<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03022253</url>
  </required_header>
  <id_info>
    <org_study_id>INT/IEC/2016/1090</org_study_id>
    <nct_id>NCT03022253</nct_id>
  </id_info>
  <brief_title>Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Postgraduate Institute of Medical Education and Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Postgraduate Institute of Medical Education and Research</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patent ductus arteriosus (PDA) is a common problem in preterm babies. Recently there have&#xD;
      been various studies for and against an association between thrombocytopenia and PDA. A&#xD;
      meta-analysis published in 2015 showed a marginally significant positive association between&#xD;
      PDA and thrombocytopenia but these were all observational studies and there are no randomized&#xD;
      controlled trials (RCT) on it. The investigators decided to conduct an RCT to determine&#xD;
      whether liberal platelet transfusion criteria achieve earlier PDA closure rates than standard&#xD;
      restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (&lt;35 weeks'&#xD;
      gestation) with hemodynamically significant PDA presenting within the first 14 days of life.&#xD;
      The investigators primary objective is to determine whether liberal platelet transfusion&#xD;
      criteria achieve earlier PDA closure rates within 120 hours compared to standard restrictive&#xD;
      platelet transfusion criteria among thrombocytopenic preterm neonates (&lt;35 weeks' gestation)&#xD;
      with hemodynamically significant PDA presenting within the first 14 days of life.&#xD;
&#xD;
      The investigators will stratify the study population based on platelet count, i.e &lt; 50000 and&#xD;
      50000-100000 per microlitre, and will randomly allocate participants to control and&#xD;
      intervention group. Babies in the intervention group will receive platelet transfusion to&#xD;
      maintain the platelet count above 100,000 per microlitre. Babies in control group will&#xD;
      receive platelets only when clinically indicated and as per current standard indications. The&#xD;
      investigators will perform an echocardiogram at baseline to document a hemodynamically&#xD;
      significant PDA (hsPDA) and then serially to look for the closure of PDA. Medical management&#xD;
      of PDA will be as per unit policy. The investigators will follow the baby till PDA closes or&#xD;
      120 hours post randomization.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Background:&#xD;
&#xD;
      Preterm babies are a unique group of patients in Newborn Intensive Care Unit. Patent ductus&#xD;
      arteriosus (PDA) is a common complication related to the gestational age of preterm birth. In&#xD;
      infants born at less than 32 weeks of gestation, the frequency of PDA has been reported from&#xD;
      50% to 80%. Physiologic ductus arteriosus closure occurs in the first 3 days after birth. The&#xD;
      persistence of a PDA beyond the first postnatal days of life, however, is frequently&#xD;
      associated with multiple severe complications, predominantly in the most immature infants It&#xD;
      is currently believed that ductus arteriosus (DA) closure involves a two-step process. The&#xD;
      first, 'provisional' closure is accomplished by smooth muscle cell contraction and ductus&#xD;
      arteriosus (DA) constriction. Subsequently, the proliferation of cells within the former DA&#xD;
      lumen leads to anatomical remodeling of the DA and permits permanent closure. Recently an&#xD;
      association between the absolute platelet count and the closure of ductus arteriosus has been&#xD;
      the focus of research. Various prospective and retrospective studies have been conducted for&#xD;
      the same. In 2015 systematic review and meta-analysis by Sorina et al showed a significant&#xD;
      positive association between PDA and thrombocytopenia. Hence the investigators planned&#xD;
      randomized controlled trial to look for the effect of platelet transfusion on closure rates&#xD;
      of ductus arteriosus.&#xD;
&#xD;
      Research question:&#xD;
&#xD;
      Do liberal platelet transfusion criteria achieve earlier PDA closure rates than standard&#xD;
      restrictive platelet transfusion criteria among thrombocytopenic preterm neonates (&lt;35 weeks&#xD;
      gestation) with hemodynamically significant PDA presenting within the first 14 days of life?&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary objective: To determine whether liberal platelet transfusion criteria achieve earlier&#xD;
      PDA closure rates within 120 hours compared to standard restrictive platelet transfusion&#xD;
      criteria among thrombocytopenic preterm neonates (&lt;35 weeks gestation) with hemodynamically&#xD;
      significant PDA presenting within the first 14 days of life.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To determine the time period between platelet transfusion and closure of PDA.&#xD;
&#xD;
        2. To compare between the 2 groups:&#xD;
&#xD;
             1. Proportion in whom PDA is open at 24 hours after the last dose of the course of&#xD;
                medication&#xD;
&#xD;
             2. Proportion in whom PDA is echocardiographically hemodynamically significant at 24&#xD;
                hours after the last dose of the course of medication&#xD;
&#xD;
             3. Proportion in whom PDA is echocardiographically hemodynamically significant at 120&#xD;
                hours after randomization&#xD;
&#xD;
             4. Cumulative volume of platelet concentrate received within 120 hours after&#xD;
                randomization&#xD;
&#xD;
             5. Any kind of clinical bleed within 120 hours after randomization&#xD;
&#xD;
             6. New onset Intraventricular hemorrhage (IVH) of any grade within 120 hours after&#xD;
                randomization&#xD;
&#xD;
             7. New onset IVH of grade 3,4 within 120 hours after randomization&#xD;
&#xD;
             8. Mortality within 120 hours after randomization&#xD;
&#xD;
             9. Mortality anytime during hospital stay&#xD;
&#xD;
            10. Duration of hospital stay&#xD;
&#xD;
            11. Reopening rate of PDA that had initially closed within 120 hours of randomization&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      This will be a randomized, open-label, controlled trial.&#xD;
&#xD;
      Place of study Newborn unit of the Department of Pediatrics Post Graduate Institute of&#xD;
      Medical Education and Research (PGIMER), Chandigarh, India&#xD;
&#xD;
      Study period:&#xD;
&#xD;
        -  Subject recruitment and data collection: January 2016 to December 2016 (12 months)&#xD;
&#xD;
        -  Data analysis: January 2017 to March 2017 (3 months)&#xD;
&#xD;
        -  Writing of dissertation: April 2017 to June 2017 (3 months)&#xD;
&#xD;
      Screening criteria (all must be fulfilled):&#xD;
&#xD;
      The investigators will screen all inborn and outborn neonates (admitted in Neonatal intensive&#xD;
      care unit (NICU) or Neonatal nursery (NNN) for the following:&#xD;
&#xD;
        1. Gestational age up to 346/7 weeks&#xD;
&#xD;
        2. PDA detected for the first time at less than 14 days of postnatal age&#xD;
&#xD;
      Infants who meet the screening criteria will undergo an echocardiogram conducted by the 1st&#xD;
      investigator and a platelet count and will be included if they fulfill all the following&#xD;
      inclusion criteria mentioned below.&#xD;
&#xD;
      Procedure of platelet count:&#xD;
&#xD;
      The investigators will draw 0.5 ml of blood into an Ethylene diamine tetraacetic acid (EDTA)&#xD;
      Container and immediately send it for analysis to the emergency lab Room No. 24 situated in&#xD;
      Advanced Trauma Centre PGIMER Chandigarh. A technician will measure the platelet count by&#xD;
      using an automated blood cell coulter (Sysmex KX-21 Coulter) situated in this lab. One of the&#xD;
      co-investigators (N.V.) will ensure that the facility of platelet counts is available&#xD;
      round-the-clock within a turnaround time of about 2 hours for subjects enrolled in the trial,&#xD;
      and will also ensure quality control of the procedure.&#xD;
&#xD;
      Procedure of echocardiography:&#xD;
&#xD;
      The first investigator (JK) will perform the echocardiogram on a SonoSite MicroMaxx Portable&#xD;
      Ultrasound Machine. Extremely low birth neonates (ELBW) neonates will be screened in first 48&#xD;
      hours as per unit policy, and the rest will undergo echocardiography only when there are&#xD;
      clinical signs of PDA. Before performing the echocardiogram, the first investigator will use&#xD;
      a website-generated unique, random code number as the patient identifier. The first&#xD;
      investigator will take a backup of each echocardiogram immediately on an external hard drive&#xD;
      and the video files will be named with the same website-generated random code number. One of&#xD;
      the co-investigators (VS or SS) will review the code numbered echocardiograms. VS and SS will&#xD;
      be masked to the identity and clinical details of the patients. The key to the code numbers&#xD;
      will be maintained by JK and Sourabh Dutta (SD). The echocardiographic diagnosis of PDA by VS&#xD;
      or SS will be considered to be the gold standard.&#xD;
&#xD;
      The following information will be recorded for each echocardiogram:&#xD;
&#xD;
        1. Whether the ductus arteriosus is patent or closed.&#xD;
&#xD;
        2. If it is patent, Transductal diameter, Ductal velocity, Antegrade left PA diastolic&#xD;
           flow, Left Atrium/Aorta (LA/Ao) ratio, E/A, Isovolumic relaxation time (IVRT) , Absent&#xD;
           or reversed diastolic blood flow pattern in descending thoracic aorta.&#xD;
&#xD;
      Patient information and informed consent:&#xD;
&#xD;
      The 1st investigator (J.K.) will approach parents of subjects that meet the above eligibility&#xD;
      criteria for possible enrollment in the study. The first investigator will provide them a&#xD;
      detailed information sheet and also give a verbal explanation about the study. The first&#xD;
      investigator will enroll neonates only after obtaining written informed consent from one of&#xD;
      the parents.&#xD;
&#xD;
      Baseline data:&#xD;
&#xD;
      The investigators will record baseline maternal and neonatal data.&#xD;
&#xD;
      Medical treatment of PDA:&#xD;
&#xD;
      As all subjects recruited in the trial will have hemodynamically significant PDA, they will&#xD;
      all be medically treated. Details are given under intervention heading.&#xD;
&#xD;
      Some subjects may be recruited in another ongoing RCT during the initial months of this&#xD;
      trial. The other RCT compares paracetamol and ibuprofen in a blinded fashion amongst subjects&#xD;
      with hemodynamically significant PDA for the closure of PDA. For such subjects, the trial&#xD;
      drug regime will be followed. The index trial will not be affected by being co-recruited in&#xD;
      the other ongoing RCT. If a particular dose of medication cannot be given because of a&#xD;
      contraindication (an adverse effect or adverse clinical condition) that arises during the&#xD;
      course of treatment, that dose will be deferred until it is safe to administer the dose. The&#xD;
      duration of medical treatment will be taken as the total duration inclusive of the deferred&#xD;
      dose/s.&#xD;
&#xD;
      Randomization:&#xD;
&#xD;
      The investigators will allocate patients according to a stratified, block randomised design.&#xD;
      The investigators will stratify patients into the following strata: a) platelet count &lt;&#xD;
      50,000 per microliter b) platelet count 50,000-100,000 per microliter. The Chief guide&#xD;
      Sourabh Dutta (S.D.) will generate the randomisation sequence and construct randomly varying,&#xD;
      permuted, even-numbered blocks for each stratum. The chief guide will conceal the block sizes&#xD;
      until the end of the study. Each stratum will have its independent randomisation sequence.&#xD;
      After the 1st investigator identifies the stratum, S.D. will randomly allocate subjects to an&#xD;
      intervention or control group. The investigators will ensure concealment of allocation by&#xD;
      using serially numbered opaque sealed envelopes which will bear a slip of paper with the&#xD;
      allocation group.&#xD;
&#xD;
      Allocation groups:&#xD;
&#xD;
      Intervention group: The investigators will transfuse platelet concentrates to maintain&#xD;
      platelet count above 1, 00,000 per microliter (details are given under Arms and Intervention)&#xD;
      The investigators will aggressively monitor platelet counts in the intervention group,&#xD;
      depending upon the stratum in which the subject is enrolled.&#xD;
&#xD;
      In the stratum that has a baseline platelet count less than 50,000 per microliter, there is&#xD;
      very little chance that the platelet count will rise to more than 100,000 per microliter with&#xD;
      a single platelet concentrate transfusion. In this stratum, two back to back platelet&#xD;
      concentrates (20 ml/kg each) will be transfused without performing a platelet count in&#xD;
      between the 2 tests transfusions.&#xD;
&#xD;
      In the stratum that has a baseline platelet count from 50,000 to 100,000 per microliter, a&#xD;
      platelet count will be performed after a single transfusion.&#xD;
&#xD;
      In both strata, platelet count will be repeated in a window period of 2 hours after the end&#xD;
      of the platelet transfusion. The investigators will attempt to club this platelet count with&#xD;
      another blood sampling for clinical indications if possible. The investigators will attempt&#xD;
      to get the post-transfusion platelet count within a turnaround time of 2 hours. If the&#xD;
      subject has a platelet count less than 100,000 per microliter, the investigators will repeat&#xD;
      a platelet transfusion, and so on, subject to a maximum volume of 40 ml/kg/day of platelet&#xD;
      concentrates in a 24-hour period (defined as 8 AM to 8 AM next day). The investigators will&#xD;
      temporarily stop transfusing platelet concentrates once the investigators get a value of&#xD;
      above 100,000 per microliter. In addition to the platelet counts performed post-transfusion,&#xD;
      the investigators will also perform platelet counts for the following indications:&#xD;
&#xD;
      (i) Clinical bleeds (ii) A routine platelet count once in every 24 hours until PDA closes or&#xD;
      the criterion of 120 hours post randomization is met.&#xD;
&#xD;
      The platelet count for clinical bleeds and routine platelet counts will not be repeated in&#xD;
      case a platelet count post-transfusion is already available within a window period of 4 hours&#xD;
      prior.&#xD;
&#xD;
      Control group: (details are given under Arms and Intervention) In the control group, the&#xD;
      investigators will perform platelet counts as per the standard unit practices. A platelet&#xD;
      count will be repeated whenever the subject is next sampled for a clinical indication or a&#xD;
      longer with routine samples in the evening or morning. A platelet transfusion will be&#xD;
      repeated if the platelet count falls to less than 20,000 per microliter or if any of the&#xD;
      above criteria are met.&#xD;
&#xD;
      In both groups, platelet concentrates will be transfused according to platelet count prior to&#xD;
      transfusion. In babies with platelet count &lt; 50000, 50-75000 and 75-1, 00, 00 per microliter&#xD;
      the investigators will transfuse @ 20, 15 and 10 ml/kg/transfusion respectively up to a&#xD;
      maximum of 40 ml/kg/day. The investigators will administer injection furosemide 0.5 mg/kg as&#xD;
      slow IV injection midway through the transfusion if the treating team clinically feels that&#xD;
      the patient is likely to develop congestive cardiac failure or pulmonary edema.&#xD;
&#xD;
      Study endpoints:&#xD;
&#xD;
      Subjects will be followed up in the study until the earliest among&#xD;
&#xD;
        1. Withdrawal of consent&#xD;
&#xD;
        2. Discharge from hospital&#xD;
&#xD;
        3. Death&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2016</start_date>
  <completion_date type="Actual">March 20, 2017</completion_date>
  <primary_completion_date type="Actual">March 20, 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to closure of PDA post randomization</measure>
    <time_frame>within 120 hours post randomisation</time_frame>
    <description>Time point at which closure (Absence of flow in PDA on colour doppler) is documented first time will be considered as time to closure of PDA</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants in whom PDA is open</measure>
    <time_frame>at 120 hours after randomization</time_frame>
    <description>PDA will be considered open if there is presence of flow on colour doppler</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of participants in whom PDA is echocardiographically hemodynamically significant</measure>
    <time_frame>at 120 hours after randomization</time_frame>
    <description>hemodynamic significance is defined somewhere else in text</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative volume of platelet concentrate received</measure>
    <time_frame>within 120 hours after randomization</time_frame>
    <description>Total volume in ml/kg will be recorded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Clinical bleed of any kind ( defined below)</measure>
    <time_frame>within 120 hours after randomization</time_frame>
    <description>Any visible fresh oral, nasal, endotracheal, gastrointestinal or skin bleed will be considered as clinical bleed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New onset IVH of any grade</measure>
    <time_frame>within 120 hours after randomization</time_frame>
    <description>Cranial ultrasound will be done as per protocol to look for IVH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New onset IVH of grade 3or 4</measure>
    <time_frame>within 120 hours after randomization</time_frame>
    <description>Cranial ultrasound will be done as per protocol to look for IVH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>within 120 hours after randomization</time_frame>
    <description>It stands for all cause mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>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</time_frame>
    <description>It stands for all cause mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospital stay</measure>
    <time_frame>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</time_frame>
    <description>Duration of stay will be from date of birth to date of discharge/referral or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reopening rate of PDA that had initially closed</measure>
    <time_frame>within 120 hours of randomization</time_frame>
    <description>It will include situation where PDA closure was documented on two consecutive occasions 24 hours apart and then at later stage it opens.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">44</enrollment>
  <condition>Patent Ductus Arteriosus</condition>
  <arm_group>
    <arm_group_label>Liberal Platelet transfusion group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Platelet transfusion to maintain a platelet count above 1,00,000 per microliter until one of the endpoints is met.&#xD;
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:&#xD;
Ibuprofen:&#xD;
Dosage-10 mg/kg stat followed by 5 mg/kg/dose x 2 doses at 24 hours intervals Route- oral&#xD;
Paracetamol:&#xD;
Dosage-15 mg/kg/dose every 6 hourly x 12 doses Route - IV</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Restrictive platelet transfusion group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Platelet transfusion for standard criteria.&#xD;
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:&#xD;
Ibuprofen:&#xD;
Dosage-10 mg/kg stat followed by 5 mg/kg/dose x 2 doses at 24 hours intervals Route- oral&#xD;
Paracetamol:&#xD;
Dosage-15 mg/kg/dose every 6 hourly x 12 doses Route - IV</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Liberal platelet transfusion</intervention_name>
    <description>Liberal platelet transfusion: In Intervention group the investigators will transfuse platelet concentrates to maintain a platelet count above 1,00,000 per microliter until one of the following endpoints is met, whichever is applicable:&#xD;
PDA closes or&#xD;
A maximum of 120 hours after the point of randomisation</description>
    <arm_group_label>Liberal Platelet transfusion group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Restrictive platelet transfusion</intervention_name>
    <description>The investigators will transfuse platelets only if:&#xD;
(i) Platelet count is &lt; 20,000 per microliter or (ii) Subject has a clinical bleed or (iii) Subject has platelet count &lt; 50000 per microliter and requires a major non-neurosurgical interventional procedure as per the current standard of care, or (iv) Subject has a platelet count &lt; 1, 00,000 per microliter and requires a neurosurgical procedure</description>
    <arm_group_label>Restrictive platelet transfusion group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paracetamol</intervention_name>
    <description>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:&#xD;
Paracetamol:&#xD;
Dosage-15 mg/kg/dose every 6 hourly x 12 doses Route - IV</description>
    <arm_group_label>Liberal Platelet transfusion group</arm_group_label>
    <arm_group_label>Restrictive platelet transfusion group</arm_group_label>
    <other_name>Crocin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibuprofen</intervention_name>
    <description>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:&#xD;
Ibuprofen:&#xD;
Dosage-10 mg/kg stat followed by 5 mg/kg/dose x 2 doses at 24 hours intervals Route- oral</description>
    <arm_group_label>Liberal Platelet transfusion group</arm_group_label>
    <arm_group_label>Restrictive platelet transfusion group</arm_group_label>
    <other_name>Brufen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Gestational age up to 34 6/7 weeks&#xD;
&#xD;
          2. PDA detected for the first time at less than 14 days of postnatal age&#xD;
&#xD;
          3. Clinically and/or echocardiographically hemodynamically significant PDA Note: ELBW&#xD;
             neonates will be screened in first 48 hours as per unit policy; the rest will undergo&#xD;
             echocardiography only when there are clinical signs of PDA.&#xD;
&#xD;
          4. Platelet count within 24 hours prior to inclusion is less than 100,000 per microliter.&#xD;
&#xD;
        Note: If a platelet count is already available within 24 hours prior to inclusion it will&#xD;
        be accepted as a valid platelet count. If not, an urgent absolute platelet count will be&#xD;
        performed.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Echocardiographically proven structural congenital heart disease.&#xD;
&#xD;
          2. Major life-threatening malformation&#xD;
&#xD;
          3. Received platelet concentrate between the last available platelet count and the point&#xD;
             of randomisation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>14 Days</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sourabh Dutta, MD</last_name>
    <role>Study Director</role>
    <affiliation>Post Graduate Institute of Medical Education and Research; Chandigarh, India</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Post Graduate Institute of Medical Education and Research</name>
      <address>
        <city>Chandigarh</city>
        <zip>160012</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <link>
    <url>http://www.transfusionguidelines.org.uk.</url>
    <description>Transfusion guidelines for surgical procedures.</description>
  </link>
  <reference>
    <citation>Bancalari E, Claure N, Gonzalez A. Patent ductus arteriosus and respiratory outcome in premature infants. Biol Neonate. 2005;88(3):192-201. doi: 10.1159/000087582.</citation>
    <PMID>16210841</PMID>
  </reference>
  <reference>
    <citation>Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K, Carlo WA, Kennedy KA, Poindexter BB, Finer NN, Ehrenkranz RA, Duara S, Sanchez PJ, O'Shea TM, Goldberg RN, Van Meurs KP, Faix RG, Phelps DL, Frantz ID 3rd, Watterberg KL, Saha S, Das A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010 Sep;126(3):443-56. doi: 10.1542/peds.2009-2959. Epub 2010 Aug 23.</citation>
    <PMID>20732945</PMID>
  </reference>
  <reference>
    <citation>Adrouche-Amrani L, Green RS, Gluck KM, Lin J. Failure of a repeat course of cyclooxygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in ELBW infants. BMC Pediatr. 2012 Jan 27;12:10. doi: 10.1186/1471-2431-12-10.</citation>
    <PMID>22284694</PMID>
  </reference>
  <reference>
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  <verification_date>April 2018</verification_date>
  <study_first_submitted>June 25, 2016</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>April 5, 2018</last_update_submitted>
  <last_update_submitted_qc>April 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Postgraduate Institute of Medical Education and Research</investigator_affiliation>
    <investigator_full_name>Sourabh Dutta</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>PDA</keyword>
  <keyword>Platelets</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ductus Arteriosus, Patent</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Ibuprofen</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03022253
org study id: INT/IEC/2016/1090
nct id: NCT03022253
lead sponsor: 
has dmc: No
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.
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to closure of PDA post randomization
time frame: within 120 hours post randomisation
description: Time point at which closure (Absence of flow in PDA on colour doppler) is documented first time will be considered as time to closure of PDA
measure: Proportion of participants in whom PDA is open
time frame: at 120 hours after randomization
description: PDA will be considered open if there is presence of flow on colour doppler
measure: Proportion of participants in whom PDA is echocardiographically hemodynamically significant
time frame: at 120 hours after randomization
description: hemodynamic significance is defined somewhere else in text
measure: Cumulative volume of platelet concentrate received
time frame: within 120 hours after randomization
description: Total volume in ml/kg will be recorded
measure: Number of participants with Clinical bleed of any kind ( defined below)
time frame: within 120 hours after randomization
description: Any visible fresh oral, nasal, endotracheal, gastrointestinal or skin bleed will be considered as clinical bleed.
measure: New onset IVH of any grade
time frame: within 120 hours after randomization
description: Cranial ultrasound will be done as per protocol to look for IVH
measure: New onset IVH of grade 3or 4
time frame: within 120 hours after randomization
description: Cranial ultrasound will be done as per protocol to look for IVH
measure: Mortality
time frame: within 120 hours after randomization
description: It stands for all cause mortality
measure: Mortality
time frame: 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
description: It stands for all cause mortality
measure: Duration of hospital stay
time frame: 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
description: Duration of stay will be from date of birth to date of discharge/referral or death
measure: Reopening rate of PDA that had initially closed
time frame: within 120 hours of randomization
description: It will include situation where PDA closure was documented on two consecutive occasions 24 hours apart and then at later stage it opens.
arm group label: Liberal Platelet transfusion group
arm group type: Experimental
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
arm group label: Restrictive platelet transfusion group
arm group type: Active Comparator
description: Platelet transfusion for standard criteria.
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
intervention type: Biological
intervention name: Liberal platelet transfusion
description: Liberal platelet transfusion: In Intervention group the investigators will transfuse platelet concentrates to maintain a platelet count above 1,00,000 per microliter until one of the following endpoints is met, whichever is applicable:
PDA closes or
A maximum of 120 hours after the point of randomisation
arm group label: Liberal Platelet transfusion group
intervention type: Biological
intervention name: Restrictive platelet transfusion
description: The investigators will transfuse platelets only if:
(i) Platelet count is < 20,000 per microliter or (ii) Subject has a clinical bleed or (iii) Subject has platelet count < 50000 per microliter and requires a major non-neurosurgical interventional procedure as per the current standard of care, or (iv) Subject has a platelet count < 1, 00,000 per microliter and requires a neurosurgical procedure
arm group label: Restrictive platelet transfusion group
intervention type: Drug
intervention name: Paracetamol
description: 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:
Paracetamol:
Dosage-15 mg/kg/dose every 6 hourly x 12 doses Route - IV
arm group label: Liberal Platelet transfusion group
arm group label: Restrictive platelet transfusion group
other name: Crocin
intervention type: Drug
intervention name: Ibuprofen
description: 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
arm group label: Liberal Platelet transfusion group
arm group label: Restrictive platelet transfusion group
other name: Brufen
criteria: 
gender: All
minimum age: 1 Day
maximum age: 14 Days
healthy volunteers: No
last name: Sourabh Dutta, MD
role: Study Director
affiliation: Post Graduate Institute of Medical Education and Research; Chandigarh, India
facility: 
country: India
url: http://www.transfusionguidelines.org.uk.
description: Transfusion guidelines for surgical procedures.
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responsible party type: Principal Investigator
investigator affiliation: Postgraduate Institute of Medical Education and Research
investigator full name: Sourabh Dutta
investigator title: Dr
mesh term: Ductus Arteriosus, Patent
mesh term: Acetaminophen
mesh term: Ibuprofen
sharing ipd: No