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

Background: allelic variant). Methods: We conducted a phase 1/2a, randomised, double-blind, placebo-controlled, crossover trial at one academic medical centre in Columbus, OH, USA. We compared placebo versus droxidopa treatment in adults with Menkes disease or occipital horn syndrome who manifested symptoms of dysautonomia (including orthostatic hypotension). Participants were recruited by invitation, screened, and randomly assigned to receive droxidopa or placebo for 6 weeks (Arm 1). Following a 7-10 day washout period, participants received the opposite treatment for 6 weeks (Arm 2/Crossover treatment). An open-label dose titration was utilised in advance to determine each participant's maximally tolerated dose (100, 200, or 300 mg) of droxidopa. The primary outcome of this trial was safety and tolerability assessed at 6 weeks, as reflected in the type and incidence of adverse events in the droxidopa treatment versus placebo groups. This trial is registered with ClinicalTrials.gov, NCT04977388. Findings: Between July 12, 2021 and Oct 30, 2023, three male participants were enrolled: two individuals with Menkes disease (19 and 26 years old) and one individual with occipital horn syndrome (age 35). We found significant improvements in norepinephrine levels (P < 0.01) and in a critical parameter of orthostatic hypotension, diastolic blood pressure drop during tilt table testing, while receiving droxidopa (-8.6, 95% CI -15.5 to -1.7; P = 0.018). There was no substantial difference in adverse events between the droxidopa and placebo groups. Interpretation: -related disorders. Further research is required, including in younger individuals with these conditions. Funding: The Menkes Disease Foundation UK, Associazione Angeli Per La Vita, and the Abigail Wexner Research Institute at Nationwide Children's Hospital.