ORAL PARACETAMOL VERSUS ORAL IBUPROFEN IN PATENT DUCTUS

ARTERIOSUS: A NON-INFERIORITY TRIAL

Dr. Rahul S. GosaviMd pediatrics , dnb neonatology.

Dept. of Neonatology.

HYDERABAD, India Website : www.fernandezhospital.com

Introduction

Hemodynamically significant patent ductusarteriosus (hsPDA) is a common cause ofmorbidity and mortality in preterm neonates

Indomethacin and ibuprofen are the twocommonly used drugs for closure of PDA

Conventional drugs for closure of patentductus arteriosus are associated with adverseeffects

Research Question (PICOT)

inborn preterm neonates of <32 weeks’ gestation with hsPDA (population) whether oral paracetamol (intervention) is non-inferior to oral ibuprofen (control) in closing hsPDAwith an ‘a priori’ non-inferiority margin of 15% (outcome) by 24 hours from the last dose of study drug (time)

Hypothesis

Null Hypothesis: Rate of closure of PDA in the Test group that would receive Oral Paracetamol is inferior by a non-inferiority margin (D) of 15 % to administering Oral Ibuprofen in control group.

Alternate Hypothesis: Oral Paracetamol is notinferior by a non-inferiority margin (D) of 15 % to administering Oral Ibuprofen in control group.

Methods

Study was randomized, two-arm, active-controlled, blinded, non-inferiority trial

Approved by hospital’s local academic research ethics committee

Registered with CTRI with registration number of CTRI/2014/08/004805.

Study was conducted at three centres across India between April 2014 and June 2017

PGI ChandigarhFernandez HospitalICH Chennai

Study Population

Inclusion criteria

Consecutively born preterm neonates of <32 weeks’ gestation with hsPDA

screening echocardiography was performed in asymptomatic neonates to detect hsPDA(between 48-72 hours of age in 29-31 weeks’ gestation and first 48 hours in ≤28 weeks’ gestation

Study PopulationExclusion Criteria

Suspected or diagnosed structural heart disease,

Contraindications for enteral feeding and administration of any one of the study drugs

blood urea >60mg/dl, serum creatinine >1.6 mg/ dl, platelet count<60000/uL,

Clinical bleeding from any site, deranged coagulogram,

Clinical or radiological evidence of NEC,

IVH grade III with or without intra-parenchymalextension or progression of IVH from an earlier ultrasound,

Study population

Serum bilirubin level within 2 mg/dl from the exchange transfusion cut-off value and

Whose parents refused consent

Randomization

Stratified, block-randomization was used in this study

Stratification was based on study center and gestational age groups (<28 weeks, 28-29 and 30-31 weeks).Randomly varying, permuted, even numbered blocks (sizes 4, 6 and 8) were generated from a website http://www.randomization.com

The person who generated the random sequence was not involved in any other aspect of the trial.

Allocation concealment and blinding

written consent was obtained from the parents of eligible infant

The drugs were prepared by the clinical pharmacy department of the Institute in 5 ml volumes.

Allocation concealment was ensured by dispensing the prepared drugs in serially numbered opaque vials as per the group of allocation

drugs were prepared to have a similar color, flavor, and viscosity to facilitate blinding.

Blinding

To avoid unblinding due to differences in dosage same concentration of both the drugs were prepared

To avoid unblinding due to differences in frequency of administration, an identical-looking placebo was used for ibuprofen arm

The treating team, investigators, outcome assessors and the pharmacy personnel were blinded.

Intervention

Oral paracetamol

Primary therapy Paracetamol oral suspension (Calpol, GlaxoSmith Kline Asia Pvt Ltd) was administered through an orogastric tube at 15 mg/kg/dose in 6 hourly intervals for three consecutive days

Oral Ibuprofen

Ibuprofen oral suspension (Ibugesic, Cipla India Ltd.) was administered at 10 mg/kg/dose followed by 5 mg/kg/dose after 24 and 48 hours from the first dose

the drugs were flushed with 1 ml sterile water

Those infants where the hsPDA remained open or reopened received a second course of the study drug or an appropriate open label drug if any contraindication to the study drug was

observed.

Outcomes

Primary Outcome

The primary outcome(non-inferiority comparison) was closure of hsPDA by 24 hours from the last dose of the study drug, irrespective of the course of the drug

Outcomes

Secondary Outcomes

closure of hsPDA by 24 hours after the first course of the study drug,

rate of reopening following the first course,

subjects requiring surgical ligation for hsPDA closure,

all-cause mortality in hospital

Outcomes

• adverse events with onset after the start of administration of the study drug like

– azotemia,

– oliguria,

– hepatitis with deranged liver transaminases,

– deranged coagulogram,

– severe IVH(grade 3 and intra-parenchymal extension),

– PVL,

– NEC (definite and advanced stage as per modified Bell’s staging),

– BPD, and

– ROP requiring therapy

Sample Size The frequency of failure of PDA closure with oral Ibuprofen treatment is

15%.

Assuming a non-inferiority margin of 15%, a one-sided alpha error of 2.5%, power of 90% and 1:1 allocation ratio, 196 neonates were required in this trial.

A margin size of 15% was considered as size which would be clinically irrelevant.

Both intention-to-treat (ITT) and per-protocol analysis were conducted

the confidence interval (CI) approach was also used to test non-inferiority

Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductusarteriosus in preterm or low birth weight (or both) infants. Cochrane

Database Syst Rev. 2018;9:CD003481.

Statistical AnalysisVariable Expression Test

Discrete Percentage (%) Chi-square or Fisher’s exact test

Continuous Mean ± SD Student’s t test or nonparametric tests

A ‘p’ value of 0.025 was considered significant for the primary outcome and 0.05 for the remaining outcomes. IBM-SPSS version 23 was used for data entry and statistical analysis

RESULTS

Baseline Characteristics of Mother and Infant

Variables Pcm group(n=81)Iboprofen group

(n= 80)

Mean Birth weight (gram ± SD) 1167 (249) 1129 (268)

Gestation (Mean ,SD) 28.7 (1.6) 28.7 (1.7)

Extreme prematurity (<28 weeks) 20 (25) 20 (25)

Male Gender (n, %) 42 (52) 38 (48)

Respiratory distress 72 (89) 74 (93)

Vaginal mode of delivery 32 (40) 42 (53)

Extreme low birth weight (<1000 grams) 18 (22) 23 (29)

Antenatal steroids (any dose) 68 (84) 64 (80)

Baseline Characteristics

Variables Pcm group(n=81)Iboprofen group

(n= 80)

Transductal diameter (mm); median

(IQR)

2.3 (1.8, 2.6) 2.1 (1.9, 2.5)

Transductal diameter 1.5 mm 81 (100) 80 (100)

Left atrium: Aorta root diameter 1.4 78 (96) 67 (84)

Ductal velocity < 2m/sec 28 (35) 32 (40)

Antegrade LPA diastolic velocity >20

cm/sec

78 (96) 75 (94)

Primary Outcome

Variables

Oral

pcm

(n=81);

n (%)

Oral

brufen

(n=80)

n (%)

RR or RD or MD

(95% C.I)

P

Closure of ductus arteriosus

after two courses (modified ITT

analysis*) – primary outcome

63/71

(89)

65/73

(89)

RR: 0.99 (0.89, 1.12)

RD: -0.3 (-11, 10)

0.47

(one

tailed)

Closure of ductus arteriosus

after two courses of trial drug

(per protocol analysis)

62/65

(95.4)

63/67

(94)

RR: 1.01 (0.94, 1.1)

RD: 1.4 (-6, 9)

0.37

(one

tailed)

Secondary Outcomes

Variables

Oral Pcm

(n=81); n

(%)

Oral

brufen

(n=80); n

(%)

RR or RD

(95% C.I)

P

Closure of ductus arteriosus after

first course**(ITT analysis)

52/81 (64) 62/80

(78)

0.8(0.68, 1.01) 0.07

Closure of ductus arteriosus after

two courses of trial drug (worst

case scenario for experimental

arm)

63/74 (85) 70/74

(94.6)

0.9 (0.8, 1.004) 0.063

Rate of reopening of ductus

arteriosus after first course of

trial drug

5/57 (8.8) 4/66 (6.1) 1.45 (0.41, 5.1) 0.58

Closure after second course of

trial drug (n=17)

9/12 (75) 1/5 (20) 3.8 (0.63, 22.3) 0.063

Secondary outcome

Variables

Oral Pcm

(n=81); n

(%)

Oral

brufen

(n=80); n

(%)

RR or RD

(95% C.I)

P

Ductus arteriosus that underwent

surgical ligation

2/81 (2.5) 4/80 (5) 0.49 (0.09, 2.62) 0.44

Non-compliance to trial drug

Received alternate trial drug

Received non-trial open label

drug

1/81 (1.2)

0 (0)

1/81 (1.2)

5/80 (6.3)

0 (0)

5/80 (6.3)

0.19 (0.02, 1.7) 0.1

Safety outcomes

Variables

Oral Pcm

(n=81); n

(%)

Oral

brufen

(n=80); n

(%)

RR or RD

(95% C.I)

P

Azotemia 12/81 14/79 0.84 (0.4,1.7) 0.62

Oliguria 10/81 16/80 0.62 (0.3,1.3) 0.2

Deranged transaminases 1/78 0/78 2.0 (0.07,59) 0.78

Deranged coagulogram 10/80 9/78 1.08 (0.5,2.5) 0.86

Safety outcomes

Variables

Oral Pcm

(n=81); n

(%)

Oral

brufen

(n=80); n

(%)

RR or RD

(95% C.I)

P

Major intraventricular hemorrhage(

grade 3)

2/71 7/70 0.28 (0.06,1.3) 0.09

Periventricular leukomalacia

( grade 2)

3/74 0/75 6.1 (0.3,120) 0.23

Necrotizing enterocolitis (definite &

advanced stages)

11/73 4/66 2.5 (0.83,7.4) 0.09

Bronchopulmonary dysplasia 11/78 6/75 1.8 (0.7,4.5) 0.24

Sub group analysis

• A subgroup analysis by gestational age strata showed similar closure rates following both courses as well as single course between the study groups

• An ITT analysis showed similar results as the per protocol analysis [63 (89%) versus 65 (89%); RR (95% CI): 0.99 (0.89, 1.12); RD (95% CI): -0.3 (-11,10); p=0.47].

Establishment of non-inferiority

• For the primary outcome, the risk difference was observed to be -0.3% by ITT analysis and 1.4% by per protocol analysis, with a one-sided ‘p’ of 0.47 and 0.37, respectively.

• The historical RR comparing oral ibuprofen with placebo or no treatment was 2.08 (1.33, 3.24) for closure of ductusarteriosus and hence the ‘dmax’ was 1.33. By the CI approach, the upper bound of the 1-sided 97.5% CI of the observed RR of 1.1 was observed to lie within the ‘dmax’

Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2018;9:CD003481

Strength of Study

• Blinded randomized control trial

• Predefined criteria for patient selection that included both clinical and Echo evidence of HS PDA

• Serial Echo to detect closure of PDA

• Low risk of bias in random allocation and allocation concealment

• No loss to follow up of subjects who were alive

Limitations

Inability to recruit the required sample size

Long term follow up was not done

Analyse the osmolality of the final preparation of the study drugs was not done

Not analysed of plasma levels of paracetamol

We could not prove that oral paracetamolwas safer than oral ibuprofen

Conclusion• Oral Paracetamol is not inferior to oral ibuprofen in closure

of hsPDA in preterm neonates of <32 weeks’ gestation.

• No difference was observed between the study arms in the adverse events

• Reopening rate was higher in the oral paracetamol arm, but was not statistically significant.

• More neonates in the paracetamol arm required second course of the trial drug for PDA closure implying that a dose response design study must be undertaken to understand the right dose, frequency and duration of oral paracetamolfor effective PDA closure.

Implication For Practice

oral paracetamol can be considered for closure of hsPDA in preterm neonates of <32 weeks’ gestation.

Thank You