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

Extreme Prematurity Clinical Trial

Official title:

Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis: An International Comparative Effectiveness Research Project

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05347238
• Other study ID #: CTO 4009
• Status: Recruiting
• Start date: February 6, 2023
• Est. completion date: March 31, 2027

Study information

• Verified date: February 2024
• Source: Mount Sinai Hospital, Canada
• Contact: Amish Jain, MBBS, MRCPCH, PhD
• Phone: 416-586-4800
• Email: amish.jain[@]sinaihealth.ca
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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 an international 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, 4 centers in Ireland, 2 centers in Israel and 6 centers in the United States 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 550
• Est. completion date: March 31, 2027
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Weeks to 32 Weeks

Eligibility

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

Related Conditions & MeSH terms

• Extreme Prematurity
• Hypotension
• Late-Onset Neonatal Sepsis
• Neonatal Hypotension
• Neonatal Sepsis
• Sepsis
• Toxemia

Intervention

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
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

Locations

Country	Name	City	State
Canada	Foothill's Medical Centre	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	CHU Sainte- Justine	Montréal	Quebec
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Montreal Children's Hospital	Montréal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	BC Women's Hospital	Vancouver	British Columbia
Canada	Windsor Regional Hospital	Windsor	Ontario
Canada	St.Boniface Hospital	Winnipeg	Manitoba
Canada	Winnipeg Health Sciences Centre	Winnipeg	Manitoba
Ireland	University Cork College	Cork
Ireland	Coombe Women & Infants University Hospital	Dublin
Ireland	National Maternity Hospital	Dublin
Ireland	The Rotunda Hospital	Dublin
Israel	Shamir Medical Center	Be'er Ya'aqov
Israel	Dana-Dwek Children's Hospital	Tel Aviv
United States	Dayton Children's Hospital	Dayton	Ohio
United States	El Paso Children's Hospital	El Paso	Texas
United States	The Woman's Hospital of Texas	Houston	Texas
United States	Banner-University Medical Center Phoenix	Phoenix	Arizona
United States	Christus Health	San Antonio	Texas
United States	Methodist Healthcare	San Antonio	Texas

Sponsors (28)

Lead Sponsor

Collaborator

Mount Sinai Hospital, Canada

Assaf-Harofeh Medical Center, Banner University Medical Center, Children's Hospital of Eastern Ontario, CHRISTUS Health, Coombe Women and Infants University Hospital, Dayton Children's Hospital, El Paso Children's Hospital, Foothills Medical Centre, Health Sciences Centre, Winnipeg, Manitoba, Island Health, Victoria, BC, IWK Health Centre, Jewish General Hospital, London Health Sciences Centre, McMaster Children's Hospital, Methodist Healthcare, Montreal Children's Hospital of the MUHC, National Maternity Hospital, Ireland, St. Boniface Hospital, St. Justine's Hospital, Sunnybrook Health Sciences Centre, Tel-Aviv Sourasky Medical Center, The Hospital for Sick Children, The Rotunda Hospital, The Woman's Hospital of Texas, University College Cork, University of British Columbia, Windsor Regional Hospital

Countries where clinical trial is conducted

United States,  Canada,  Ireland,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All cause in-hospital mortality	Death before discharge	From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
Secondary	Episode-related death	Episode-related death (yes or no- binary variable)	<14 days from illness onset
Secondary	Treatment failure rate	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)	90 minutes after initial vasopressor initiation (or sooner if secondary dose added or primary agent replaced as per clinical discretion)
Secondary	New diagnosis of severe neurological injury	Grade III or Grade IV intraventricular hemorrhage or periventricular leukomalacia (yes or no- binary variable)	From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
Secondary	Bronchopulmonary dysplasia	Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA) (yes or no- binary variable)	Assessed at 36 weeks PMA
Secondary	Retinopathy of prematurity	Diagnosis of retinopathy of prematurity - assessed by clinical staff (yes or no - binary variable)	From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
Secondary	Length of hospital stay	Length of entire neonatal intensive care unit stay from admission to discharge	From admission date to discharge date - assessed up to a maximum of 36 weeks after date of birth