Midodrine for Sepsis

Overseen By Aysun Tekin, M.D., M.S.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Mayo Clinic

Must not be taking: Monoamine oxidase inhibitors, Fludrocortisone

Disqualifiers: High-dose vasopressors, Cardiogenic shock, Recent stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 4 weeks

270 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot participate if you are currently using monoamine oxidase inhibitors or fludrocortisone acetate. If you are on these medications, you would need to stop them to join the trial.

Is Midodrine generally safe for human use?

There is no relevant safety information about Midodrine in the provided research articles. ^{1 2 3 4 5}

How does the drug Midodrine differ from other treatments for sepsis?

Midodrine is unique in treating sepsis because it is primarily used to increase blood pressure by constricting blood vessels, which can be crucial in managing the low blood pressure often seen in sepsis. Unlike other treatments that may focus on infection control or organ support, Midodrine specifically targets the vascular system to stabilize blood pressure. ^{2 4 6 7 8}

What is the purpose of this trial?

This study is being done to determine if early administration of Midodrine can improve outcomes by maintaining a higher mean blood pressure off of intravenous medications. Researchers want to see if Midodrine can help people with sepsis need fewer vasopressors, which could mean shorter hospital stays, less time with uncomfortable tubes, and a smoother recovery overall.

Research Team

Amos Lal, MBBS

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for individuals with sepsis and low blood pressure who may benefit from an alternative to intravenous medications. Specific eligibility criteria are not provided, but typically participants would need to meet certain health conditions.

Inclusion Criteria

I was diagnosed with sepsis within a day of meeting the specific criteria for it.

I was admitted to the hospital for a suspected infection and my organ function has worsened.

I have low blood pressure despite receiving fluids in the ED or ICU.

Exclusion Criteria

I cannot consent for myself and have no one to consent for me.

I have had a stroke in the last 3 months.

I have been treated for peripheral vascular disease in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive standard care for sepsis and three doses of midodrine every 8 hours

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Midodrine

Trial Overview The study tests if Midodrine, taken early on, can help maintain higher blood pressure in septic shock patients without needing IV meds. It's compared against a placebo to see if it reduces the need for vasopressors.

Participant Groups

Group I: Standard of Care with Midodrine Group Experimental Treatment 1 Intervention

Subjects will receive standard of care for sepsis and three doses of midodrine every 8 hours.

Group II: Standard of Care Group Active Control 1 Intervention

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

Dimebon (latrepirdine) shows potential as a therapeutic agent for neurodegenerative diseases by improving cellular energy balance and stabilizing mitochondrial function, which is crucial for brain health.

In preclinical models, Dimebon treatment reduced harmful protein aggregates and activated autophagy, suggesting it may modify disease progression, especially when administered early in the disease onset.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). Ustyugov, A., Shevtsova, E., Bachurin, S.[2020]

Structural modifications of oxotremorine and its acetamide analogue revealed that increasing the size of quaternary ammonium groups reduces their muscarinic potency, indicating a clear relationship between molecular structure and activity.

Tertiary amines showed a decrease in muscarinic activity due to loss of efficacy, with higher homologues acting as partial agonists or antagonists, suggesting that the design of these compounds can influence their therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscarinic activity of some secondary and tertiary amines and quaternary ammonium salts structurally related to oxotremorine. Resul, B., Ringdahl, B., Dahlbom, R., et al.[2019]

Dimebon, originally an anti-histamine, shows potential as a treatment for Alzheimer's and Huntington's diseases due to its high affinity for multiple receptors, including serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting a complex mechanism of action.

The drug's ability to inhibit butyrylcholinesterase and interact with various histamine receptors indicates a pharmacological basis for its re-purposing, which could lead to more effective multi-target therapies for these neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon. Okun, I., Tkachenko, SE., Khvat, A., et al.[2019]

Oxotremorine-M is highly effective in inducing tremor and salivation when administered directly into the brain (intracerebroventricular), but its effectiveness decreases significantly when given under the skin (subcutaneous), indicating that its action is primarily central rather than peripheral.

The study shows that both central and peripheral mechanisms are involved in regulating hypothermia and salivation, with central mechanisms being more dominant, and that certain antagonists like N-methylscopolamine can effectively block these effects regardless of the administration route.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central and peripheral mediation of hypothermia, tremor and salivation induced by muscarinic agonists in mice. Sánchez, C., Meier, E.[2019]

In a study involving 10 male patients with Alzheimer's disease, CI-979 was found to be well tolerated at a dose of 1-mg every 6 hours, while higher doses (2.5-mg and 3-mg) led to significant adverse effects, including cholinergic symptoms and signs of parkinsonism.

The study indicated that the frequency and intensity of adverse events increased with higher doses of CI-979, leading to the conclusion that a maximum dose of 2-mg every 6 hours will be used in future efficacy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of CI-979 in patients with Alzheimer's disease. Sramek, JJ., Sedman, AJ., Reece, PA., et al.[2019]

Fluoroethylnormemantine (FENM) demonstrated significant anti-amnesic and neuroprotective effects in a mouse model of Alzheimer's disease, particularly enhancing short-term memory when combined with sigma-1 receptor (S1R) agonists.

The study found that combinations of FENM with S1R agonists provided synergistic protection against learning deficits caused by Alzheimer's-related amyloid-beta, suggesting that these combinations could be a promising approach for treating cognitive impairments in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluoroethylnormemantine (FENM) shows synergistic protection in combination with a sigma-1 receptor agonist in a mouse model of Alzheimer's disease. Freyssin, A., Carles, A., Guehairia, S., et al.[2023]

Arecoline, a cholinergic agonist, safely improved memory in five out of nine subjects with mild to moderate Alzheimer's disease when administered at low doses via continuous intravenous infusion for up to 2 weeks.

In a placebo-controlled trial, five out of six subjects who responded to the treatment showed improved verbal memory, indicating that lower doses of cholinergic agonists may be effective for enhancing memory in Alzheimer's patients without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease. Soncrant, TT., Raffaele, KC., Asthana, S., et al.[2019]

The compound 5-iodomethyl-2-amino-2-thiazoline hydroiodide shows strong spasmogenic activity in isolated rat ileum, with an EC50 of 13 µM, making it comparable to the cholinergic agent pilocarpine (EC50 = 14 µM).

This compound's effects can be inhibited by atropine, indicating its mechanism of action is similar to that of cholinergic agents, although it exhibits very weak anti-AChE activity with an IC50 of 0.39 mM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[2-Amino-2-thiazoline derivatives--a novel chemotype possessing muscarinomimetic effect]. Ivanov, IuIa., Tkachenko, SE., Proshin, AN., et al.[2017]

References

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

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). [2020]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Muscarinic activity of some secondary and tertiary amines and quaternary ammonium salts structurally related to oxotremorine. [2019]

3. United Arab Emirates pubmed.ncbi.nlm.nih.gov

From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon. [2019]

4. Denmark pubmed.ncbi.nlm.nih.gov

Central and peripheral mediation of hypothermia, tremor and salivation induced by muscarinic agonists in mice. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of CI-979 in patients with Alzheimer's disease. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Fluoroethylnormemantine (FENM) shows synergistic protection in combination with a sigma-1 receptor agonist in a mouse model of Alzheimer's disease. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease. [2019]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[2-Amino-2-thiazoline derivatives--a novel chemotype possessing muscarinomimetic effect]. [2017]