Evaluation of Choline Chloride Injection Versus Placebo in Adolescents and Adults with Intestinal Failure on Long-Term Parenteral Support

The primary objective of this study is to evaluate the **safety** and pharmacokinetic (PK) parameters of **Choline Chloride for Injection** in patients with **Intestinal Failure**. This is crucial for determining the appropriate dosing and ensuring the treatment's safety profile, which is essential for patients receiving long-term parenteral support. The study aims to demonstrate Choline Chloride as a source of choline at Week 8 and assess its safety compared to a placebo.

Secondary objectives include:

• Assessing changes in liver enzymes, CPK, and homocysteine levels post-treatment.
• Describing QTc interval changes and plasma free choline concentration increases.
• Evaluating anthropomorphic changes and hepatic steatosis alterations.
• Exploring the effect on patient-reported quality of life.

The clinical trial involves a total of **27 participants** diagnosed with **intestinal failure**. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on their condition of receiving long-term parenteral support (PS) due to the inability to maintain adequate nutrition through oral or enteral means. The trial includes individuals who are on a stable regimen of lipid emulsion, dextrose, amino acids, and are receiving vitamin B12 and folic acid supplements. The health status of participants is characterized by their reliance on PS, and they must have been on a stable PS regimen for at least four weeks prior to screening. Females of childbearing potential are required to have a negative urine pregnancy test at screening. The trial population is considered vulnerable due to their medical condition and reliance on PS. Participants have voluntarily provided informed consent, with provisions for legally authorized representatives or guardians to consent for minors or those unable to do so themselves. The study does not specify any particular lifestyle considerations such as diet or physical activity beyond the medical requirements for participation.

The clinical trial is designed to evaluate the **safety** and efficacy of **Choline Chloride for Injection** in adolescents and adults with **intestinal failure** receiving long-term parenteral support. This study is structured as a Phase 2b/3 trial, incorporating a randomized, open-label dose-selection phase followed by a randomized, double-blind, placebo-controlled phase, with an open-label extension. The trial aims to assess pharmacokinetic parameters, safety, and efficacy of both low and high doses of the investigational product compared to a placebo. The trial is expected to commence recruitment on September 3, 2025, and conclude by March 26, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, informed consent, and stable parenteral support. The trial includes multiple follow-up visits to monitor safety and efficacy outcomes, with key assessments at Weeks 1, 8, 24, and 64. The end-of-study visit will finalize data collection and assess long-term outcomes. The expected duration of participant involvement is up to 64 weeks, depending on the cohort and phase of the study.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The primary endpoints include changes in plasma free choline concentrations and the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs). Secondary endpoints focus on biochemical markers, quality of life assessments, and changes in body composition. The investigational product, **Choline Chloride for Injection**, is administered intravenously, with a maximum daily dose of 4 grams and a total dose not exceeding 1680 grams over the treatment period.

The clinical trial involves the administration of **Choline Chloride for Injection**, a **solution for injection** developed by Protara Therapeutics. This investigational medicinal product is administered **intravenously**. The study evaluates two dosing regimens: a low dose and a high dose. The maximum daily dose is set at **4 grams**, with a cumulative maximum dose of **1680 grams** over a treatment period of up to **60 days**. The primary objective is to assess the pharmacokinetic parameters and safety profile of Choline Chloride for Injection in adolescents and adults with intestinal failure who are receiving long-term parenteral support.

The trial also includes a **placebo** group, which receives a placebo designed to match the Choline Chloride for Injection. The placebo is used as a comparator to evaluate the efficacy and safety of the investigational product in a double-blind manner. The placebo does not contain any active pharmaceutical ingredients and is administered in a manner consistent with the investigational product to maintain blinding. The inclusion of a placebo group allows for a rigorous assessment of the treatment's effects by providing a baseline for comparison.

The efficacy of Choline Chloride for Injection in the treatment of **intestinal failure** will be assessed through a series of primary and secondary endpoints across different phases of the clinical trial. The primary endpoints include the evaluation of non-compartmental plasma free choline pharmacokinetic (PK) parameters during Week 1 and Week 8 visits, and the changes in these PK parameters from Baseline to Week 8. Additionally, the change from Baseline in time-matched plasma free choline concentrations at Week 8 will be measured. The incidence and severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) will also be monitored as part of the safety assessment.

Secondary endpoints will focus on various biochemical and physiological parameters. These include changes from Baseline to Week 8 in levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), very-low-density lipoprotein (VLDL), total bilirubin, direct bilirubin, creatine phosphokinase (CPK), homocysteine, and albumin. Triplicate QTc measurements will be collected during Week 1 and Week 8, with changes from pre-infusion QTc at Week 1 to all post-baseline timepoints being analyzed. The percentage of participants achieving and maintaining plasma free choline concentration Cmax ≥ 9.5 nmol/mL at Week 8 will be recorded, along with changes in height, weight, and body mass index (BMI). The assessment of steatosis and fibrosis will be conducted using MRI-PDFF and MRE/ELF tests, respectively, to determine any improvements or lack of worsening from Baseline to Week 24. Quality of Life will be evaluated using the Chronic Liver Disease Questionnaire (CLDQ) and Patient Global Impression of Change (PGIC) at specified timepoints.