Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension

Background: Droxidopa, a prodrug of norepinephrine, was approved for treatment of neurogenic orthostatic hypotension (nOH) due to primary autonomic disorders based on 3 randomized double-blind studies. We performed safety and efficacy analyses of this pooled dataset (n = 460). Methods: Efficacy was assessed using Orthostatic Hypotension Questionnaire (OHQ) scores (composite and individual items). Safety and tolerability were also examined. Results: Droxidopa improved virtually all nOH symptom scores compared with placebo, significantly reducing OHQ composite score (-2.68 +/- 2.20 vs -1.82 +/- 2.34 units; P < 0.001), dizziness/lightheadedness score (-3.0 +/- 2.9 vs -1.8 +/- 3.1 units; P < 0.001), and 3 of 5 other symptom assessments (visual disturbances, weakness, and fatigue [P <= 0.010]). Droxidopa significantly improved 3 of 4 measures of activities of daily living (standing a long time, walking a short time, and walking a long time [P <= 0.003]) and significantly increased upright systolic blood pressure (11.5 +/- 20.5 vs 4.8 +/- 21.0 mmHg for placebo; P < 0.001). Droxidopa was effective in patients using inhibitors of dopa decarboxylase (DDCI; the enzyme that converts droxidopa to norepinephrine), but its efficacy was numerically greater in non-DDCI users. Droxidopa was well-tolerated. Rates of most adverse events were similar between groups. Supine hypertension rates were low, but slightly higher in patients receiving droxidopa (<= 7.9% vs <= 4.6% for placebo); patients with severe hypertension at screening were excluded from these studies. Conclusions: Droxidopa is effective for the treatment of nOH in patients with primary autonomic disorders and is generally well-tolerated. A longer trial is underway to confirm efficacy beyond the <= 2 to 10 - week period assessed in the current trials.