Midodrine + Droxidopa for Autonomic Failure

Overseen By Cyndya A Shibao, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Diabetes, Hypertension, Pregnancy, others

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

Compensation: Varies

Number of Visits: 4

Duration: 2 days

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two medications, midodrine and droxidopa, affect blood pressure control in individuals with conditions like Parkinson's disease or Multiple System Atrophy, which cause autonomic failure. The focus is on treating orthostatic hypotension, a condition where a significant drop in blood pressure upon standing leads to dizziness or fainting. Participants will receive either the actual medication or a placebo to compare effects. Suitable participants have experienced this type of blood pressure drop with specific neurological conditions and can provide informed consent. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team to get a clear answer.

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

Research has shown that droxidopa is generally safe and well-tolerated. In a large group of patients with neurogenic orthostatic hypotension (a condition causing dizziness or fainting when standing), droxidopa was used safely over a long period. However, some individuals experienced higher blood pressure while lying down, with 4.9% encountering this issue compared to 2.5% who took a placebo.

In contrast, the safety of midodrine remains less clear. Some studies have not found sufficient evidence to fully support its use for orthostatic hypotension, and information on its long-term safety is limited. Midodrine is approved for severe cases when other treatments fail, but potential safety concerns should be considered.

These findings suggest that while droxidopa is mostly safe for short-term use, both treatments require caution. Participants should discuss any concerns with their healthcare providers before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments midodrine and droxidopa for autonomic failure because they offer unique approaches compared to current options like fludrocortisone and beta blockers. Midodrine works by tightening blood vessels, which can help raise blood pressure quickly, offering a new mechanism of action in managing symptoms. Droxidopa, on the other hand, is converted into norepinephrine in the body, helping to increase blood pressure and improve symptoms of dizziness and fatigue more directly. These distinct mechanisms could offer more targeted relief and improve quality of life for patients suffering from autonomic failure.

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

Research has shown that midodrine, one of the treatments in this trial, effectively treats low blood pressure when standing, known as orthostatic hypotension. Studies have found that it can raise standing blood pressure by about 22 mmHg, helping people feel more stable when they stand up. Midodrine is generally well-tolerated and has been the standard treatment for this condition.

Droxidopa, another treatment option in this trial, also shows promise for treating orthostatic hypotension symptoms. It has been proven to reduce dizziness and lightheadedness, making daily activities easier for patients. Droxidopa works by converting into norepinephrine, a chemical that helps control blood pressure. Both medications have strong evidence supporting their use for improving symptoms of low blood pressure when standing. ^{3 6 7 8 9}

Who Is on the Research Team?

Italo Biaggioni, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 40-80 with certain neurological conditions (Multiple System Atrophy, Pure Autonomic Failure, or Parkinson's) that cause low blood pressure when standing. Participants must have a specific drop in blood pressure and no other causes of autonomic neuropathy. They can't join if they have high resting blood pressure, are pregnant, or have had recent major surgeries among other exclusions.

Inclusion Criteria

I am between 40-80 years old and may have Multiple System Atrophy, Pure Autonomic Failure, or Parkinson's.

Subjects able and willing to provide informed consent

My blood pressure drops significantly when I stand, due to nerve issues.

Exclusion Criteria

You cannot tolerate any increase in pressure inside your abdomen.

I have no medical devices in my abdomen that could affect abdominal pressure.

I haven't had a major heart, brain event, or any condition that would stop me from completing the study in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 days

1 visit (in-person)

Treatment

Participants are randomized to receive either droxidopa or midodrine, with testing on two separate days including tilt table tests and various measurements

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Droxidopa
• Midodrine
• Placebo

Trial Overview The study at Vanderbilt University Medical Center tests the effects of Midodrine and Droxidopa on abdominal veins in patients with autonomic failure. It involves screening and two testing days over approximately five days to see how these drugs treat orthostatic hypotension (low blood pressure upon standing).

How Is the Trial Designed?

Group I: Midodrine and Placebo Experimental Treatment 2 Interventions

Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of placebo after the first tilt table test, followed two hours later by a single oral dose of either midodrine 10 mg or placebo.

Group II: Droxidopa and Placebo Experimental Treatment 2 Interventions

Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of either droxidopa 300 mg or placebo after the first tilt table test, followed two hours later by a single oral dose of placebo.

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?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

Droxidopa is effective in treating neurogenic orthostatic hypotension (nOH), with a number needed to treat (NNT) of less than 10, indicating that fewer than 10 patients need to be treated for one to experience significant improvement in dizziness/lightheadedness.

The safety profile of droxidopa is acceptable, with a number needed to harm (NNH) of 81 for adverse events leading to discontinuation, suggesting that it is more likely to provide benefit than cause harm in patients with nOH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension. François, C., Rowse, GJ., Hewitt, LA., et al.[2019]

Treatment with d,l-threo-3,4-dihydroxyphenylserine (DOPS) effectively restored normal blood pressure and eliminated symptoms of orthostatic hypotension in two patients with congenital dopamine beta-hydroxylase deficiency over a period of 6 to 12 months.

DOPS acts as a substrate for the enzyme aromatic-l-amino-acid decarboxylase, allowing the production of noradrenaline from dopamine, thereby demonstrating that the sympathetic neurons remain functionally intact despite the deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

d,l-threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine beta-hydroxylase deficiency. Man in 't Veld, AJ., Boomsma, F., van den Meiracker, AH., et al.[2019]

Droxidopa has been evaluated for its effectiveness in improving standing blood pressure and reducing symptoms of orthostatic intolerance in adults with neurogenic orthostatic hypotension, compared to midodrine.

The review aims to clarify which treatment is more effective for managing these symptoms, although specific results and data from the studies are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of droxidopa compared to midodrine in standing blood pressure and orthostatic tolerance in adults with neurogenic orthostatic hypotension: a systematic review protocol. Patrick, K., Martin, T.[2019]

Droxidopa, when used alongside midodrine, effectively treated refractory neurogenic orthostatic hypotension in a patient with amyloidosis, leading to significant improvements in blood pressure and overall well-being during a 30-day hospital stay.

The treatment also appeared to reduce episodes of reflex bradycardia, potentially due to increased systemic norepinephrine, and was well-tolerated with no reported side effects, suggesting a promising safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Droxidopa as an effective treatment for refractory neurogenic orthostatic hypotension and reflex bradycardia in amyloid light-chain amyloidosis: a case report. Ho, AH., Kinter, CW., Wight, J., et al.[2021]

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 (NORTHERA™) is effective in treating symptoms of neurogenic orthostatic hypotension, showing improvements in dizziness and standing blood pressure in adults with conditions like Parkinson's disease, based on clinical reviews.

The medication is generally well tolerated, but patients need monitoring for potential supine hypertension, indicating a need for caution in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Droxidopa: a review of its use in symptomatic neurogenic orthostatic hypotension. Keating, GM.[2018]

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]

Droxidopa is a promising treatment for neurogenic orthostatic hypotension, particularly in conditions like pure autonomic failure, multiple system atrophy, and Parkinson's disease, as it effectively increases noradrenaline levels after conversion in the body.

The review highlights the need for further research on the safety and efficacy of Droxidopa, especially regarding its use alongside other Parkinson's treatments, as current experience is limited mainly to specific patient populations in Europe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. Mathias, CJ.[2021]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4115605/

Droxidopa for neurogenic orthostatic hypotension Overall, this short-term, multicenter trial showed that droxidopa treatment led to significant amelioration of multiple symptoms of nOH (dizziness, vision ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00633880

NCT00633880 | Clinical Study of Droxidopa in Patients ... Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy Drager syndrome (Multiple System ...

3. bmcneurol.biomedcentral.com bmcneurol.biomedcentral.com/articles/10.1186/s12883-017-0867-5

Integrated analysis of droxidopa trials for neurogenic ... Droxidopa was significantly more effective than placebo in decreasing dizziness/lightheadedness symptoms in patients with a diagnosis of PD or ...

4. northerahcp.com northerahcp.com/about/efficacy/real-world-experience

real-world-experience NORTHERA (droxidopa) is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult ...

5. ahajournals.org ahajournals.org/doi/10.1161/hypertensionaha.114.04035

Randomized Withdrawal Study of Patients With ... We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/203202s007lbl.pdf

NORTHERA® (droxidopa) capsules, for oral use The safety evaluation of NORTHERA is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies. 301 and 302), one 8-week placebo-controlled ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/droxidopa-oral-route/description/drg-20095142

Droxidopa (oral route) - Side effects & dosage Droxidopa is used to treat neurogenic orthostatic hypotension (lightheadedness, dizziness, or fainting) caused by primary autonomic failure.

8. sciencedirect.com sciencedirect.com/science/article/pii/S193317111630451X

Long-term safety of droxidopa in patients with symptomatic ... In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well tolerated during long-term use.

9. northerahcp.com northerahcp.com/

NORTHERA® (droxidopa) for Healthcare Professionals NORTHERA is the only treatment specifically studied to reduce the classic symptoms of neurogenic orthostatic hypotension (nOH).1,2. SEE THE CLINICAL DATA.