Clinical trial NCT06293378: Safety and Effectiveness of Sulfasalazine in the Treatment of Liver Fibrosis/Cirrhosis.
Official title: Safety and Effectiveness of Sulfasalazine in the Treatment of Liver Fibrosis/Cirrhosis.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cirrhosis, Liver
Fibrosis, Liver
Lead sponsor: The Second Affiliated Hospital of Chongqing Medical University
Sponsor class: OTHER
First posted: 2024-03-05
Enrollment: 330
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a controlled, observational clinical study initiated by investigators to investigate the efficacy and safety of sulfasalazine in the treatment of cirrhosis in patients with cirrhosis. Four cohorts were planned: primary biliary cirrhosis, hepatitis B and C cirrhosis, and alcoholic cirrhosis. The four groups were divided into experimental group and control group, and the experimental group: each group of patients was orally treated sulfasalazine for 12 months, taken three times a day, each time taking 0.5g. The control group did not take sulfasalazine. After 12 months, Observe changes in patients' biochemical and imaging indicators, liver stiffness values, fecal microbiota, and metabolites before and after the use of sulfasalazine.

Detailed description: This study is a controlled and observational clinical study initiated by the investigators to study the efficacy and safety of sulfasalazine in the treatment of cirrhosis in patients with cirrhosis, and to observe changes in patients' biochemical and imaging indicators, liver stiffness values, fecal microbiota, and metabolites before and after the use of sulfasalazine.

Four cohorts were planned to be included in this study:

Cohort A: Differences in cirrhosis changes with the addition of sulfasalazine to UDCA in PBC patients with an inadequate response to UDCA and treatment-naïve PBC patients.

Cohort B: Differences in changes in cirrhosis in patients with viral hepatitis B cirrhosis compared with the addition of sulfasalazine to antiviral (if possible, the same antiviral) therapy.

Cohort C: Differences in changes in cirrhosis in patients with viral hepatitis C cirrhosis compared with the addition of sulfasalazine to antiviral (if possible, the same antiviral) therapy.

Cohort D: Differences in differences in changes in cirrhosis compared with sulfasalazine in patients with alcoholic hepatitis cirrhosis.

Treatment options:

1. Patients with PBC who did not respond adequately to UDCA: 30 patients with poor response to treated PBC continued to take UDCA, 30 patients with poor response to treated PBC received UDCA+SASP (0.5 g orally three times daily), and 30 patients with poor response received SASP (0.5 g orally three times daily) for 12 months and were followed up for 12 months.

   Treatment-naïve PBC patients: 30 treatment-naïve PBC patients took UDCA, and 30 treatment-naïve PBC patients took UDCA+SASP (0.5 g orally three times a day) for 12 months and followed up for 12 months.
2. Treatment group of hepatitis B (hepatitis C) viral liver cirrhosis: 60 patients with hepatitis B (hepatitis C) viral cirrhosis were collected (using the same dose of antiviral drugs), 30 patients with hepatitis B (hepatitis C) viral cirrhosis took antiviral drugs, and 30 patients with hepatitis B (hepatitis C) virus cirrhosis were treated with sulfasalazine (0.5g three times a day) on the basis of taking antiviral drugs, and follow-up observation was observed for 12 months.
3. Treatment group of alcoholic hepatitis cirrhosis: 60 patients with alcoholic cirrhosis were collected, 30 patients with alcoholic cirrhosis did not take antifibrotic drugs, 30 cases of alcoholic cirrhosis took sulfasalazine (0.5g three times a day), and follow-up observation was observed for 12 months.

Eligibility criteria: Inclusion Criteria:

1. Sign the informed consent form before the trial and be able to complete the study in accordance with the requirements of the trial protocol;
2. The age is 18\~70 years old (including boundary value), the weight of male subjects is not less than 45 kg, and the weight of female subjects is not less than 40 kg. Body mass index (BMI) in the range of 18\~32kg/m2 (including critical value);
3. Enrolled patients also need to meet:

A:Patients with PBC cirrhosis PBC patients who have been treated and show an inadequate response to UDCA：(1) according to the biochemical response criteria for 2021 PBC, Enrolled patients need to meet the criteria of ALP ≥1.67 × ULN as a poor biochemical response to UDCA after 12 months of UDCA treatment; (2) meeting the diagnostic criteria for primary cholangitis (PBC) , i.e. meeting at least two of the following criteria: 1.indicators of cholestasis such as elevated Alkaline phosphatase; 2.Anti-mitochondrial antibody AMA or AMA-m2 positive, or if AMA negative, PBC-specific antibodies (anti-GP210 Andor anti-SP100) positive .3 liver biopsy consistent with PBC; Patients with newly diagnosed primary cholangitis (PBC-RRB- met the diagnostic criteria of at least two of the following): 1.indicators of cholestasis such as elevated Alkaline phosphatase; 2.Anti-mitochondrial antibody AMA or AMA-m2 positive, or if AMA negative, PBC-specific antibodies (anti-GP210 Andor anti-SP100) positive 3. liver biopsy consistent with PBC; B:Patients with hepatitis B cirrhosis Diagnosis of hepatitis B cirrhosis based on clinical history, histology or imaging.

C:Patients with hepatitis C cirrhosis Diagnosis of hepatitis C cirrhosis based on clinical history, histology or imaging.

D:Alcoholic hepatitis cirrhosis Diagnosis of alcoholic cirrhosis based on clinical history, histology, or imaging.

Exclusion Criteria:

1. Those who have a history of allergies in the past, or the investigator suspects that they are allergic to the active ingredients of the drug or their excipients under study;
2. Allergy to sulfasalazine and its metabolites, sulfonamides or salicylic acid;
3. Patients with intestinal obstruction or urinary tract obstruction;
4. Patients with porphyria, such as sulfonamides, have been reported to cause acute attacks.
5. Acute and chronic liver disease with clinical significance caused by infections other than HBV, HCV, PBC, and alcoholic liver disease;
6. Primary liver cancer; alpha-fetoprotein (AFP) greater than 50 ug/L or imaging suggests malignant liver mass; Those with other malignancies or a history of other malignancies in the 5 years prior to screening (except for complete remission of malignant tumors after treatment and no additional medical or surgical intervention within 3 years prior to screening);
7. The investigator judged that there is impaired gastrointestinal function or gastrointestinal diseases that may affect the absorption of oral drugs, such as severe gastric ulcer, erosive gastritis, partial gastrectomy, and persistent \>Grade 2 gastrointestinal symptoms (e.g., nausea, vomiting, or diarrhoea);
8. Serious diseases of circulatory, respiratory, urinary, blood, metabolic, immune, psychiatric, neurological, renal and other systems;
9. Those who have had major trauma or undergone major surgery within 3 months before screening; or those who plan to undergo surgery during the study;
10. Donated blood or lost blood ≥ 400mL within 3 months before screening, or received blood transfusion; or ≥ blood donation or blood loss within 1 month prior to screening 200mL；
11. Those who are positive for AIDS antigen/antibody, positive for Treponema pallidum antibody and positive RPR test;
12. History of drug dependence or drug abuse within 1 year prior to screening;
13. Participate in clinical trials of other investigational drugs or medical devices within 3 months before screening, and take experimental drugs or use them Those who have medical devices;
14. Those who have a positive pregnancy test during lactation or screening, or who have fertility requirements in the past two years;
15. Subjects who the investigator believes have other factors that are not suitable to participate in this trial.

Primary outcomes:
measure: Hepatic fibrosis
timeFrame: baseline，1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum alkaline phosphatase (ALP)
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum γ-glutamyl transpeptidase (GGT)
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum bilirubin
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum bile acids
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum aspartate aminotransferase(AST)
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
measure: Serum alanine aminotransferase (ALT)
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
Secondary outcomes:
measure: The gut microbiota and metabolites.
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
Other outcomes:
measure: Changes in immune cells
timeFrame: baseline,1,3,6,9,12 months after treatment and 1 month after the end of treatment.
Locations:
city: Chongqing
country: China
facility: Chongqing Medical University
state: Chongqing
city: Chongqing
country: China
facility: Chongqing
state: Chongqing
Study officials:
affiliation: The Second Affiliated Hospital of Chongqing Medical University
name: Mingli Peng, Doctor
role: STUDY_CHAIR
affiliation: Doctor
name: Yinghua Lan, Doctor
role: STUDY_CHAIR
References:
citation: Gulamhusein AF, Hirschfield GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol. 2020 Feb;17(2):93-110. doi: 10.1038/s41575-019-0226-7. Epub 2019 Dec 9.
citation: Lv T, Chen S, Li M, Zhang D, Kong Y, Jia J. Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2021 Jun;36(6):1423-1434. doi: 10.1111/jgh.15329. Epub 2020 Dec 6.
citation: Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases. Hepatology. 2022 Apr;75(4):1012-1013. doi: 10.1002/hep.32117. Epub 2021 Dec 20. No abstract available.