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

870 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether an oral medication called midodrine can help ICU patients with low blood pressure reduce their need for IV vasopressors, which stabilize blood pressure. The goal is to determine if midodrine can maintain blood pressure as patients recover and require less intensive treatment. Participants will receive either midodrine or a placebo (a sugar pill with no active medicine) to evaluate midodrine's effectiveness. This trial may suit ICU patients whose blood pressure is improving with current IV support. As a Phase 4 trial, midodrine is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

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 is the safety track record for midodrine?

Research has shown that midodrine is generally safe for very sick patients. One study found that adding midodrine to other treatments was safe for patients in intensive care after heart surgery. Another review highlighted its safety for patients with low blood pressure due to dialysis. However, some studies noted that using midodrine after heart surgery could lead to longer intensive care stays and higher death rates. Overall, evidence suggests midodrine is usually well-tolerated, but some risks require consideration. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Midodrine is unique because it offers a new approach to managing vasoplegic syndrome by directly targeting blood vessel constriction. Unlike standard treatments, which often involve vasopressors administered intravenously, Midodrine is taken orally or via a nasogastric tube, making it potentially more convenient and less invasive. Researchers are excited because Midodrine works by activating alpha-1 adrenergic receptors to increase blood pressure, which could provide a more targeted and effective option for patients who do not respond well to current therapies.

What evidence suggests that midodrine might be an effective treatment for vasoplegic syndrome?

Research has shown that midodrine, which participants in this trial may receive, can effectively manage low blood pressure. It raises blood pressure by tightening blood vessels. Studies have found midodrine useful for treating conditions like vasovagal syncope, where blood pressure suddenly drops. In very sick patients, midodrine has reduced the need for IV medications that maintain blood pressure. Although some research results vary, its use in intensive care is increasing due to its potential benefits. Overall, midodrine is considered safe and can be a helpful option for people with certain blood pressure issues. ^{2 3 6 7 8}

Who Is on the Research Team?

Oleksa Rewa, MD

Principal Investigator

University of Alberta

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9301979/

Midodrine for the prevention of vasovagal syncope The primary outcome occurred in 210 patients (48%), consisting of 63% (147 of 234 patients) prescribed a control therapy and 32% (63 of 199 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04668859

Midodrine as Novel Treatment of Post-Cardiopulmonary ... Midodrine as Novel Treatment of Post-Cardiopulmonary Bypass Vasoplegic Syndrome. ClinicalTrials.gov ID NCT04668859. Sponsor Medstar Health ...

3. thecardiologyadvisor.com thecardiologyadvisor.com/news/midodrine-most-effective-pharmacological-intervention-for-vasovagal-syncope/

Midodrine Most Effective Pharmacological Intervention for ... Researchers have found that midodrine is a safe and effective therapy for management of patients with vasovagal syncope.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1441277223000364

Midodrine use in critically ill patients: a narrative review Midodrine is a peripherally acting, oral α-agonist that is increasingly used in intensive care units despite conflicting evidence for its effectiveness.

5. acc.org acc.org/latest-in-cardiology/journal-scans/2021/08/10/16/37/midodrine-for-the-prevention

Midodrine for Prevention of Vasovagal Syncope Oral midodrine significantly decreased the proportion of recurrent syncope, in young healthy individuals with vasovagal syncope, when it was ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7490305/

Potential risks in using midodrine for persistent ... The administration of midodrine for sustained hypotension after cardiac surgery with CPB was associated with fewer days free from ICU and higher mortality.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9986154/

The Use of Midodrine as an Adjunctive Therapy to Liberate ... The aim of our study was to evaluate the efficacy and safety of midodrine as an adjunctive therapy to liberate patients with shock from IV vasopressors.

8. academic.oup.com academic.oup.com/eurheartj/article/43/Supplement_2/ehac544.1098/6744793

Midodrine in treatment of post coronary revascularization ... Midodrine add-on inotrope therapy was a safe medication with appropriate compliance in ICU admitted patients after cardiac surgery.