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Trial registered on ANZCTR


Registration number
ACTRN12618001158257
Ethics application status
Approved
Date submitted
2/07/2018
Date registered
13/07/2018
Date last updated
16/11/2018
Date data sharing statement initially provided
16/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Midodrine as an Adjunctive VasoprEssor for Refractory Hypotension in Intensive Care (MAVERIC) Study
Scientific title
A Pilot, Randomised Controlled Trial of Midodrine to reduce the duration of blood pressure supporting medicines as an Adjunctive Vasopressor sparing approach for Fluid-Refractory Hypotension in Intensive Care Patients
Secondary ID [1] 295354 0
None
Universal Trial Number (UTN)
Trial acronym
MAVERIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory hypotension 308573 0
Condition category
Condition code
Cardiovascular 307528 307528 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a pilot randomised controlled trial. Patients with refractory hypotension on an intravenous vasopressor infusion for more than 24 hours but deemed clinically stable by the treating clinician and receiving no more than 10 mcg/min of noradrenaline infusion or no more than 100 mcg/min of metaraminol infusion will be eligible to be enrolled in the study. Patients may receive either midodrine 10 mg three times a day, taken orally and concurrently with ongoing intravenous vasopressor therapy or receive usual care. All other treatment and investigations will remain equal. The allocation to medication will be randomised. The study drug will be weaned once the primary outcome is reached (cessation of intravenous vasopressor) at the following rate:
•10 mg three times a day orally for the first 24 hours after cessation of intravenous vasopressor
•7.5 mg three times a day orally for the following 24 hours
•5 mg three times a day orally for the following 24 hours (48 hours after cessation of intravenous vasopressor)
•Cessation of midodrine (72 hours after cessation of intravenous vasopressor)
There is no set duration of time for which enrolled participants will receive vasopressor support as the decision on use and administer vasopressor support will remain that of the participant's treating clinicians. Each enrolled patient will have daily clinical rounding by members of the research team and clinical staff, including medical doctors, pharmacists and intensive care nurses will be informed of the study protocol. Bedside tools and alerts will be provided to facilitate appropriate reduction in intravenous vasopressor medicines.
Intervention code [1] 301676 0
Treatment: Drugs
Comparator / control treatment
The control group will receive standard care based on the accepted current practice for the management of critically ill patients in the study setting which is use of and titration to effect of vasopressor mediciations at the discretion of the patient's treating intensive care consultant. This is an unblinded study..
Control group
Active

Outcomes
Primary outcome [1] 306508 0
Cessation of intravenous vasopressor use.
Timepoint [1] 306508 0
Time from enrollment to the cessation of vasopresser support following enrollment will be determined via medical record audit following the participant's discharge from hospital.
Secondary outcome [1] 348710 0
Time to intensive care unit discharge
Timepoint [1] 348710 0
Time from enrollment until discharge from the intensive care unit in days which will be determined via medical record audit following the participant's discharge from hospital.
Secondary outcome [2] 348711 0
Time to hospital discharge
Timepoint [2] 348711 0
Time from enrollment until discharge from the hospital in days which will be determined via medical record audit following the participant's discharge from hospital.

Eligibility
Key inclusion criteria
Admission to the Austin Hospital ICU
Age 18 years or greater
Refractory hypotension (as defined above), requiring treatment with a single intravenous vasopressor at low dose (as defined above)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Clinical haemodynamic instability, including high vasopressor requirement (i.e. noradrenaline > 10 mcg/min; metaraminol > 100 mcg/min)
Severe shock state, as evidenced by a lactate > 4 mmol/L or multiple vasopressor infusions
Renal failure as evidenced by a KDIGO Stage 1 Acute Kidney Injury, whereby creatinine is 1.5-1.9 times baseline OR urine output is <0.5 mL/kg/hr for 6-12 hours
Alternate treatable cause for refractory hypotension (i.e. bleeding, hypovolemic shock, cardiogenic shock, obstructive shock)
Patients with liver failure, severe heart disease, pregnancy, thyrotoxicosis
Acute brain pathology in which the treating clinician deems it inadvisable to enrol the patient, for example subarachnoid haemorrhage or those with current cerebral perfusion pressure (CPP) therapies in place
Bradycardia, heart rate less than 50 bpm
Those being feed via a jejunal tube
Those with no enteral route available

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed in sequentially numbered sealed, opaque envelopes to be opened after consent it obtained,
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed with the use of a computer-generated randomization list with permuted blocks of 2 or 4 or 6 patients also in random sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The study analysis will be by intention to treat. We will analyse our data using the log-rank test to determine whether time from initiation of midodrine until discontinuation of IV vasopressors and ICU and hospital length of stay differs between groups. Using Fisher’s exact test, we will test whether rates of ICU readmission and incidence of adverse events is different between treatment groups. All comparisons of continuous variables related to secondary outcomes will be by non-parametric statistics. All comparisons of ordinal variables related to secondary outcomes will be by Fisher’s exact test. A p value of < 0.05 will be considered statistically significant. All analyses will be conducted by a statistician blinded to intervention group assignment.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11261 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 23140 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 299946 0
Hospital
Name [1] 299946 0
Austin Hospital
Address [1] 299946 0
145 Studley Rd,, Heidelberg VIC 3084
Country [1] 299946 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
145 Studley Rd,, Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 299322 0
None
Name [1] 299322 0
Address [1] 299322 0
Country [1] 299322 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300812 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 300812 0
145 Studley Rd, Heidelberg VIC 3084
Ethics committee country [1] 300812 0
Australia
Date submitted for ethics approval [1] 300812 0
28/02/2018
Approval date [1] 300812 0
17/05/2018
Ethics approval number [1] 300812 0
HREC/18/Austin/84

Summary
Brief summary
Low blood pressure (hypotension) that does not improve with administration of fluids is a common reason for admission to intensive care. These patients usually require drugs that tighten blood vessels (vasopressor) to be given by continuous drip into a vein (intravenous infusion) to support the circulation and maintain a sage blood pressure for a period of time until the patient improves. Underlying causes of this hypotension may relate to sepsis, inflammatory conditions such as pancreatitis, use of medications and inflammation as sometimes seen in patients after surgery.

Midodrine is a drug that tightens blood vessels that can be taken by mouth and has been successfully used in many patients with diseases that cause low blood pressure and faintness when standing (orthostatic hypotension). It can be given as a tablet and is well tolerated. Recent studies have focused on its use in patients with other causes of hypotension and suggest it may be safely used in critically unwell patients already receiving vasopressor infusions for hypotension to shorten the length of time requiring such infusions. This may have additional patient benefits with shorter length of time of invasive monitoring and shorter length of ICU and hospital stay. There are, however, no randomised controlled trials assessing this effect, making it unclear whether reports published so far are correct.

We aim to compare the effect of midodrine added to usual care against usual care in critically ill patients on low dose vasopressor infusions for fluid-unresponsive hypotension. We plan to enrol a total of thirty patients who have required a vasopressor infusion for more than 24 hours and remain on an infusion due to continuing hypotension. These thirty patients will be randomly (like the toss of coin) assigned to receive either midodrine in three divided doses of 10 mg each per day or usual care. To understand the effect of the midodrine administration, we will record routinely recorded patient demographic data, circulation data (such as blood pressure, heart rate, central venous pressure and cardiac output), baseline laboratory data (haemoglobin, white cell count, alanine aminotransferase, international normalised ratio, bilirubin, urea, creatinine, troponin, lactate), urine output and fluid balance and dose of intravenous vasopressor. The primary outcome measure will be time in hours from initial administration of Midodrine to cessation of intravenous vasopressor. Secondary outcome measures, such as length of ICU and hospital stay, will also be recorded. The results of this study will provide insight into the effects of midodrine in attenuating duration of vasopressor infusions in intensive care patients with fluid resistant hypotension and, if positive, will allow our patients to be able to stop their infusion and return to the ward and home more quickly.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84894 0
Prof Rinaldo Bellomo
Address 84894 0
Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084
Country 84894 0
Australia
Phone 84894 0
+61394965000
Fax 84894 0
+61394963932
Email 84894 0
rinaldo.bellomo@austin.org.au
Contact person for public queries
Name 84895 0
Prof Rinaldo Bellomo
Address 84895 0
Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084
Country 84895 0
Australia
Phone 84895 0
+61394965000
Fax 84895 0
+61394963932
Email 84895 0
rinaldo.bellomo@austin.org.au
Contact person for scientific queries
Name 84896 0
Prof Rinaldo Bellomo
Address 84896 0
Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084
Country 84896 0
Australia
Phone 84896 0
+61394965000
Fax 84896 0
+61394963932
Email 84896 0
rinaldo.bellomo@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
This is a single-centre pilot investigation and the IPD decision has not yet been made by the investigating team members.
What supporting documents are/will be available?
No other documents available
Summary results
No Results