Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Pediatric Survivors of Menkes Disease.

Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Pediatric Survivors of Menkes Disease: Double-blind Placebo-controlled Randomized Crossover Clinical Trial.

This clinical trial will evaluate the safety, tolerability, dosing, and efficacy of Northera (Droxidopa) in children with Menkes disease aged 7 to 17 years who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. The investigator hypothesizes that Northera (Droxidopa) treatment in pediatric Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, and bowel or bladder dysfunction) from deficiency of the cuproenzyme, dopamine-beta-hydroxylase, will be safe and will correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and a better quality of life. The investigator will test this hypothesis, in six to ten child or adolescent Menkes disease survivors through a placebo-controlled trial to evaluate adverse event rates and whether oral administration of Northera (Droxidopa) at doses established for individual subjects by careful dose titration improves plasma norepinephrine and dihydroxyphenylglycol (DHPG) levels, raises systolic blood pressure, and improves performance on tests of physical exertion. As an exploratory outcome measure, the study will validate the Orthostatic Hypotension Symptom Assessment (OHSA) questionnaire for this population for two four-week periods of either active or placebo treatment.

Aim 1. Determine the safety of Droxidopa in Menkes disease pediatric survivors.

Aim 2. Determine the efficacy of Droxidopa in Menkes disease survivors. The investigator hypothesizes that low-dose Droxidopa treatment in classic Menkes disease survivors aged 7 to 17 will improve orthostatic hypotension and ameliorate other signs and symptoms of dysautonomia. This pilot study will employ an ascending dose paradigm in a double-blind placebo-controlled randomized crossover design to optimize statistical power and rigorously discern treatment effects on 1) tilt table tests of orthostatic hypotension, 2) systolic and diastolic blood pressure, 3) plasma neurochemical levels and 4) tests of physical exertion. The trial will also validate the Orthostatic Hypotension Symptom Assessment (OHSA) questionnaire for this population of children and adolescents. This study addresses an important unmet clinical need for subjects with a rare disease, Menkes disease.

Study Overview

• Status: Recruiting
• Conditions: Menkes Disease
• Intervention / Treatment: Drug: Droxidopa Oral Product; Other: Placebo Control

Detailed Description

This proposal outlines a concerted effort to evaluate the safety and efficacy of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (Droxidopa) for the symptoms of dysautonomia that are common in pediatric survivors of Menkes disease. Classic Menkes disease is a fatal X-linked recessive disorder of copper homeostasis that results from variants in a copper transporter gene, ATP7A, and has an estimated birth prevalence of 1 in 35,000 males. The tragedy of Menkes disease involves the apparent good health of affected infants both prenatally and during the first 6-8 weeks of life, after which signs and symptoms of central nervous system (CNS) degeneration emerge. Our prior clinical research demonstrated that early diagnosis (within approximately 28 days of birth) and three years of daily treatment with subcutaneous injections of Copper Histidinate (NDA #34,166) can extend survival and markedly improve neurodevelopmental and neurocognitive outcomes. However, survivors of the illness's severe CNS effects often develop symptoms of dysautonomia, such as syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction beginning in middle childhood. These problems are caused by partial deficiency of dopamine-beta-hydroxylase (DBH), which requires ATP7A to deliver Cu to intracellular compartments for incorporation as its enzymatic cofactor. DBH normally converts dopamine to norepinephrine, and similar symptoms are reported in individuals with congenital absence of DBH, an autosomal recessive disorder. The drug Droxidopa is a synthetic amino acid L-threo-3,4-dihydroxyphenylserine and can be metabolized by the non-copper dependent enzyme DOPA decarboxylase to produce norepinephrine, bypassing the DBH enzymatic defect. The investigator has demonstrated neurochemical improvements in a mouse model of Menkes disease with this compound, as well as in adult Menkes disease survivors over age 18 in a detailed trial (NCT04977388). The investigator recently developed a new liquid suspension of Droxidopa to test smaller doses in pediatric survivors of Menkes disease in a clinical trial.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Stephen G Kaler, MD, MPH; Phone Number: 212 305-3669; Email: sgk2141@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Vagelos College of Physicians and Surgeons, Columbia University
      • Contact: Stephen G Kaler, MD; Phone Number: 212 305-3669; Email: sgk2141@cumc.columbia.edu
      • Contact: Maryann Kaler, MS; Email: mk5169@cumc.columbia.edu
      • Principal Investigator: Stephen G Kaler, MD
      • Sub-Investigator: Maryann Kaler, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Children or adolescents with Menkes disease who survived beyond the expected natural history, attained independent ambulation, and attend school after early CuHis treatment for three years, 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.
2. 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.
3. Documented mutation in ATP7A.
4. One parent must sign and date an Informed Consent Form (ICF) and patient must also assent.
5. Age 7 to 17 years. (Enrollment will be staggered so that at least the first two children enrolled are aged 12-17 years.)
6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen.
7. Willingness to comply with all study visits and procedures.

Exclusion Criteria:

1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min).
2. History of age-adjusted stage 1 hypertension (≥ 95th percentile) [1] (Also see Attachment A).
3. History of anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses.
4. 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.
5. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Droxidopa Treatment Arm; Oral administration of droxidopa study drug.	Drug: Droxidopa Oral Product; 1 month supply will contain pre-prepared capsules containing either 20mg, 40mg, or 60mg Droxidopa, plus 300 ml of simple syrup. For each dose, add the contents of 1 capsule and 10 ml of simple syrup to a plastic 1 ounce medication cup. Simple syrup will be dispensed from a larger bottle using a 10mL syringe. Mix by swirling briefly and consume the entire contents. Prepare the suspension freshly for each dose and take the prescribed dose twice daily, at approximately 8am and 2pm.; Other Names: NORTHERA
Placebo Comparator: Placebo Control Arm; Oral administration of placebo control capsules that are indistinguishable from study drug.	Other: Placebo Control; 1 month supply will contain pre-prepared capsules containing cellulose microcrystalline placebo, plus 300 ml of simple syrup. For each dose, add the contents of 1 capsule and 10 ml of simple syrup to a plastic 1 ounce medication cup. Simple syrup will be dispensed from a larger bottle using a 10mL syringe. Mix by swirling briefly and consume the entire contents. Prepare the suspension freshly for each dose and take the prescribed dose twice daily, at approximately 8am and 2pm.; Other Names: Placebo pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of SAEs	This is to measure safety and tolerability of study drug in children and adolescents with Menkes disease. The study will determine the adverse event profile of the formulation by comparing the time-to-event of serious adverse events (SAEs) and adverse events (AEs) between treatment and placebo arms as defined in the protocol.	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in level of plasma norepinephrine and dihydroxyphenylglycol after Northera (Droxidopa)	Plasma L-DOPS levels: Levels of L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa) may be measured for comparison to the known pharmacokinetic (PK) profile of Northera (Droxidopa) (peak level at approximately 3 hrs). The assay for plasma LDOPS and plasma catecholamines (High Performance Liquid Chromatography with electrochemical detection) is the same. Measurements of L-DOPS may permit correlation between plasma L-DOPS and plasma norepinephrine levels.	Baseline and post intervention at 4 weeks
Change in systolic blood pressure	Blood pressure (BP) will be measured using a standard blood pressure monitor while subjects are standing, and between supine and head-up tilt table positions after Northera (Droxidopa). Unit: mm Hg. Tilt Table testing involves positioning a patient onto the tilt table with feet resting on footplates. Continuous blood pressure monitors are then attached to the subject. The entire table can be tilted to move from 0˚ to 60˚angle in approximately 45s, allowing determination of changes in pulse and blood pressure based on supine (0˚) and standing (60˚) positions.	Baseline and post intervention at 4 weeks
Average number of daily bowel movements	Gastrointestinal symptoms will be monitored using irritable bowel syndrome-diarrhea report. Decreased daily bowel movements counts as an improvement.	Baseline, 4 weeks
Average time standing	This is to measure any improvement in physicality using performance of physical exertion tests. The longer the time standing, the greater the improvement. Unit: minutes.	Baseline and post intervention at 4 weeks
Average 6-minute walk distance	This is to measure any improvement in physicality using performance of physical exertion tests. The further the distance, the greater the improvement. The primary measurement taken from a 6-minute walk test (6MWT) is the final distance someone manages to walk, which we refer to as the 6MWD (6-minute walk distance), which can be used to assess a patient's functional status. For everyday healthy people, the average distance walked during this test is between 400 and 700 meters.	Baseline and post intervention at 4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in scores on the Orthostatic Hypotension Symptom Assessment questionnaire after Northera (Droxidopa)	The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. Lower the OHQ scores, less severe the symptoms.	Baseline and post intervention at 4 weeks

Collaborators and Investigators

• Sponsor: Stephen G. Kaler
• Investigators: Principal Investigator: Stephen G Kaler, MD, MPH, Columbia University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2030

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 4, 2026
• First Posted (Actual): February 10, 2026

Study Record Updates

• Last Update Posted (Actual): February 10, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Menkes disease, dysautonomia, orthostatic hypotension
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurobehavioral Manifestations; Skin Diseases; Hair Diseases; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Primary Dysautonomias; Orthostatic Intolerance; Metal Metabolism, Inborn Errors; Hypotension; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; X-Linked Intellectual Disability; Hypotension, Orthostatic; Autonomic Nervous System Diseases; Menkes Kinky Hair Syndrome; Amino Acids, Peptides, and Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Amino Acids; Catechols; Phenols; Benzene Derivatives; Catecholamines; Norepinephrine; Serine; Amino Acids, Neutral; Droxidopa
• Other Study ID Numbers: ACYY0326

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No