NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome

Study Overview
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Brief Summary
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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.

Detailed Description
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This pilot clinical trial will evaluate the safety, tolerability, dosing, and preliminary efficacy of Northera (Droxidopa) treatment in young adults who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. We hypothesize that Northera (Droxidopa) in Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction) from persistent deficiency of the copper-dependent enzyme, dopamine-β-hydroxylase, will be safe, and correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and better overall quality of life. We will test this hypothesis in six to ten Menkes disease survivors or OHS patients in a double-blind placebo-controlled randomized crossover clinical trial.

Official Title
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Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Adults With Occipital Horn Syndrome: Double-blind Placebo-controlled Randomized Crossover Clinical Trial

Conditions
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Menkes Disease, Occipital Horn Syndrome

Intervention / Treatment
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* Drug: Droxidopa
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult persons with Menkes disease who survived beyond the expected natural history, attained independent ambulation, attend (or attended) school, and reached adulthood after early CuHis treatment for three years or adults with Occipital Horn Syndrome, who manifest clinical signs and symptoms of dysautonomia, e.g., orthostatic hypotension: specifically, a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within three minutes after standing, and/or chronic diarrhea: production of loose stools with or without increased stool frequency for more than four weeks immediately preceding enrollment. History of at least thrice weekly occurrence of dizziness/feeling lightheaded while standing upright and/or thrice weekly episodes of diarrhea or an urgent need to defecate after food ingestion for more than four weeks immediately preceding enrollment. Documented mutation in ATP7A. Must sign and date an Informed Consent Form (ICF). Age ≥ 18 years of age. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen. Willingness to comply with all study visits and procedures. Exclusion Criteria: Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min). History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses. Any disease or condition that, in the opinion of the Investigator, has a high probability of precluding the subject from completing the study or where the subject cannot or will not appropriately comply with study requirements. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Northera™ (Droxidopa) (Treatment A)<br>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. | Drug: Droxidopa<br>* Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.<br>* Other names: Northera;|
| Placebo Comparator: Placebo (Treatment B)<br>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 | Other: Placebo<br>* Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 tool | Grade 1-5 with increasing severity from 1 to 5 | Six week periods of Active drug versus Placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma catechol levels after Northera (Droxidopa) | Serial determinations of norepinephrine and dihydroxyphenylglycol | Six week periods of active drug versus placebo | 
| Changes in systolic blood pressure after Northera (Droxidopa) | Serial BP measurements including at-home monitoring | Six week periods of active drug versus placebo | 
| Changes in gastrointestinal symptoms after Northera (Droxidopa) | As reflected in the Irritable Bowel Syndrome-Diarrhea report | Six week periods of active drug versus placebo | 
| Changes in Time standing duration after Northera (Droxidopa) | Measured in time seconds | Six week periods of active drug versus placebo | 
| Changes in Up and Go test performance after Northera (Droxidopa) | Measured in time (seconds) needed to stand up from a chair, walk 3 m and return to a seated position on the chair. | Six week periods of active drug versus placebo | 
| Changes in 6 minute walk test performance after Northera (Droxidopa) | Measured in distance (meters) walked in 6 minutes | Six week periods of active drug versus placebo | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysautonomia