Rationale and Design of the Neurogenic Orthostatic Hypotension to Assess Sustained Effects of Droxidopa Therapy (RESTORE) Study (P5.131)

Objective: To evaluate time to treatment intervention in patients with primary autonomic failure (Parkinson disease [PD], multiple system atrophy [MSA], and pure autonomic failure), dopamine β-hydroxylase deficiency (DBHD), and nondiabetic autonomic neuropathy (NDAN) who have been previously stabilized with droxidopa therapy for symptoms of symptomatic neurogenic orthostatic hypotension (nOH); secondary objectives include assessment of long-term efficacy, safety, and tolerability of droxidopa in patients with symptomatic nOH. Background: Droxidopa is indicated in the United States for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic nOH caused by primary autonomic failure (PD, MSA, and pure autonomic failure), DBHD, and NDAN. In randomized, placebo-controlled, phase 3 trials, droxidopa treatment was shown to reduce the symptoms of nOH compared with placebo in this patient population. Long-term efficacy and safety remain to be confirmed. Methods: The present study will evaluate the efficacy and safety of droxidopa vs placebo over a 12-week double-blind treatment period in 482 patients with symptomatic nOH who have previously received up to 16 weeks of open-label droxidopa at an individually optimized dose (randomized withdrawal design). This placebo-controlled, double-blind study, conducted in 125 US sites and lasting up to 36 weeks, consists of 5 periods. Results: The primary endpoint, the time to treatment intervention during the double-blind period, will be summarized using the Kaplan-Meier method. The log-rank test will be used to compare the treatment groups and the Cox regression model to estimate the hazard ratio. Patients requiring treatment intervention for nOH symptoms will be discontinued from the study if any of the withdrawal criteria are met. Recruitment is ongoing. Conclusions: The results of this rigorous ongoing study will provide the basis for the appropriate long-term use of droxidopa in clinical practice. Support: Lundbeck Disclosure: Dr. Owen has received personal compensation for activities with Lundbeck as an employee. Dr. Peng has received personal compensation for activities with Lundbeck. Dr. Gorny has received personal compensation for activities with Lundbeck. Dr. Cram has received personal compensation for activities with Lundbeck. Dr. Rowse has received personal compensation for activities with Lundbeck Research USA, Inc. as an employee.