Droxidopa for Dysautonomia in Menkes Disease

Overseen By Stephen G. Kaler, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stephen G. Kaler, MD

Must be taking: Northera

Must not be taking: Alpha-1 agonists, Beta-blockers

Disqualifiers: Liver disease, Kidney disease, Hypertension, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to evaluate whether Northera (Droxidopa) is safe and effective in young adults with Menkes disease who survived the most severe complications of their illness or adults with occipital horn syndrome (OHS), who have trouble with intermittent low blood pressure and other symptoms of dysautonomia. The outcomes and information from this study may help adult survivors of Menkes disease and individuals with OHS lead more normal day-to-day lives.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication.

Is Droxidopa generally safe for humans?

There is no specific safety data for Droxidopa in the provided research articles. ^{1 2 3 4 5}

How is the drug droxidopa unique for treating dysautonomia in Menkes Disease?

Droxidopa is unique because it is a norepinephrine prodrug that can cross the blood-brain barrier, potentially offering central effects that other treatments do not. It is also effective in increasing blood pressure by converting to norepinephrine outside the brain, which is beneficial for conditions with low norepinephrine levels. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Droxidopa for treating dysautonomia in Menkes Disease?

While there is no direct evidence for Droxidopa in Menkes Disease, similar treatments like levodopa have shown effectiveness in conditions with dopamine-related issues, such as dopa-responsive dystonia, where patients responded well to long-term treatment. ^{1 11 12 13 14}

Who Is on the Research Team?

Stephen G Kaler, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

Adults over 18 with Menkes disease or Occipital Horn Syndrome who have survived severe complications and experience symptoms like low blood pressure when standing or chronic diarrhea. Participants must have a specific genetic mutation, be able to take oral medication, and commit to study visits. Those with liver or kidney diseases, heart issues, hypertension, or on certain medications cannot join.

Inclusion Criteria

I often feel dizzy or urgently need the bathroom after eating, for over a month.

I am an adult with Menkes disease or Occipital Horn Syndrome, treated early and have symptoms like low blood pressure upon standing or chronic diarrhea.

Must sign and date an Informed Consent Form (ICF).

Exclusion Criteria

I am not taking any medication for blood pressure, Parkinson's, or migraines.

I have a history of high blood pressure, heart issues, or bleeding disorders.

I have liver or kidney disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Northera (Droxidopa) or placebo in a double-blind crossover design for six weeks

6 weeks

Twice daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Droxidopa
• Placebo

Trial Overview The trial is testing Northera (Droxidopa) against a placebo to see if it can safely improve symptoms of dysautonomia such as intermittent low blood pressure and chronic diarrhea in adult survivors of Menkes disease and those with Occipital Horn Syndrome.

How Is the Trial Designed?

Group I: Northera™ (Droxidopa) (Treatment A) Active Control 1 Intervention

Northera (Droxidopa) (Treatment A) will be provided to adult subjects as a capsule with 100mg, 200mg, or 300mg of Northera (Droxidopa) contained within gelatin color capsules (sky blue and white, size 0) based on findings from the dose titration visit. These capsules are physically indistinguishable from the Treatment B (placebo) capsules. Frequency of administration (by mouth) will be twice daily for six weeks.

Group II: Placebo (Treatment B) Placebo Group 1 Intervention

Empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from Treatment A capsules. Frequency of administration (by mouth) will be twice daily for six weeks

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?

Stephen G. Kaler, MD

Lead Sponsor

Trials

1

Recruited

6+

Published Research Related to This Trial

A 16-month-old boy with autosomal-recessive dopa-responsive dystonia (DRD) was found to have compound heterozygous mutations in the TH gene, confirming the genetic basis of his condition.

Treatment with low-dose levodopa led to significant improvement in his dystonia symptoms, highlighting the efficacy of this intervention for managing DRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report. Feng, B., Sun, G., Kong, Q., et al.[2022]

In a study involving 12 patients with familial dysautonomia, carbidopa was found to be a safe and effective treatment for severe cyclical nausea and retching, significantly reducing symptoms compared to a placebo.

Carbidopa works by inhibiting the synthesis of dopamine outside the brain, which was confirmed by a significant decrease in urinary dopamine excretion while on the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Norcliffe-Kaufmann, L., Martinez, J., Axelrod, F., et al.[2022]

In a study of 20 patients with dopa-responsive dystonia (DRD) who were treated with levodopa for over 3 years, most showed significant improvement in their symptoms, indicating that long-term levodopa treatment is generally effective for this disorder.

However, 15% of patients with TH gene variants developed new motor symptoms during treatment, suggesting that these patients may experience dopamine insufficiency and may benefit from gradual increases in levodopa dosage to manage their symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes. Li, XY., Yang, YM., Li, LB., et al.[2021]

In a study involving six marmosets with L-DOPA-induced dyskinesia, nelotanserin significantly reduced peak dose dyskinesia by 47% and 69% at doses of 0.3 mg/kg and 1 mg/kg, respectively, without affecting the anti-parkinsonian effects of L-DOPA.

These results suggest that nelotanserin may be an effective treatment for alleviating drug-induced dyskinesia in Parkinson's disease, supporting the role of 5-HT2A/2C receptor antagonism as a therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset. Kwan, C., Frouni, I., Bédard, D., et al.[2023]

In a study of 9 children with dopa-responsive dystonia (DRD) caused by variations in the TH gene, most exhibited severe symptoms such as motor delay and hypotonia, with effective treatment using levodopa and benserazide hydrochloride tablets.

The treatment showed stable long-term effects without the need for increased dosages, and while one patient experienced early dyskinesia, it was manageable with additional medication, indicating a generally safe profile for the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical and genetic characteristics of children with dopa-responsive dystonia caused by tyrosine hydroxylase gene variations]. Zhang, GY., Cai, ZJ., Zhang, XL., et al.[2023]

The selective 5-HT(1a) agonist (R)-(+)-8-OHDPAT effectively reduced levodopa-induced chorea in MPTP-treated common marmosets without affecting dystonic movements, indicating potential for managing specific dyskinesias.

However, (R)-(+)-8-OHDPAT also decreased overall locomotor activity and did not improve motor disability, suggesting that while it may help with certain dyskinesias, it could worsen parkinsonism symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with increased motor disability. Iravani, MM., Tayarani-Binazir, K., Chu, WB., et al.[2018]

Dopamine receptor agonists, including both ergolinic and non-ergolinic types, are effective for treating symptoms of Parkinson's disease and can help reduce motor complications related to levodopa, but they do not demonstrate a disease-modifying effect.

While these medications can improve symptoms, they also carry risks of adverse reactions such as nausea, hallucinations, and impulse-control disorders, which were identified during both pre-marketing trials and post-marketing surveillance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopamine receptor agonists for the treatment of early or advanced Parkinson's disease. Perez-Lloret, S., Rascol, O.[2021]

The selective D1 antagonist SCH 23390 caused significant motor impairments in healthy African green monkeys, mimicking parkinsonian symptoms such as motor freezing, bradykinesia, and tremor.

In MPTP-treated monkeys, SCH 23390 worsened existing parkinsonism, highlighting the role of D1 receptors in motor function and raising concerns about potential parkinsonian side effects when using D1 antagonists in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The D1 receptor antagonist, SCH 23390, induces signs of parkinsonism in African green monkeys. Lawrence, MS., Redmond, DE., Elsworth, JD., et al.[2019]

Dihydrexidine (DHX) is a full D1 receptor agonist that shows significant effects in rats, indicating it may produce similar subjective effects in humans as other D1 receptor agonists.

In substitution tests, several D1 receptor agonists fully substituted for DHX, with DHX demonstrating the highest potency, suggesting its strong efficacy in activating D1 receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine. Gleason, SD., Witkin, JM.[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]

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]

L-DOPS (droxydopa) is an effective treatment for neurogenic orthostatic hypotension, as it increases blood pressure by enhancing the production of norepinephrine (NE) outside the brain, particularly in patients with conditions like pure autonomic failure and multiple system atrophy.

The drug's mechanism involves its conversion to NE via L-aromatic-amino-acid decarboxylase (LAAAD), and its efficacy can be inhibited by carbidopa, which prevents NE production, highlighting the importance of L-DOPS in managing NE deficiency in various syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. Goldstein, DS.[2021]

In a 10-week study involving 225 Parkinson's disease patients with neurogenic orthostatic hypotension, those treated with droxidopa experienced significantly fewer falls compared to those on placebo, with a 77% relative risk reduction in fall rates.

Droxidopa treatment also resulted in fewer fall-related injuries, with 16.7% of patients experiencing injuries compared to 26.9% in the placebo group, suggesting it may enhance safety for patients prone to falls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Droxidopa and Reduced Falls in a Trial of Parkinson Disease Patients With Neurogenic Orthostatic Hypotension. Hauser, RA., Heritier, S., Rowse, GJ., et al.[2022]

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]

Citations

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

Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report. [2022]

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

Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes. [2021]

4. France pubmed.ncbi.nlm.nih.gov

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset. [2023]

5. China pubmed.ncbi.nlm.nih.gov

[Clinical and genetic characteristics of children with dopa-responsive dystonia caused by tyrosine hydroxylase gene variations]. [2023]

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

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with increased motor disability. [2018]

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

Dopamine receptor agonists for the treatment of early or advanced Parkinson's disease. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The D1 receptor antagonist, SCH 23390, induces signs of parkinsonism in African green monkeys. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine. [2018]

10. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. [2021]

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

Droxidopa and Reduced Falls in a Trial of Parkinson Disease Patients With Neurogenic Orthostatic Hypotension. [2022]

14. England pubmed.ncbi.nlm.nih.gov

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