Study of Choline Chloride for Injection in Adolescent and Adult Patients With Intestinal Failure Receiving Long Term Parenteral Support

Official title

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

Overview

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.

Interventions

• Drug Choline Chloride for Injection
  Intravenous use
• Drug Placebo
  Intravenous use

Primary outcome measures

• Open-Label Dose-Selection Phase: PK of plasma free choline (Cmax) during Week 1 and Week 8 Visits [Time frame: Week 1 to Week 8]
• Open-Label Dose-Selection Phase: Open-Label Dose-Selection Phase: PK of plasma free choline (Tmax) during Week 1 and Week 8 Visits [Time frame: Week 1 to Week 8]
• Open-Label Dose-Selection Phase: PK of plasma free choline (AUC(0-TAU)) during Week 1 and Week 8 Visits [Time frame: Week 1 to Week 8]
• Open-Label Dose-Selection Phase: Change from Baseline in plasma free choline concentrations at Week 8 [Time frame: 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 [Time frame: Week 1 to Week 64]
• 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 [Time frame: Week 1 to Week 8]
• 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 [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: Week 8 to Week 64]

Secondary outcome measures (12)

• 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Week 1 to Week 8]
• Open-Label Dose-Selection Phase: Change from Baseline to Week 8 in height, weight and BMI [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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) [Time frame: Week 1 to Week 24]
• Double-Blind, Placebo-Controlled Phase: Change from Baseline to Week 8 and Week 24 in height, weight and BMI [Time frame: 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 [Time frame: Week 1 to Week 24]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• Patients taking steatogenic medications for ≥ 12 weeks in the past 12 months; those taking any medicine that could affect the measurement of hepatic steatosis within 12 weeks prior to study entry
• 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
• Fulminant liver failure, with active bleeding and/or encephalopathy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 7 centers

• University of Colorado School of Medicine — Aurora
• Floridian Clinical Research — Miami Lakes
• Nebraska Medicine — Omaha
• Columbia University Medical Center/ New York Presbyterian Hospital — New York
• Duke Clinic - Abdominal Transplant Research Office — Durham
• Cleveland Clinic — Cleveland
• Pinnacle Clinical Research- San Antonio — San Antonio

France · 3 centers

• Beaujon Hospital - APHP — Clichy
• Rennes University Hospital Center - Pontchaillou Site — Rennes
• CHRU Nancy - Barbois Hospital — Vandœuvre-lès-Nancy

Denmark · 2 centers

• Aalborg University Hospital, Department of Medical Gastroenterology — Aalborg
• Rigshospitalet - University Hospital Copenhagen — Copenhagen

Germany · 2 centers

• Charite - University Hospital Berlin — Berlin
• University Duisburg-Essen, University Hospital Essen — Essen

Poland · 2 centers

• M. Pirogow Provincial Specialized Hospital in Lodz, Nutritional Treatment Center — Lodz
• Czerniakowski Hospital Sp. z o.o. (LCC) — Warsaw

Belgium · 1 center

• University Hospitals Leuven, Campus Gasthuisberg — Leuven

Identifiers

NCT: NCT06910943 · TARA-001-301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗