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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