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

Trial Summary

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.

What data supports the effectiveness of the drug Droxidopa for autonomic failure?

Droxidopa has been shown to be effective in treating symptoms of neurogenic orthostatic hypotension, a condition related to autonomic failure, by increasing standing blood pressure and improving symptoms like dizziness and lightheadedness. ^{1 2 3 4 5}

Is the combination of Midodrine and Droxidopa generally safe for humans?

Droxidopa is generally well tolerated in humans, but patients should be monitored for supine hypertension (high blood pressure when lying down). There is also a concern about contamination with a toxic substance called DOPAL, which may be present after taking droxidopa. ^{1 2 5 6 7}

What makes the drug combination of Midodrine and Droxidopa unique for treating autonomic failure?

The combination of Midodrine and Droxidopa is unique because it targets neurogenic orthostatic hypotension by using two different mechanisms: Midodrine increases blood pressure by constricting blood vessels, while Droxidopa is converted into norepinephrine to enhance blood pressure and potentially protect against reflex bradycardia. This dual approach may offer benefits for patients with severe or refractory cases, such as those with amyloidosis. ^{1 3 6 8 9}

What is the purpose of this trial?

The purpose of this study is to learn more about the effects of midodrine and droxidopa, two medications used for the treatment of orthostatic hypotension (low blood pressure on standing), on the veins of the abdomen of patients with autonomic failure. The study will be conducted at Vanderbilt University Medical Center, and consists of 2 parts: a screening and 2 testing days. The total length of the study will be about 5 days. About 34 participants will be screened for the study.

Research Team

Italo Biaggioni, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

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

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)

Treatment Details

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).

Participant Groups

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+

Findings from Research

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 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 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]

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 (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'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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

4. England pubmed.ncbi.nlm.nih.gov

d,l-threo-3,4-dihydroxyphenylserine restores sympathetic control and cures orthostatic hypotension in dopamine beta-hydroxylase deficiency. [2019]

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

Droxidopa: a review of its use in symptomatic neurogenic orthostatic hypotension. [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]

7. England pubmed.ncbi.nlm.nih.gov

Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension. [2019]

8. Australia 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. [2019]

9. England 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. [2021]