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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Northeraâ„¢ (Droxidopa) (Treatment A) | Active Comparator | 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. |
|
| Placebo (Treatment B) | Placebo Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Droxidopa | Drug | Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Related Adverse Events as Assessed by CTCAE v4.0 | Treatment related adverse events as assessed by CTCAE v 4.0 by study arm | TEAEs in 6 week periods of either active drug (droxidopa) or placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change in Systolic Blood Pressure in Tilt Position | Change in systolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. | Change in systolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. |
| Mean Change in Diastolic Blood Pressure in Tilt Position |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Stephen G Kaler, MD | Vagelos College of Physicians & Surgeons, Columbia University, New York, NY | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vagelos College of Physicians and Surgeons, Columbia University | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42016919 | Derived | Kaler MM, Brock G, Jeanty CJ, Iammarino MA, Hampton KA, Pham MT, Sabo BT, Lowes LP, Sullivan P, Goldstein DS, Kaler SG. Safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease and occipital horn syndrome in the USA: a randomised phase 1/2a crossover trial. EClinicalMedicine. 2026 Apr 13;94:103898. doi: 10.1016/j.eclinm.2026.103898. eCollection 2026 Apr. |
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Three Adult participants were assigned randomly to receive either Northera (droxidopa) then placebo placebo (Arm 1) or Placebo then Northera (droxidopa) (Arm 2). An open label dose titration was utilized in advance to determine each participant's maximally tolerated dose (100, 200, or 300mg) of droxidopa. Participants then underwent a 7 to 10 day washout period prior to beginning the treatment arms. There was also a washout period of 7 to 10 days between each of the two treatment arms.
Three adult participants were consented and screened for eligibility between July 2021 and October 2023.
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1 (Northeraâ„¢ (Droxidopa) First Then Placebo) | Participants in Arm 1 received Northera (Droxidopa) first then placebo based on prior randomization. The dosage for Northera (Droxidopa), 100mg, 200mg or 300mg, was based on the findings of the open label titration period and unique to each participant. Northera (droxidopa) was provided as gelatin capsules (sky blue and white, size 0); the placebo capsules were empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline. Capsules of Northera/Droxidopa were physically indistinguishable from the Placebo capsules. Frequency of administration (by mouth) was twice daily for six weeks. Partcipants self-administered capsules of Northera (Droxidopa) or Placebo by mouth twice daily for six weeks. |
| FG001 | Arm 2- Placebo First Then Northera (Droxidopa) | Participants in Arm 2 received Placebo first then Northera (Droxidopa) based on prior randomization. The placebo capsules were empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline. The dosage for Northera (Droxidopa), 100mg, 200mg or 300mg, was based on the findings of the open label titration period and unique to each participant. Northera (droxidopa) was provided as gelatin capsules (sky blue and white, size 0); Capsules of Northera/Droxidopa were physically indistinguishable from the Placebo capsules. Frequency of administration (by mouth) was twice daily for six weeks. Partcipants self-administered capsules of Northera (Droxidopa) or Placebo by mouth twice daily for six weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (6 weeks) |
| |||||||||||||
| Washout (7-10 days) |
| |||||||||||||
| Second Intervention (6 weeks) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Northera (Droxidopa) First Then Placebo | Participants received Northera (droxidopa) first then Placebo. Northera (Droxidopa) was 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 placebo capsules. Frequency of administration (by mouth) was twice daily for six weeks. Placebo consists of empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from the Northera (droxidopa). Frequency of administration (by mouth) will be twice daily for six weeks |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | Mean Change in Systolic Blood Pressure in Tilt Position | Change in systolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. | Posted | Mean | Standard Error | mm/Hg | Change in systolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. |
|
From enrollment up to 20 weeks
We identified a total of 16 non-serious adverse events among 3 subjects.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Open Label: Northera (Droxidopa) | The open label dose titration plan was initiated to determine each participant's maximally tolerated dose. Ascending doses of droxidopa of 100mg, 200mg, 300mg (maximum) were administered as tolerated based on the algorithm for determining droxidopa dose (see protocol). The droxidopa dose ascension was dependent on blood pressure less than 140mm Hg systolic and 90mm Hg diastolic and absence of symptoms of headache and/or nausea longer than two hours. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | CTCAE | Systematic Assessment | 2 of episodes occurred while on drug; 1 grade 2 minor, 1 grade 1 minor: other 2 episodes were while on placebo and were both grade 1 minor |
No specific study limitations and caveats.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stephen G. Kaler MD | Vagelos College of Physicians & Surgeons; Columbia University | 2123053669 | sgk2141@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 15, 2022 | Dec 19, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007706 | Menkes Kinky Hair Syndrome |
| C537860 | Occipital horn syndrome |
| D001342 | Autonomic Nervous System Diseases |
| ID | Term |
|---|---|
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D015103 | Droxidopa |
| ID | Term |
|---|---|
| D009638 | Norepinephrine |
| D002395 | Catecholamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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Double-blind Placebo-controlled Randomized Crossover Clinical Trial
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| Placebo | Other | Subjects will self-administer capsules of placebo by mouth twice daily for six weeks. |
|
The change in diastolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. |
| The change in diastolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. |
| Plasma Catechol Levels | Change in plasma catechols between placebo and droxidopa treatment arms | Change in plasma catechols between each 6 week treatment arm (droxidopa and placebo) |
| Change From Baseline in Daily Bowel Movements | Change from baseline in daily bowel movements | Change from baseline in daily bowel movements per day during each 6 week treatment arm (droxidopa and placebo). |
| Change From Baseline in Time Standing Duration | Change from baseline in Time standing duration | Change from baseline in standing time duration during each 6 week treatment arm (droxidopa and placebo). |
| Change From Baseline in Timed Up and Go (TUG) Test Performance | Change from baseline in Timed Up and Go (TUG) test performance | Change from baseline in TUG test performance during each 6 week treatment arm (droxidopa and placebo) |
| Change From Baseline in 6 Minute Walk Test Performance | Change from baseline in 6 minute walk test performance | Change from baseline in the 6MW distance during each 6 week treatment arm (droxidopa and placebo) |
| Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire | Change from baseline in scores on the Orthostatic Hypotension Symptom Assessment questionnaire. The scale rates the severity of OH symptoms from 0 to 10 ; with 10 defined as the worst possible. | Change from baseline in OHSA score during each 6 week treatment arm (droxidopa and placebo) |
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| NOT COMPLETED |
|
| BG001 | Placebo First Then Northera (Droxidopa) | Participants received Placebo first then Northera (droxidopa). Northera (Droxidopa) was 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 placebo capsules. Frequency of administration (by mouth) was twice daily for six weeks.Placebo consists of empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from the Northera (droxidopa). Frequency of administration (by mouth) will be twice daily for six weeks. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | As an X-linked recessive condition, nearly 100% of affected individuals are male. | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Height | Mean | Full Range | cm |
|
| Weight | Mean | Full Range | kg |
|
| OG001 |
| Placebo |
This group includes all three participants who received placebo during the entire course of this crossover study. Placebo consists of empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from the Northera (droxidopa). Participants self-administered capsules of placebo by mouth twice daily for six weeks during this crossover study. |
|
|
| Secondary | Mean Change in Diastolic Blood Pressure in Tilt Position | The change in diastolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. | Posted | Mean | Standard Error | mmHg | The change in diastolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. |
|
|
|
| Secondary | Plasma Catechol Levels | Change in plasma catechols between placebo and droxidopa treatment arms | Posted | Mean | Standard Error | pg/ml | Change in plasma catechols between each 6 week treatment arm (droxidopa and placebo) |
|
|
|
| Secondary | Change From Baseline in Daily Bowel Movements | Change from baseline in daily bowel movements | Posted | Mean | Standard Deviation | bowel movements per day | Change from baseline in daily bowel movements per day during each 6 week treatment arm (droxidopa and placebo). |
|
|
|
| Secondary | Change From Baseline in Time Standing Duration | Change from baseline in Time standing duration | Posted | Mean | Standard Error | Seconds | Change from baseline in standing time duration during each 6 week treatment arm (droxidopa and placebo). |
|
|
|
| Secondary | Change From Baseline in Timed Up and Go (TUG) Test Performance | Change from baseline in Timed Up and Go (TUG) test performance | Posted | Mean | Standard Error | seconds | Change from baseline in TUG test performance during each 6 week treatment arm (droxidopa and placebo) |
|
|
|
| Secondary | Change From Baseline in 6 Minute Walk Test Performance | Change from baseline in 6 minute walk test performance | Posted | Mean | Standard Error | meters | Change from baseline in the 6MW distance during each 6 week treatment arm (droxidopa and placebo) |
|
|
|
| Primary | Treatment Related Adverse Events as Assessed by CTCAE v4.0 | Treatment related adverse events as assessed by CTCAE v 4.0 by study arm | Posted | Number | adverse events | TEAEs in 6 week periods of either active drug (droxidopa) or placebo |
|
|
|
| Secondary | Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire | Change from baseline in scores on the Orthostatic Hypotension Symptom Assessment questionnaire. The scale rates the severity of OH symptoms from 0 to 10 ; with 10 defined as the worst possible. | Posted | Mean | 95% Confidence Interval | Scores on a scale | Change from baseline in OHSA score during each 6 week treatment arm (droxidopa and placebo) |
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| 1 |
| 3 |
| EG001 | Crossover: Northera (Droxidopa) | This group includes adverse events from all three participants while on Northera (Droxidopa). The dosage for Northera (Droxidopa), 100mg, 200mg or 300mg, was based on the findings of the open label titration period and unique to each participant. Participants self-administered capsules of Northera (Droxidopa) by mouth twice daily for six weeks. | 0 | 3 | 0 | 3 | 3 | 3 |
| EG002 | Crossover: Placebo | This group includes adverse events from all three participants while on placebo. Participants self-administered capsules of placebo by mouth twice daily for six weeks. | 0 | 3 | 0 | 3 | 1 | 3 |
|
| Headache | Nervous system disorders | CTCAE | Systematic Assessment | All episodes of headache were while on study drug; 3 were grade 1 minor and 1 was grade 2 minor |
|
| Elevated blood pressure | Cardiac disorders | CTCAE | Systematic Assessment | Two episodes of elevated blood pressure were while on study medication; both were grade 2 minor |
|
| potential Urinary Tract infection | Renal and urinary disorders | CTCAE | Systematic Assessment | CTCAE grade 1 minor while on investigational drug |
|
| Pre-syncopal episode while on baseline tilt table test | Nervous system disorders | CTCAE | Systematic Assessment | Grade 2 Major while on placebo |
|
| Minimally elevated creatinine level | Renal and urinary disorders | CTCAE | Systematic Assessment | Grade 1 minor while on placebo |
|
| Moderate Occult blood noted on urinalysis | Renal and urinary disorders | CTCAE | Systematic Assessment | Grade 1 Minor while on Placebo |
|
| Seizure | Nervous system disorders | CTCAE | Systematic Assessment | Grade 2 Major while on placebo |
|
| Proteinuria | Renal and urinary disorders | CTCAE | Systematic Assessment | Grade 1 Minor while on placebo |
|
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| D009422 | Nervous System Diseases |
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D008661 | Metabolism, Inborn Errors |
| D008664 | Metal Metabolism, Inborn Errors |
| D006201 | Hair Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D002396 |
| Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012694 | Serine |
| D021542 | Amino Acids, Neutral |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |