评估 inclisiran 在纯合子和杂合子家族性高胆固醇血症青少年中的疗效、安全性和耐受性的两项试验的原理和设计。
Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.
机构信息
Department of Paediatrics, Amsterdam UMC, Location AMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Global Drug Development, Cardiovascular, Renal and Metabolism, Novartis Pharma AG, Basel, Switzerland.
出版信息
Eur J Prev Cardiol. 2022 Jul 20;29(9):1361-1368. doi: 10.1093/eurjpc/zwac025.
BACKGROUND
Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option.
OBJECTIVES
The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16).
STUDY DESIGN
ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation.
CLINICAL TRIAL REGISTRATION
https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).
背景
依洛尤单抗是一种小干扰 RNA 分子，通过抑制前蛋白转化酶枯草溶菌素/糜蛋白酶 9 来降低低密度脂蛋白胆固醇（LDL-C）。这种皮下注射、每半年给药一次的药物已被证明可有效且安全地降低已患有动脉粥样硬化性心血管疾病的成年患者、有动脉粥样硬化性心血管疾病高危因素的成年患者以及杂合子家族性高胆固醇血症的成年患者的 LDL-C。鉴于目前在儿童中治疗严重杂合子家族性高胆固醇血症、纯合子家族性高胆固醇血症或他汀类药物不耐受的治疗选择有限，依洛尤单抗可能是一种有价值的新治疗选择。
目的
这些正在进行的研究旨在调查依洛尤单抗在诊断为纯合子家族性高胆固醇血症（ORION-13）或杂合子家族性高胆固醇血症（ORION-16）的青少年中的疗效、安全性和耐受性。
研究设计
ORION-13 和 ORION-16 均为两部分（1 年双盲依洛尤单抗与安慰剂/1 年开放标签依洛尤单抗）多中心试验，纳入年龄在 12 岁至<18 岁之间诊断为家族性高胆固醇血症的青少年。ORION-13 将纳入约 12 名诊断为纯合子家族性高胆固醇血症的患者，ORION-16 将纳入约 150 名诊断为杂合子家族性高胆固醇血症的患者。主要终点是 LDL-C 从基线到第 330 天的百分比变化。次要疗效和安全性终点包括其他脂质参数和治疗出现的不良事件以及实验室参数和生命体征的变化。探索性终点包括参与者的个体反应以及根据潜在致病突变类型的 LDL-C 变化。
临床试验注册
[临床试验注册编号]https://www.clinicaltrials.gov/。唯一标识符：NCT04659863（ORION-13）和 NCT04652726（ORION-16）。
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