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Optimal VAsopressor TitraTION in Patients 65 Years and Older (OVATION-65)

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ClinicalTrials.gov Identifier: NCT03431181
Recruitment Status : Active, not recruiting
First Posted : February 13, 2018
Last Update Posted : April 30, 2021
Sponsor:
Information provided by (Responsible Party):
François Lamontagne, Université de Sherbrooke

Tracking Information
First Submitted Date  ICMJE February 4, 2018
First Posted Date  ICMJE February 13, 2018
Last Update Posted Date April 30, 2021
Actual Study Start Date  ICMJE February 16, 2018
Actual Primary Completion Date February 21, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2020)
Plasma high-sensitivity cardiac troponin T at day 3 (primary mechanistic outcome) [ Time Frame: Day 3 ]
Plasma high-sensitivity cardiac troponin T (hsTnT) at day 3 (corrected for baseline levels) (primary mechanistic outcome)
Original Primary Outcome Measures  ICMJE
 (submitted: February 12, 2018)
Mean peak high-sensitivity cardiac troponins (primary mechanistic outcome) [ Time Frame: 7 days ]
Mean peak high-sensitivity cardiac troponins (hs cTn) (primary mechanistic outcome)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2020)
  • Concentration of biomarkers associated with tissue injury to the brain [ Time Frame: Days 1 (baseline),3 and 7 ]
    Concentration of biomarkers associated with tissue injury to the brain (plasma GFAP, plasma Myelin Basic Protein and serum NSE)
  • Concentration of biomarker associated with tissue injury to the liver [ Time Frame: Days 1 (baseline),3 and 7 ]
    Concentration of biomarker associated with tissue injury to the liver (plasma ALT)
  • Concentration of biomarker associated with tissue injury to the intestine [ Time Frame: Days 1 (baseline),3 and 7 ]
    Concentration of biomarker associated with tissue injury to the intestine (plasma fatty acid binding protein (FABP))
  • Concentration of biomarker associated with tissue injury to the skeletal muscle [ Time Frame: Days 1 (baseline),3 and 7 ]
    Concentration of biomarker associated with tissue injury to the skeletal muscle (plasma creatinine kinase).
  • Concentration of biomarker associated with cardiac wall stress [ Time Frame: Days 1 (baseline),3 and 7 ]
    Concentration of biomarker associated with cardiac wall stress (plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP]).
  • Global tissue dysoxia [ Time Frame: Days 1 (baseline),3 and 7 ]
    Global tissue dysoxia will be assessed through plasma lactate
  • Plasma high-sensitivity cardiac troponin T (hsTnT) [ Time Frame: Day 7 ]
    Plasma high-sensitivity cardiac troponin T (hsTnT) at day 7
  • Pre-specified adverse events [ Time Frame: 28 days ]
    Pre-specified adverse events assessed by events of stroke, clinically detected supraventricular arrhythmia, acute kidney injury (KDIGO stage 3), limb or intestinal ischemia
  • Organ function [ Time Frame: Days 1 (baseline), 2, 3, 4, 7, 10, 14 and 28 ]
    Organ function using SOFA score (measured at baseline (day 1) and on days 2,3,4,7,10,14 and 28 while in the ICU)
  • Mortality [ Time Frame: 90 days and 6 months ]
    Mortality at 90 days and at 6 months will be assessed during the phone call at 6 months
  • 6-month cognitive impairment [ Time Frame: 6 months ]
    6-month cognitive impairment assessed by Telephone Interview for Cognitive Status (TICS)
  • Healthcare utilization [ Time Frame: 28 days ]
    Healthcare utilization assessed by measuring duration of mechanical ventilation, renal replacement therapy, vasopressor therapy and ICU and hospital stay (through days of utilization)
  • Plasma level of ascorbic acid (outcome for ancillary study) [ Time Frame: Day 1 (baseline) ]
    Plasma level of ascorbic acid (measured at baseline (day 1))
  • Biomarkers of ascorbic acid deficiency-related organ injury (outcome for ancillary study) [ Time Frame: Days 1 (baseline), 3 and 7 ]
    Inflammation (IL-1ß; TNF-α; CRP) and endothelial injury (thrombomodulin, angiopoietin-2)
  • Discovery proteomic approach to identify peptides and proteins expressed in the urine (outcome for ancillary study) [ Time Frame: Days 1 (baseline), 3 and 7 ]
    Discovery proteomic approach through novel urine biomarkers
  • Validate the predictive value of five prespecified biomarkers of renal injury in urine using a proteomic approach (outcome for ancillary study): TIMP2, NGAL, FABPL, CYTC, IGFBP7 [ Time Frame: Days 1 (baseline), 3 and 7 ]
    Proteomic discovery approach through validation of prespecified urine biomarkers: TIMP2, NGAL, FABPL, CYTC, IGFBP7
  • Impact of vasopressor regimen on the immune response, adrenergic receptor activity and related proteomic signature of peripheral blood mononuclear cell (PBMC) (outcome for ancillary study) [ Time Frame: Day 1 (baseline) and 7 ]
    Immune response, adrenergic receptor activity and proteomic profile through Th1/Th2 profiling, PBMC adrenergic receptors AMPc activity and proteomic signature and associations with responses to catecholamines.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2018)
  • Mean peak concentration of biomarkers associated with tissue injury to the brain [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated with tissue injury to the brain (serum S100B protein)
  • Mean peak concentration of biomarkers associated with tissue injury to the kidney [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated with tissue injury to the kidney (urinary TIMP2-IGFBP7 and/or blinded analysis of urinary sediment)
  • Mean peak concentration of biomarkers associated with tissue injury to the liver [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated with tissue injury to the liver (serum ALT)
  • Mean peak concentration of biomarkers associated with tissue injury to the intestine [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated with tissue injury to the intestine (serum fatty acid binding protein)
  • Mean peak concentration of biomarkers associated with tissue injury to the skeletal muscle [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated with tissue injury to the skeletal muscle (serum CK).
  • Mean peak concentration of biomarkers associated to cardiac wall stress [ Time Frame: 7 days ]
    Mean peak concentration of biomarkers associated to cardiac wall stress (serum N-terminal pro-B-type natriuretic peptide [NT-proBNP]31).
  • Global tissue dysoxia [ Time Frame: 7 days ]
    Global tissue dysoxia will be assessed through serum lactate
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Optimal VAsopressor TitraTION in Patients 65 Years and Older
Official Title  ICMJE Optimal VAsopressor TitraTION in Patients 65 Years and Older (OVATION-65)
Brief Summary We have designed OVATION-65 to evaluate the effects of permissive low blood pressure compared to usual care on markers of organ injury and survival in older patients.
Detailed Description

Background:

When it is severe, hypotension compromises tissue perfusion and organ function, leading to multiple organ failure and death. Commonly in intensive care units (ICUs), excessive vasodilation causes hypotension. In response, clinicians administer vasopressors to induce vasoconstriction and thereby raise blood pressure. However, these medications may reduce blood flow to vital organs, including the heart, and therefore damage them. Titrating vasopressors therefore requires balancing the risks of organ dysfunction arising from vasopressors or hypotension. Current guidelines recommend titrating vasopressors to a mean arterial pressure (MAP) of 65 mmHg. By not specifying an upper limit, guidelines and clinicians put more emphasis on preventing hypotension than on minimizing vasopressor exposure. Permissive hypotension, defined as a MAP target below traditional levels, may reduce vasopressor-induced harm while avoiding organ dysfunction induced by severe hypotension.

Observational data show that the average MAP in Canadian patients on vasopressors is 75 mmHg, 10 mmHg above current guideline recommendations and self-reported practices.The recent CIHR-funded OVATION pilot RCT (n=118) of permissive hypotension met feasibility objectives of demonstrating a separation in mean MAP between arms (9 mmHg, p<0.0001) and enrolling patients efficiently (2.3 patients/site/month). Investigators have also completed an individual patient data meta-analysis with the French SEPSISPAM trial and found that a lower MAP target may be beneficial in patients 65 years old.

Objective:

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 reduces the risk of harm associated with usual vasopressor therapy. The proposed RCT has specific objectives to ascertain the effect of permissive hypotension vs. usual care on: 1) markers of organ injury (primarily in the heart at day 3, secondarily (on day 3 and day 7) in the brain, liver, intestine, and skeletal muscle); 2) global tissue dysoxia (assessed by plasma lactate); 3) organ function (assessed by Sequential Organ Failure Assessment [SOFA] Score ); 4) resource utilization, 5) pre-specified adverse events, 6) mortality at 90 days and 6 months; 7) cognitive impairment in survivors at 6 months.

Methods:

Eligible patients will be randomized to target MAP 60-65 mmHg vs. usual care. By comparing permissive hypotension to usual care, we improve acceptance from clinicians and reduce the risk that the control group will diverge widely from usual care. Investigators will enroll patients in 7 Canadian ICUs. The deferred consent model will be adopted, successfully used in the pilot trial. Risk of bias will be minimized by allocation concealment, blinding of outcome assessors, complete hospital follow-up and intention-to-treat analysis.

Relevance:

This RCT proposal is embedded in the international OVATION-65 program of research, which includes the ongoing NIHR-funded UK65 Trial which measures 90-day mortality as the primary outcome. The Canadian OVATION-65 RCT is the only trial that measures organ injury biomarkers, providing crucial clinical information regardless of the effect on mortality. Results are expected to be incorporated into guidelines to inform practice worldwide.

Sample size:

The OVATION-65 Trial was designed to be complementary to the 65 Trial conducted in the United Kingdom. The original proposal, which consisted in a larger and simpler trial (n=800 participants, focused on biomarkers of organ injury) was abandoned because funding applications to the Canadian Institutes for Health Research and the Canadian Frailty Network were unsuccessful. The current trial was supported by a combination of multiple more modest operating grants awarded by the Université de Sherbrooke and the Centre de Recherche du CHU de Sherbrooke (see Funding sources). However, each grant required a distinct objective increasing the complexity of the analysis plan and sample size calculation. Certain analyses were incorporated into funding applications for local experiments on a small scale. By combining funds from multiple sources, we are able to enroll up to 200 participants, however we lack resources to measure every outcome on 200 participants. Outcomes that cannot be measured on every participant or as well as those that were planned originally but that remain unfunded are described briefly in the secondary outcomes section and specified as ancillary studies. They will be reported separately.

Attempts to obtain funding for a larger OVATION-65 Trial continued until the end of 2018. Sufficient funding was secured to enroll up to 200 patients, but trial enrollment was terminated on 21 February 2020 after 159 patients were enrolled, on the recommendation of the DSMC following publication of the 65 trial. Six-month follow-up will be complete in August 2020. The statistical analysis plan will be registered and published before analyzing the data.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Other
Condition  ICMJE
  • Vasopressors
  • Hypotension
  • Mean Arterial Pressure Targets
  • Usual Care
Intervention  ICMJE
  • Behavioral: MAP target 60-65 mmHg
    Treating teams will adjust vasopressors to a target MAP range of 60 to 65 mmHg, avoiding vasopressor-induced MAP above this range.
  • Behavioral: Usual care
    Patients in the control arm will receive usual care (as per local practices).
Study Arms  ICMJE
  • Experimental: MAP target 60-65 mmHg
    Treating teams will adjust vasopressors to a target MAP range of 60 to 65 mmHg, avoiding vasopressor-induced MAP above this range.
    Intervention: Behavioral: MAP target 60-65 mmHg
  • Active Comparator: Usual Care
    Patients in the control arm will receive usual care (as per local practices).
    Intervention: Behavioral: Usual care
Publications * Masse MH, Battista MC, Wilcox ME, Pinto R, Marinoff N, D'Aragon F, St-Arnaud C, Mayette M, Leclair MA, Quiroz Martinez H, Grondin-Beaudoin B, Poulin Y, Carbonneau É, Seely AJE, Watpool I, Porteous R, Chassé M, Lebrasseur M, Lauzier F, Turgeon AF, Bellemare D, Mehta S, Charbonney E, Belley-Côté É, Botton É, Cohen D, Lamontagne F, Adhikari NKJ; OVATION-65 team members; Canadian Critical Care Trials Group. Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial. BMJ Open. 2020 Nov 14;10(11):e037947. doi: 10.1136/bmjopen-2020-037947.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 28, 2020)
159
Original Estimated Enrollment  ICMJE
 (submitted: February 12, 2018)
200
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date February 21, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age 65 years or older
  2. Working diagnosis of vasodilatory hypotension as assessed by treating team
  3. Vasopressors started for 12 hours or less (window from ICU admission after/during adequate fluid resuscitation as assessed by treating physician)
  4. Vasopressors expected for 6 additional hours as assessed by the treating team

Exclusion Criteria:

  1. Actively treated for spinal cord injury or acute brain injury
  2. Vasopressors being given solely for bleeding, acute ventricular failure or post-cardiopulmonary bypass vasoplegia
  3. Lacking commitment to life-sustaining therapies (expected withdrawal of life-sustaining treatments within the next 48 hours
  4. Death perceived as imminent
  5. Previously enrolled in OVATION-65
  6. Organ transplant within the last year
  7. Extra corporeal life support at baseline
  8. The treating physician(s) lacks equipoise regarding the overall effects of permissive hypotension versus usual care on patient important outcomes.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03431181
Other Study ID Numbers  ICMJE MP-31-2018-1789
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party François Lamontagne, Université de Sherbrooke
Study Sponsor  ICMJE Université de Sherbrooke
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: François Lamontagne, MD FRCPC MSc University of Sherbrooke and CIUSSS de l'Estrie-CHUS
Principal Investigator: Neill Adhikari, MDCM MSc Sunnybrook Health Sciences Centre, University of Toronto
PRS Account Université de Sherbrooke
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP