A Randomized, Double-Blind, Placebo-Controlled, With an Open Label Extension, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Patients With Familial Partial Lipodystrophy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 52 weeks in a randomized treatment (RT) period in participants with familial partial lipodystrophy (FPL). Following the randomized treatment period, participants who did not enter the open-label extension (OLE) period went straight to the 13-week post-treatment (PT) follow-up period and participants who were entered in the OLE period continued to receive volanesorsen for another 52 weeks (Weeks 53 to 104). Following the Week 104 visit of the OLE period, participants had an option of continued dosing for up to an additional 52 weeks (Week 105 to 156). Participants who did not enter the OLE period went straight to a 13-week post-treatment follow-up period. Following the Week 104 OLE period, participants were entered a 13-week post-treatment follow-up period, if they did not choose the option for continued dosing.
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, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must give written informed consent to participate in the study (signed and dated) and any authorizations required by law.
- •Clinical diagnosis of familial partial lipodystrophy (FPL) plus diagnosis of type 2 diabetes mellitus, hypertriglyceridemia, and fatty liver.
- •Diagnosis of FPL is based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination and low skinfold thickness in anterior thigh by caliper measurement: men (less than or equal to [≤] 10 millimeters [mm]) and women (≤ 22 mm), and at least 1 of the following:
- •Genetic diagnosis of FPL OR
- •Family history of FPL or of similar abnormal fat distribution plus 1 Minor Criteria OR
- •In the absence of FPL-associated genetic variant or family history, 2 Minor Criteria and body mass index (BMI) less than (<) 35 kilogram per meter square (kg/m^2).
- •Diabetes not well controlled on antidiabetic therapy with glycated hemoglobin (Hb) HbA1c more than or equal to (≥) 7 percentage (%) to ≤ 12% at Screening.
- •Hypertriglyceridemia with fasting triglycerides (TG) levels greater than or equal to (≥) 500 milligrams per deciliter (mg/dL) (≥ 5.7 millimoles per liter [mmol/L]) at Screening and Qualification visit, or Fasting TG levels ≥ 200 (≥ 2.26 mmol/L) at both Screening and Qualification Visits for participants who meet the genetic or family history criteria.
- •Presence of hepatosteatosis (fatty liver), as evidenced by a screening magnetic resonance imaging (MRI) indicating a hepatic fat fraction (HFF) ≥ 6.4%.
排除标准
- •A diagnosis of generalized lipodystrophy.
- •A diagnosis of acquired partial lipodystrophy.
- •Acute pancreatitis within 4 weeks of Screening.
- •History within 6 months of Screening of acute or unstable cardiac condition.
- •Low-density lipoprotein cholesterol (LDL-C) more than (>) 130 mg/dL on maximal tolerated statin therapy.
- •Platelet count < lower limit of normal (LLN).
- •Treatment with metreleptin within the last 3 months prior to Screening.
研究组 & 干预措施
Placebo/Volanesorsen
Randomized Period: Volanesorsen-matching placebo as SC, QW for Weeks 1-52. Participants who received volanesorsen-matching placebo in RT period and not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed.
OLE Period: Participants who received volanesorsen-matching placebo in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Weeks 105-156). Participants not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE.
干预措施: volanesorsen (Drug)
Placebo/Volanesorsen
Randomized Period: Volanesorsen-matching placebo as SC, QW for Weeks 1-52. Participants who received volanesorsen-matching placebo in RT period and not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed.
OLE Period: Participants who received volanesorsen-matching placebo in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Weeks 105-156). Participants not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE.
干预措施: Placebo (Drug)
Volanesorsen
Randomized Period: 300 mg of volanesorsen as SC, QW for Weeks 1-52. Participants who received 300 mg of volanesorsen in RT period and did not enter in OLE period went straight to 13-week PT follow-up period. Dose adjustment based on monitoring rules were allowed.
OLE Period: Participants who received volanesorsen in RT period and completed RT period, were to receive 300 mg of volanesorsen as SC QW for 52 weeks (Weeks 53-104) in OLE period. Dose adjustment based on monitoring rules were allowed. After Week 104, participants had option of continuing treatment with 300 mg of volanesorsen as SC injection for up to additional 52 weeks (Week 105-156). Participants who were not entered in option for additional 52 weeks of dosing in OLE PT period went straight to 13-week PT follow-up period after completion of first 52 weeks (Weeks 53-104) of OLE. Participants entered in OLE PT period went straight to 13-week PT follow-up period after completion of Week 156 of OLE.
干预措施: volanesorsen (Drug)
结局指标
主要结局
Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG)
时间窗: Baseline to Month 3
Baseline was defined as the average of Day 1 predose fasting assessment and the last fasting measurement prior to Day 1 predose fasting assessment. Month 3 value was defined as the average of Week 12 and Week 13 fasting TG assessments of the randomized treatment period. The data was analyzed using an analysis of covariance (ANCOVA) model with the randomization stratification factor (diagnosis of disease with or without genetics and family history) and treatment group as factors and log-transformed baseline fasting TG as a covariate.
次要结局
- Randomized Treatment Period: Change From Baseline in Hemoglobin A1c (HbA1c)(Baseline, Months 3, 6, 9, and 12)
- Randomized Treatment Period: Percentage of Participants Who Achieved Greater Than or Equal to (≥) 40% Reduction in Fasting Triglyceride and ≥ 30% Reduction of Hepatic Fat Fraction at Month 6(Month 6)
- Randomized Treatment Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using Magnetic Resonance Imaging (MRI)(Baseline, Months 6 and 12)
- Open Label Extension Period: Patient-Reported Pain(From the first dose of study drug in open label extension period up to Week 117)
- Open Label Extension Period: Patient-Reported Hunger(From the first dose of study drug in open label extension period up to Week 117)
- Open-Label Extension Period: Percent Change From Baseline in Hepatic Steatosis as Assessed by Hepatic Fat Fraction Using MRI(Baseline, Months 6 and 12)
- Randomized Treatment Period: Patient-Reported Hunger(From the first dose of study drug up to Week 52)
- Randomized Treatment Period: Change From Baseline in Mean Short Form-36 (SF-36) Weighted Sum of Scores(Baseline, Weeks 13, 26 and 52)
- Open Label Extension Period: Change From Baseline in HbA1c(Baseline, Months 3, 6, 9, and 12)
- Randomized Treatment Period: Change From Baseline in Disease Burden Score(From the first dose of study drug to Week 52)
- Open-Label Extension Period: Change From Baseline in Disease Burden Score(From the first dose of study drug in open label extension period to Week 117)
- Randomized Treatment Period: Patient-Reported Pain(From the first dose of study drug up to Week 52)
- Open-Label Extension Period: Change From Baseline in Mean SF-36 Weighted Sum of Scores(Baseline, Weeks 65, 78 and 104)
- Randomized Treatment Period: Change From Baseline in Mean EQ-5D: Index Scores and Visual Analog Scale (VAS)(Baseline, Weeks 13, 26 and 52)
- Open-Label Extension Period: Change From Baseline in Mean EQ-5D: Index and Visual Analog Scale (VAS) Scores(Baseline, Weeks 65, 78 and 104)