Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study

Abstract

Objective: Midodrine hydrochloride is a short-acting pressor agent that raises blood pressure in the upright position in patients with orthostatic hypotension. The US Food and Drug Administration's Subpart H approval, under which midodrine was initially approved, requires post-marketing studies to confirm midodrine's clinical benefit in this indication. The purpose of this study was to evaluate the clinical benefit of midodrine with regard to symptom response.

Methods: This was a double-blind, placebo-controlled, randomized, crossover, multicenter study (NCT01518946). Following screening, patients aged ≥18 years with severe symptomatic orthostatic hypotension and on a stable dose of midodrine for at least 3 months were randomized to treatment with either their previous midodrine dose or placebo on day 1 and the respective alternate treatment on day 2. The primary endpoint measured time to syncopal symptoms or near-syncope using a 45-min tilt-table test at 1 h post-dose.

Results: Thirty-three patients were screened for inclusion: 19 received at least one dose of midodrine and had at least one post-dose measurement of the primary endpoint. The least-squares mean time to syncopal symptoms or near-syncope after tilt-table initiation (mean ± standard error) was 1626.6 ± 186.8 s for midodrine and 1105.6 ± 186.8 s for placebo (difference, 521.0 s; 95 % confidence interval 124.2-971.7 s; p = 0.0131). There were 15 adverse events in 10 patients; all of these were mild or moderate in severity, with none considered by the investigators to be related to midodrine.

Interpretation: Midodrine is a well-tolerated and clinically effective treatment for symptomatic orthostatic hypotension.

Keywords: Clinical trial; Midodrine; Orthostatic hypotension.

Fig. 1

Study design. This was a double-blind, placebo-controlled, randomized, crossover, multicenter study. After an open-label screening period of 28 days, during which patients continued their usual, pre-study midodrine dose, baseline assessments of the severity of symptomatic orthostatic hypotension were undertaken on day −1. Midodrine treatment was withdrawn on day 1 (Part A) after which eligible participants entered the double-blind, randomized, crossover period (Part B). Patients were discharged on day 4, and their previous midodrine dose was reinstated. They were then followed up for 5–7 days

Fig. 2

Participant flow. Thirty-three patients were screened for inclusion in the study and participated in the assessments on day −1 and day 1; of these, nine did not meet the inclusion criteria. The enrollment set comprised 24 participants. Four patients were withdrawn from the study during Part A. The randomized set comprised the 20 participants who received at least one dose of midodrine in Part B. One participant did not complete the study because of technical problems with the tilt-table on day 2 and was excluded from the final analysis set

Fig. 3

Time to onset of syncopal symptoms/near-syncope after initiation of a tilt-table test in patients receiving midodrine or placebo in the final analysis set The time to onset of syncopal symptoms/near-syncopal symptoms was defined as the duration (in seconds) from the initiation of the protocol-defined tilt-table test until syncopal symptoms/near-syncope (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). For patients who completed the tilt-table test and did not achieve onset of syncopal symptoms/near-syncope, the time to onset was set to 2700 s. The p value was based on type III sum of squares from an ANOVA (analysis of variance) model for time to onset of syncopal symptoms/near-syncopal symptoms, including treatment sequence (two levels), treatment (two levels), and treatment period (two levels) as fixed effects and subject-within-sequence as a random effect