Clinical trial NCT03022253: Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates
Official title: Liberal Versus Restrictive Platelet Transfusion for Treatment of Hemodynamically Significant Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates- A Randomized Open Label, Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Patent Ductus Arteriosus
Keywords: PDA
Platelets
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2017-01-16
Enrollment: 44
Sex: ALL
Minimum age (years): 1
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patent ductus arteriosus (PDA) is a common problem in preterm babies. Recently there have been various studies for and against an association between thrombocytopenia and PDA. A meta-analysis published in 2015 showed a marginally significant positive association between PDA and thrombocytopenia but these were all observational studies and there are no randomized controlled trials (RCT) on it. The investigators decided to conduct an RCT to determine whether liberal platelet transfusion criteria achieve earlier PDA closure rates than standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks' gestation) with hemodynamically significant PDA presenting within the first 14 days of life. The investigators primary objective is to determine whether liberal platelet transfusion criteria achieve earlier PDA closure rates within 120 hours compared to standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks' gestation) with hemodynamically significant PDA presenting within the first 14 days of life.

The investigators will stratify the study population based on platelet count, i.e \< 50000 and 50000-100000 per microlitre, and will randomly allocate participants to control and intervention group. Babies in the intervention group will receive platelet transfusion to maintain the platelet count above 100,000 per microlitre. Babies in control group will receive platelets only when clinically indicated and as per current standard indications. The investigators will perform an echocardiogram at baseline to document a hemodynamically significant PDA (hsPDA) and then serially to look for the closure of PDA. Medical management of PDA will be as per unit policy. The investigators will follow the baby till PDA closes or 120 hours post randomization.

Detailed description: Study Background:

Preterm babies are a unique group of patients in Newborn Intensive Care Unit. Patent ductus arteriosus (PDA) is a common complication related to the gestational age of preterm birth. In infants born at less than 32 weeks of gestation, the frequency of PDA has been reported from 50% to 80%. Physiologic ductus arteriosus closure occurs in the first 3 days after birth. The persistence of a PDA beyond the first postnatal days of life, however, is frequently associated with multiple severe complications, predominantly in the most immature infants It is currently believed that ductus arteriosus (DA) closure involves a two-step process. The first, 'provisional' closure is accomplished by smooth muscle cell contraction and ductus arteriosus (DA) constriction. Subsequently, the proliferation of cells within the former DA lumen leads to anatomical remodeling of the DA and permits permanent closure. Recently an association between the absolute platelet count and the closure of ductus arteriosus has been the focus of research. Various prospective and retrospective studies have been conducted for the same. In 2015 systematic review and meta-analysis by Sorina et al showed a significant positive association between PDA and thrombocytopenia. Hence the investigators planned randomized controlled trial to look for the effect of platelet transfusion on closure rates of ductus arteriosus.

Research question:

Do liberal platelet transfusion criteria achieve earlier PDA closure rates than standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks gestation) with hemodynamically significant PDA presenting within the first 14 days of life?

Objectives:

Primary objective: To determine whether liberal platelet transfusion criteria achieve earlier PDA closure rates within 120 hours compared to standard restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (\<35 weeks gestation) with hemodynamically significant PDA presenting within the first 14 days of life.

Secondary objectives:

1. To determine the time period between platelet transfusion and closure of PDA.
2. To compare between the 2 groups:

   1. Proportion in whom PDA is open at 24 hours after the last dose of the course of medication
   2. Proportion in whom PDA is echocardiographically hemodynamically significant at 24 hours after the last dose of the course of medication
   3. Proportion in whom PDA is echocardiographically hemodynamically significant at 120 hours after randomization
   4. Cumulative volume of platelet concentrate received within 120 hours after randomization
   5. Any kind of clinical bleed within 120 hours after randomization
   6. New onset Intraventricular hemorrhage (IVH) of any grade within 120 hours after randomization
   7. New onset IVH of grade 3,4 within 120 hours after randomization
   8. Mortality within 120 hours after randomization
   9. Mortality anytime during hospital stay
   10. Duration of hospital stay
   11. Reopening rate of PDA that had initially closed within 120 hours of randomization

Study Design:

This will be a randomized, open-label, controlled trial.

Place of study Newborn unit of the Department of Pediatrics Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Study period:

* Subject recruitment and data collection: January 2016 to December 2016 (12 months)
* Data analysis: January 2017 to March 2017 (3 months)
* Writing of dissertation: April 2017 to June 2017 (3 months)

Screening criteria (all must be fulfilled):

The investigators will screen all inborn and outborn neonates (admitted in Neonatal intensive care unit (NICU) or Neonatal nursery (NNN) for the following:

1. Gestational age up to 346/7 weeks
2. PDA detected for the first time at less than 14 days of postnatal age

Infants who meet the screening criteria will undergo an echocardiogram conducted by the 1st investigator and a platelet count and will be included if they fulfill all the following inclusion criteria mentioned below.

Procedure of platelet count:

The investigators will draw 0.5 ml of blood into an Ethylene diamine tetraacetic acid (EDTA) Container and immediately send it for analysis to the emergency lab Room No. 24 situated in Advanced Trauma Centre PGIMER Chandigarh. A technician will measure the platelet count by using an automated blood cell coulter (Sysmex KX-21 Coulter) situated in this lab. One of the co-investigators (N.V.) will ensure that the facility of platelet counts is available round-the-clock within a turnaround time of about 2 hours for subjects enrolled in the trial, and will also ensure quality control of the procedure.

Procedure of echocardiography:

The first investigator (JK) will perform the echocardiogram on a SonoSite MicroMaxx Portable Ultrasound Machine. Extremely low birth neonates (ELBW) neonates will be screened in first 48 hours as per unit policy, and the rest will undergo echocardiography only when there are clinical signs of PDA. Before performing the echocardiogram, the first investigator will use a website-generated unique, random code number as the patient identifier. The first investigator will take a backup of each echocardiogram immediately on an external hard drive and the video files will be named with the same website-generated random code number. One of the co-investigators (VS or SS) will review the code numbered echocardiograms. VS and SS will be masked to the identity and clinical details of the patients. The key to the code numbers will be maintained by JK and Sourabh Dutta (SD). The echocardiographic diagnosis of PDA by VS or SS will be considered to be the gold standard.

The following information will be recorded for each echocardiogram:

1. Whether the ductus arteriosus is patent or closed.
2. If it is patent, Transductal diameter, Ductal velocity, Antegrade left PA diastolic flow, Left Atrium/Aorta (LA/Ao) ratio, E/A, Isovolumic relaxation time (IVRT) , Absent or reversed diastolic blood flow pattern in descending thoracic aorta.

Patient information and informed consent:

The 1st investigator (J.K.) will approach parents of subjects that meet the above eligibility criteria for possible enrollment in the study. The first investigator will provide them a detailed information sheet and also give a verbal explanation about the study. The first investigator will enroll neonates only after obtaining written informed consent from one of the parents.

Baseline data:

The investigators will record baseline maternal and neonatal data.

Medical treatment of PDA:

As all subjects recruited in the trial will have hemodynamically significant PDA, they will all be medically treated. Details are given under intervention heading.

Some subjects may be recruited in another ongoing RCT during the initial months of this trial. The other RCT compares paracetamol and ibuprofen in a blinded fashion amongst subjects with hemodynamically significant PDA for the closure of PDA. For such subjects, the trial drug regime will be followed. The index trial will not be affected by being co-recruited in the other ongoing RCT. If a particular dose of medication cannot be given because of a contraindication (an adverse effect or adverse clinical condition) that arises during the course of treatment, that dose will be deferred until it is safe to administer the dose. The duration of medical treatment will be taken as the total duration inclusive of the deferred dose/s.

Randomization:

The investigators will allocate patients according to a stratified, block randomised design. The investigators will stratify patients into the following strata: a) platelet count \< 50,000 per microliter b) platelet count 50,000-100,000 per microliter. The Chief guide Sourabh Dutta (S.D.) will generate the randomisation sequence and construct randomly varying, permuted, even-numbered blocks for each stratum. The chief guide will conceal the block sizes until the end of the study. Each stratum will have its independent randomisation sequence. After the 1st investigator identifies the stratum, S.D. will randomly allocate subjects to an intervention or control group. The investigators will ensure concealment of allocation by using serially numbered opaque sealed envelopes which will bear a slip of paper with the allocation group.

Allocation groups:

Intervention group: The investigators will transfuse platelet concentrates to maintain platelet count above 1, 00,000 per microliter (details are given under Arms and Intervention) The investigators will aggressively monitor platelet counts in the intervention group, depending upon the stratum in which the subject is enrolled.

In the stratum that has a baseline platelet count less than 50,000 per microliter, there is very little chance that the platelet count will rise to more than 100,000 per microliter with a single platelet concentrate transfusion. In this stratum, two back to back platelet concentrates (20 ml/kg each) will be transfused without performing a platelet count in between the 2 tests transfusions.

In the stratum that has a baseline platelet count from 50,000 to 100,000 per microliter, a platelet count will be performed after a single transfusion.

In both strata, platelet count will be repeated in a window period of 2 hours after the end of the platelet transfusion. The investigators will attempt to club this platelet count with another blood sampling for clinical indications if possible. The investigators will attempt to get the post-transfusion platelet count within a turnaround time of 2 hours. If the subject has a platelet count less than 100,000 per microliter, the investigators will repeat a platelet transfusion, and so on, subject to a maximum volume of 40 ml/kg/day of platelet concentrates in a 24-hour period (defined as 8 AM to 8 AM next day). The investigators will temporarily stop transfusing platelet concentrates once the investigators get a value of above 100,000 per microliter. In addition to the platelet counts performed post-transfusion, the investigators will also perform platelet counts for the following indications:

(i) Clinical bleeds (ii) A routine platelet count once in every 24 hours until PDA closes or the criterion of 120 hours post randomization is met.

The platelet count for clinical bleeds and routine platelet counts will not be repeated in case a platelet count post-transfusion is already available within a window period of 4 hours prior.

Control group: (details are given under Arms and Intervention) In the control group, the investigators will perform platelet counts as per the standard unit practices. A platelet count will be repeated whenever the subject is next sampled for a clinical indication or a longer with routine samples in the evening or morning. A platelet transfusion will be repeated if the platelet count falls to less than 20,000 per microliter or if any of the above criteria are met.

In both groups, platelet concentrates will be transfused according to platelet count prior to transfusion. In babies with platelet count \< 50000, 50-75000 and 75-1, 00, 00 per microliter the investigators will transfuse @ 20, 15 and 10 ml/kg/transfusion respectively up to a maximum of 40 ml/kg/day. The investigators will administer injection furosemide 0.5 mg/kg as slow IV injection midway through the transfusion if the treating team clinically feels that the patient is likely to develop congestive cardiac failure or pulmonary edema.

Study endpoints:

Subjects will be followed up in the study until the earliest among

1. Withdrawal of consent
2. Discharge from hospital
3. Death

Eligibility criteria: Inclusion Criteria:

1. Gestational age up to 34 6/7 weeks
2. PDA detected for the first time at less than 14 days of postnatal age
3. Clinically and/or echocardiographically hemodynamically significant PDA Note: ELBW neonates will be screened in first 48 hours as per unit policy; the rest will undergo echocardiography only when there are clinical signs of PDA.
4. Platelet count within 24 hours prior to inclusion is less than 100,000 per microliter.

Note: If a platelet count is already available within 24 hours prior to inclusion it will be accepted as a valid platelet count. If not, an urgent absolute platelet count will be performed.

Exclusion Criteria:

1. Echocardiographically proven structural congenital heart disease.
2. Major life-threatening malformation
3. Received platelet concentrate between the last available platelet count and the point of randomisation

Primary outcomes:
measure: Time to closure of PDA post randomization
timeFrame: within 120 hours post randomisation
Secondary outcomes:
measure: Proportion of participants in whom PDA is open
timeFrame: at 120 hours after randomization
measure: Proportion of participants in whom PDA is echocardiographically hemodynamically significant
timeFrame: at 120 hours after randomization
measure: Cumulative volume of platelet concentrate received
timeFrame: within 120 hours after randomization
measure: Number of participants with Clinical bleed of any kind ( defined below)
timeFrame: within 120 hours after randomization
measure: New onset IVH of any grade
timeFrame: within 120 hours after randomization
measure: New onset IVH of grade 3or 4
timeFrame: within 120 hours after randomization
measure: Mortality
timeFrame: within 120 hours after randomization
measure: Mortality
timeFrame: All subjects will be part of the study until death or discharge from the hospital. Timeframe for measuring mortality as an outcome is from the point of randomisation through the study period which will be approximately upto 30 days post randomisation
measure: Duration of hospital stay
timeFrame: All subjects will be part of the study until death or discharge from the hospital.Timeframe for measuring duration of hospital stay is from the point of randomisation through the study period which will be approximately upto 30 days post randomisation
measure: Reopening rate of PDA that had initially closed
timeFrame: within 120 hours of randomization
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
Study officials:
affiliation: Post Graduate Institute of Medical Education and Research; Chandigarh, India
name: Sourabh Dutta, MD
role: STUDY_DIRECTOR
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