ANZCTR - Registration

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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

14/02/2022

Date data sharing statement initially provided

16/11/2018

Date results provided

7/12/2020

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]

None

Universal Trial Number (UTN)

Trial acronym

MAVERIC

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Refractory hypotension

Condition category

Condition code

Cardiovascular

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]

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]

Cessation of intravenous vasopressor use.

Timepoint [1]

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]

Time to intensive care unit discharge

Timepoint [1]

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]

Time to hospital discharge

Timepoint [2]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

23/07/2018

Actual

1/08/2018

Date of last participant enrolment

Anticipated

31/12/2019

Actual

15/04/2020

Date of last data collection

Anticipated

31/03/2020

Actual

22/07/2020

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

The Alfred - Melbourne

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3004 - Melbourne

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Country [2]

New Zealand

State/province [2]

South Island

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Hospital

Address [1]

145 Studley Rd,, Heidelberg VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Hospital

Address

145 Studley Rd,, Heidelberg VIC 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

145 Studley Rd, Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/02/2018

Approval date [1]

17/05/2018

Ethics approval number [1]

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

Attachments [1]

/AnzctrAttachments/375459-MAVERIC Study - Protocol - Version 5 dated 4th June 2018 - clean.docx (Protocol)

Attachments [2]

/AnzctrAttachments/375459-MAVERIC Study - Austin Hospital_PICF_PR_Enrol_v3_4th June 2018 - clean.docx (Participant information/consent)

Attachments [3]

/AnzctrAttachments/375459-MAVERIC Study - Austin Hospital_PICF_PR_continue_v3_4th June 2018 - clean.docx (Participant information/consent)

Attachments [4]

/AnzctrAttachments/375459-MAVERIC Study - Austin Hospital_PICF_Patient_enrol_v3_4th June 2018 - clean.docx (Participant information/consent)

Attachments [5]

/AnzctrAttachments/375459-MAVERIC Study - Austin Hospital_PICF_Patient_continue_v3_4th June 2018 - clean.docx (Participant information/consent)

Attachments [6]

/AnzctrAttachments/375459-20180517 HREC18Austin84 June18 (FULL ETHICS APPROVAL).pdf (Ethics approval)

Contacts

Principal investigator

Name

Prof Rinaldo Bellomo

Address

Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084

Country

Australia

Phone

+61394965000

Fax

+61394963932

rinaldo.bellomo@austin.org.au

Contact person for public queries

Name

Rinaldo Bellomo

Address

Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084

Country

Australia

Phone

+61394965000

Fax

+61394963932

rinaldo.bellomo@austin.org.au

Contact person for scientific queries

Name

Rinaldo Bellomo

Address

Austin Hospital, 145 Studley Rd, Heidelberg VIC 3084

Country

Australia

Phone

+61394965000

Fax

+61394963932

rinaldo.bellomo@austin.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

De-identified patient data following ethical approval and following the agreement of the investigating team members

When will data be available (start and end dates)?

Six months following main results publication; no end date determined.

Available to whom?

Clinical investigators with a clearly defined and methodologically sound proposal, case-by-case basis of the primary sponsor.

Available for what types of analyses?

Only to achieve the aims in the approved proposal. Will be reviewed at the time of the data sharing request by members of the investigating team.

How or where can data be obtained?

Invitation to chief principal investigator

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Current Study Results

Type	Is Peer Reviewed?	Citations or Other Details	Attachment
Study results article	Yes	Journal of Critical Care. Citation - J Crit Care; ... [More Details]
Basic results	No		375459-(Uploaded-07-02-2022-10-35-26)-Basic results summary.pdf
Plain language summary	No	The addition of midodrine therapy was feasible wit... [More Details]

Update to Study Results

Doc. No.	Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
1553	Study results article	Yes		Journal of Critical Care. Citation - J Crit Care; ... [More Details]
2316	Basic results	No			375459-(Uploaded-07-02-2022-10-35-26)-Basic results summary.pdf
2851	Plain language summary	No		The addition of midodrine therapy was feasible wit... [More Details]
5282	Study results article	No	https://doi.org/ DOI: 10.1016/j.jcrc.2021.11.004	Costa-Pinto R, Yong ZT, Yanase F, Young C, Brown A... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study.	2022	https://dx.doi.org/10.1016/j.jcrc.2021.11.004

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Registering a new trial?

Documents added manually

Documents added automatically