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Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period (NeoCirc-001)

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ClinicalTrials.gov Identifier: NCT03311178
Recruitment Status : Terminated (Substudy 001B is not required at this stage of the PIP)
First Posted : October 17, 2017
Last Update Posted : October 17, 2017
Sponsor:
Collaborators:
Hospital Universitario La Paz
Brighton and Sussex University Hospitals NHS Trust
University of Luebeck
Servicio Vasco de Salud Osakidetza, Spain
University of Liverpool
Vest Children´s Hospital, Germany
Datteln University Witten-Herdecke
Iuliu Hatieganu University of Medicine and Pharmacy
Semmelweis University
University of Pecs
Gazi University
Tufts Medical Center
Hannover Medical School
Onorach Clinical Dundee, Scotland
Proveca Limited Daresbury, England
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Brief Summary:

Haemodynamic insufficiency after birth is seen commonly in babies born prematurely and is associated with adverse outcomes. In current clinical practice, a combination of blood pressure and clinical signs is used to guide therapy. However, blood pressure is a poor surrogate of systemic and organ (brain) blood flow distribution during transitional circulation. This state is characterised by increased peripheral vascular resistance and increased afterload causing myocardial depression and impaired blood flow distribution in spite of 'normal' blood pressure. Echocardiography-Doppler (Echo-D) measurement of superior vena cava (SVC) flow has been proposed as a more clinically relevant marker of circulatory impairment shortly after birth than systemic hypotension. When there is low SVC flow, several small-scale clinical trials have suggested dobutamine as the optimal therapeutic option. However the associations between SVC flow and short- and long- term outcomes are not strong enough to allow SVC flow alone to be the basis for the inclusion of patients into a confirmatory trial to demonstrate the efficacy and safety of dobutamine.

NeoCirc-001 - The primary objective is to answer some important questions required for the design of a subsequent placebo-controlled trial (NeoCirc-003), which will evaluate the effectiveness of a new neonatal formulation of dobutamine to treat haemodynamic insufficiency in the first 72 hours after birth in babies born at less than 33 weeks' gestation. Observational data will be collected from this population with a view to determining the degree to which diagnostic measures influence treatment decisions. The primary outcome is death or worst cranial ultrasound (CUS) appearance at or before 36 weeks' gestation.

NeoCirc-001A - The primary objective is to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates.

NeoCirc-001B - The primary objective is to construct a population pharmacokinetic pharmacodynamic model that will be validated using samples collected during the confirmatory trial (NeoCirc-003).


Condition or disease Intervention/treatment Phase
Shock Drug: Dobutamine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An International Multicentre Open-label Comparative Therapeutic Exploratory Trial to Investigate the Role of a New Neonatal Formulation of Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period
Actual Study Start Date : May 30, 2014
Actual Primary Completion Date : October 13, 2015
Actual Study Completion Date : October 10, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Experimental: Dobutamine
Infants who meet the definition of poor perfusion state will be treated at the discretion of the responsible physician following the standard local policies. The interventions will be dobutamine from a new neonatal formulation developed for NeoCirc and/or other treatments (including any other cardiovascular drug or volume replacement with normal saline).
Drug: Dobutamine
Infants who meet the definition of poor perfusion state will be treated at the discretion of the responsible physician following the standard local policies. The interventions will be dobutamine from a new neonatal formulation developed for NeoCirc and/or other treatments (including any other cardiovascular drug or volume replacement with normal saline).




Primary Outcome Measures :
  1. Mortality, or intraventricular haemorrhage (IVH) grades 3 or 4, or cystic and non-cystic periventricular leukomalacia (PVL), or porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage. [ Time Frame: at 36 (+/-2 weeks) postmenstrual age ]

    A composite endpoint is defined as follows: treatment failure is when one of the following is true at or before gestational age 36 (+/-2 weeks), when all surviving patients will have a cranial ultrasound (CUS)-

    1. Neonate dies, or
    2. Intraventricular haemorrhage (IVH) grades 3 or 4, or
    3. cystic and non-cystic periventricular leukomalacia (PVL), or
    4. porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage.

  2. Half-life of the neonatal formulation of dobutamine. [ Time Frame: The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases. The second sample will be taken at different study time points after the end of infusion (from 5 min to 6 hours). ]

    NeoCirc-001A: Half-life of the neonatal formulation of dobutamine.

    The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases reaching the systemic circulation of the neonate, defined as time end (te). To calculate the end of infusion (te) the dead space used in each unit will be taken into account (see below). The second sample will be taken at different study time points after the end of infusion:

    • 5 min after te
    • 15 min after te
    • 45 min after te
    • 2 hours after te
    • 6 hours after te Two infants will be allocated to each time point. Sampling times will be assigned randomly to the patients.


Secondary Outcome Measures :
  1. Arterial blood pressure [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  2. Capillary refill time [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  3. Urine output [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  4. Blood lactate concentration [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  5. Base excess [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  6. cerebral regional tissue oxygen saturation (rStO2) [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    Cerebral regional tissue oxygen saturation (rStO2) measured by means of near-infrared spectroscopy

  7. Background pattern [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    Background pattern measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)

  8. Superior vena cava flow [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  9. Right cardiac output [ Time Frame: First 72 hours of life (data collection every 9 ±3 hrs) ]
    Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support

  10. Cerebral fractional oxygen extraction (FOE) [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    FOE= [peripheral oxygen saturation (SaO2)-rStO2] /SaO2

  11. Interburst interval (IBI) [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    Interburst interval (IBI) measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)

  12. Discontinuity [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    Discontinuity measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)

  13. Amplitude [ Time Frame: Fist 72 hours of life (data collection every 6 ±1 hrs) ]
    The amplitude measured by means of aEEG/EEG

  14. Presence of abnormal transients [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    The presence of abnormal transients measured by means of aEEG/EEG

  15. Synchrony [ Time Frame: First 72 hours of life (data collection every 6 ±1 hrs) ]
    The synchrony measured by means of aEEG/EEG

  16. Mortality [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  17. Intraventricular haemorrhage 2-4 [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  18. Survival free of severe brain injury [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
    Survival free of severe brain injury measured by means of cranial ultrasound studies

  19. Hypotension [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  20. Hypertension [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  21. Necrotizing enterocolitis [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  22. Patent ductus (PDA) [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]
  23. Retinopathy of prematurity [ Time Frame: at 36 (+/-2 weeks) postmenstrual age ]
  24. Chronic lung disease [ Time Frame: at 36 (+/-2 weeks) postmenstrual age ]
  25. Oxygen-dependency at discharge [ Time Frame: At discharge ]
  26. early infection [ Time Frame: From birth to 72 hours after birth ]
  27. Nosocomial infection [ Time Frame: From birth to 36 (+/-2 weeks) postmenstrual age ]

Other Outcome Measures:
  1. Number of participants with adverse events [ Time Frame: Daily during the first four days of life, at 36±2 weeks' gestation or discharge and at 38±2 weeks' gestation or discharge ]
    Number of Participants with Adverse Events as a Measure of Safety and Tolerability



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Ages Eligible for Study:   up to 72 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria for NeoCirc-001, 001A and 001B -

Target population for informed consent:

  • neonates 24 to 32+6 weeks´ gestation,
  • postnatal age <72 hours;

Infants eligible for circulatory failure pathway:

  • parental informed consent obtained;
  • The infants will be assessed, as per routine clinical practice, for clinical signs indicating infants at risk of poor perfusion, and will be recruited if they develop haemodynamic insufficiency defined as: either two or more of: (i) Mean blood pressure (MBP) < gestational age (GA)-1 mmHg (invasive/non-invasive, two readings 15 min apart); (ii) SVC flow < 51 ml/kg/min; (iii) capillary refill time (CRT) > 4 sec; (iv) Lactate > 4 mmol/l (v) Base excess <-9 mmol/l or: MBP < GA -5 mmHg (invasive/non-invasive, two readings 15 min apart)

Exclusion Criteria: NeoCirc-001, 001A and 001B -

  • non-viability;
  • congenital hydrops or malformations likely to affect cardiovascular adaptation;
  • surgery planned within 72 hours of birth;
  • chromosomal anomalies;
  • informed consent form (ICF) not signed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03311178


Locations
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Spain
La Paz University Hospital, Department of Neonatology
Madrid, Spain, 28046
Sponsors and Collaborators
Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
Hospital Universitario La Paz
Brighton and Sussex University Hospitals NHS Trust
University of Luebeck
Servicio Vasco de Salud Osakidetza, Spain
University of Liverpool
Vest Children´s Hospital, Germany
Datteln University Witten-Herdecke
Iuliu Hatieganu University of Medicine and Pharmacy
Semmelweis University
University of Pecs
Gazi University
Tufts Medical Center
Hannover Medical School
Onorach Clinical Dundee, Scotland
Proveca Limited Daresbury, England
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Study Chair: Adelina Pellicer, MD PhD SERMAS La Paz University Hospital
Study Director: Heike Rabe, MD PhD Brighton and Sussex University Hospitals (BSUH)
Principal Investigator: Fernando Cabañas, MD PhD Servicio Madrileño de Salud (SERMAS)

Publications:
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Responsible Party: Adelina Pellicer, Chief Investigator, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
ClinicalTrials.gov Identifier: NCT03311178     History of Changes
Other Study ID Numbers: Neocirculation 001
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: October 17, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz:
Shock
Preterm infant
Dobutamine
Additional relevant MeSH terms:
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Shock
Pathologic Processes
Dobutamine
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents