ADVANCE: A Phase III Multi-Centre, Randomised, Double-Blind, Double-Dummy Clinical Trial Comparing Essentiale® Liquid vs. Capsules for MASLD/MASH, Alcoholic Liver Disease, and Chronic Viral Hepatitis B

The primary objective of this study is to demonstrate clinical non-inferiority of Essentiale® EPL liquid 1800 mg administered on top of standard of care compared to Essentiale® EPL oral capsule on top of standard of care. This comparison is clinically relevant for establishing therapeutic equivalence between different formulations of essential phospholipids in the management of chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, alcoholic liver disease, and chronic viral hepatitis B.

The secondary objectives include: • Evaluation of key individual symptoms in participants receiving Essentiale® EPL liquid 1800 mg compared to those receiving Essentiale® EPL oral capsule or placebo, all administered on top of standard of care. • Assessment of quality of life in participants receiving Essentiale® EPL liquid 1800 mg compared to those receiving Essentiale® EPL oral capsule or placebo, all administered on top of standard of care. • Assessment of the safety profile of Essentiale® EPL liquid 1800 mg compared to Essentiale® EPL oral capsule and placebo, all administered on top of standard of care.

The sponsor does not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of **adult participants** aged **18 to 70 years**, inclusive, of both **male** and **female** gender. Participants are individuals diagnosed with at least one of the following **chronic liver diseases**: **Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)** or **Metabolic Dysfunction-Associated Steatohepatitis (MASH)**, **Alcoholic Liver Disease (ALD)**, or **Chronic Viral Hepatitis B**. All participants present with specific symptoms including **energy loss (asthenia)**, feeling depressed, **abdominal pain** or discomfort, **fatigue**, sleeping disorder, appetite loss, and **nausea**, as assessed by a Global Overall Symptom score of 3 or higher at baseline. The trial population was selected based on physician diagnosis and the presence of pre-existing liver disease, with all participants receiving standard care for their condition. Relevant lifestyle considerations include participants' willingness to abstain from alcohol consumption and undergo alcohol withdrawal programs if they have a history of alcoholism, as well as their commitment to implement diet control and exercise programs as required. The study includes a vulnerable population and requires participants to demonstrate the ability to take oral therapy and comply with trial procedures throughout the study duration.

This is a Phase III, multi-centre, randomized, double-blind, double-dummy clinical trial designed to compare the efficacy and safety of Essentiale liquid formulation versus capsule formulation in patients with chronic liver diseases. The trial will evaluate participants diagnosed with **metabolic dysfunction-associated steatotic liver disease** (MASLD), **metabolic dysfunction-associated steatohepatitis** (MASH), **alcoholic liver disease**, or **chronic viral hepatitis B**. The study employs a non-inferiority design to demonstrate that the liquid formulation of **phosphatidylcholine** (1800 mg daily) administered on top of standard of care is clinically equivalent to the capsule formulation on top of standard of care.

The trial involves the use of investigational medicinal products including NC0304 Phosphatidylcholine oral liquid containing **de-oiled enriched phospholipids from soya-beans**, Essentiale Forte 300 mg hard capsules containing phosphatidyl choline, and matching placebos for both formulations. The test placebo is an oily liquid in stick packs designed to match the appearance, taste, smell, and mouthfeel of the test product, while the comparator placebo consists of hard capsules visually identical to the marketed capsule formulation. All investigational products are administered via the **oral route**. The maximum daily dose is 1800 mg, with a maximum total dose of 156,600 mg over the treatment period of 87 days.

Eligible participants include adults aged 18 to 70 years who present with symptoms such as **asthenia**, feeling depressed, **abdominal pain** or discomfort, **fatigue**, sleeping disorder, appetite loss, and **nausea**, assessed by a Global Overall Symptom score of 3 or higher at baseline. Participants must have a physician-confirmed diagnosis of one of the specified chronic liver diseases based on existing medical records or history. All participants must be receiving standard care for their pre-existing liver condition and must be willing to abstain from alcohol consumption, undergo alcohol withdrawal programmes if applicable, and implement diet control and exercise programmes as required. Women of childbearing potential must use at least one highly effective contraceptive method throughout the study and for 30 days after the last dose, while male participants with partners of childbearing potential must use condoms in addition to their partner's use of a highly effective contraceptive method during the study and for 30 days after the last dose.

The primary endpoint of the trial is the change in overall symptoms evaluation using the Global Overall Symptom score. Secondary endpoints include changes in key individual symptoms using the GOS scale, change in Chronic Liver Disease Questionnaire global score, and the incidence and severity of treatment-emergent adverse events. The trial is estimated to commence recruitment in February 2026 and is expected to conclude by October 2026. The duration of participant involvement is 87 days of active treatment. Participants may be withdrawn from the study early if they fail to comply with trial procedures, experience unacceptable adverse events, withdraw consent, or at the discretion of the investigator for safety or protocol compliance reasons.

The experimental treatment consists of NC0304 Phosphatidylcholine, an oral liquid formulation containing de-oiled enriched phospholipids from soya-beans as the active substance. The product is administered via the oral route at a maximum daily dose of 1800 mg. The maximum total dose administered over the treatment period is 156600 mg, with a maximum treatment duration of 87 days. This investigational medicinal product is provided in stick packs containing 1.8 g of oily liquid and is administered on top of standard-of-care therapy.

The comparator treatment is Essentiale Forte 300 mg, presented as hard capsules containing phosphatidyl choline as the active substance. This marketed formulation is administered orally at a maximum daily dose of 1800 mg, with a maximum total dose of 156600 mg over a maximum treatment period of 87 days. The comparator product consists of bulk capsules repackaged in equivalent blister foil and is administered on top of standard-of-care therapy.

A test placebo is utilized to maintain blinding for the experimental treatment. This placebo is formulated as an oily liquid in stick packs containing 1.8 g, designed to match the test product in appearance, taste, smell, and mouthfeel. The placebo has a different qualitative and quantitative composition from the experimental product but is packaged in identical primary packaging to ensure non-differentiation between active and placebo treatments.

A comparator placebo is employed to maintain blinding for the comparator treatment. This standard placebo is formulated as hard capsules with a different qualitative and quantitative composition from the marketed Essentiale 300 mg capsules, but with an identical appearance to ensure proper blinding in this double-blind, double-dummy clinical trial design.

Efficacy will be assessed through the evaluation of overall symptoms and quality of life measures in participants with chronic liver disease. The primary endpoint is the change in overall symptoms using the Global Overall Symptom (GOS) score, which evaluates symptoms including energy loss (asthenia), feeling depressed, abdominal pain or discomfort, fatigue, sleeping disorder, appetite loss, and nausea. Secondary efficacy endpoints include changes in key individual symptoms using the GOS scale, change in CLDQ global score (Chronic Liver Disease Questionnaire), and the incidence and severity of treatment-emergent adverse events. The treatment period extends for 87 days, during which efficacy parameters will be measured and analyzed to demonstrate clinical non-inferiority of the investigational liquid formulation compared to the capsule formulation, both administered on top of standard of care.