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Principal Investigators
Dr. François Lamontagne
Dr. Neill Adhikari
Dr Elizabeth Wilcox

Project Leaders
Marie-Hélène Masse
Marie-Claude Battista



 

Thanks to all Participating Centers and collaborators for engaging in this research program!

Thanks to the CCCTG for endorsing this research project.

Clinical Trials NCT03431181

Ovation-65 Trial Overview


Objectives

The overarching goal of this randomized controlled trial (RCT) of permissive hypotension vs. usual blood pressure targets in hypotensive patients ≥65 years old is to determine whether permissive hypotension can reduce the risk of harm associated with more aggressive vasopressor therapy. The proposed RCT has nine specific objectives which is to evaluate the effect of permissive hypotension on mechanistic outcome: 1) markers of organ injury, primarily in the heart, secondarily in the brain, kidney, liver, intestine, and skeletal muscle; 2) global tissue dysoxia, assessed by serum lactate; 3) organ function, assessed by the multiple organ dysfunction score (MODS); 4) immune response; 5) resource utilization, 6) pre-specified adverse events, 7) the genetic traits as well as the epigenetic marks (methylation and miRNA) of adrenergic receptors and the potential biomarkers of organ injury determined at aim 2; 8) 90-day and 6-month mortality and 6-month cognitive impairment in survivors and 9) the association between baseline level of ascorbic acid and biomarkers of organ injury.

Study Design

Canadian multicentre parallel group RCT embedded in the OVATION-65 international collaboration.


Setting

The Unité de Recherche Clinique et Épidémiologique (URCE) is the Coordinating Centre for this trial in the ICUs across Canada.


Study population

200 subjects, male or female, 65 years old or older, with a diagnosis of vasodilatory hypotension which vasopressors were started ≤ 12 hours and before randomization are expected for ≥ 6 additional hours.


Study Intervention

The intervention is permissive hypotension to carefully minimize dose and duration of vasopressors. For participants allocated to this arm, treating teams will adjust vasopressors to a target MAP range of 60 to 65 mmHg, avoiding vasopressor-induced MAP above this range.

The duration of the trial intervention will be determined by the duration of the hypotensive episode up to a maximum of 28 days. The hypotensive episode will end when vasopressors are discontinued for 24 consecutive hours.


Outcomes

Primary mechanistic outcome of the OVATION-65 Trial
  • Mean peak high-sensitivity cardiac troponin (hs cTn)
Secondary outcome measures
  • Mean peak concentration of biomarkers associated with tissue injury to the:
    • brain (GFAP, UCHL1, Myelin Basic Protein and NSE),
    • kidney (renal biomarker TBD),
    • liver (serum ALT),
    • intestine (serum fatty acid binding protein (FABP))
    • skeletal muscle (serum CKM)
    • cardiac wall stress (serum N-terminal pro-B-type natriuretic [NT- proBNP])
  • Global tissue dysoxia will also be assessed through serum lactate.
  • Organ function using SOFA score
  • Atrial fibrillation (will rely on the ascertainment of clinically detected supraventricular arrhythmia)
  • Acute healthcare utilization by measuring durations of:
    • mechanical ventilation,
    • renal replacement therapy
    • vasopressor therapy
    • ICU and hospital stay.
  • Mortality at 28 and 90 days and the incidence of the prespecified adverse events of stroke, acute kidney injury (KDIGO stage 3), and limb or intestinal ischemia as defined in the OVATION pilot trial.
  • Baseline ascorbic levels
  • Impact of vasopressor regimen on the immune response and related proteomic profile (IL-1 and TNFa).
  • Genetic traits, inherited or shaped by the environment (epigenetic – methylation and miRNA) of the OVATION-65 participants in relation to the catecholamine receptors or the biomarkers determined above.