Clinical trial NCT05058612: Midodrine for the Early Liberation of Vasopressor Support in the ICU (LIBERATE Multi-Site)
Official title: Midodrine for the Early Liberation From Vasopressor Support in the ICU - The LIBERATE Multi-Site Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Vasoplegia
Keywords: critical care medicine
intensive care
shock
midodrine
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: University Hospital Foundation
name: Institute of Health Economics, Canada
name: Alberta Health services
First posted: 2021-09-28
Enrollment: 850
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Vasopressors are medications that are given intravenously to increase the blood pressure of patients with illnesses that cause dangerous blood pressure drops. When a doctor prescribes a vasopressor, they ask that the dose be adjusted to achieve a specific blood pressure. This kind of medical support with intravenous (IV) vasopressors are usual treatments in intensive care unit (ICU) settings. Oral vasopressors, such as midodrine, have been historically used to maintain blood pressure in non-critically ill patients. In this study, the investigators will be using midodrine to reduce the need for IV vasopressors as blood pressure improves during the stay in the ICU.

This LIBERATE multi-site study will continue the work of the LIBERATE feasibility RCT study to evaluate the role of midodrine for patients with low blood pressure in the ICU. It is comprised of the multi centre pilot RCT followed by the definitive multi centre RCT.

Detailed description: Purpose: Resuscitation and hemodynamic support with intravenous (IV) vasopressors is a prime indication of treatment in intensive care unit (ICU) settings. Hemodynamic support is typically provided with intravenous (IV) vasopressors. However, these have been shown to have significant negative effects including increased central venous catheter line associated infections, venous thromboembolic disease, impaired mobility and gastrointestinal injury and ischemia. Oral vasopressors, such as midodrine, have been historically used for hemodynamic support in non-critically ill patients, but their study in patients as IV pressor sparing therapy has been limited.

Hypothesis: to evaluate the expanded role of midodrine for any vasoplegic patients in the ICU.

Justification: In 2018, there were 1,613 admissions to the adult general systems ICU (GSICU) at the University of Alberta Hospital (UAH). Patients were sick, with a mean Acute Physiology and Chronic Health Evaluation II (APACHE) score of 21.3, with 36.4% requiring vasopressors on admission, accounting for 1942 patient-days (data from eCritical TRACER database). In the environment strained healthcare resources and limited ICU capacity, the ability to safely wean patients from IV vasopressors with transition to oral hemodynamic supporting agents would greatly improve how patients navigate through the healthcare system. This in turn will improve patient-centered case.

Primary Objective:

To compare the effect of enteral midodrine vs. placebo in critically ill patients with vasoplegia receiving continuous IV vasopressor therapy on ICU length of stay.

Secondary Objectives: To compare the effect of enteral midodrine vs. placebo on: Total and post-hospital length of stay, Duration of IV vasopressor support, 90-day all-cause mortality, Rates of ICU re-admission, Rate of re-initiation of IV vasopressors.

Tertiary Objectives: To determine the health economic effects of the usage of midodrine vs placebo on: ICU costs, Hospital costs, Total healthcare costs, Cost-effectiveness.

Safety Endpoints: Adverse drug reactions, Serious adverse drug reactions, Suspected unexpected serious adverse reactions.

Research Method/Procedures: The LIBERATE Trial is a multi center, concealed-allocation parallel-group blinded randomized controlled trial. Patients will be randomly assigned to midodrine (enteral, 10mg every 8h) or placebo (microcrystalline cellulose) for the duration of their IV vasopressor therapy and 24h following the discontinuation of their IV vasopressor therapy. The recruitment target for the multi centre pilot RCT is 350 subjects (i.e., 175 subjects per arm), followed by the definitive RCT with a recruitment target of 850 subjects (425 subjects per arm). A blinded multi site pilot analysis will be conducted after the enrolment of the first 20% of study subjects (170 subjects).

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Ongoing vasopressor support
* Decreasing vasopressor dose(s)

Exclusion Criteria:

* Greater than 24 hours from peak vasopressor dose
* Contraindication to enteral medications
* Previously received midodrine in last 7 days
* Expected death or anticipated withdrawal of life-sustaining therapies in next 24 hours
* Pregnancy
* Known allergy to midodrine

Primary outcomes:
measure: Hierarchical composite of 30-day mortality and ICU length of stay
timeFrame: 1 year
Secondary outcomes:
measure: Total and post-ICU length of stay
timeFrame: 1 year
measure: Duration of vasopressor support
timeFrame: 1 year
measure: ICU readmission
timeFrame: 1 year
measure: Re-initiation of vasopressors
timeFrame: 1 year
measure: Mortality
timeFrame: 1 year
measure: ICU costs
timeFrame: 1 year
measure: Hospital costs
timeFrame: 1 year
measure: Total health care costs
timeFrame: 1 year
measure: Cost effectiveness
timeFrame: 1 year
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
Study officials:
affiliation: University of Alberta
name: Oleksa Rewa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Opgenorth D, Baig N, Fiest K, Karvellas C, Kutsogiannis J, Lau V, Macintyre E, Senaratne J, Slemko J, Sligl W, Wang X, Bagshaw SM, Rewa OG. LIBERATE: a study protocol for midodrine for the early liberation from vasopressor support in the intensive care unit (LIBERATE): protocol for a randomized controlled trial. Trials. 2022 Mar 4;23(1):194. doi: 10.1186/s13063-022-06115-0.