Hauser Robert A, Isaacson Stuart, Lisk Jerome P, Hewitt L Arthur, Rowse Gerry
University of South Florida, Tampa, Florida, USA.
Mov Disord. 2015 Apr 15;30(5):646-54. doi: 10.1002/mds.26086. Epub 2014 Dec 9.
Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s-SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinson's disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo, followed by 8 weeks of double-blind maintenance treatment (100-600 mg thrice-daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 ("dizziness, lightheadedness, feeling faint, or feeling like you might black out") of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s-SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse-event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s-SBP) evidence of short-term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD.
神经源性直立性低血压(nOH)是由于去甲肾上腺素对体位变化的反应未能维持站立时的收缩压(s-SBP)所致。屈昔多巴是去甲肾上腺素的口服前体药物。nOH306研究纳入了帕金森病(PD)合并症状性nOH的患者。受试者接受了长达2周的屈昔多巴或安慰剂双盲滴定,随后进行8周的双盲维持治疗(每日三次,每次100 - 600 mg)。对于最初的51名受试者(nOH306A研究,先前已报道),主要疗效指标直立性低血压问卷(OHQ)综合评分在维持治疗第8周时与安慰剂相比未显示出显著变化。对于随后的171名受试者(nOH306B研究,在此报道),主要疗效指标是维持治疗第1周时OHQ的直立性低血压症状评估(OHSA)子部分中第1项(“头晕、头重脚轻、感觉虚弱或感觉可能会昏厥”)相对于安慰剂的变化。在第1周时,屈昔多巴组OHSA第1项的平均(标准差)改善为2.3(2.95),而安慰剂组为1.3(3.16)(P = 0.018)。此外,第1周时屈昔多巴组s-SBP的平均升高为6.4(18.85)mmHg,而安慰剂组为0.7(20.18)mmHg(名义P值:0.032)。从基线到维持治疗第2、4和8周,OHSA第1项评分的变化差异无统计学意义。各治疗组的不良事件(AE)发生率相似,但因AE而退出的屈昔多巴组受试者为12.4%,安慰剂组为6.1%。屈昔多巴组(与安慰剂组相比)最常见的AE是头痛(13.5%对7.3%)和头晕(10.1%对4.9%)。nOH306B研究证明了屈昔多巴(与安慰剂相比)对PD合并症状性nOH具有短期疗效的主观(OHSA第1项)和客观(s-SBP)证据。