An Early Phase 1 interventional study of Antituberculosis drugs Group in Drug-Induced Acute Liver Injury and Tuberculosis (TB), sponsored by Assiut University. Not yet recruiting at 1 site in Egypt. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-21.
Sponsored by Assiut University · Early Phase 1, Interventional, and Prevention
Worldwide, tuberculosis (TB) infection caused by Mycobacterium Tuberculosis, remains one of the top 10 deadly diseases having a significant socioeconomic burden in the world, especially in developing countries. According to global estimates, the latest global TB report indicates that in 2022, roughly 1.3 million individuals died from TB.
The WHO estimated the TB incidence in Egypt in 2019 is 12,000 per 100,000 population. Although Between 1990 and 2019, TB incidence in Egypt declined from 35 to 12 per 100,000 population, while TB mortality declined from 3.5 to 0.43 per 100,000 population. This burden is still a matter of concern, particularly in light of the fact that 66% of TB cases occur among the socially and economically productive age groups of 15-54 years.
TB is a preventable and curable disease, bout 85% of people who develop TB disease can be successfully treated. Anti-tuberculosis chemotherapy is the primary treatment for tuberculosis with first-line drugs, including isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), are commonly used. The WHO recommends (2HRZE/4HR regimen) as a treatment option.
However, Anti-tuberculosis Chemotherapy has serious problems such as disease relapse, the emergence of resistance to drugs and drug-induced liver injury which is a major toxicity of anti-TB treatment.
Among the patients receiving the combination treatment, ATDILI is the most prevalent within the first two months of treatment, which occurs in 4.8% to as high as 36% of patients. Half of ATDILI occurs within 2 weeks of treatment initiation.
Several studies have been conducted in animal models to show the beneficial hepatoprotective effect of some drugs and herbal medicine to prevent and reduce hepatotoxicity from antituberculosis drugs, from these drugs (silymarin and N-acetylcysteine).
It has been proposed that hepatoprotective actions of silymarin may result from the scavenging of free radicals and inhibition of lipid peroxidation, leading to faster recovery after injury.
N-acetylcysteine (NAC) is an antioxidant which exerts its hepato-protective effect by replenishing glutathione stores and enhancing the cellular antioxidant defense mechanism. NAC has been previously studied and used for many years in the treatment of paracetamol-induced hepatotoxicity, with good evidence of efficacy and safety, also was found to be beneficial in non-paracetamol induced acute liver failure. It was demonstrated that the mortality was reduced to 28% using NAC compared to 53% using a placebo.
both silymarin and N-acetylcysteine have been investigated as hepatoprotective agents, but there are relatively few direct head-to-head comparisons in patients receiving anti-TB therapy. Despite the results of animal studies showing the protective effect of silymarin against ATDILI, RCT addressing this issue are limited with inconclusive results. Unfortunately, there are no comprehensive scientific reports on NAC hepato-protective effect on ATDILI.
As there is a lack of randomized controlled trials from Egypt comparing silymarin or N-acetylcysteine for the prevention of Anti-tuberculosis drug-induced liver injury, highlighting the need for locally generated evidence.
Therefore, this study is designed to evaluate the preventive effect of silymarin against the development of ATDH in new TB cases on a standard anti TB drug regimen, also evaluating the effects of NAC on TB treatment.
Worldwide, tuberculosis (TB) infection caused by Mycobacterium Tuberculosis, remains one of the top 10 deadly diseases having a significant socioeconomic burden in the world, especially in developing countries. According to global estimates, the latest global TB report indicates that in 2022, roughly 1.3 million individuals died from TB.
The WHO estimated the TB incidence in Egypt in 2019 is 12,000 per 100,000 population. Although Between 1990 and 2019, TB incidence in Egypt declined from 35 to 12 per 100,000 population, while TB mortality declined from 3.5 to 0.43 per 100,000 population. Also, TB treatment covered about 69% in 2019 while treatment success rate was 86%, this burden is still a matter of concern, particularly in light of the fact that 66% of TB cases occur among the socially and economically productive age groups of 15-54 years (National TB control guidelines 2022) TB is a preventable and curable disease, bout 85% of people who develop TB disease can be successfully treated. Anti-tuberculosis chemotherapy is the primary treatment for tuberculosis with first-line drugs, including isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), are commonly used. The WHO recommends 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) follow by 4 months of isoniazid (H) and rifampicin (R) (2HRZE/4HR regimen) as a treatment option.
However, Anti-tuberculosis Chemotherapy has serious problems such as disease relapse, the emergence of resistance to drugs and drug-induced liver injury which is a major toxicity of anti-TB treatment.
Anti tuberculosis-drug induced liver injury (ATDILI) varies from asymptomatic elevation of liver enzymes to fulminant hepatic failure leading to increased morbidity and mortality, treatment withdrawal, drug interruption, and dose reduction.
Data indicated that among hospitalized patients with ATDILI 20.1% experience severe liver injury, with a mortality rate of 34.5% due to liver failure.
Among the patients receiving the combination treatment, ATDILI is the most prevalent within the first two months of treatment, which occurs in 4.8% to as high as 36% of patients. Half of ATDILI occurs within 2 weeks and nearly 90% within 8 weeks of treatment initiation.
The exact mechanism of ATDILI is still unknown. Drug-induced liver injury from isoniazid and pyrazinamide (may share similar mechanisms, i.e. through the pathways of escalating oxidative stress and increased oxygen free radical regeneration.
Several studies have been conducted in animal models to show the beneficial hepatoprotective effect of some drugs and herbal medicine to prevent and reduce hepatotoxicity from anti tuberculosis drugs, from these drugs (silymarin and N-acetylcysteine).
Silymarin is a standardized extract of the milk thistle seeds (the plant Silybum marianum) has been used as a hepatoprotective supplement for over 2000 years, The main components of silymarin which all are derivatives of flavonols comprise silybin, isosilybin silydianin and silychrisin.
It has been proposed that hepatoprotective actions of silymarin may result from the scavenging of free radicals and inhibition of lipid peroxidation, leading to faster recovery after injury.
N-acetylcysteine (NAC) is an antioxidant which exerts its hepato-protective effect by replenishing glutathione stores and enhancing the cellular antioxidant defense mechanism. It is well established that by augmenting cellular antioxidative defense system, especially by increasing glutathione (GSH), cells can be protected against oxidative stress induced injuries produced by various drugs and chemicals.
NAC has been previously studied and used for many years in the treatment of paracetamol-induced hepatotoxicity, with good evidence of efficacy and safety, also was found to be beneficial in non-paracetamol induced acute liver failure. It was demonstrated that the mortality was reduced to 28% using NAC compared to 53% using a placebo.
A prospective, randomized clinical trials, double blinded study conducted in India evaluated the prophylactic effect of NAC in patients receiving anti-tuberculosis treatment by evaluating the LFT parameters (AST, ALT, ALP and bilirubin), oxidative stress biomarkers (NO and GSH) and Quality of life (QOL) scores. The study demonstrated that patients receiving NAC had significally lower ALT and bilirubin at 2, 4 and 8 weeks compared with baseline, signifying its hepatoprotective effect. In addition, NAC improved oxidative stress biomarkers by enhancing antioxidant status, which was associated with better nutritional status and quality of life. No serious adverse events were reported, supporting the safety and tolerability of NAC in patients receiving anti-TB treatment.
both silymarin and N-acetylcysteine have been investigated as hepatoprotective agents, but there are relatively few direct head-to-head comparisons in patients receiving anti-TB therapy. Despite the results of animal studies showing the protective effect of silymarin against ATDILI, RCT addressing this issue are limited with inconclusive results. Unfortunately, there are no comprehensive scientific reports on NAC hepato-protective effect on ATDILI.
As there is a lack of randomized controlled trials from Egypt comparing silymarin or N-acetylcysteine for the prevention of Anti-tuberculosis drug-induced liver injury, highlighting the need for locally generated evidence.
Therefore, this study is designed to evaluate the preventive effect of silymarin against the development of ATDH in new TB cases on a standard anti TB drug regimen, also evaluating the effects of NAC on TB treatment.
78 studies on the registry are indexed under Chemical and Drug Induced Liver Injury; 22 are open to participants now.
This study's planned enrollment of 102 is above the median of 80 across 39 interventional studies indexed under Chemical and Drug Induced Liver Injury.
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Exclusion Criteria:
Patients taking standard anti tuberculous drugs only.
Drug: Antituberculosis drugs Group
Patients taking standard anti tuberculous drugs with silymarin (140 mg 3 times daily) starting concurrently from first day of treatment till the end of 2nd month.
Drug: Antituberculosis drugs Group
patients taking anti-tuberculous drugs with N-acetylcysteine (600 mg twice daily) starting concurrently from first day of treatment till the end of 2nd month.
Drug: Antituberculosis drugs Group
As there is a lack of randomized controlled trials from Egypt comparing silymarin or N-acetylcysteine for the prevention of Anti-tuberculosis drug-induced liver injury, highlighting the need for locally generated evidence. Therefore, this study is designed to evaluate the preventive effect of silymarin against the development of ATDH in new TB cases on a standard anti TB drug regimen, also evaluating the effects of NAC on TB treatment. so It compare placebo, Silymarin and N-acetylcysteine protective effect in one study
primary outcome will be assessment of the incidence of developing ATDILI.
ATDILI was defined based on Guidelines for diagnosis and management of drug-induced liver injury caused by anti-tuberculosis drugs, established by Chinese Medical Association Tuberculosis Branch 2024 which include meeting at least one of the following criteria: (i) Alanine aminotransferase (ALT) and/or AST levels ≥5 times the upper limit of normal (ULN) (ii) Alkaline phosphatase (ALP) ≥2 × ULN (iii) Alanine aminotransferase (ALT) and/or AST levels ≥3 times the upper limit of normal (ULN) and simultaneous elevation of bilirubin concentration exceeding 2× ULN.
Time frame: 2 years
Secondary outcomes will be assessment of severity of ATDILI
severity of ATDILI which will be graded according to the modified 4-point scale proposed by an International DILI Expert working group: Mild: Alt \>5xULN or ALP \> 2xULN and TB \< 2xULN. Moderate Alt \>5xULN or ALP \> 2xULN and TB \> 2xULN. Severe: Alt \>5xULN or ALP \> 2xULN and TB \> 2xULN and at least one of the following: (i) hepatic failure (INR\>1.5, ascites, encephalopathy); (ii) other organ failure due to DILI. Fetal: patient dies or undergo liver transplantation of DILI.
Time frame: 2 years
Plan to share: No
Start is estimated for Oct 2026; primary completion for Oct 2028, 24 months later.
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