Midodrine for Vasoplegic Syndrome

Overseen By Oleksa Rewa, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Alberta

Must be taking: Vasopressors

Disqualifiers: Pregnancy, Allergy to midodrine, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Varies based on individual patient needs

850 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug midodrine for vasoplegic syndrome?

Midodrine is effective in treating low blood pressure conditions like orthostatic hypotension by tightening blood vessels, which could help in vasoplegic syndrome where blood vessels are too relaxed. It has been used successfully in other conditions with similar symptoms, suggesting it might be helpful for vasoplegic syndrome as well. ^{1 2 3 4 5}

How does the drug Midodrine differ from other treatments for vasoplegic syndrome?

Midodrine is unique because it is an oral medication that works by constricting blood vessels to increase blood pressure, which is particularly useful in treating low blood pressure conditions like vasoplegic syndrome. Unlike other treatments that may require intravenous administration, Midodrine offers a convenient oral route, making it easier for patients to manage. ^{6 7 8 9 10}

Research Team

Oleksa Rewa, MD

Principal Investigator

University of Alberta

Eligibility Criteria

This trial is for adults over 18 in the ICU needing lower doses of IV blood pressure meds. They can't have taken midodrine recently, be pregnant, allergic to midodrine, or expected to pass away or stop life support within a day.

Inclusion Criteria

I am on a lower dose of medication to raise my blood pressure.

I am older than 18 years.

I am currently on medication to raise my blood pressure.

Exclusion Criteria

You are allergic to midodrine.

I cannot take medications by mouth due to a medical condition.

It has been over 24 hours since my highest dose of medication to raise blood pressure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive midodrine or placebo for the duration of their IV vasopressor therapy and 24 hours following discontinuation

Varies based on individual patient needs

Follow-up

Participants are monitored for safety and effectiveness after treatment, including 90-day all-cause mortality and ICU readmission rates

90 days

Extension

Long-term monitoring of health economic effects and cost-effectiveness

1 year

Treatment Details

Interventions

• Midodrine
• Placebo

Trial Overview The study tests if midodrine, an oral medication, can help wean patients off IV blood pressure drugs faster in the ICU compared to a placebo (a pill with no active drug).

Participant Groups

Group I: Midodrine Experimental Treatment 1 Intervention

Midodrine 10 mg PO/NG q8h

Group II: Placebo Placebo Group 1 Intervention

Microcrystalline cellulose PO/NG q8h

Midodrine is already approved in United States, European Union for the following indications:

Approved in United States as ProAmatine for:

• Symptomatic hypotension
• Orthostatic hypotension

Approved in European Union as Orvaten for:

• Symptomatic hypotension
• Orthostatic hypotension

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

Institute of Health Economics, Canada

Collaborator

Trials

9

Recruited

3,800+

University Hospital Foundation

Collaborator

Trials

8

Recruited

1,800+

Alberta Health services

Collaborator

Trials

168

Recruited

658,000+

Findings from Research

After short space-flights, orthostatic hypotension is linked to plasma volume depletion and activation of the Bezold-Jarisch reflex, which can cause fainting, while longer flights may lead to loss of cardiovascular reflex control similar to conditions seen in patients with autonomic failure.

Midodrine, an alpha-one agonist that causes blood vessel constriction without increasing heart rate, shows promise as a treatment for orthostatic hypotension after space flights and may help prevent vasovagal syncope, making it a potential adjunctive therapy for astronauts upon reentry.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of postspace-flight orthostatic intolerance to vasovagal syncope and autonomic failure and the potential use of the alpha agonist midodrine for these conditions. Piwinski, SE., Jankovic, J., McElligott, MA.[2019]

Midodrine effectively increases standing blood pressure and alleviates symptoms of orthostatic hypotension, such as weakness and fatigue, without causing cardiac stimulation, making it a safe option for patients.

In comparative studies, midodrine demonstrated at least equal efficacy to other sympathomimetic agents while causing fewer severe side effects, suggesting it is a preferable choice for managing hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. McTavish, D., Goa, KL.[2018]

In a study of 57 children with postural orthostatic tachycardia syndrome (POTS), higher plasma levels of the midregional fragment of pro-adrenomedullin (MR-proADM) were found in those who responded to midodrine hydrochloride treatment compared to nonresponders, indicating its potential as a predictive biomarker.

The study demonstrated that MR-proADM levels can effectively predict the therapeutic efficacy of midodrine hydrochloride, with a cutoff value of 61.5 pg/ml showing 100% sensitivity and 71.6% specificity, making it a useful tool for guiding treatment decisions in children with POTS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. Zhang, F., Li, X., Ochs, T., et al.[2022]

In a pilot study involving 62 patients with vasopressor-dependent hypotension, adjunctive midodrine was found to be feasible and had a good safety profile, with high protocol compliance (96.9%).

However, midodrine did not show significant physiological or clinical efficacy compared to usual care, as there was no meaningful difference in the time to cessation of vasopressor therapy or length of ICU and hospital stays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study. Costa-Pinto, R., Yong, ZT., Yanase, F., et al.[2022]

Midodrine, an FDA-approved medication for orthostatic hypotension, is now being explored for treating vasoplegic conditions like intradialytic hypotension and refractory ascites, showing good tolerance at doses of 2.5 mg, 5 mg, and 10 mg.

While midodrine has potential benefits for patients with septic shock, especially those not suitable for ICU care, there is currently a lack of clinical data to fully support its use in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Midodrine for Hypotension Outside of the Intensive Care Unit. Gutman, LB., Wilson, BJ.[2020]

Disopyramide, pirmenol, and pentisomide all inhibit the binding of a specific ligand to muscarinic receptors in guinea pig tissues, indicating their potential interactions with these receptors in the body.

Pirmenol shows a significantly lower affinity for glandular-type muscarinic receptors compared to cardiac-type receptors, while disopyramide and pentisomide exhibit comparable affinities at both receptor types, suggesting different mechanisms of action and potential therapeutic implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selectivity of class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide for peripheral muscarinic M2 and M3 receptors. Endou, M., Hattori, Y., Gando, S., et al.[2013]

3-iodothyronamine (T1AM) binds to all muscarinic receptor subtypes and acts as a weak antagonist, particularly affecting the muscarinic type 3 receptor, which is involved in urinary bladder function.

T1AM was shown to reduce acetylcholine-induced activation of pERK1/2 and decrease contractions in isolated rat urinary bladder, suggesting potential therapeutic applications for conditions like overactive bladder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors. Laurino, A., Matucci, R., Vistoli, G., et al.[2017]

Amiodarone acts as a novel positive allosteric modulator specifically for the M(5) muscarinic receptor, enhancing the efficacy of acetylcholine without increasing its potency, which is a unique finding among muscarinic receptors.

The study indicates that amiodarone can bind simultaneously with orthosteric antagonists, suggesting a new mechanism of action that could lead to more selective therapeutic strategies for central nervous system disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel allosteric effects of amiodarone at the muscarinic M5 receptor. Stahl, E., Ellis, J.[2021]

The introduction of tritiated iperoxo, a superagonist for muscarinic M₂ receptors, allows for more effective labeling of all five muscarinic receptor subtypes, demonstrating its high affinity and stability compared to traditional radioagonists.

Iperoxo's binding behavior reveals significant differences in receptor affinity and highlights its potential as a tool for studying activation-related changes in muscarinic receptors, particularly showing that the Gi protein enhances its binding while other proteins do not affect it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New insight into active muscarinic receptors with the novel radioagonist [³H]iperoxo. Schrage, R., Holze, J., Klöckner, J., et al.[2014]

Tripitramine is a potent and selective antagonist of cardiac M2 receptors, effectively blocking the decrease in heart rate in pithed rats without significantly affecting vascular M3 receptors.

In comparative studies, tripitramine demonstrated greater potency and selectivity for M2 receptors than the well-known antagonist methoctramine, indicating its potential as a targeted treatment for cardiac conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective blockade of muscarinic M2 receptors in vivo by the new antagonist tripitramine. Angeli, P., Cantalamessa, F., Gulini, U., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

A comparison of postspace-flight orthostatic intolerance to vasovagal syncope and autonomic failure and the potential use of the alpha agonist midodrine for these conditions. [2019]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

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]

5. Australia pubmed.ncbi.nlm.nih.gov

The Role of Midodrine for Hypotension Outside of the Intensive Care Unit. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Selectivity of class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide for peripheral muscarinic M2 and M3 receptors. [2013]

7. Netherlands pubmed.ncbi.nlm.nih.gov

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Novel allosteric effects of amiodarone at the muscarinic M5 receptor. [2021]

9. England pubmed.ncbi.nlm.nih.gov

New insight into active muscarinic receptors with the novel radioagonist [³H]iperoxo. [2014]

10. Germany pubmed.ncbi.nlm.nih.gov

Selective blockade of muscarinic M2 receptors in vivo by the new antagonist tripitramine. [2019]