Droxidopa + Pyridostigmine for Low Blood Pressure

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Methylphenidate, Atypical antipsychotics

Disqualifiers: Diabetes, Congestive heart failure, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 days

30 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

You may need to stop certain medications that affect autonomic function 48 hours before testing, but this will be reviewed on a case-by-case basis. Some medications like fludrocortisone and stable doses of antidepressants are allowed. If stopping a medication is unsafe, the withdrawal period might be shortened.

What data supports the effectiveness of the drug Droxidopa for treating low blood pressure?

Research shows that Droxidopa, a norepinephrine precursor, can improve symptoms of neurogenic orthostatic hypotension (a condition where blood pressure drops significantly when standing up) by increasing blood pressure in patients with conditions like Parkinson's disease and multiple system atrophy. ^{1 2 3 4 5}

Is Droxidopa safe for humans?

Droxidopa has been used to treat low blood pressure in conditions like Parkinson's disease and has shown some effects on blood pressure and norepinephrine levels. However, there is a concern about contamination with a toxic substance called DOPAL, which could affect nerve cells. ^{1 2 3 4 5}

What makes the drug Droxidopa + Pyridostigmine unique for treating low blood pressure?

Droxidopa is unique because it is a norepinephrine precursor that can cross the blood-brain barrier, potentially affecting both central and peripheral systems, unlike other treatments that do not have this capability. Additionally, it is converted to norepinephrine in the kidneys, which may contribute to its blood pressure-raising effects. ^{1 2 3 4 6}

What is the purpose of this trial?

This study is being done to study the combination of pyridostigmine and low-dose Droxidopa for the treatment of orthostatic hypotension.

Research Team

Phillip A Low, M.D.

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for individuals with orthostatic hypotension, which means they get dizzy due to a significant drop in blood pressure upon standing. Participants must have this condition confirmed by specific tests showing it's caused by nerve problems.

Inclusion Criteria

The presence of orthostatic hypotension (fall in systolic BP >=30 mm Hg) is required for this study.

My low blood pressure when standing is caused by a nerve issue.

Exclusion Criteria

I can stop taking certain medications that affect my nervous system before testing.

Pregnant or lactating females.

I have severe joint or heart/lung problems affecting my daily activities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive various combinations of Droxidopa, Pyridostigmine, and placebo over a 4-day period

4 days

Daily visits for medication administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Droxidopa
• Pyridostigmine Bromide

Trial Overview The study is testing whether combining two drugs, pyridostigmine and low-dose Droxidopa, can effectively treat low blood pressure when a person stands up. Some participants will receive the actual medications while others may receive a placebo for comparison.

Participant Groups

Group I: Droxidopa and Pyridostigmine, Then Droxidopa and Placebo Experimental Treatment 3 Interventions

participants first receive Droxidopa by mouth 3 times a day, for treatment day 3. Then participants receive Placebo by mouth 3 times a day for treatment day 4.

Group II: Drioxidopa and Placebo, Then Drioxidopa and Pyridostigmine Experimental Treatment 3 Interventions

participants first receive placebo by mouth 3 times a day, for treatment day 3. Then participants receive Droxidopa by mouth 3 times a day for treatment day 4.

Group III: Placebo, Then Pyridostigmine Active Control 2 Interventions

participants first receive placebo by mouth 3 times a day, for treatment day 1. Then participants receive pyridostigmine by mouth 3 times a day for treatment day 2.

Group IV: Pyridostigmine, Then Placebo Active Control 2 Interventions

participants first receive pyridostigmine by mouth 3 times a day, for treatment day 1. Then participants receive placebo by mouth 3 times a day for treatment day 2.

Droxidopa is already approved in United States for the following indications:

Approved in United States as Northera for:

• Neurogenic Orthostatic Hypotension (NOH)

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

In a study involving six subjects with severe orthostatic hypotension, DL-DOPS significantly increased norepinephrine excretion by 10,000%, indicating a strong biochemical response.

Despite the increase in norepinephrine levels, DL-DOPS did not lead to any significant changes in blood pressure, suggesting it may not be effective as a treatment for orthostatic hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DL-Threo-3,4-dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension. Hoeldtke, RD., Cilmi, KM., Mattis-Graves, K.[2019]

Droxidopa, a norepinephrine prodrug for treating orthostatic hypotension, was found to be contaminated with DOPAL, a toxic compound, at a concentration of 0.01%.

After administering droxidopa to 13 subjects, all showed detectable levels of DOPAL in their plasma, indicating that droxidopa can convert to DOPAL in the body, raising concerns about its safety and potential neurotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contamination of the norepinephrine prodrug droxidopa by dihydroxyphenylacetaldehyde. Holmes, C., Whittaker, N., Heredia-Moya, J., et al.[2019]

In a study of 101 patients treated with droxidopa for neurogenic orthostatic hypotension, six patients developed cognitive and behavioral side effects, such as memory difficulties and irritability, shortly after starting the medication.

These symptoms appeared early in the treatment and were linked to low doses of droxidopa, suggesting that while droxidopa is effective in managing blood pressure, it may also have significant central nervous system effects that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review. McDonell, KE., Shibao, CA., Biaggioni, I., et al.[2020]

Droxidopa's absorption is significantly affected by food intake; taking it with a high-fat meal reduces peak concentration and overall exposure, suggesting it should be taken consistently either with or without food for optimal effect.

The pharmacokinetic profile of droxidopa remains similar whether administered as a single dose or three times a day, indicating that dosing frequency does not alter its absorption characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects. Chen, JJ., Hewitt, LA.[2021]

References

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

DL-Threo-3,4-dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Contamination of the norepinephrine prodrug droxidopa by dihydroxyphenylacetaldehyde. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Substantial renal conversion of L-threo-3,4-dihydroxyphenylserine (droxidopa) to norepinephrine in patients with neurogenic orthostatic hypotension. [2021]

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

Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment of orthostatic hypotension in Shy-Drager syndrome with DL-threo-3,4-dihydroxyphenylserine: a case report. [2018]

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

Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects. [2021]