Droxidopa + Pyridostigmine for Low Blood Pressure

No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Prior Safety DataThis treatment has passed at least one previous human trial

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two medicines, Droxidopa and Pyridostigmine, to treat orthostatic hypotension—a condition where blood pressure drops upon standing, causing dizziness or fainting. Participants will receive various combinations of these treatments and placebos to determine the most effective option. It suits individuals diagnosed with orthostatic hypotension due to nervous system issues. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Droxidopa is generally well-tolerated. In clinical studies, some participants experienced side effects such as increased blood pressure or mild high blood pressure, affecting about 2% to 7% of participants. Other side effects, like a slight slowing of the heart's electrical signals, were rare.

Pyridostigmine is also considered safe and manages a drop in blood pressure when standing, without causing high blood pressure when lying down.

The combination of Droxidopa and Pyridostigmine is currently under testing, with more safety information being gathered. Droxidopa has already received FDA approval for certain conditions, providing some reassurance about its safety. However, as this is a Phase 2 trial, the full safety profile of the combination is still under exploration.12345

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target low blood pressure with a novel combination approach. Droxidopa, a norepinephrine precursor, directly boosts blood pressure by increasing norepinephrine levels, which is different from many standard treatments like fludrocortisone or midodrine that work more indirectly. Pyridostigmine, on the other hand, inhibits the breakdown of acetylcholine, potentially enhancing communication between nerves and muscles, which can stabilize blood pressure. This dual-action strategy, combining Droxidopa and Pyridostigmine, offers a potential advantage by tackling low blood pressure from both a neurochemical and muscular angle, setting it apart from existing single-mechanism treatments.

What evidence suggests that this trial's treatments could be effective for orthostatic hypotension?

Research has shown that Droxidopa and Pyridostigmine can help increase blood pressure in individuals with orthostatic hypotension, a condition where blood pressure drops upon standing. In this trial, some participants will receive Droxidopa, which studies indicate effectively raises blood pressure and reduces symptoms like dizziness and lightheadedness. Others will receive Pyridostigmine, which can improve blood pressure without affecting it when lying down. The trial will also evaluate the combination of Droxidopa and Pyridostigmine, which might better manage low blood pressure symptoms. Early findings suggest this combination could be a promising option for those dealing with these symptoms.12456

Who Is on the Research Team?

WS

Wolfgang Singer, M.D.

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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.
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Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.
How Is the Trial Designed?
4Treatment groups
Experimental Treatment
Active Control
Group I: Droxidopa and Pyridostigmine, Then Droxidopa and PlaceboExperimental Treatment3 Interventions
Group II: Drioxidopa and Placebo, Then Drioxidopa and PyridostigmineExperimental Treatment3 Interventions
Group III: Placebo, Then PyridostigmineActive Control2 Interventions
Group IV: Pyridostigmine, Then PlaceboActive Control2 Interventions

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

🇺🇸
Approved in United States as Northera for:

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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+

Published Research Related to This Trial

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

Citations

NCT03602014 | Dose Response to the Norepinephrine ...The goal of this study is to determine the efficacy of the drug Droxidopa ( Northera ) in increasing blood pressure in subject with hypotension, low blood ...
Clinical Correlates of Efficacy of Pyridostigmine in the ...A greater pressor response to pyridostigmine was associated with lower supine blood pressure and shorter pressure recovery time in patients with ...
real-world-experienceNORTHERA (droxidopa) is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult ...
Pyridostigmine in the management of orthostatic hypotensionPyridostigmine could serve as a treatment alternative which may improve symptoms of OH without impacting supine blood pressure. What this study ...
Droxidopa in neurogenic orthostatic hypotension - PMCIn a double blind study of 58 patients with nOH, 2 hours after taking 60 mg of pyridostigmine, upright systolic blood pressure was 4 mm Hg higher in the ...
Cardiovascular Safety Considerations in the Treatment of ...In the droxidopa clinical trials, the rates of hypertension (2% to 7%), blood pressure increase (0% to 7%), first-degree atrioventricular block ...
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