Clinical trial NCT06105060: Clinical Effects of New Approach on Patients With Non-alcoholic Steatohepatitis
Official title: Clinical and Biochemical Study of the Effects of Rosuvastatin, Vitamin E, and N-Acetyl Cysteine on Patients With Non-alcoholic Steatohepatitis: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Non-alcoholic Steatohepatitis
Keywords: Rosuvastain
N-Acetyl Cysteine
Vitamine E
NASH
Fibroscan
Lead sponsor: Beni-Suef University
Sponsor class: OTHER
First posted: 2023-10-27
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will be randomized controlled, parallel and prospective 6-months duration study. Accepted patients will be randomized into 4 groups. The size of the sample is calculated using open EPI software (www.openepi.com) and according to NASH prevalence in Egypt.
Primary purpose: TREATMENT

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 \&#34;two hits\&#34; 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\&#39;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.

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.

Primary outcomes:
measure: Blood pressure
timeFrame: 6 months
measure: Hight
timeFrame: 6 months
measure: Weight
timeFrame: 6 months
measure: Waist circumference
timeFrame: 6 months
measure: Body mass index (BMI)
timeFrame: 6 months
measure: Clinical examination
timeFrame: 6 months
measure: FibroScan-AST (FAST Score):
timeFrame: 6 months
measure: Liver Fibrosis Index FIB-4 score (FIB-4 score):
timeFrame: 6 months
measure: Fasting blood glucose level
timeFrame: 6 months
measure: Homeostasis Model Assessment (HOMA-IR),
timeFrame: 6 months
measure: Kidney function tests:
timeFrame: 6 months
measure: Lipid profile:
timeFrame: 6 months
measure: Liver function tests:
timeFrame: 6 months
measure: Serum Malondialdehyde (MDA) level (nM):
timeFrame: 6 months
measure: The NOD-like receptor family protein 3 (ng /ml)
timeFrame: 6 months
measure: Serum cytokeratin-18 (U/L)
timeFrame: 6 months
Secondary outcomes:
measure: Adverse effects of the intervening drugs
timeFrame: 6 months
Other outcomes:
Locations:
city: Tanta
country: Egypt
facility: Tanta university hospital
state: Gharbyia
Study officials:
affiliation: Beni-Suef University
name: Asmaa Mohammed Hussein, Assis.Prof
role: STUDY_CHAIR
affiliation: Beni-Suef University
name: Mona Ahmed Emam, Lecturer
role: STUDY_DIRECTOR
affiliation: Beni-Suef University
name: Hasnaa Osama Hamed, Lecturer
role: STUDY_DIRECTOR
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