Stephen G. Kaler
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.
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 whi…
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.…
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.
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.