A Phase 2b/3 Randomized Open-Label Dose-Selection Study With Open-Label Extension and Randomized Double-Blind, Placebo-Controlled Study With Open-Label Extension to Evaluate the Safety and Efficacy of Choline Chloride for Injection (Low Dose and High Dose) Versus Placebo in Adolescents and Adults With Intestinal Failure Receiving Long-Term Parenteral Support
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 129
- 试验地点
- 32
- 主要终点
- Open-Label Dose-Selection Phase: PK of plasma free choline (Cmax) during Week 1 and Week 8 Visits
研究概览
简要总结
TARA-001-301 is a Phase 2b/3 randomized Open-Label Dose-Selection study with an Open-Label Extension and randomized Double-Blind, Placebo-Controlled Study with Open-Label Extension to investigate the safety and efficacy of Choline Chloride for Injection (Low Dose and High Dose) versus Placebo in adolescents (ages 12 to < 18 years of age) and adults (≥ 18 years of age) with intestinal failure receiving long-term PS when oral or enteral nutrition is not possible, insufficient, or contraindicated.
Participants will be enrolled in one of 2 parts, each part will be followed by an open-label extension period of approximately a year.
Part 1: Open-Label Dose-Selection Phase Part 2: Double-Blind, Placebo-Controlled Phase
The purpose of the Open-Label Dose-Selection Phase is to evaluate the safety, tolerability, how Choline Chloride for Injection (study drug) is distributed in the body, and to select 2 of 3 doses for testing in the Double-Blind, Placebo-Controlled Phase.
The purpose of the Double-Blind, Placebo-Controlled Phase is to assess the safety of the study drug and how well the study drug works at the 2 selected dose levels.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The Open-Label Dose-Selection Phase will be open label, and the Double-Blind, Placebo-Controlled Phase will be double blind. The Open Label Extension Phase will be open label.
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female 12 years of age or older at the time of signing the informed consent
- •Individuals who have voluntarily given written informed consent after the nature of the study has been explained according to applicable requirements, prior to study entry
- •Individuals with intestinal failure receiving long-term PS when oral or enteral nutrition is not possible, insufficient, or contraindicated who are receiving stable PS at time of screening and for the duration of the study; Note: Long-Term PS = Participant must have been receiving PS for at least 6 months prior to screening and requiring PS at least 3 times per week
- •Females of childbearing potential must have a negative urine pregnancy test at screening
排除标准
- •Participants taking steatogenic medications or any medicine that could affect the measurement of hepatic steatosis within 12 weeks prior to signing consent
- •Evidence of systemic active infection at the time of dosing
- •Participants intending to take non-study drug choline supplements or choline-containing multivitamins during the course of the study
- •Participants unwilling to limit alcohol intake to no more than 20/g a day for 24 hours prior to their screening visit and for the duration of the study
- •Active malignancy (excluding basal cell skin tumor, low or very low risk prostate cancer, cervical carcinoma in situ and local resected cervical cancer)
- •Clinically significant renal disease
- •Low B12 or low serum folic acid levels that are less than the normal range
- •Participants with severe hepatic impairment, defined as Child-Turcotte-Pugh (CTP) Class C (score ≥10) at screening.
研究组 & 干预措施
Open-Label, Dose-Selection: Dose 2
干预措施: Choline Chloride for Injection (Drug)
Open-Label, Dose-Selection: Dose 3
干预措施: Choline Chloride for Injection (Drug)
Double-Blind, Placebo-Controlled: High Dose
干预措施: Choline Chloride for Injection (Drug)
Open-Label, Dose-Selection: Dose 1
干预措施: Choline Chloride for Injection (Drug)
Double-Blind, Placebo-Controlled: Low Dose
干预措施: Choline Chloride for Injection (Drug)
Double-Blind, Placebo-Controlled: Placebo
干预措施: Placebo (Drug)
Open Label Extension: High Dose
干预措施: Choline Chloride for Injection (Drug)
Open Label Extension: Low Dose
干预措施: Choline Chloride for Injection (Drug)
结局指标
主要结局
Open-Label Dose-Selection Phase: PK of plasma free choline (Cmax) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
Cmax = maximum concentration
Open-Label Dose-Selection Phase: Open-Label Dose-Selection Phase: PK of plasma free choline (Tmax) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
Tmax = time of maximum concentration
Open-Label Dose-Selection Phase: PK of plasma free choline (AUC(0-TAU)) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
AUC = area under the curve, AUC(0-TAU) = AUC at end of dosing
Open-Label Dose-Selection Phase: Change from Baseline in plasma free choline concentrations at Week 8
时间窗: Week 1 to Week 8
Open-Label Dose-Selection Phase: PK of plasma free choline (Cmax) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
Cmax = maximum concentration
Open-Label Dose-Selection Phase: Open-Label Dose-Selection Phase: PK of plasma free choline (Tmax) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
Tmax = time of maximum concentration
Open-Label Dose-Selection Phase: PK of plasma free choline (AUC(0-TAU)) during Week 1 and Week 8 Visits
时间窗: Week 1 to Week 8
AUC = area under the curve, AUC(0-TAU) = AUC at end of dosing
Open-Label Dose-Selection Phase: Change from Baseline in plasma free choline concentrations at Week 8
时间窗: Week 1 to Week 8
Open-Label Dose-Selection Phase and Double-Blind, Placebo-Controlled Phase, Open-Label Extension Phase: Incidence and severity of TEAEs Incidence of TESAEs
时间窗: Week 1 to Week 64
TEAE = treatment emergent adverse event, TESAE = treatment emergent serious adverse event
Double-Blind, Placebo-Controlled Phase: Change from Baseline in peak plasma free choline concentrations (Cmax) at Week 8 in participants receiving Choline Chloride for Injection versus Placebo
时间窗: Week 1 to Week 8
Tmax = time of maximum concentration
Open-Label Extension Phase: Participants from Open-Label Dose-Selection Phase: Percentage of participants with plasma free choline concentrations of ≥ 9.5 nmol/mL at Week 64
时间窗: Week 64
Open-Label Extension Phase: Percentage of participants maintaining plasma free choline concentrations of ≥ 9.5 nmol/mL at Week 8 and Week 64 (ie, both timepoints)
时间窗: Week 8 to Week 64
Open-Label Extension Phase: Participants from Double-Blind, Placebo-Controlled Phase: % with plasma free choline concentrations of ≥9.5 nmol/mL at Week 64
时间窗: Week 1 to Week 64
Open-Label Extension Phase: Participants from Double-Blind Placebo-Controlled Phase: % maintaining plasma free choline concentrations of ≥ 9.5 nmol/mL at Week 8, Week 24 and Week 64 for participants who previously received Choline Chloride for Injection
时间窗: Week 8 to Week 64
次要结局
- Open-Label Dose-Selection Phase: Change from Baseline to Week 8 in ALP, AST, ALT, GGT, VLDL, total bilirubin, direct bilirubin levels, CPK, homocysteine and albumin levels(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Triplicate QTc measurements collected during Week 1 and Week 8, and changes from pre-infusion QTc at Week 1 to all post-baseline timepoints(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants achieving plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants maintaining plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Change from Baseline to Week 8 in height, weight and BMI(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants with no worsening of steatosis from Baseline to Week 8 as measured by MRI-PDFF(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants with any improvement of steatosis from Baseline to Week 8 as measured by MRI-PDFF(Week 1 to Week 8)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants achieving plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants maintaining plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8 and Week 24 (ie, through Week 24)(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Change from Baseline to Week 8 and Week 24 in height, weight and BMI(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Change from Baseline to Week 8 and Week 24 in ALP, AST, ALT, GGT, VLDL, total bilirubin, direct bilirubin levels, CPK, homocysteine and albumin levels(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with no worsening of steatosis from Baseline to Week 24 as measured by MRI-PDFF(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with any improvement of steatosis from Baseline on MRI-PDFF at Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with no worsening in fibrosis grade from Baseline to Week 24, as measured by MRE and ELF test(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement in fibrosis grade from Baseline to Week 24, as measured by MRE and ELF test(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement of steatosis from Baseline on MRI-PDFF with improvement of ALP from Baseline to Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement of steatosis from Baseline on MRI-PDFF with improvement of ALT or AST from Baseline to Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Assessment of Quality of Life based on CLDQ at Baseline and Week 24(Week 1 to Week 24)
- Open-Label Dose-Selection Phase: Change from Baseline to Week 8 in ALP, AST, ALT, GGT, VLDL, total bilirubin, direct bilirubin levels, CPK, homocysteine and albumin levels(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Triplicate QTc measurements collected during Week 1 and Week 8, and changes from pre-infusion QTc at Week 1 to all post-baseline timepoints(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants achieving plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants maintaining plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Change from Baseline to Week 8 in height, weight and BMI(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants with no worsening of steatosis from Baseline to Week 8 as measured by MRI-PDFF(Week 1 to Week 8)
- Open-Label Dose-Selection Phase: Percentage of participants with any improvement of steatosis from Baseline to Week 8 as measured by MRI-PDFF(Week 1 to Week 8)
- Double-Blind, Placebo-Controlled Phase: Change from Baseline and Week 8 in peak plasma free choline concentrations (Cmax) at Week 24 in participants receiving Choline Chloride for Injection versus Placebo(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants achieving plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8(Week 1 to Week 8)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants maintaining plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8 and Week 24 (ie, through Week 24)(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Change from Baseline to Week 8 and Week 24 in height, weight and BMI(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Change from Baseline to Week 8 and Week 24 in ALP, AST, ALT, GGT, VLDL, total bilirubin, direct bilirubin levels, CPK, homocysteine and albumin levels(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with no worsening of steatosis from Baseline to Week 24 as measured by MRI-PDFF(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with any improvement of steatosis from Baseline on MRI-PDFF at Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with no worsening in fibrosis grade from Baseline to Week 24, as measured by MRE and ELF test(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement in fibrosis grade from Baseline to Week 24, as measured by MRE and ELF test(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement of steatosis from Baseline on MRI-PDFF with improvement of ALP from Baseline to Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Percentage of participants with improvement of steatosis from Baseline on MRI-PDFF with improvement of ALT or AST from Baseline to Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Assessment of Quality of Life based on CLDQ at Baseline and Week 24(Week 1 to Week 24)
- Double-Blind, Placebo-Controlled Phase: Assessment of Quality of Life based on PGIS at Baseline and PGIC at Week 24(Week 1 to Week 24)
- Open-Label Extension Phase: Participants from Open-Label Dose-Selection Phase: Change from Baseline (Week 1) to Week 64 in ALP, AST, ALT, GGT, VLDL, total bilirubin, direct bilirubin levels, CPK, homocysteine and albumin levels(Week 1 to Week 64)
- Open-Label Extension Phase: Double-Blind, Placebo-Controlled Phase: Change from W1 to W64 in Choline Chloride for Injection group, and change from W24 to W64 in Placebo group in ALP, AST, ALT, GGT, VLDL, TBIL, DBil levels, CPK, homocysteine and albumin(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Open-Label Dose-Selection Phase Change from Baseline (Week 1) to Week 64 in height, weight and BMI(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Double-Blind, Placebo-Controlled Phase: Change from W1 to W64 for participants in Choline Chloride for Injection group, and change from W24 to W64 for participants in Placebo group in height, weight and BMI(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Open-Label Dose-Selection Phase: Percentage of participants with no worsening of steatosis as measured by MRI-PDFF from Baseline (Week 1) to Week 64(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Open-Label Dose-Selection Phase: Percentage of participants with improvement of steatosis as measured by MRI-PDFF from Baseline (Week 1) to Week 64(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Double-Blind, Placebo-Controlled Phase: % of participants with no worsening of steatosis measured by MRI-PDFF from W1 to W64 in Choline Chloride for Injection group, and from W24 to W64 in Placebo group(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Double-Blind, Placebo-Controlled Phase: % of participants with improvement of steatosis measured by MRI-PDFF from W1 to W64 in Choline Chloride for Injection group, and from W24 to W64 in Placebo group(Week 1 to Week 64)
- Open-Label Extension Phase: Double-Blind, Placebo-Controlled Phase: % of participants with no worsening in fibrosis grade measured by MRE and ELF test from W1 to W64 in Choline Chloride for Injection group, and from W24 to W64 in Placebo group(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Double-Blind, Placebo-Controlled Phase: % of participants with improvement in fibrosis measured by MRE and ELF test from W1 to W64 in Choline Chloride for Injection group, and W24 to W64 in Placebo group(Week 1 to Week 64)
- Open-Label Extension Phase: Participants from Double-Blind Placebo-Controlled Phase: Assessment of QOL based on CLDQ at Week 64(Week 64)
- Open-Label Extension Phase: Participants from Double-Blind Placebo-Controlled Phase: Assessment of QOL based on PGIC at Week 64(Week 64)