New Approach Combination-Dosed Therapy for Nonalcoholic Steatohepatitis Versus Vitamin E: A Randomized Controlled Trial.

2025-08
Clinical therapeutics 47(8)
- Amr Y Zakaria
- Rehab Badawi
- Hasnaa Osama
- Mona A Abdelrahman
- Asmaa M El-Kalaawy

PubMed: 40480879
DOI: 10.1016/j.clinthera.2025.05.006

Study Design

Type: Randomized Controlled Trial (RCT)
Sample size: n = 45
Population: 90 patients who met the eligibility criteria, with nonalcoholic steatohepatitis (NASH)
Methods: parallel, double-blinded, randomized controlled trial; Group 1: vitamin E 400 IU twice daily for 6 months; Group 2: NAC 1200 mg twice daily plus rosuvastatin 20 mg twice daily for 6 months
Blinding: Double-blind
Duration: 6 months

Purpose

There is currently no US Food and Drug Administration-approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH.

Methods

This study was designed as a parallel, double-blinded, randomized controlled trial. Ninety patients who met the eligibility criteria were enrolled in this study. Subsequently, 45 patients were allocated to each group as follows: group 1 reported consistent administration of vitamin E 400 IU^Ⓡ (PHARCO-Pharmaceuticals) twice daily over a duration of 6 months. Group 2 included patients with NASH who received NAC, Gemacysteine 300 mg^Ⓡ (GEMA-Pharma) at 1200 mg twice daily, along with RSV, Crestor 20 mg^Ⓡ (AstraZeneca). To achieve the study's objective, FibroScan^Ⓡ examination of liver tissue and fibrosis scores, as well as tests for liver aminotransferases, lipid profile, glycemic parameters, and hepatic and renal functions, besides health-related quality of life using the Short-Form 36 were evaluated before and after 6 months of treatment.

Findings

In group 1, a statistically significant decrease in the mean value of steatosis was observed after 6 months by 6.05% (P = 0.017), whereas treated group 2 exhibited a reduction of 16.49% (P = 0.001). Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001). Fibrosis-4 Index score's significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%. MACK-3 score which is a combination of homeostatic model assessment, aspartate aminotransferase, and cytokeratin-18, exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001). Concerning biological markers, malondialdehyde, both groups reported significant reductions in mean values of 11.90% (P = 0.006) and 27.43% (P = 0.001), respectively. Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40%, tumor necrosis factor-α by 9.64%, tissue inhibitor of metalloproteinases 1 by 10.28%, N-terminal propeptide of procollagen type III by 14.58%, cytokeratin-18 by 23.44%, and fibroblast growth factor-21 by 15.08% (P < 0.05), whereas group 1 did not demonstrate significant differences. Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters.

Implications

Patients in group 2 treated with the combination of NAC/RSV exhibited tolerability and efficacy in improving liver steatosis and fibrosis, besides metabolic parameters, indicating a new combination approach to the management of NASH.

Clinicaltrials

gov identifier: NCT06105060.

Research Insights

N-Acetyl Cysteine→Improved Health-related Quality of Life
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Improved Liver Steatosis
treated group 2 exhibited a reduction of 16.49% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Improved Metabolic Parameters
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Cytokeratin-18 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... cytokeratin-18 by 23.44% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Fibroblast Growth Factor-21 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... fibroblast growth factor-21 by 15.08% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Fibrosis-4 Index
Fibrosis-4 Index score's significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%
Effect
Beneficial
Effect size
Large
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Liver Fibrosis
Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced MACK-3 Score
MACK-3 score... exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Malondialdehyde
both groups reported significant reductions in mean values of ... 27.43% (P = 0.001), respectively
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced N-terminal Propeptide of Procollagen Type III Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... N-terminal propeptide of procollagen type III by 14.58% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced NOD-like Receptor-associated Protein 3 Inflammasome Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Tissue Inhibitor of Metalloproteinase 1 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... tissue inhibitor of metalloproteinases 1 by 10.28% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily
N-Acetyl Cysteine→Reduced Tumor Necrosis Factor Alpha
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... tumor necrosis factor-α by 9.64% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily
Vitamin E→Improved Health-related Quality of Life
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Improved Liver Steatosis
treated group 2 exhibited a reduction of 16.49% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Improved Metabolic Parameters
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced Cytokeratin-18 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... cytokeratin-18 by 23.44% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced Fibroblast Growth Factor-21 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... fibroblast growth factor-21 by 15.08% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced Fibrosis-4 Index
Fibrosis-4 Index score's significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%
Effect
Beneficial
Effect size
Large
Dose
1200 mg twice daily
Vitamin E→Reduced Liver Fibrosis
Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced MACK-3 Score
MACK-3 score... exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced Malondialdehyde
both groups reported significant reductions in mean values of ... 27.43% (P = 0.001), respectively
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced N-terminal Propeptide of Procollagen Type III Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... N-terminal propeptide of procollagen type III by 14.58% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily
Vitamin E→Reduced NOD-like Receptor-associated Protein 3 Inflammasome Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40% (P < 0.05)
Effect
Beneficial
Effect size
Moderate
Dose
1200 mg twice daily
Vitamin E→Reduced Tissue Inhibitor of Metalloproteinase 1 Level
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... tissue inhibitor of metalloproteinases 1 by 10.28% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily
Vitamin E→Reduced Tumor Necrosis Factor Alpha
Group 2 exhibited substantial reductions in mean levels of all biological markers: ... tumor necrosis factor-α by 9.64% (P < 0.05)
Effect
Beneficial
Effect size
Small
Dose
1200 mg twice daily

Adverse Events Reported

Vitamin E→Overall tolerability
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters.
Finding
Reported
N-Acetyl Cysteine→Overall tolerability
Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters.
Finding
Reported