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临床试验/NCT03851705
NCT03851705已完成3 期

A Two-Part (Double-Blind Placebo Controlled/Open-Label) Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in Subjects With Homozygous Familial Hypercholesterolemia (Hofh) (ORION-5)

Novartis Pharmaceuticals13 个研究点 分布在 8 个国家目标入组 56 人开始时间: 2019年2月6日最近更新:
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适应症
干预措施

试验速览

阶段
3 期
状态
已完成
入组人数
56
试验地点
13
主要终点
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This study was a Phase III,A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH).

详细描述

This study had two sequential parts:

  • Part 1: 6-month double-blind period in which subjects were randomized to receive either inclisiran or placebo
  • Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 were transitioned to inclisiran at Day 180 and all subjects who participated in an open-label follow-up period of inclisiran only

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Parallel
主要目的
Treatment
盲法
Double (Participant, Investigator)

盲法说明

Double-blind

入排标准

年龄范围
18 Years 至 80 Years（Adult, Older Adult）
性别
All
接受健康志愿者
是

入选标准

  • •Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents
  • •Stable on a low-fat diet.
  • •Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse events.
  • •Subjects not receiving statins must have documented evidence of intolerance to at least two different statins.
  • •Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.
  • •Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L).
  • •Triglyceride concentration <400 mg/dL (4.5 mmol/L)
  • •No current or planned renal dialysis or renal transplantation
  • •Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the apheresis during the study, if needed.
  • •Subjects must be willing and able to give written informed consent before initiation of any study-related procedures. The subject should be willing to comply with all required study procedures.
  • •Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

排除标准

  • •Use of Mipomersen or Lomitapide therapy within 5 months of screening
  • •Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9
  • •New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%
  • •Major adverse cardiovascular event within 3 months prior to randomization
  • •Planned cardiac surgery or revascularization
  • •Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy
  • •Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >3x ULN, or total bilirubin >2x upper limit of normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart
  • •Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than the duration of the trial
  • •History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or commencement of systemic therapy as treatment during the 3 years prior to randomization
  • •Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one acceptable effective method of contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long- term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion:
  • •Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND more than 55 years of age
  • •Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of enrolment
  • •Women who are surgically sterilized at least 3 months prior to enrolment
  • •Known history of alcohol and/or drug abuse within 5 years
  • •Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
  • •Subjects who are unable to communicate or to cooperate with the investigator.
  • •Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)
  • •Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study)
  • •Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study
  • •Persons directly involved in the conduct of the study
  • •Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study
  • •Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the Investigator, might interfere with the interpretation of clinical study results
  • •Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer
  • •Previous participation in the study
  • •Hypersensitivity to any of the ingredients of Inclisiran
  • •The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

研究组 & 干预措施

Part 1 - Placebo

Placebo Comparator

Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90.

干预措施: Placebo (Drug)

Part 1 - Placebo

Placebo Comparator

Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90.

干预措施: Placebos (Drug)

Part 1 - Inclisiran

Experimental

Participants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90.

干预措施: Inclisiran Sodium for injection (Drug)

Part 2 - Inclisiran

Experimental

Participants who received a dose of 300 mg inclisiran sodium for injection administered by SC injection on Day 270, Day 450 and Day 630. In addition, participants who were assigned to the placebo arm in Part 1 will receive a dose of 300 mg inclisiran sodium administered by SC injection on Day 180 after completion of Part 1.

干预措施: Inclisiran Sodium for injection (Drug)

结局指标

主要结局

Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150

时间窗: Baseline, Day 150

Percentage Change in LDL-C levels from Baseline to Day 150

次要结局

  • Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150(Baseline, Day 150)
  • Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Proportional Responsiveness: Part 1(Days 150, 180)
  • Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Individual Responsiveness of Subjects: Part 2(Days 330, 510, 690 and 720)
  • Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150 and 180)
  • Percent Change in Total Cholesterol From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Percent Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Apolipoprotein B (Apo B) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • LDL-C Reduction ≥20% or ≥30% From Baseline: Part 1(Baseline, Days 90, 150, 180)
  • Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Very-Low-Density-Lipoprotein Cholesterol Levels (VLDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Apolipoprotein A-1 (Apo-A1) mg/dL From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 270, 330, 450, 510, 630, 690, and 720)
  • Individual Responsiveness of Subjects: Part 1(Days 150, 180)
  • Percent Change in Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Total Cholesterol From Baseline to Day 150(Baseline, Day 150)
  • Absolute Change in Apolipoprotein B (apoB) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Absolute Change in Non-HDL Cholesterol (Non-HDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Proportional Responsiveness of Subjects: Part 2(Days 330, 510, 690 and 720)
  • Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in Very-Low-Density-Lipoprotein Cholesterol Levels (VLDL-C) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Percent Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2(Baseline, Days 330, 510 ,690, 720)
  • Proportion of Subjects With ≥30% LDL-C Reduction of From Baseline at Day 150(Baseline, Day 150)
  • LDL-C Reduction ≥20% or ≥30% From Baseline: Part 2(Baseline, Days 330, 510, 690, and 720)
  • Percent Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Absolute Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1(Baseline, Days 90, 150, 180)
  • Percent Change in Apo-B From Baseline to Day 150(Baseline, Day 150)
  • Absolute Change Apolipoprotein A-1 (Apo-A1) From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 720(Baseline, Days 330, 450, 510, 630, 690, and 720)
  • Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 720: Part 2(Baseline, Days 330, 510, 690, 720)
  • Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Subsequent Visits up to Day 180(Baseline, Days 90, 150, 180)
  • Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) From Baseline to Subsequent Visits up to Day 180: Part 1(Baseline, Days 90, 150, 180)
  • Percent Change in Non-HDL-C From Baseline to Day 150(Baseline, Day 150)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (13)

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