEs whether related or unrelated will be reported within 24 hours of the site 
becoming aware of the event. The SAE form will describe the nature of event, date of onset, 
severity, corrective therapies given, outcome and causality (and expectedness, for related 
events). The CI would sign the SAE form. If the CI is not available, then another clinician (PI) 
listed on the delegation log will sign the form.  Should all delegated signatories be absent, the 
report would be sent unsigned, in order to meet the 24-hour requirement.   
 
The report will then be sent by email to the sponsor’s adverse event reporting email address: 
adverse.events@mft.nhs.uk. Additional information would be sent within five days if the event 
has not resolved at the time of reporting. 
 
 
7.4 Assessment of causality 
The Investigator responsible for the care of the participant will assess whether the AE/SAE is 
likely to be related to treatment according to the definitions mentioned above.  All AEs/SAEs 
judged as having a reasonable suspected causal relationship (e.g. possibly, probably, almost 
certainly) to the study treatment will be considered as reactions and will be assessed for 
expectedness.  If concomitant or rescue/escape drugs are given, the Investigator will also make 
an assessment of whether the AE/SAE is likely to be related to an interaction between the study 
treatment and concomitant or rescue/escape drugs or whether the AE/SAE might be linked to 
either the study treatment or concomitant or rescue/escape drugs but cannot be attributed to 
only one of these drugs.  All AEs/SAEs judged as being related (e.g. possibly, probably, almost 
certainly) to an interaction between the study treatment and concomitant or rescue/escape 
drugs, or any AE/SAE with unknown cause would be considered to be ARs/SARs.  
 
Alternative causes such as natural history of the underlying disease, other risk factors and the 
temporal relationship of the event to the treatment would be considered and investigated. 
 
7.5 Assessment of expectedness 
The sponsor’s assessment of expectedness for events considered to be possibly, probably or 
almost certainly related to the IMP will be made by the CI (or designated person like PI, in the 
CI’s absence) following the receipt of the SAE form.  If the CI is the reporting investigator the 
assessment of expectedness will be undertaken by the designated individual who is assigned 
the duty in CI’s absence.  
 
Events considered unrelated to the IMP do not need to be assessed for expectedness.  
 
7.6 Follow up procedures 
After initially recording an AE or recording and reporting an SAE, the Investigators would follow 
each participant until resolution. All information and follow up information on SAEs, SARs and 
SUSARs would be reported to the Sponsor in real time and sent to adverse.events@mft.nhs.uk 
to ensure the reports are monitored appropriately.   
 
7.7 Criteria for premature termination of study 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 18 of 24 
IRAS ID: 1003574 
 
The study may be considered for termination if  
• 
There is new safety data or evidence from other studies; 
• 
There is concerns from safety data (number and nature of SUSARs);  
• 
If fewer than three babies were recruited over the first six months.  
The decision to terminate the study would be taken by TSC.  
 
7.8 Regulatory reporting requirements 
Fatal or life threatening SUSARs will be reported by the Sponsor no later than seven calendar 
days after the Sponsor first became aware of the reaction. All other SUSARs will be reported no 
later than 15 calendar days after the Sponsor is first aware of the reaction. 
 
7.9 Safety reports / Development Safety Update Report (DSUR) 
The Development Safety Update Report (DSUR) will be prepared and submitted by the Sponsor 
in conjunction with the Chief Investigator. This will be submitted annually within 60 days of the 
Data Lock Point (DLP).  The DLP will be set at the last day of the one-year reporting period.  
 
7.10 Potential serious breach 
Following the decision that a serious breach of the protocol or GCP has occurred, the TMG will 
liaise with the Sponsor and other involved parties to establish:  
i. 
The extent of the breach  
ii. 
Whether a substantial amendment or urgent safety measures is required 
iii. 
Other corrective actions/training that are identified  
 
If the Sponsor has clear and unequivocal evidence that a serious breach has occurred, the 
sponsor would notify the MHRA within seven days, and investigate and take action 
simultaneously or after notification. 
 
The Sponsor will inform the TMG of its decision regarding the potential serious breach and 
confirm that onward reporting to the REC and the MHRA has occurred where appropriate. Any 
requests for additional information from the Sponsor or MHRA will be actioned promptly and 
open communication will be maintained with Sponsor and oversight committees to ensure 
appropriate corrective actions are taken and documented. 
 
7.11 Urgent safety measures 
An urgent safety measure is a procedure not defined by the protocol. Implementation may take 
place prior to authorisation by the regulatory authority and REC in order to protect clinical study 
participants from any immediate hazard to their health and safety. 
 
If an immediate hazard to the health and safety of participants in PAIR is detected, the sponsor 
shall immediately, and in any event no later than three days from the date the measures are 
taken, give written notice to the regulatory authority and the relevant ethics committee of the 
measures taken and the circumstances giving rise to those measures. 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 19 of 24 
IRAS ID: 1003574 
 
 
The CI and sponsor will together determine the appropriate course of action.  Once the 
appropriate course of action has been determined, the CI must take the agreed action to ensure 
trial subjects are made safe. 
 
The MHRA and REC will be informed of Urgent Safety Measures by means of a completed 
substantial amendment form.   
 
If PAIR study is temporarily halted for any reason, the sponsor would notify the MHRA and Ethics 
Committees immediately and at least within 15 days from when the trial is temporarily halted.  
The notification would be made as a substantial amendment using the Notification of 
Amendment form and clearly explain what has been halted (e.g. stopping recruitment and/or 
interrupting treatment of subjects already included) and the reasons for the temporary halt.  
 
In this case the study may not recommence until authorised to do so by the responsible 
regulatory authority and REC.  
 
If the study is temporarily halted and the decision is then made to permanently end the trial 
before the date specified for its conclusion (in the application), the Sponsor would notify the 
regulatory authority and REC within 15 days of the date of the decision to terminate the trial by 
submitting a declaration of End of Trial form and including a description of the reason for 
discontinuation. 
 
7.12 Accountability  
Medications are kept in the neonatal unit as standard stock. If there is any stock supply 
disruption, available stock will be checked before randomising a subject. Standard prescribing 
practice will be followed.  
As per risk-adapted approach to IMP accountability there is no requirement for: 
 
i) Shipping receipt and destruction records 
ii) Master or patient level accountability logs 
iii) Recording batch numbers and expiry dates 
 
As the subjects will be inpatients, compliance will be recorded on the medication chart as per 
standard practice.  
 
 
8     Outcomes  
 
8.1  Primary Outcome 
Conversion of hsPDA (defined in section 8.4) to non-hsPDA (defined in section 8.5) 
 
8.2 Secondary Outcomes and Follow-up duration 
i) 
BPD free survival at 36 weeks PMA 
ii) 
Incidence of complications of extreme prematurity  

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 20 of 24 
IRAS ID: 1003574 
 
 
NEC (Bell stage ≥IIa) 
 
Significant IVH (grade 3/4) 
 
ROP requiring treatment 
 
iii) 
Evidence of adverse effects of Ibuprofen/Paracetamol  
 
Renal impairment (elevated urea and creatinine > upper limit of normal range)  
 
Hepatic impairment (elevated liver enzymes ALT or AST > upper limit of normal) 
 
Significant gastrointestinal/ non-gastrointestinal bleeding requiring intervention 
 
Follow-up Duration: Participating infants will undergo follow-up till the point of discharge to home 
or a corrected gestational age of 36 completed weeks, whichever comes earlier.  
 
As this is a Pilot Trial, we will also look at the feasibility of the Trial design, including recruitment, 
retention, acceptability of randomisation, primary and secondary outcomes along with data on 
any adverse effects of the trial medications. The results of these outcomes will inform the 
feasibility and help with sample size calculation for an envisaged larger multicentre randomized 
controlled trial.  
 
8.3 Other recorded study parameters  
The following clinical details/findings will be documented using standard medical records; 
Administration of antenatal steroids • Maternal disease (pre-eclampsia) • Mode of delivery • 
Multiple birth • Duration of rupture of membranes prior to birth • Gestational age at birth • Birth 
weight • Apgar scores at 5 minutes • Blood gas analysis • Resuscitation after birth • Surfactant 
administration • Postnatal steroid administration. These factors are taken into consideration as 
part of routine standard of care for treating PDA.  
 
Echocardiogram evidence of changes in cardiovascular haemodynamics, ductal size changes 
and any evidence of changes in ductal steal pre- and post-treatment with trial medications. 
 
None of the study parameters would need review of maternal medical records.  
 
 
8.4 Definition of Hemodynamically significant PDA (hsPDA) 
The following echocardiographic indices and thresholds should be used to define as hsPDA11 
i) 
PDA diameter ≥2.0 mm in 2D  
ii) 
Ductal flow pattern (‘growing' pattern or pulsatile with Vmax/Vmin ≥ 2)  
iii) 
Retrograde post ductal aortic/coeliac/SMA diastolic flow  
iv) 
LA/Ao ratio ≥ 2  
v) 
LVO ≥ 300 ml/kg/min  
vi) 
Mitral valve E/A ratio ≥ 1 
The diagnosis of hsPDA will be made in the presence of supportive clinical signs and at least 
three of the above echo indices.  
 
8.5 Definition of non-hsPDA following treatment  

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 21 of 24 
IRAS ID: 1003574 
 
An echocardiogram will be carried out within 72 hours of the last dose and PDA will be classified 
as non-hsPDA based on the following criteria –  
PDA closed OR any two of the following three parameters  
i) 
Reduction of PDA diameter >50% (2D)                
ii) 
Restrictive or closing Ductal flow pattern    
iii) 
LA: Ao ratio < 1.5 
 
9 Study Monitoring 
 
Trial monitoring is carried out to ensure that the rights and well-being of human participants are 
protected during the course of a clinical trial. A detailed risk assessment is performed for each 
trial to determine the level and type of monitoring required for specific hazards. The nature and 
extent of monitoring will be specific to the individual trial; this is outlined in the Trial Monitoring 
Plan. Monitoring activities will be carried out by the Sponsor / Sponsor representative. 
 
The monitoring of the PAIR study will be in line with the Sponsor organisation policies. 
 
9.1 Data Collection 
Data will be collected from participants at indicated time points into source documents.  
 
All SAEs will be reported by completing the information on the SAE report form and sent to the 
Sponsor. A Data Management Plan will be in line with the Sponsor and host organisation 
policies. 
 
9.2 Direct access to data 
The Chief Investigator will permit study-related monitoring, audits, REC review, and regulatory 
inspection and provide direct access to source data and documents. 
 
Source data: All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). 
 
Source documents: Original documents, data, and records (e.g., hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate copies, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial). A source 
document identification list will be produced prior to trial initiation.  
 
9.3 Site monitoring 
The investigators will permit trial-related monitoring, audits, ethics committee review and 
regulatory inspections by providing direct access to source data/documents to sponsors for 
monitoring purposes.  

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 22 of 24 
IRAS ID: 1003574 
 
 
10 Confidentiality and data protection 
 
10.1 
Confidentiality  
Clinical information will not be released without the written permission of the participant, except 
as necessary for monitoring and auditing by the Sponsor, Regulatory Authorities, or the REC. 
 
The Investigator and study site staff involved with this study will not disclose or use for any 
purpose other than performance of the study, any data, record, or other unpublished, confidential 
information disclosed to those individuals for the purpose of the study. 
 
Prior written agreement from the Sponsor or its designee would be obtained for the disclosure 
of any confidential information to other parties. 
 
Personal data recorded on all documents will be regarded as strictly confidential and will be 
handled and stored in accordance with the Data Protection Act 1998.  Participants will be 
identified using only their unique study number, date of birth, and initials on the database.  
 
10.2 
Data protection 
Data will be collected in accordance with the "Caldicott Principles", the Data Protection Act (DPA) 
and the General Data Protection Regulation (GDPR). All babies recruited will be allocated a 
screening number and randomisation number which will be linked to their identifiable information 
held in a separate file stored within the research unit.  
 
All outcome data will be entered onto a password protected database within the NICU research 
office, accessible only to members of the research team. All electronic data will be anonymised, 
and no identifiable data will be stored on this database.  
 
Published results will not contain any personal data that could allow identification of individual 
participants. 
 
11 Study conduct 
 
Protocol violations / deviations / serious breaches 
In the event of a breach of protocol or GCP the trial team would follow the instructions found in 
section 7.11 of this document and report appropriately. 
 
12 Study record retention 
 
In line with the Medicines for Human Use (Clinical Studies) Regulations, once data collection is 
complete on all participants, all data will be stored for 25 years. Long-term off-site data archiving 
facilities will be advised for storage. 
 
13 End of study  
 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 23 of 24 
IRAS ID: 1003574 
 
The end of the study is defined to be the date of database lock. This is the date on which data 
modification privileges are withdrawn from the study database. 
 
The Sponsor and/or the TSC will have the right at any time to terminate the study for clinical or 
administrative reasons. The end of the study will be reported to the REC/MHRA within the 
required timeframe (15 days if the study is terminated prematurely or 90 days otherwise). 
Investigators will inform participants of any premature termination of the study and ensure that 
the appropriate follow up is arranged for all involved. A summary report of the study will be 
provided to the REC within the required timeframe.  
 
14 Peer review 
 
This proposal has been peer reviewed by  
i) 
Dr C Harikumar, Head of neonatal services & Lead consultant neonatologist, 
University hospital of North Tees, Stockton on Tees, TS19 8PE, United Kingdom.  
ii) 
Prof APS Hungin, Faculty of Medical Sciences, Newcastle University, 4 Butts Lane, 
Egglescliffe, Stockton on Tees, TS16 9BT, United Kingdom. 
 
15 Indemnity 
 
The PAIR study is sponsored by the Manchester University NHS Foundation Trust. The 
Manchester University NHS Foundation Trust cover for negligent harm is in place through the 
Clinical Negligence Scheme for Trusts. For NHS Sponsored research HSG(96)48 reference no.2 
refers ‘If there is any negligent harm during the study when the NHS body owes a duty of care 
to their person harmed, NHS indemnity covers NHS staff, medical academic staff with honorary 
contracts, and those conducting the trial. NHS indemnity does not offer no-fault compensation 
and is unable to agree in advance to pay compensation for non-negligent harm. Ex-gratia 
payments may be considered in the case of a claim’. 
 
16 Statistical Analysis 
 
All analyses will be conducted on an intention-to-treat basis and will include all patients who 
have undergone randomisation. Both intention-to-treat and per-protocol analysis will be done to 
assess the effect of contamination and quantify the protocol violations on the primary outcome.   
 
All variables will be examined descriptively with appropriate statistics and graphics for 
completeness and form.  No imputation will be done for missing data, but numbers will be noted 
and used to inform the larger study. 
 
The primary outcome will be presented as a frequency with 95% binomial confidence intervals.  
Exploratory comparisons between groups will be made using a fisher’s exact test. Exploratory 
univariate logistic-regression analysis will be used to identify potential baseline covariates 
associated with the primary outcome.  
 
Secondary outcomes will be presented descriptively using appropriate statistics both overall and 
by group.  Exploratory discrete comparisons will be made via Fisher’s exact test. Continuous 

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 24 of 24 
IRAS ID: 1003574 
 
variables will be compared with an unpaired t-test or the Mann–Whitney U (Wilcoxon rank sum) 
test. For time dependant variables, survival statistics will be presented.  
 
As this is a pilot trial, adverse events for both groups will be described both as total number of 
events and number of patients experiencing each event, with consideration for those occurring 
due to the proposed treatment (Paracetamol/Ibuprofen) for which we will use descriptive 
statistical analysis. All analyses would be conducted with the use of SPSS software (IBM) and 
R v3.6.0. A two-sided p-value of less than 0.05 will be considered to indicate statistical 
significance. The statistical analysis will be supervised by Dr Catherine Fullwood, Senior 
Statistician, Manchester University NHS Foundation Trust.  
 
17 Ethics and dissemination 
 
The trial will follow international code of ethics for clinical trials. The trial protocol will be approved 
by a Research Ethics Committee. All serious adverse events will be recorded in accordance with 
the protocol and analysed accordingly. The trial will also be registered on clinical trials.gov.  
 
 
18 Publication Plan 
 
At the end of the study, it is intended that the results will be analysed and published in 
medical journals and will be presented in medical seminars and conferences. None of the 
individual participants will be identified in any report or the publication of the study. A copy 
of the journal article can be requested from the Chief investigator.  
 
 
 
 
 
19 References 
 
1. 
Semberova J, Sirc J, Miletin J, Kucera J, Berka I, Sebkova S, O'Sullivan S,Franklin O, Stranak Z. Spontaneous Closure 
of Patent Ductus Arteriosus in Infants ≤1500 g. Pediatrics. 2017 Aug;140(2). pii: e20164258. doi:10.1542/peds.2016-4258. 
2. 
Sellmer A, Bjerre JV, Schmidt MR, McNamara PJ, Hjortdal VE, Høst B, Bech BH,Henriksen TB. Morbidity and mortality 
in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed. 2013 Nov;98(6): F505-10. doi: 
10.1136/archdischild-2013-303816. Epub 2013 Jul 26. 
3. 
Marconi E, Bettiol A, Ambrosio G, Perduca V, Vannacci A, Troiani S, Dani C, Mugelli A, Lucenteforte E. Efficacy and 
safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical 
trials and observational studies. Pharmacol Res. 2019 Oct; 148:104418. doi: 10.1016/j.phrs.2019.104418. Epub 2019 Aug 31. 
4. 
Cuzzolin L, Bardanzellu F, Fanos V. The dark side of ibuprofen in the treatment of patent ductus arteriosus: could 
paracetamol be the solution?  Expert Opin Drug Metab Toxicol. 2018 Aug; 14(8):855-868. doi: 10.1080/17425255.2018.1492550. 
Epub 2018 Jul 2. 
5. 
Huang X, Wang F, Wang K. Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus in preterm 
neonates: a meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med. 2018 Aug;31(16):2216-2222. 
doi:10.1080/14767058.2017.1338263. Epub 2017 Jul 18. 
6. 
McPherson C, Luecke CM, Liviskie CJ, Zeller BN, Vesoulis ZA. Acetaminophen Serum Concentrations in Infants 
Treated Intravenously for Patent Ductus Arteriosus. J Pediatr Pharmacol Ther. 2019 Mar-Apr;24(2):134-137. doi:10.5863/1551-

 
 
PAIR protocol, version 5.0 , 21st May 2021                                Page 25 of 24 
IRAS ID: 1003574 
 
6776-24.2.134. 
7. 
Peter M; Marie H A. Paracetamol levels following intravenous therapy in neonates less than 28 weeks gestation. Arch 
Dis Childhood; Feb 2018; vol 103 (no. 2) 
8. 
Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O, Dilmen U. Intravenous paracetamol treatment 
in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology. 2013;103(3):166-9. 
doi:10.1159/000345337. Epub 2012 Dec 19. 
9. 
Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent 
ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med. 2016 Oct;12(4):2531-2536. Epub 2016 Sep 6. 
10. 
Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. 
Cochrane Database Syst Rev. 2020 Jan 27; 1:CD010061. doi: 10.1002/14651858.CD010061.pub4. 
11. 
van Laere D, van Overmeire B, Gupta S, El-Khuffash A, Savoia M, McNamara PJ,Schwarz CE, de Boode WP; 
European Special Interest Group ‘Neonatologist Performed Echocardiography’ (NPE). Application of NPE in the assessment of a 
patent ductus arteriosus. Pediatr Res. 2018 Jul;84(Suppl 1):46-56. doi:10.1038/s41390-018-0077-x. 
12. 
BNFc HYPERLINK: https://bnfc.nice.org.uk/drug/paracetamol.html 
13. 
NICE CG17 Jaundice guidelines/charts. https://www.nice.org.uk/guidance/cg98 
14. 
Browne RH. On the use of a pilot sample for sample size determination. Stat Med. 1995;14(17):1933-1940. 
doi:10.1002/sim.4780141709 
15. 
Mukherjee A, Jadhav V, Gupta A; Off-label use of paracetamol in managing patent ductus arteriosus across neonatal 
intensive care units in the UK; Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online First: 26 October 
2020. doi:10.1136/archdischild-2020-320207