Adams David, Suhr Ole B, Dyck Peter J, Litchy William J, Leahy Raina G, Chen Jihong, Gollob Jared, Coelho Teresa
CHU Hôpital Bicêtre, Le Kremlin-Bicêtre CEDEX, Paris, France.
Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
BMC Neurol. 2017 Sep 11;17(1):181. doi: 10.1186/s12883-017-0948-5.
Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.
Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of ≥2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score ≤IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study.
APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease.
This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.
帕替拉韦是一种处于研发阶段的RNA干扰（RNAi）疗法，用于治疗遗传性转甲状腺素蛋白淀粉样变性（hATTR），这是一种与严重残疾、发病率和死亡率相关的进行性疾病。
在此，我们描述了3期APOLLO研究的基本原理和设计，这是一项随机、双盲、安慰剂对照的全球研究，旨在评估帕替拉韦在患有hATTR淀粉样变性多发性神经病患者中的疗效和安全性。符合条件的患者年龄在18至85岁之间，患有hATTR淀粉样变性，研究者估计生存期≥2年，神经病变损害评分（NIS）为5至130，多发性神经病残疾评分≤IIIb。患者按2:1随机分组，每3周接受一次静脉注射帕替拉韦0.3mg/kg或安慰剂。主要目标是根据帕替拉韦组和安慰剂组之间改良NIS+7（运动强度、感觉、反射、神经传导和自主神经功能的综合指标）变化的差异，确定18个月时帕替拉韦的疗效。次要目标是评估帕替拉韦对诺福克糖尿病神经病变生活质量问卷评分、营养状况（通过改良体重指数评估）、运动功能（通过NIS-虚弱和定时10米步行试验测量）和自主神经症状（通过综合自主神经症状评分-31问卷测量）的影响。探索性目标包括评估心脏功能和进行病理评估以评估神经纤维支配和淀粉样蛋白负荷。在整个研究过程中，将评估帕替拉韦的安全性。
APOLLO是迄今为止在hATTR淀粉样变性患者中开展的规模最大的随机3期研究，其终点指标体现了该疾病的多系统性质。
本试验已在clinicaltrials.gov注册（NCT01960348）；2013年10月9日。
