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

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.

• Droxidopa (Drug), also known as Northera: Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.
• Placebo (Other): Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.

Primary outcomes

• Treatment Related Adverse Events as Assessed by CTCAE v4.0 [TEAEs in 6 week periods of either active drug (droxidopa) or placebo]: Treatment related adverse events as assessed by CTCAE v 4.0 by study arm

Secondary outcomes

• Mean Change in Systolic Blood Pressure in Tilt Position [Change in systolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline.]: Change in systolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline.
• Mean Change in Diastolic Blood Pressure in Tilt Position [The change in diastolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline.]: The change in diastolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline.
• Plasma Catechol Levels [Change in plasma catechols between each 6 week treatment arm (droxidopa and placebo)]: Change in plasma catechols between placebo and droxidopa treatment arms
• 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 daily bowel movements
• 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 Time standing duration
• 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 Timed Up and Go (TUG) 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 6 minute walk test performance
• Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire [Change from baseline in OHSA score during each 6 week treatment arm (droxidopa and placebo)]: 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.

Sex: All, ages: 18 Years to 50 Years

Inclusion Criteria:

1. 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.
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. Must sign and date an Informed Consent Form (ICF).
5. Age ≥ 18 years of age.
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 hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses.
3. 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.
4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

Participant flow

Outcome results

• Mean Change in Systolic Blood Pressure in Tilt Position (Secondary), Mean, mm/Hg: Northera (Droxidopa) -25 (29.1 to 83.2); Placebo -22 (0 to 0)
• Mean Change in Diastolic Blood Pressure in Tilt Position (Secondary), Mean, mmHg: Northera (Droxidopa) -8.6 (16.3 to 38.1); Placebo -15 (0 to 0)
• Plasma Catechol Levels (Secondary), Mean, pg/ml: Northera (Droxidopa) 65 +/- 8; Placebo 20 +/- 4
• Change From Baseline in Daily Bowel Movements (Secondary), Mean, bowel movements per day: Northera™ (Droxidopa) 7 (0.83 to 1.06); Placebo 8 (0 to 0)
• Change From Baseline in Time Standing Duration (Secondary), Mean, Seconds: Northera (Droxidopa) 300 +/- 50; Placebo 175 +/- 25
• Change From Baseline in Timed Up and Go (TUG) Test Performance (Secondary), Mean, seconds: Northera (Droxidopa) 10 +/- 2; Placebo 9 +/- 1
• Change From Baseline in 6 Minute Walk Test Performance (Secondary), Mean, meters: Northera (Droxidopa) 250 +/- 75; Placebo 200 +/- 75
• Treatment Related Adverse Events as Assessed by CTCAE v4.0 (Primary), Number, adverse events: Northera (Droxidopa) 10; Placebo 6
• Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire (Secondary), Mean, Scores on a scale: Northera (Droxidopa) -0.67 (-1.55 to 0.22); Placebo 0 (0 to 0)

Adverse events

Time frame: From enrollment up to 20 weeks

Other adverse events by term

Limitations and caveats: No specific study limitations and caveats.

• Results publication: 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. PMID 42016919

• Study Protocol and Statistical Analysis Plan (PDF, 2022-03-15)

• Stephen G Kaler, MD, Principal investigator, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY