Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial

Abstract

Objective: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH).

Methods: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities.

Results: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events.

Conclusions: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated.

Classification of evidence: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Figure 1. Patient disposition

AE = adverse event; DB = double-blind; OL = open-label.

Figure 2. Treatment-group differences in OHQ score change, randomization to EOS, with 95% CIs (all treated patients; LOCF)

^aAverage of nonzero item scores. ^bAverage of symptom and symptom-impact composite scores. *p < 0.05; **p < 0.01; ***p < 0.001; droxidopa vs placebo, analysis of covariance adjusted for treatment group and value at randomization. CI = confidence interval; EOS = end of study; LOCF = last observation carried forward; OHQ = Orthostatic Hypotension Questionnaire.

Figure 3. Mean (SE) standing systolic BP during the study (all treated patients; LOCF)

*p < 0.001, droxidopa vs placebo from randomization to end of study; analysis of covariance adjusted for treatment group and value at randomization. BP = blood pressure; LOCF = last observation carried forward; SE = standard error.

Figure 4. Change in OHQ composite score vs standing systolic BP, randomization to EOS (missing values excluded)

The BP scale (but not the statistical analysis) omits one patient, a placebo recipient at (−125, −0.4). BP = blood pressure; EOS = end of study; OHQ = Orthostatic Hypotension Questionnaire.