Clinical Effects of New Approach on Patients With Non-alcoholic Steatohepatitis

NCT ID: NCT06105060

Last Updated: 2025-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 175 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-12-17
• Study Completion Date: 2024-06-27

Brief Summary

This study aims to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

The primary endpoint of this 6-month study would be an improved degree of fibrosis with no worsening of NASH or NASH resolution with no worsening of fibrosis and steatosis that the study considered successful if either 1ry endpoint is met.

The secondary endpoint of this study is the improvement of biochemical markers related to steatosis, inflammation, oxidative stress, insulin resistance, and liver fibrosis.

Detailed Description

Nonalcoholic fatty liver disease (NAFLD) is the buildup of excessive fat in the liver without of extensive alcohol consumption and the lack of any secondary cause. The prevalence of NAFLD has risen dramatically, now affecting 20-40% of the population. NAFLD is one of the most frequent chronic liver diseases currently attributed to the rising rates of obesity and type 2 diabetes. The condition can proceed from simple steatosis to nonalcoholic steatohepatitis (NASH), characterized by hepatic damage with inflammatory infiltration, and then on to liver fibrosis, cirrhosis, and hepatocellular cancer. Currently, there is no approved drug for NASH. Consequently adjustments to lifestyle remain the mainstay of treatment despite the considerable disease burden and mortality associated predominantly with advanced diseases, i.e., NASH and fibrosis. Regarding the development of NAFLD, Despite widespread consensus on the "two hits" hypothesis linking insulin resistance (IR) and oxidative stress, the mechanism of NAFLD was thought to be highly nuanced and unexplained.

The free, un-esterified form of cholesterol appears toxic to hepatocytes, leading to inflammation and fibrosis in the liver. In particular, the steatotic liver cells form crown-like structures due to the accumulation of cholesterol crystals within the hepatocytes, which triggers an inflammatory response via activated Kupffer cells surrounding the hepatocytes. In addition, cholesterol crystals stimulate the inflammasome in Kupffer cells by activating the Nucleotide-binding oligomerization domain (NOD), leucine-rich repeats (LRR), and pyrin domain-containing protein 3 (NLRP3).

Herein, drugs known as statins block the enzyme 3-hydroxy-3-methyglutaryl coenzyme A reductase. Statins are effective medications for decreasing cholesterol and lowering the risk of cardiovascular events. Because NAFLD is characterized by free cholesterol aggregation in hepatocytes, their ability to reduce cholesterol levels is thought to be helpful. Statins also reduce the production of isoprenoids, which are byproducts of the mevalonate pathway. Isoprenoids modulate the intracellular signalling of many receptors regulating liver inflammation and fibrosis by prenylating/activating small guanosine triphosphate (GTP)ases. The significant anti-inflammatory and anti-fibrotic benefits were shown in an experimental model of NAFLD and NASH after statin-related suppression of this isoprenoid dependent mechanism.

Rosuvastatin showed promising results in enhancing liver-specific outcomes of NAFLD in preliminary investigations. Six individuals without diabetes and hypertension who were dyslipidemic and had metabolic syndrome and biopsy-proven NASH had treated with rosuvastatin 10 mg/day. After 12 months, a second biopsy and liver ultrasonography revealed that all symptoms associated with NASH (steatosis, necroinflammation, and fibrosis) had disappeared in 5 of 6 individuals. Rosuvastatin was additionally associated to a 76% and 61% decrease in ALT and AST activity, respectively. Another small prospective study with 23 NAFLD patients with dyslipidemia, rosuvastatin 10mg/day yielded similar results.

Recently, oxidative stress is characterized by an imbalance between the production and elimination of free radical species, is a hallmark of metabolic syndrome. Numerous studies have established a connection between elevated oxidative stress indicators and the development of NAFLD. Although oxidative stress is a major factor in how the liver functions in NAFLD, inflammation has also been shown to have a significant role.

Interleukin (IL)-6, tumor necrosis factor alpha (TNF-), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), and transforming growth factor beta (TGF )-1 are pro-inflammatory mediators that, when elevated for an extended period of time, accelerate NASH and liver fibrosis.

The pharmaceutical therapies with strong antioxidant characteristics, such as N-acetyl cysteine (NAC), are crucial in reducing oxidative stress and inflammation caused by metabolic dysfunction. Its efficacy in restoring glutathione (GSH) levels in hepatocytes and decreasing pro-inflammatory cytokines has been demonstrated in animal models of nonalcoholic fatty liver disease. In a comprehensive analysis of literature published in 2015, it has been hypothesized that NAC can reduce oxidative stress and inflammation in the liver, hence enhancing its functional capacity. Since then, a plethora of studies have been published looking at NAC's effectiveness in reducing metabolic syndrome symptoms.

Vitamin E is the most abundant lipid-soluble chain-breaking antioxidant in the human body. Vitamin E family compounds are anti-atherogenic, anti-inflammatory and being powerful antioxidants.The American Association for the Study of Liver Diseases (AASLD) and the National Institute for Health and Care Excellence (NICE) recommend 800 IU of vitamin E daily for persons with biopsy-proven NASH.

NAFLD is a worldwide epidemic expected to be the leading cause of chronic liver disease in the next decade. Patients with NASH have high risk to develop liver complications such as cirrhosis, cancer, hepatic failure, morbidity and mortality. While numerous drugs have undergone clinical testing, most have shown inconsistent outcomes and have poorly tolerated side effects. Currently, there is no FDA-approved medication for the treatment of NASH. Consequently, exerting great effort is to find specific treatment for patients with NASH.

Conditions

Non-alcoholic Steatohepatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Group 1 (Rosuvastatin group):

40 patients will receive Crestor (Rosuvastatin 20mg/day orally for 6 months).

Group Type: ACTIVE_COMPARATOR

Rosuvastatin 20mg

Intervention Type: DRUG

to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

Group 2 (N-acetyl cysteine group (NAC):

40 patients will receive high dose of NATURAL TRUTH'S NAC cap 2400 mg /day for 6 months.

Group Type: ACTIVE_COMPARATOR

Rosuvastatin 20mg

Intervention Type: DRUG

to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

Group 3 Two separate drugs ("N-acetyl cysteine" and "Rosuvastatin group"):

40 patients will receive "NAC dose 2400 mg" and "Rosuvastatin 20mg /day" for 6 months.

Group Type: ACTIVE_COMPARATOR

Rosuvastatin 20mg

Intervention Type: DRUG

to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

Group 4 (Control group):

40 patients will receive Vitamin E 400 mg twice daily for 6 months.

Group Type: PLACEBO_COMPARATOR

Rosuvastatin 20mg

Intervention Type: DRUG

to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

Interventions

Rosuvastatin 20mg

to evaluate and compare the protective outcomes of using Rosuvastatin, Vitamin E, and N-acetyl cysteine in Egyptian patients with NASH.

Intervention Type: DRUG

Other Intervention Names

N-acetyl cysteine; Vitamin E

Eligibility Criteria

Inclusion Criteria

• All patients are diagnosed to have fatty liver grading 1, 2 or 3 on abdominal ultrasound with Hepatic steatosis index > 36 to be considered as a NAFLD patient.
• NASH diagnosis using Fibroscan detecting the degree of steatosis and fibrosis.
• NASH diagnosis is by non-invasive Scoring such as (FAST Score) Cytokeratin-18 >240 U/L Mild to moderate elevation of hepatic liver enzymes: serum aminotransferases (>2 but <5 times upper normal limit)
• Stable dietary habits and physical activity pattern.

Exclusion Criteria

• Current or history of significant alcohol consumption.
• Use of drugs historically associated with nonalcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins).
• Prior or planned bariatric surgery.
• Uncontrolled diabetes defined as Hemoglobin A1c 9.5% or higher.
• Evidence of other forms of chronic liver disease as Hepatitis B, Hepatitis C, Wilson's disease, Alpha-1-antitrypsin(A1AT) deficiency, Hemochromatosis, drug-induced liver disease.
• The presence of contra-indications of NAC or rosuvastatin.
• Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial and breast feeding.
• Use of other drugs known to have possible positive effects on steatosis.
• If there are any conditions where fibroscan could be contra-indicated. The patients refuse participating or completing study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beni-Suef University

OTHER

Sponsor Role: lead

Responsible Party

Amr Yahia Zakaria Abu Hamza

Assistant Lecturer of Clinical Pharmacy (pharmacy practice department)Faculty of Pharmacy

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Asmaa Mohammed Hussein, Assis.Prof

Role: STUDY_CHAIR

Beni-Suef University

Mona Ahmed Emam, Lecturer

Role: STUDY_DIRECTOR

Beni-Suef University

Hasnaa Osama Hamed, Lecturer

Role: STUDY_DIRECTOR

Beni-Suef University

Locations

Tanta university hospital

Tanta, Gharbyia, Egypt

Countries

Egypt

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Other Identifiers

Comparative study of NASH

Identifier Type: -

Identifier Source: org_study_id