Proliverenol Supplementation for Non-Alcoholic Fatty Liver Disease (NAFLD)

Study Overview
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Brief Summary
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This is a 4-arm, prospective, randomized, double-blind, double-dummy, and placebo-controlled clinical study comparing Proliverenol at a dose of 500 mg twice daily; Proliverenol at a dose of 1000 mg once daily; Proliverenol at a dose of 1000 mg twice daily; and Placebo two caplets daily for a 12-week course of therapy. Proliverenol is a bioactive fraction derived from the dried fruit of Phaleria macrocarpa (Scheff.) Boerl (Thymelaeaceae). Proliverenol possesses a hepatoprotective activity via anti-inflammation, DNA repairing, and the antiapoptosis properties. Pre-clinical study of Proliverenol showed that it exerted the hepatoprotective activity through increasing cell survival via: 1) up-regulation of DNA repair enzyme; 2) down-regulation of NF-kB, TNFα and caspase-8 expressions, to prevent ALT leakage in HepG2 cells. Proliverenol repressed ALT expression, which could also be significantly important as possible alternative mechanism for increased blood transaminase activities. Caspase-8 pathway seemed to be involved in the molecular pathway rather than directly inducing mitochondrial damage. Taken together, ethanol induced apoptosis through NF-kB-TNFα-caspase-8 pathway, and Proliverenol protected the cells from the toxicity conditions.

Detailed Description
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There will be 4 groups of treatment; each group will consist of 20 subjects with the treatment regimens for 12 weeks: Treatment I : 1 caplet of Proliverenol 500 mg twice daily Treatment II : 2 caplets of Proliverenol 500 mg once daily Treatment III : 2 caplets of Proliverenol 500 mg twice daily Treatment I : 2 caplets of Placebo daily The eligible subjects will be randomly allocated to receive study medication (Treatment 1 or Treatment 2) for 12 weeks of treatment, in a double blind fashion. They will be asked to come to the clinic every 4-week interval throughout the study period. Subjects will be evaluated for treatment efficacy at baseline and at interval of 4 weeks over the 12-week course of therapy. Throughout the 12-week therapy, subjects should record the product consumption and adverse event occurred during the study in the provided Patient's Diary. The safety profile of study medication other than vital signs and adverse event will be measured at baseline and end of study.

Official Title
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The Effect of Proliverenol Supplementation on Liver Function in Patients With Non-Alcoholic Fatty Liver Disease (NAFLD)

Conditions
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Non-Alcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Drug: Proliverenol
* Drug: Placebo caplets of Proliverenol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Male or female subjects with age of 18 years or older at screening. Diagnosed as NAFLD with liver ultrasonography (USG). Patients with bright liver appearance based on USG, will be followed by CAP examination. Steatosis is defined if CAP >263 dB/m Presence of hepatic impairment, defined as any of serum ALT level > ULN Able to take oral medication. Exclusion Criteria: Suspected positive COVID-19 based on clinical symptoms or SARS-COV-2 antigen test Pregnancy and lactation period. Suspected alcoholic liver disease History of or presence of autoimmune liver diseases Presence of Bilirubin level > 2x ULN Uncontrolled Diabetes Mellitus with HbA1c ≥ 9.0% History or presence of significant/advanced CV, metabolic, acute or chronic infectious diseases, including viral hepatitis (B and C), or malignancy. Suspected cirrhosis as supported by biochemical profile (PLT count, albumin) Presence of severe renal dysfunction Current or regular use of drug-induced hepatotoxicity, such as: such as non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anti-epileptic drugs (e.g. carbamazepines, phenytoin, barbiturates), or anti-tuberculous drugs other than the investigational product Current or regular use of herbal medicines with hepato-protective properties Known or suspected hypersensitivity to the trial product or related products

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1<br>1 caplet of Proliverenol 500 mg twice daily | Drug: Proliverenol<br>* 1 caplet of Proliverenol 500 mg twice daily 2 caplets of Proliverenol 500 mg once daily 2 caplets of Proliverenol 500 mg twice daily<br>|
| Experimental: Treatment 2<br>2 caplets of Proliverenol 500 mg once daily | Drug: Proliverenol<br>* 1 caplet of Proliverenol 500 mg twice daily 2 caplets of Proliverenol 500 mg once daily 2 caplets of Proliverenol 500 mg twice daily<br>|
| Experimental: Treatment 3<br>2 caplets of Proliverenol 500 mg twice daily | Drug: Proliverenol<br>* 1 caplet of Proliverenol 500 mg twice daily 2 caplets of Proliverenol 500 mg once daily 2 caplets of Proliverenol 500 mg twice daily<br>|
| Placebo Comparator: Treatment 4<br>2 caplets of Placebo daily | Drug: Placebo caplets of Proliverenol<br>* 2 caplets of Proliverenol Placebo daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of serum ALT | Changes of serum ALT from baseline to Week 4, 8, and 12 of study treatment | 4, 8, and 12 weeks | 
| Changes of serum AST | Changes of serum AST from baseline to Week 4, 8, and 12 of study treatment | 4, 8, and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| USG examination for Controlled Attenuated Parameter (CAP) | USG examination for Controlled Attenuated Parameter (CAP) measurement will be performed on baseline and week 12 of study treatment | 0 and 12 weeks | 
| USG examination for Transient elastography (TE) | USG examination for Transient elastography (TE) measurement will be performed on baseline and week 12 of study treatment | 0 and 12 weeks | 
| Aspartate transaminase (AST) to alanine transaminase (ALT) ratio | Aspartate transaminase (AST) to alanine transaminase (ALT) ratio at Week 4, 8, and 12 of study treatment | 4, 8, and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, Proliverenol