Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Impact of Permissive Hypotension on End-organ Damage in the Elderly (OVATION-65)

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: NCT03431181
Recruitment Status : Recruiting
First Posted : February 13, 2018
Last Update Posted : August 27, 2019
Sponsor:
Information provided by (Responsible Party):
François Lamontagne, Université de Sherbrooke

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.

Condition or disease Intervention/treatment Phase
Vasopressors Hypotension Mean Arterial Pressure Targets Usual Care Behavioral: MAP target 60-65 mmHg Behavioral: Usual care Not Applicable

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) 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.

Work by the investigators group Observational data from the investigators group 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 OVATION-65 RCT will evaluate the effect of permissive hypotension vs. usual care in patients 65 years old with vasodilatory hypotension treated with vasopressors for ≤12 hours on the primary outcome of myocardial injury (high sensitivity cardiac troponin [cTn], a validated marker of myocardial injury and powerful prognostic factor in ICU patients). Secondary outcomes will include other end-organ biomarkers, global dysoxia, organ function, immune response, resource utilization, pre-specified adverse events, genetic traits and epigenetic marks, 90-day and 6-month mortality and finally, the association between baseline level of ascorbic acid and biomarkers of organ injury . Investigators hypothesize that permissive hypotension will reduce organ injury and death.

Methods:

Eligible patients will be randomized to target MAP 60-65 mmHg vs. usual care. Investigators selected usual care to avoid protocol misalignment with standard practices and after ascertaining contemporary vasopressor use in Canada, which suggests that the risk of contamination is low. Investigators will enroll 200 patients in 5 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 OVATION65 program of research, which includes the ongoing NIHR-funded UK65 Trial, designed by the investigators group, which measures 90-day mortality as the primary outcome. The pooled analysis of both RCTs will be powered to detect a plausible difference of 6% in mortality. The proposed Canadian OVATION65 RCT will be the only trial that measures organ injury biomarkers, providing crucial clinical information regardless of the effect on mortality. Results will be incorporated into guidelines to inform practice worldwide.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Other
Official Title: OVATION-65 Impact of Permissive Hypotension on End-organ Damage in the Elderly
Actual Study Start Date : February 16, 2018
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : January 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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.

Active Comparator: Usual Care
Patients in the control arm will receive usual care (as per local practices).
Behavioral: Usual care
Patients in the control arm will receive usual care (as per local practices).




Primary Outcome Measures :
  1. Mean peak high-sensitivity cardiac troponins T (primary mechanistic outcome) [ Time Frame: 7 days ]
    Mean peak high-sensitivity cardiac troponins T (hsTnT) (primary mechanistic outcome)


Secondary Outcome Measures :
  1. 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 (GFAP, UCHL1, Myelin Basic Protein and NSE)

  2. 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 (renal biomarker TBD)

  3. 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)

  4. 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 (FABP))

  5. 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 CKM).

  6. 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]).

  7. Global tissue dysoxia [ Time Frame: 7 days ]
    Global tissue dysoxia will be assessed through serum lactate

  8. Organ function [ Time Frame: 28 days ]
    Organ function assessed by the Multiple Organ Dysfunction Score (MODS) (scale range from 0 to 24 (a high score is associated to a worse outcome)

  9. Immune response [ Time Frame: 7 days ]
    Immune response will be assessed through plasma IL-1 and TNFa

  10. Pre-specified adverse events [ Time Frame: 28 days ]
    Pre-specified adverse events assessed by events of stroke, acute kidney injury (KDIGO stage 3), limb or intestinal ischemia

  11. Genetic traits and epigenetic marks [ Time Frame: 7 days ]
    Genetic traits and epigenetic marks assessed by miRNA

  12. 6-month cognitive impairment [ Time Frame: 6 months ]
    6-month cognitive impairment assessed by Telephone Interview for Cognitive Status (TICS)

  13. Baseline level of ascorbic acid associated with organ injury [ Time Frame: 7 days ]
    Baseline level of ascorbic acid assessed by blood measure of ascorbic acid

  14. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT03431181


Contacts
Layout table for location contacts
Contact: Marie-Hélène Masse, Mrs 819-346-1110 ext 14173 mhmasse.chus@ssss.gouv.qc.ca
Contact: Marie-Claude Battista, Mrs 819-346-1110 ext 12480 marie-claude.battista@usherbrooke.ca

Locations
Layout table for location information
Canada, Quebec
CIUSSS de l'Estrie-CHUS Recruiting
Sherbrooke, Quebec, Canada, J1H5N4
Contact: Marie-Hélène Masse    819-346-1110 ext 14173    mhmasse.chus@ssss.gouv.qc.ca   
Contact: Marie-Claude Battista    819-346-1110 ext 12480    marie-claude.battista@usherbrooke.ca   
Principal Investigator: François Lamontagne, MD FRCPC MSc         
Sponsors and Collaborators
Université de Sherbrooke
Investigators
Layout table for investigator information
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

Layout table for additonal information
Responsible Party: François Lamontagne, Doctor, professor and researcher, Université de Sherbrooke
ClinicalTrials.gov Identifier: NCT03431181     History of Changes
Other Study ID Numbers: MP-31-2018-1789
First Posted: February 13, 2018    Key Record Dates
Last Update Posted: August 27, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Hypotension
Vascular Diseases
Cardiovascular Diseases