Midodrine for Sepsis

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

Age: 18+

Sex: Any

Trial Phase: Phase 2

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

308 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Midodrine, a medication that raises blood pressure, can help people with sepsis by maintaining steady blood pressure and reducing the need for IV medications. The goal is to determine if it can decrease the need for vasopressors, potentially leading to shorter hospital stays and easier recovery. Participants must have sepsis and low blood pressure that hasn't improved with hospital-administered fluids. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that Midodrine is likely to be safe for humans?

Research shows that midodrine is generally safe for people with sepsis. In studies, midodrine has been used with patients experiencing septic shock and appeared to reduce hospital deaths. One study found that 43.3% of people taking midodrine died, compared to 73.3% in another group using norepinephrine, a different treatment. Another study examined midodrine's safety in very sick patients and confirmed its safe use in these cases. While research suggests midodrine might help patients leave the hospital sooner, the difference was not significant. Overall, these findings suggest midodrine is well-tolerated and might help improve outcomes for sepsis patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sepsis?

Researchers are excited about midodrine for treating sepsis because it offers a fresh approach compared to the usual treatments, like antibiotics and IV fluids. Midodrine is unique as it’s typically used to raise blood pressure in people with chronic low blood pressure. For sepsis, it could help maintain better blood pressure levels without relying solely on IV medications, potentially reducing the need for intensive care. This could be a game-changer for patients by making sepsis management more straightforward and less invasive.

What evidence suggests that Midodrine might be an effective treatment for sepsis?

This trial will compare the effectiveness of standard care alone versus standard care combined with midodrine for sepsis. Studies have shown that midodrine can benefit people with sepsis, a serious infection affecting the whole body. One study found that patients taking midodrine had lower hospital death rates compared to those receiving only norepinephrine, another treatment option. Specifically, the death rate was 43.3% for the midodrine group versus 73.3% for the norepinephrine group. Midodrine raises blood pressure, which is crucial for people with septic shock. Early results suggest it might also reduce the time needed for IV medications to maintain blood pressure. While it doesn't significantly shorten ICU stays, midodrine shows promise in improving survival rates for sepsis patients. ^{1 2 3 4 6}

Who Is on the Research Team?

Amos Lal, MBBS

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37203847/

Effect of midodrine on the prognosis of patients with septic ... Adding midodrine to patients with septic shock was associated with a reduction in hospital mortality [risk ratio (RR) 0.76; 95% CI, 0.57-1.00; p=0.05] and ...

2. accpjournals.onlinelibrary.wiley.com accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.70018

Efficacy of adjuvant use of midodrine in patients with septic ... In that study, mortality was 43.3% in the midodrine group versus 73.3% in the norepinephrine group (p = 0.018). The discrepancy between our ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8104269/

Oral Midodrine Administration During the First 24 Hours of ... We designed this clinical trial to evaluate the feasibility of use of midodrine hydrochloride in early sepsis to reduce the duration for IV vasopressors.

4. europeanreview.org europeanreview.org/wp/wp-content/uploads/4211-4220.pdf

Effect of midodrine on the prognosis of patients with septic ... The result showed that midodrine did not significantly decrease the length of ICU stay in patients with septic shock (p=0.54) (Figure 9).

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

Midodrine use in critically ill patients: a narrative review An early observational study also demonstrated midodrine's safety and efficacy in increasing blood pressure in children with septic shock.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03129542?cond=Midon&lastUpdPost=2020-02-07_&viewType=Table&rank=2

NCT03129542 | Midodrine Hydrochloride in Early Sepsis To study the potential side effects attributable to Midodrine use in diagnosis of Sepsis.