Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension

Abstract

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.

Trial registration: ClinicalTrials.gov identifiers: NCT00782340 , first received October 29, 2008; NCT00633880 , first received March 5, 2008; and NCT01176240 , first received July 30, 2010.

Keywords: Autonomic nervous system; Norepinephrine; Parkinson disease.

Figures

Fig. 1

OHQ items evaluate orthostatic symptoms (OHSA; n = 6) and activities of daily living (OHDAS; n = 4) [14]. OHDAS = Orthostatic Hypotension Daily Activity Scale; OHQ = Orthostatic Hypotension Questionnaire; OHSA = Orthostatic Hypotension Symptom Assessment

Fig. 2

Patient disposition. DB = double-blind; OL = open-label. *Population used for the integrated analyses

Fig. 3

Frequency distribution of the optimized droxidopa dose in patients randomized to double-blind droxidopa (n = 244). TID = 3 times daily

Fig. 4

Mean score change* from baseline to week 1/EOS: (a) OHQ, (b) OHSA, and (c) OHDAS. EOS = end of study; OHDAS = Orthostatic Hypotension Daily Activity Scale; OHQ = Orthostatic Hypotension Questionnaire; OHSA = Orthostatic Hypotension Symptom Assessment. *Score change on a rating scale from 0 (none/no interference) to 10 (worst possible/complete interference). A negative change represents a decrease in symptom burden

Fig. 5

Changes in standing systolic and diastolic BP from baseline to week 1/EOS. EOS = end of study; BP = blood pressure

Fig. 6

Changes in CGI-S scores* (a) and nOH severity categorization (b) from baseline to week 1/EOS. CGI-S = Clinical Global Impression–Severity; EOS = end of study; nOH = neurogenic orthostatic hypotension. *Score change on a rating scale from 1 (no symptoms) to 7 (severe symptoms)

Fig. 7

OHSA Item 1* score change: diagnosis (a), age (b), sex (c), and DDCI use (d). DDCI = dopa decarboxylase inhibitor; OHSA = Orthostatic Hypotension Symptom Assessment. *Score change on a rating scale from 0 (none) to 10 (worst possible). A negative change represents a decrease in symptom burden of dizziness/lightheadedness