Primary Sclerosing Cholangitis (PSC)
Conditions
Brief summary
The goal of this clinical trial is to test whether a type of cell death called disulfidptosis plays a role in primary sclerosing cholangitis (PSC) in adults aged 18 to 70. Researchers will do this by giving participants a study diet and four oral agents designed to block disulfidptosis, then checking whether liver blood tests change. This study is not designed to show that the combination treats PSC. PSC is a long-term liver disease. In PSC, the bile ducts become inflamed and scarred over time. Bile ducts are small tubes that carry bile from the liver to the gut. Researchers are testing a new idea about why bile duct cells are damaged in PSC. Cells need a balance of certain sulfur-containing building blocks and the energy to process them. When this balance breaks down, proteins inside the cell can stick together the wrong way. This can cause the cell's inner structure to collapse, and the cell dies. This type of cell death is called disulfidptosis. Researchers think disulfidptosis may contribute to bile duct damage in PSC. This is a proof-of-principle study. This means it is an early, small study to test whether this idea is correct and worth studying further. Participants will follow a study diet and take four oral agents. Each agent was chosen because it may help protect cells from disulfidptosis: Alpha-lipoic acid (ALA), a natural antioxidant that helps cells manage stress N-acetylcysteine (NAC), which helps the body make glutathione, a natural antioxidant Nicotinamide riboside (NR), a form of vitamin B3 that helps cells make energy Metformin, a common diabetes medicine that changes how cells use sugar and energy The main questions it aims to answer are: 1. Does blocking disulfidptosis with the study diet and agents lower alkaline phosphatase (ALP)? ALP is a liver blood test that is often high in people with PSC. 2. Does it change other blood markers of liver health and inflammation? 3. What medical problems do participants have while on the study diet and agents? There is no comparison group in this study. All participants will receive the study diet and all four agents. Participants will: 1. Have a screening visit to check if they can join the study 2. Follow a study diet for the length of the study, with guidance from study dietitians 3. Receive help from the study to buy groceries that fit the study diet 4. Take photos of their meals and snacks using a phone app, so dietitians can review what they eat and give advice 5. Take the four study agents by mouth each day, starting at lower doses that are raised step by step over the first weeks 6. Visit the clinic in Boston about 11 times over about 18 weeks 7. Give blood samples at study visits to check liver tests, safety tests, and other markers 8. Answer questions about their health, symptoms, and any side effects Researchers will watch closely for side effects throughout the study. If liver tests rise too much, researchers will follow set safety steps, which may include stopping one or more study agents. About 15 people will take part.
Interventions
DIETARY_SUPPLEMENTN-Acetyl Cysteine (NAC)
N-acetylcysteine (NAC) capsules (Pure Encapsulations), taken orally. Dose: 1200 mg/day through Week 16. Selected as a precursor of glutathione to support cellular thiol and redox balance as part of a regimen targeting disulfidptosis.
DIETARY_SUPPLEMENTAlpha-Lipoic Acid (ALA)
Alpha-lipoic acid (ALA) capsules (Pure Encapsulations), taken orally. Dose: 600 mg once daily in Week 0, then 600 mg twice daily from Week 1 through Week 16. Selected to support cellular antioxidant capacity and redox balance as part of a regimen targeting disulfidptosis.
DIETARY_SUPPLEMENTNicotinamide Riboside (NR)
Nicotinamide riboside (NR) chloride 250 mg capsules (Tru Niagen, ChromaDex), taken orally. Dose: 500 mg twice daily (1,000 mg/day) through Week 16. Selected as an NAD+ precursor to support cellular NADPH availability as part of a regimen targeting disulfidptosis.
Metformin hydrochloride extended-release 500 mg tablets (Granules Pharmaceuticals), taken orally. Dose titrated per protocol to 1000 mg through Week 16. Selected for its effects on cellular glucose and energy metabolism as part of a regimen targeting disulfidptosis.
OTHERStudy Diet
Participants follow a protocol-specified study diet from Baseline through Week 16, guided by study dietitians. Dietary intake is recorded through meal photographs using the MetaBite for Research app, which dietitians review to provide individualized recommendations. Participants receive grocery support to facilitate adherence.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males and females aged 18 to 70 years * Ulcerative colitis (UC) duration of at least 6 months, with diagnosis confirmed by typical endoscopic and histologic findings * Primary sclerosing cholangitis (PSC) duration of at least 6 months, with diagnosis confirmed by typical cholangiogram findings and no evidence of a secondary cause of sclerosing cholangitis * Simple Clinical Colitis Activity Index (SCCAI) of 5 or less * Serum alkaline phosphatase (ALP) greater than 1.33 times the upper limit of normal (ULN) * Platelet count greater than 150,000/mm³ * Albumin greater than 3.3 g/dL * Serum creatinine below ULN * For participants on ursodeoxycholic acid (UDCA): stable dose for at least 3 months before screening. For participants not on UDCA: no UDCA use for at least 3 months before screening * For participants on mesalamine or sulfasalazine: stable dose for at least 4 weeks before enrollment * For participants on immunomodulators or biologic agents: stable dose for at least 8 weeks, and must remain on the same dose throughout the study * For participants on oral corticosteroids: dose no greater than 20 mg prednisone or 6 mg budesonide daily at enrollment * Willing and able to give informed consent before any study-specific procedures * Willing and able to comply with scheduled visits, laboratory tests, stool collection, and other study procedures
Exclusion criteria
* Pregnant, or positive pregnancy test at screening * Women of childbearing potential who intend to become pregnant during the study or within 1 month after the last dose of study medication * Currently breastfeeding, or intending to breastfeed during the study or within 1 month after the last dose of study medication * Women of childbearing potential unwilling to use protocol-specified contraception * Alanine aminotransferase (ALT) greater than 5 times ULN * Total bilirubin greater than 2 times ULN (unless history of Gilbert's syndrome) * International normalized ratio (INR) greater than 1.2 * Decompensated cirrhosis, defined by ascites, hepatic encephalopathy, or variceal bleeding * Small duct PSC * Secondary sclerosing cholangitis (e.g., due to chronic biliary obstruction, infection, ischemic injury, IgG4-related disease, drug- or toxin-induced cholangiopathy, or malignancy) * Other causes of liver disease, including viral, metabolic, alcohol-related, and other autoimmune liver diseases. Participants with non-alcoholic fatty liver disease may be included if there is no evidence of non-alcoholic steatohepatitis (NASH) * Positive antimitochondrial antibody (AMA) * History of liver transplantation * History of hepatocellular carcinoma or cholangiocarcinoma * Ascending cholangitis within 90 days of enrollment * Severe UC flare requiring intravenous corticosteroids within 3 weeks of enrollment or during the study, or anticipated new IBD medication within 3 months * History of colectomy, ileal pouch, or ostomy, or anticipated colectomy within the next few months * Positive stool culture, ova and parasites, or C. difficile toxin within 2 months of enrollment * Use of antibiotics and/or probiotics within 6 weeks of enrollment, or planned use during the study * Use of total parenteral nutrition or exclusive enteral nutrition at enrollment or during the study * Current vegetarian or vegan diet * Inability to complete a dietary log * Participation in another therapeutic clinical trial within 30 days or 5 half-lives of the other study drug (whichever is longer) before screening, or concurrent participation in another therapeutic trial * Any laboratory abnormality or condition that, in the investigator's opinion, could affect participant safety or the assessment of study results * Current use of metformin, use within 8 weeks before enrollment, or anticipated start of metformin outside the study * Estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m² at screening * Confirmed diagnosis of diabetes mellitus * Known hypersensitivity to alpha-lipoic acid, N-acetylcysteine, nicotinamide riboside, metformin, or any excipient or capsule component of the study products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 16 | Baseline (Week 0) and Week 16 | Serum ALP (U/L) will be measured at Baseline and Week 16. Change will be calculated as the Week 16 value minus the Baseline value. ALP is a marker of cholestatic liver injury commonly elevated in primary sclerosing cholangitis (PSC). |
| Percentage of Participants With ≥50% Reduction in Serum ALP at Week 16 | Baseline (Week 0) and Week 16 | ALP response is defined as a reduction of 50% or more from baseline at Week 16. Reported as the proportion of participants achieving response, with 95% confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Biochemistry From Baseline to Week 16 | Baseline (Week 0) and Week 16 | Change in serum gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin from Baseline to Week 16. |
| Change in Pro-peptide of Type III Collagen (PRO-C3) From Baseline to Week 16 | Baseline (Week 0) and Week 16 | Serum PRO-C3 (ng/mL), a biomarker of liver fibrogenesis. Change from baseline to Week 16 is reported as absolute and percent change from baseline. |
| Change in Enhanced Liver Fibrosis (ELF) Score From Baseline to Week 16 | Baseline (Week 0) and Week 16 | The ELF score is a composite serum fibrosis score calculated from hyaluronic acid, amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1). Change from baseline to Week 16 is reported as absolute and percent change from baseline. |
| Change in LMR Inflammatory Panel Markers From Baseline to Weeks 8 and 16 | Baseline (Week 0), Week 8, and Week 16 | Serum inflammatory and metabolic markers measured using the LMR Inflammatory Panel. Change from baseline to Week 8 and to Week 16 is reported. |
Contacts
CONTACTJoshua R Korzenik, MD
CONTACTSamruddhi Patwardhan, PharmD, MS
PRINCIPAL_INVESTIGATORJoshua R Korzenik, MD
Brigham and Women's Hospital
Outcome results
None listed