Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates

Learn more about:
Related Clinical Trial
Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen Aminoglycosides and Duct Radiation-Free Heart Catheterization Using MRI Hemodynamic Responses to Cardio-respiratory Events in Preterm Infants Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants Impact of Maternal-infant Therapeutics on Safety, Mortality, and Disability The Pharmacology and Hemodynamics of Dexmedetomidine in Children With Congenital Heart Disease The Preterm Infants’ Paracetamol Study Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants Evaluation of the Brain and Renal Regional Oxygenation Using NIRS in Preterm Infants Feasibility, Efficacy and Safety of IBS ® for Implantaiton in the PDA in Duct-dependent Cyanotic CHD Hyperion™ International Registry Trial NIRS in PDA VLBW Infants Amplatzer Piccolo Occluder Japan Post-marketing Database Surveillance Comparison of Oral and Intravenous Ibuprofen for PDA Treatment in Premature Infants The Impact of Platelet Functions on Spontaneous Ductal Closure in Preterm Infants Lifetech CeraFlex™ Post-Market Surveillance Study Treatment of a PDA With Acetaminophen in Preterm Neonates: Exploring Various Indications Nit-Occlud PDA Post-Approval Study Ibuprofen and Renal Function in Premature Infants A New Device for Measuring of Lung Photoplethysmography and Pulmonic Arterial Saturation Canadian National PDA Treatment Study Long Term Results of 450 Percutaneous Closures of PDA in a Single Center Efficacy and Safety of Oral Versus Intravenous Ibuprofen for PDA Treatment in ELBW Infants AMPLATZER Duct Occluder II Additional Sizes A NEW SCORING SYSTEM FOR PREDICTION OF PDA Clinical Trial to Evaluate Two Guidelines for the Administration of Ibuprofen in the Treatment of Persistent Ductus Arteriosus Eco-guided: Impact in the Intestinal Prognosis Feeding During Ibuprofen or Indomethacin Treatment of Preterm Infants The Efficacy of Implementing a Treatment Algorithm in Managing Patent Ductus Arteriosus (PDA) in the Extremely Low Birth Weight Neonatal Population. Safety and Efficacy of Ibuprofen in Term Newborns With Patent Ductus Arteriosus (PDA) Ibuprofen vs. Continuous Indomethacin in the Treatment of PDA Addition of Acetaminophen in Standard PDA Management Second Course of Therapy for Resistant Patent Ductus Arteriosus (PDA) Safety/Efficacy Study of Optimizing Ibuprofen Dosing to Achieve Higher PDA Closure Rates Paracetamol Versus Ibuprofen for PDA Closure Population Pharmacokinetics and Dosage Individualization of Paracetamol and Ibuprofen in Children With PDA Timing for the Medical Treatment of Patent Ductus Arteriosus in Preterm Infants Early Treatment Versus Expectative Management of PDA in Preterm Infants International Experience in Timing And Choices for Ductal Closure in Patent Ductus Arteriosus:INTERPDA Trial Comparative Study of Efficacy and Safety of Oral Ibuprofen and Intravenous Ibuprofen in Closure of Patent Ductus Arteriosus in Very Low Birth Weight Infants Do Elevated BNP Levels Predict Hemodynamically Significant PDAs The Use of B-type Natriuretic Peptide (BNP) to Predict Closure of a Patent Ductus Arteriosus (PDA) in Premature Infants Brain, Gut and Kidney Blood Flow During Medical Closure of PDA Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus Serum Level Measurement of Oral Paracetamol and Oral Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants The Role of Fetal Ductus Arteriosus in Predicting Spontaneous Labour at Term AMPLATZER Duct Occluder II Clinical Study The Role of Fetal Ductus Arteriosus in Predicting Spontaneous Preterm Birth Paracetamol and Patent Ductus Arteriosus (PDA) Comparison of 2 Different Indomethacin Dosing Protocols to Treat Infants Delivered at Near Infrared Spectroscopy to Determine Patent Ductus Arteriosus Closure Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes Oral Paracetamol Versus Oral Ibuprofen in Management of Patent Ductus Arteriosus in Preterm Infants: A Randomised Controlled Trial Early Versus Late Use of Ibuprofen for Patent Ductus Arteriosus (PDA) Closure Pocket Echocardiography System (PES) for Detection of PDA in Neonates Treating the Resistant Patent Ductus Arteriosus (PDA) Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus IV Acetaminophen and Patent Ductus Arteriosus Closure Of Patent Ductus Arteriosus With the AMPLATZER Duct Occluder the AMPLATZER® Duct Occluder Closure of Patent Ductus Arteriosus With Indomethacin or Ibuprofen in Extreme Low Birth Weight Infants Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates Nitric Oxide, Endothelin-1, and the Patency of Ductus Arteriosus in Preterm Infants Early Ibuprofen Treatment of Patent Ductus Arteriosus (PDA) in Premature Infants (TRIOCAPI) Influence of Treatment for Patent Ductus Arteriosus on Cerebral Oxygenation in Preterm Infants An Escalating Dose Indomethacin for the Treatment of Persistent Patent Ductus Arteriosus (PDA) In Preterm Infants Patent Ductus Arteriosus and Splanchnic Oxygenation at First Feed Preliminary Percutaneous Intervention Versus Observational Trial of Arterial Ductus in Low-weight Infants Non-Invasive Detection of Tissue Oxygen Deprivation in Premature Infants With Patent Ductus Arteriosus. Safety and Effectiveness Study With a New PDA Occluder for Closure of Patent Ductus Arteriosus

Brief Title

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

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
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Time to closure of PDA post randomization

Secondary Outcome

 Proportion of participants in whom PDA is open

Condition

Patent Ductus Arteriosus

Intervention

Liberal platelet transfusion

Study Arms / Comparison Groups

 Liberal Platelet transfusion group
Description:  Platelet transfusion to maintain a platelet count above 1,00,000 per microliter until one of the endpoints is met.
As all subjects recruited in the trial will have hemodynamically significant (hs) PDA, they will all be medically treated as per standard of care. Treatment regimens will be as follows, depending on the discretion of the treating physician:
Ibuprofen:
Dosage-10 mg/kg stat followed by 5 mg/kg/dose x 2 doses at 24 hours intervals Route- oral
Paracetamol:
Dosage-15 mg/kg/dose every 6 hourly x 12 doses Route - IV

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

44

Start Date

March 2016

Completion Date

March 20, 2017

Primary Completion Date

March 20, 2017

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
      

Gender

All

Ages

N/A - 14 Days

Accepts Healthy Volunteers

No

Contacts

Sourabh Dutta, MD, , 

Location Countries

India

Location Countries

India

Administrative Informations


NCT ID

NCT03022253

Organization ID

INT/IEC/2016/1090


Responsible Party

Principal Investigator

Study Sponsor

Postgraduate Institute of Medical Education and Research


Study Sponsor

Sourabh Dutta, MD, Study Director, Post Graduate Institute of Medical Education and Research; Chandigarh, India


Verification Date

April 2018