Safety and Effectiveness of Sulfasalazine in the Treatment of Liver Fibrosis/Cirrhosis.

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, changes in fecal flora and metabolites before and after the use of sulfasalazine were observed.

Study Overview

• Status: Recruiting
• Conditions: Fibrosis, Liver; Cirrhosis, Liver
• Intervention / Treatment: Drug: Sulfasalazine enteric-coated tablets

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 the changes of fecal flora and metabolites before and after sulfasalazine use.

Three cohorts were planned to be included in this study:

Cohort A: Differences in cirrhosis changes in the addition of sulfasalazine to UDCA in patients with PBC.

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.

• Study Type: Interventional
• Enrollment (Estimated): 330
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mingli Peng, Doctor; Phone Number: +8613512362906; Email: Peng_mingli@hospital.cqmu.edu.cn
• Study Contact Backup: Name: Yinghua Lan, Doctor; Phone Number: +8613796050629; Email: lan_yinghua@163.com

Study Locations

• China
  • Chongqing
    • Chongqing, Chongqing, China, 400000
      • Recruiting
      • Chongqing Medical University
      • Contact: Mingli Peng, Doctor; Phone Number: +8613512362906; Email: Peng_mingli@hospital.cqmu.edu.cn
      • Contact: Yinghua Lan, Doctor; Phone Number: +8613796050629
    • Chongqing, Chongqing, China, 400000
      • Recruiting
      • Chongqing
      • Contact: Yinghua Lan, Doctor; Phone Number: +8613796050629
      • Contact: Mingli Peng, Doctor; Phone Number: 13512362906; Email: peng_mingli@hospital.cqmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

(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 for UDCA; (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:Diagnosis of hepatitis B (C) cirrhosis based on clinical history, histology or imaging.

Alcoholic hepatitis cirrhosis C: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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A：Patients with PBC were treated with sulfasalazine; Sulfasalazine enteric-coated tablets, 0.25 g/tablet, 2 tablets (0.5 g) each time, three times each time, were taken orally for 12 months.	Drug: Sulfasalazine enteric-coated tablets; 1. Cohort A: PBC treatment group: (1) PBC patients with poor response to UDCA after treatment: 30 patients continued to take UDCA（13-15mg/kg）, 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day), 30 patients took SASP (0.5g orally three times a day) for 12 months, and 12 months of follow-up observation. (2) Newly treated PBC patients: 30 patients took UDCA（13-15mg/kg） and 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day) for 12 months and were followed up for 12 months. 2. Cohort B-D: 60 cases were collected from each group, 30 cases continued the current treatment(people with hepatitis B cirrhosis and hepatitis C cirrhosis continue to take antivirals), and 30 patients were taking sulfasalazine for 12 months of follow-up observation. After 12 months of treatment, at the time of enrollment and the 1st/2nd/3rd/6th/9th/12 months, the liver function, fecal flora, liver fibrosis and immune related indexes were detected。
Experimental: Cohort B：Patients with HBV were treated with sulfasalazine; Sulfasalazine enteric-coated tablets, 0.25 g/tablet, 2 tablets (0.5 g) each time, three times each time, were taken orally for 12 months.	Drug: Sulfasalazine enteric-coated tablets; 1. Cohort A: PBC treatment group: (1) PBC patients with poor response to UDCA after treatment: 30 patients continued to take UDCA（13-15mg/kg）, 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day), 30 patients took SASP (0.5g orally three times a day) for 12 months, and 12 months of follow-up observation. (2) Newly treated PBC patients: 30 patients took UDCA（13-15mg/kg） and 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day) for 12 months and were followed up for 12 months. 2. Cohort B-D: 60 cases were collected from each group, 30 cases continued the current treatment(people with hepatitis B cirrhosis and hepatitis C cirrhosis continue to take antivirals), and 30 patients were taking sulfasalazine for 12 months of follow-up observation. After 12 months of treatment, at the time of enrollment and the 1st/2nd/3rd/6th/9th/12 months, the liver function, fecal flora, liver fibrosis and immune related indexes were detected。
Experimental: Cohort C：Patients with HCV were treated with sulfasalazine; Sulfasalazine enteric-coated tablets, 0.25 g/tablet, 2 tablets (0.5 g) each time, three times each time, were taken orally for 12 months.	Drug: Sulfasalazine enteric-coated tablets; 1. Cohort A: PBC treatment group: (1) PBC patients with poor response to UDCA after treatment: 30 patients continued to take UDCA（13-15mg/kg）, 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day), 30 patients took SASP (0.5g orally three times a day) for 12 months, and 12 months of follow-up observation. (2) Newly treated PBC patients: 30 patients took UDCA（13-15mg/kg） and 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day) for 12 months and were followed up for 12 months. 2. Cohort B-D: 60 cases were collected from each group, 30 cases continued the current treatment(people with hepatitis B cirrhosis and hepatitis C cirrhosis continue to take antivirals), and 30 patients were taking sulfasalazine for 12 months of follow-up observation. After 12 months of treatment, at the time of enrollment and the 1st/2nd/3rd/6th/9th/12 months, the liver function, fecal flora, liver fibrosis and immune related indexes were detected。
Experimental: Cohort D：Patients with alcoholic liver fibrosis/cirrhosis were treated with sulfasalazine; Sulfasalazine enteric-coated tablets, 0.25 g/tablet, 2 tablets (0.5 g) each time, three times each time, were taken orally for 12 months.	Drug: Sulfasalazine enteric-coated tablets; 1. Cohort A: PBC treatment group: (1) PBC patients with poor response to UDCA after treatment: 30 patients continued to take UDCA（13-15mg/kg）, 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day), 30 patients took SASP (0.5g orally three times a day) for 12 months, and 12 months of follow-up observation. (2) Newly treated PBC patients: 30 patients took UDCA（13-15mg/kg） and 30 patients took UDCA（13-15mg/kg）+SASP (0.5g orally three times a day) for 12 months and were followed up for 12 months. 2. Cohort B-D: 60 cases were collected from each group, 30 cases continued the current treatment(people with hepatitis B cirrhosis and hepatitis C cirrhosis continue to take antivirals), and 30 patients were taking sulfasalazine for 12 months of follow-up observation. After 12 months of treatment, at the time of enrollment and the 1st/2nd/3rd/6th/9th/12 months, the liver function, fecal flora, liver fibrosis and immune related indexes were detected。

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum alkaline phosphatase (ALP)	Serum alkaline phosphatase (ALP) level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.
Serum γ-glutamyl transpeptidase (GGT)	Serum γ-glutamyl transpeptidase (GGT) level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.
Serum bilirubin	Serum bilirubin level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.
Serum bile acids	Serum bile acids level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.
Serum aspartate aminotransferase(AST)	Serum aspartate aminotransferase(AST) level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.
Serum alanine aminotransferase (ALT)	Serum alanine aminotransferase (ALT) level	baseline,1,2,3,6,9,12 months after treatment and 1 month after the end of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic fibrosis and the improvement of microbial metabolites	Cohort A-D：The changes of bile acid (BA) and microflora at the first, sixth and twelfth month, and the changes of bile acid (BA) and microflora at the first, sixth and twelfth month Percentage of subjects with a decrease of ≥15% in hepatic fibrosis.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in immune cells	Cohort A-D：Pre-and post-treatment Th1 cells (CD3 + CD4 + IFN-γ +) , Th2 cells (CD3 + Cd4 + IL-4 +) , Th17 cells (CD3 + Cd4 + IL-4 +) , Treg cells (CD3 + CD4 + CD25 + CD127low) , tFH1 cells (CXCR3 + CCR6-on the basis of Tfh) , TFH2 cells (CXCR3-CCR6-on the basis of Tfh) , TFH17 cells (CXCR3-CCR6 + on the basis of Tfh) , activated CD8 + T cells (CD3 + Cd8 + CD38 +) , CD3-CD19 + cd24high cd38high b regulatory cells, b cells based on CD20lowCD27highCD38high) ratio changes.	12 months

Collaborators and Investigators

• Sponsor: The Second Affiliated Hospital of Chongqing Medical University
• Investigators: Study Chair: Mingli Peng, Doctor, The Second Affiliated Hospital of Chongqing Medical University; Study Chair: Yinghua Lan, Doctor, Doctor

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2024
• Primary Completion (Estimated): October 10, 2028
• Study Completion (Estimated): November 10, 2028

Study Registration Dates

• First Submitted: January 17, 2024
• First Submitted That Met QC Criteria: March 3, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 31, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Sulfasalazine
• Other Study ID Numbers: Pengmingli

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No