Clinical trial NCT05347238: Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis
Official title: Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis: An International Comparative Effectiveness Research Project
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Late-Onset Neonatal Sepsis
Extreme Prematurity
Neonatal Hypotension
Lead sponsor: Mount Sinai Hospital, Canada
Sponsor class: OTHER
Collaborators: name: Sunnybrook Health Sciences Centre
name: The Hospital for Sick Children
name: McMaster Children's Hospital
name: London Health Sciences Centre
name: Windsor Regional Hospital
name: Children's Hospital of Eastern Ontario
name: University of British Columbia
name: Foothills Medical Centre
name: Health Sciences Centre, Winnipeg, Manitoba
name: St. Boniface Hospital
name: Montreal Children's Hospital of the MUHC
name: Jewish General Hospital
name: St. Justine's Hospital
name: IWK Health Centre
name: The Rotunda Hospital
name: University College Cork
name: Coombe Women and Infants University Hospital
name: National Maternity Hospital, Ireland
name: Tel-Aviv Sourasky Medical Center
name: Island Health, Victoria, BC
name: Assaf-Harofeh Medical Center
name: El Paso Children's Hospital
name: The Woman's Hospital of Texas
name: Dayton Children's Hospital
name: Banner University Medical Center
name: Methodist Healthcare
name: Hospital Universitario La Paz
First posted: 2022-04-26
Enrollment: 550
Sex: ALL
Minimum age (years): 21
Maximum age (years): 32
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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 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

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.

Eligibility 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

Primary outcomes:
measure: All cause in-hospital mortality
timeFrame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
Secondary outcomes:
measure: Episode-related death
timeFrame: <14 days from illness onset
measure: Treatment failure rate
timeFrame: 90 minutes after initial vasopressor initiation (or sooner if secondary dose added or primary agent replaced as per clinical discretion)
measure: New diagnosis of severe neurological injury
timeFrame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
measure: Bronchopulmonary dysplasia
timeFrame: Assessed at 36 weeks PMA
measure: Retinopathy of prematurity
timeFrame: From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth
measure: Length of hospital stay
timeFrame: From admission date to discharge date - assessed up to a maximum of 36 weeks after date of birth
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner-University Medical Center Phoenix
state: Arizona
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: El Paso
country: United States
facility: El Paso Children's Hospital
state: Texas
city: Houston
country: United States
facility: The Woman's Hospital of Texas
state: Texas
city: San Antonio
country: United States
facility: Methodist Healthcare
state: Texas
city: Calgary
country: Canada
facility: Foothill's Medical Centre
state: Alberta
city: Vancouver
country: Canada
facility: BC Women's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St.Boniface Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: Winnipeg Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Montréal
country: Canada
facility: CHU Sainte- Justine
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Cork
country: Ireland
facility: University Cork College
city: Dublin
country: Ireland
facility: Coombe Women & Infants University Hospital
city: Dublin
country: Ireland
facility: National Maternity Hospital
city: Dublin
country: Ireland
facility: The Rotunda Hospital
city: Be'er Ya'aqov
country: Israel
facility: Shamir Medical Center
city: Tel Aviv
country: Israel
facility: Dana-Dwek Children's Hospital
Study officials:
affiliation: Mount Sinai Hospital, Canada
name: Amish Jain, MBBS, MRCPCH, PhD
role: PRINCIPAL_INVESTIGATOR
References: