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Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05347238
Recruitment Status : Not yet recruiting
First Posted : April 26, 2022
Last Update Posted : September 1, 2022
Sponsor:
Collaborators:
Sunnybrook Health Sciences Centre
The Hospital for Sick Children
McMaster Children's Hospital
London Health Sciences Centre
Windsor Regional Hospital
Children's Hospital of Eastern Ontario
University of British Columbia
Foothills Medical Centre
Health Sciences Centre, Winnipeg, Manitoba
St. Boniface Hospital
Montreal Children's Hospital of the MUHC
Jewish General Hospital
St. Justine's Hospital
IWK Health Centre
Information provided by (Responsible Party):
Mount Sinai Hospital, Canada

Brief Summary:

Fluid-unresponsive hypotension needing cardiotropic drug treatment is a serious complication in very preterm neonates with suspected late-onset sepsis (LOS; defined as culture positive or negative bloodstream infection or necrotizing enterocolitis occurring >48 hours of age). In Canada, ~250 very preterm neonates receive cardiotropic drugs for LOS related fluid-unresponsive hypotension every year; of these ~35-40% die. Unlike for adult patients, there is little evidence to inform practice. While several medications are used by clinicians, the most frequently used medications are Dopamine (DA) and Norepinephrine (NE). However, their relative impact on patient outcomes and safety is not known resulting in significant uncertainty and inter- and intra-unit variability in practice. Conducting large randomized trials in this subpopulation can be operationally challenging and expensive. Comparative effectiveness research (CER), is a feasible alternative which can generate high-quality real-world evidence using real-world data, by comparing the impact of different clinical practices.

Aim: To conduct a national CER study, using a pragmatic clinical trial design, in conjunction with the existing infrastructure of the Canadian Neonatal Network to identify the optimal management of hypotension in very preterm neonates with suspected LOS.

Objective: To compare the relative effectiveness and safety of pharmacologically equivalent dosages of DA versus NE for primary pharmacotherapy for fluid-unresponsive hypotension in preterm infants born ≤ 32 weeks gestational age with suspected LOS.

Hypothesis: Primary treatment with NE will be associated with a lower mortality

Methods: This CER project will compare management approach at the unit-level allowing inclusion of all eligible patients admitted during the study period. 15 centers in Canada have agreed to standardize their practice. All eligible patients deemed circulatory insufficient will receive fluid therapy (minimum 10-20 cc/kg). If hypotension remains unresolved:

Dopamine Units: start at 5mics/kg/min, increase every 16-30 minutes by 5 mics/kg/min to a maximum dose of 15 mics/kg/min or adequate response

Norepinephrine Units: start at 0.05 mics/kg/min, increase every 16-30 minutes by 0.05 mics/kg/min to maximum dose of 0.15/mics/kg/min or adequate response


Condition or disease Intervention/treatment
Late-Onset Neonatal Sepsis Extreme Prematurity Neonatal Hypotension Drug: Dopamine Drug: Norepinephrine

Detailed Description:

In this study, we will use real world data (RWD; defined as data generated during routine clinical practice) collected by our national Canadian Neonatal Network (CNN), which will be further expanded for this project.

The CNN is a well-established patient registry that includes members from 31 hospitals and 17 universities across Canada. The Network maintains a standardized NICU database and provides a unique opportunity for researchers to participate in collaborative projects. We will use the framework of Hypotheses Evaluating Treatment Effectiveness (HETE) research a form of comparative effectiveness research (CER).

Patient registries are emerging as a new method for assessment of treatments under the framework of CER. We will evaluate treatment effectiveness of two routinely used primary therapies for hypotension management in very preterm neonates with suspected LOS after standardizing treatment strategies and with a priori hypothesis.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 550 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 36 Weeks
Official Title: Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis: A National Comparative Effectiveness Research Project
Estimated Study Start Date : September 2022
Estimated Primary Completion Date : June 30, 2026
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Dopamine Units
Units who have standardized their practice with the use of Dopamine as a first line agent.
Drug: Dopamine
Start at 5mics/kg/min, increase every 16-30 minutes by 5 mics/kg/min to a maximum dose of 15 mics/kg/min or adequate response.

Norepinephrine Units
Units who have standardized their practice with the use of Norepinephrine as a first line agent.
Drug: Norepinephrine
Start at 0.05 mics/kg/min, increase every 16-30 minutes by 0.05 mics/kg/min to maximum dose of 0.15/mics/kg/min or adequate response




Primary Outcome Measures :
  1. All cause in-hospital mortality [ Time Frame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth ]
    Death before discharge


Secondary Outcome Measures :
  1. Episode-related death [ Time Frame: <14 days from illness onset ]
    Episode-related death (yes or no- binary variable)

  2. Treatment failure rate [ Time Frame: 90 minutes after initial vasopressor initiation (or sooner if secondary dose added or primary agent replaced as per clinical discretion) ]
    Need for further dose escalation or use of additional agents (treatment failure = hypotension unresolved after reaching max dose (15mics/kg/min in Dopamine units and 0.15 mics/kg/min in Norepinephrine units)

  3. New diagnosis of severe neurological injury [ Time Frame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth ]
    Grade III or Grade IV intraventricular hemorrhage or periventricular leukomalacia (yes or no- binary variable)

  4. Bronchopulmonary dysplasia [ Time Frame: Assessed at 36 weeks PMA ]
    Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA) (yes or no- binary variable)

  5. Retinopathy of prematurity [ Time Frame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth ]
    Diagnosis of retinopathy of prematurity - assessed by clinical staff (yes or no - binary variable)

  6. Length of hospital stay [ Time Frame: From admission date to discharge date - assessed up to a maximum of 36 weeks after date of birth ]
    Length of entire neonatal intensive care unit stay from admission to discharge



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Weeks to 32 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
All preterm infants born ≤32 weeks gestational age and > 48 hours of life with suspected sepsis with systemic hypotension admitted to the participating sites and meeting the above eligibility criteria will be included in the study.
Criteria

Inclusion Criteria:

  • ≤32 weeks gestational age and > 48 hours of life
  • Receiving primary vasopressor therapy with Dopamine or Norepinephrine in the context of suspected late-onset sepsis or necrotizing enterocolitis with systemic hypotension (defined as: culture positive or negative bloodstream infection)

Exclusion Criteria:

  • Known chromosomal or genetic anomalies
  • Receiving primary therapy with agents other than Dopamine or Norepinephrine

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): NCT05347238


Contacts
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Contact: Amish Jain, MBBS, MRCPCH, PhD 416-586-4800 ext 5459 amish.jain@sinaihealth.ca
Contact: Laura Thomas, MSc 416-586-4800 ext 172060 laura.thomas@sinaihealth.ca

Locations
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Canada, Alberta
Foothill's Medical Centre
Calgary, Alberta, Canada
Contact: Amuchou Soraisham         
Principal Investigator: Amuchou Soraisham         
Sub-Investigator: Essa El Awad         
Sub-Investigator: Majeeda Kamaluddeen         
Canada, British Columbia
BC Women's Hospital
Vancouver, British Columbia, Canada
Contact: Michael Castaldo         
Principal Investigator: Michael Castaldo         
Canada, Manitoba
St.Boniface Hospital
Winnipeg, Manitoba, Canada
Contact: Yasser ElSayed         
Principal Investigator: Yasser ElSayed         
Winnipeg Health Sciences Centre
Winnipeg, Manitoba, Canada
Contact: Deepak Louis         
Principal Investigator: Deepak Louis         
Canada, Nova Scotia
IWK Health Centre
Halifax, Nova Scotia, Canada
Contact: Souvik Mitra         
Principal Investigator: Souvik Mitra         
Canada, Ontario
McMaster Children's Hospital
Hamilton, Ontario, Canada
Contact: Amneet Sidhu         
Principal Investigator: Amneet Sidhu         
Principal Investigator: Muzafar Gani Abdul Wahab         
London Health Sciences Centre
London, Ontario, Canada
Contact: Soume Bhattacharya         
Principal Investigator: Soume Bhattacharya         
Sub-Investigator: Renjini Lalitha         
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
Contact: Nadya Ben Fadel         
Principal Investigator: Nadya Ben Fadel         
Hospital for Sick Children
Toronto, Ontario, Canada
Contact: Bonny Jasani         
Principal Investigator: Bonny Jasani         
Mount Sinai Hospital
Toronto, Ontario, Canada
Contact: Laura Thomas, MSc       laura.thomas@sinaihealth.ca   
Principal Investigator: Amish Jain         
Sub-Investigator: Prakesh Shah         
Sub-Investigator: Ashraf Kharrat         
Sub-Investigator: Poorva Deshpande         
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
Contact: Stephanie Fevrier, MSc       stephanie.fevrier@sunnybrook.ca   
Principal Investigator: Dany Weisz         
Windsor Regional Hospital
Windsor, Ontario, Canada
Contact: Sajit Augustine         
Principal Investigator: Sajit Augustine         
Canada, Quebec
CHU Sainte- Justine
Montréal, Quebec, Canada
Contact: Anie Lapointe         
Principal Investigator: Anie Lapointe         
Principal Investigator: Andreanne Villeneuve         
Jewish General Hospital
Montréal, Quebec, Canada
Contact: Nina Nouraeyan         
Principal Investigator: Nina Nouraeyan         
Montreal Children's Hospital
Montréal, Quebec, Canada
Contact: Gabriel Altit         
Principal Investigator: Gabriel Altit         
Sub-Investigator: Marc Beltempo         
Sponsors and Collaborators
Mount Sinai Hospital, Canada
Sunnybrook Health Sciences Centre
The Hospital for Sick Children
McMaster Children's Hospital
London Health Sciences Centre
Windsor Regional Hospital
Children's Hospital of Eastern Ontario
University of British Columbia
Foothills Medical Centre
Health Sciences Centre, Winnipeg, Manitoba
St. Boniface Hospital
Montreal Children's Hospital of the MUHC
Jewish General Hospital
St. Justine's Hospital
IWK Health Centre
Investigators
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Principal Investigator: Amish Jain, MBBS, MRCPCH, PhD Mount Sinai Hospital, Canada
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Responsible Party: Mount Sinai Hospital, Canada
ClinicalTrials.gov Identifier: NCT05347238    
Other Study ID Numbers: CTO 4009
First Posted: April 26, 2022    Key Record Dates
Last Update Posted: September 1, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sepsis
Toxemia
Neonatal Sepsis
Hypotension
Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Infant, Newborn, Diseases
Dopamine
Norepinephrine
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Cardiotonic Agents
Dopamine Agents
Protective Agents