A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 678354 Administered Subcutaneously to Patients With Hypertriglyceridemia and Established Cardiovascular Disease (CVD) or at a High Risk for CVD
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 114
- 试验地点
- 1
- 主要终点
- Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
研究概览
简要总结
This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- 否
入选标准
- •Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or peripheral artery disease).
- •Fasting serum triglycerides (TG) greater than or equal to (≥) 200 milligrams per deciliter (mg/dL) (≥ 2.3 millimoles per liter (mmol/L)) and less than or equal to (≤) 500 mg/dL (≥ 5.7 mmol/L) at Screening.
- •Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.
- •Must be on standard-of-care preventative therapy for known CVD risk factors.
排除标准
- •Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack (TIA).
- •Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis.
- •Heart failure New York Heart Association (NYHA) class IV.
- •Type 1 diabetes mellitus.
- •Type 2 diabetes mellitus with any of the following:
- •Newly diagnosed within 12 weeks of Screening.
- •Glycated hemoglobin (HbA1c) ≥ 9.0% at Screening.
- •Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new medication within 12 weeks of Screening [with the exception of ± 10 units of insulin].
- •Body Mass Index (BMI) greater than (>) 40 kilograms per square meter (kg/m^2).
研究组 & 干预措施
Pooled Placebo
Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354).
干预措施: Placebo (Drug)
Cohort A: ISIS 678354: 10 mg Q4W
Cohort A participants received 10 milligrams (mg) ISIS 678354, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses.
干预措施: ISIS 678354 (Drug)
Cohort C: ISIS 678354: 15 mg Q2W
Cohort C participants received 15 mg ISIS 678354, SC injection, once every 2 weeks (Q2W) for up to 51 weeks and a maximum of 26 doses.
干预措施: ISIS 678354 (Drug)
Cohort D: ISIS 678354: 10 mg QW
Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses.
干预措施: ISIS 678354 (Drug)
Cohort B: ISIS 678354: 50 mg Q4W
Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.
干预措施: ISIS 678354 (Drug)
结局指标
主要结局
Percent Change From Baseline in Fasting Triglycerides (TG) at the Primary Analysis Time Point
时间窗: Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D)
An analysis of covariance (ANCOVA) model was performed on the log ratio of TG value at the Primary Analysis Time Point to TG value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: (ratio of TG value at the Primary Analysis Time Point to TG value at Baseline - 1) × 100.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: Up to the 13-week post-treatment follow-up period (Up to approximately 15 months)
An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered to be related to the investigational drug product. A TEAE was defined as any AE starting on or after the first dose of the study drug.
次要结局
- Maximum Plasma Concentration (Cmax) of ISIS 678354(Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D))
- Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 150 mg/dL (<= 1.7 Millimoles Per Liter [mmol/L])(Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D))
- Time to Reach Maximum Plasma Concentration (Tmax) of ISIS 678354(Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D))
- Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of ISIS 678354(Predose, 1, 2, 4, 8, 24 hours post the first dose (Day 1), Week 21 (for Cohorts A and B) and Week 25 (for Cohorts C and D))
- Percent Change From Baseline in ApoC-III, TC, LDL-C, HDL-C, Non-HDL-C, VLDL-C, ApoB, and ApoA-I at the Primary Analysis Time Point(Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D))
- Percentage of Participants Who Achieved Fasting Triglycerides (TG) <= 100 mg/dL (<= 1.13 mmol/L)(Baseline and Month 6 (Week 25 for Cohorts A and B and Week 27 for Cohorts C and D))