BRS201 for Sclerosing Cholangitis

(DOLPHIN Trial)

Overseen By Sophie Mitchell, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must be taking: Ursodeoxycholic acid

Must not be taking: Vitamin C, Prednisone

Disqualifiers: Advanced liver disease, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 8 weeks

28 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a clinical trial being done to investigate the efficacy of drug BRS201 (hydroxocobalamin) as a treatment in patients with primary sclerosing cholangitis. Participation in this study will take 8 weeks long and the study is structured as a cross-over study in which participants will take the study drug for 4 weeks and a placebo drug for 4 weeks in a randomized order in the form of an oral medication. Participation may also involve receiving an IV dose of the medication. The study will require participants to attend 9 study visits, all of which will be remote. Participation will involve taking an oral medication twice daily, tracking the medication in a log, and getting blood drawn and giving a stool sample for a few lab tests throughout the study. For the lab tests, a research nurse will visit the participant in-home for the convenience of the participant.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop all current medications, but you cannot use vitamin C or prednisone during the study. If you are on ursodeoxycholic acid, you must be on a stable dose for over 6 months or have stopped it more than 4 weeks before screening.

What data supports the idea that BRS201 for Sclerosing Cholangitis is an effective treatment?

The available research does not provide specific data supporting the effectiveness of BRS201 for Sclerosing Cholangitis. Instead, it mentions other treatments like ursodeoxycholic acid, which is noted as a promising option, although its effects on liver health and survival are unclear. Liver transplantation is also discussed as a definitive treatment for severe cases, but it comes with risks of complications. No direct evidence for BRS201's effectiveness is presented in the research provided. ^{1 2 3 4 5}

How is the drug BRS201 different from other treatments for sclerosing cholangitis?

BRS201 is unique because there are currently no effective medical treatments for sclerosing cholangitis, and existing options like ursodeoxycholic acid only improve biochemical markers without extending survival. BRS201 may offer a novel approach, potentially targeting the disease differently than current symptomatic and complication-focused therapies. ^{2 6 7 8 9}

Research Team

Joshua A Korzenik, MD

Principal Investigator

Brigham and Womens Hospital

Eligibility Criteria

This trial is for people who've had primary sclerosing cholangitis (PSC) for at least 6 months, confirmed by specific imaging tests. They should have a certain liver enzyme level above normal and if taking ursodeoxycholic acid, the dose must be stable for over 6 months or stopped more than 4 weeks before screening.

Inclusion Criteria

I have been diagnosed with PSC for at least 6 months, confirmed by a specific bile duct scan.

ALP > 1.5 times the upper limit of normal (ULN) at screening.

I have been on a stable dose of ursodeoxycholic acid for over 6 months or stopped it more than 4 weeks ago.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants will take the study drug BRS201 for 4 weeks and a placebo drug for 4 weeks in a randomized order, involving oral medication and possibly an IV dose.

8 weeks

9 visits (remote), in-home visits for lab tests

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BRS201
• Placebo

Trial Overview The study tests BRS201's effectiveness in treating PSC. It's an 8-week cross-over trial where participants take BRS201 and a placebo in random order for four weeks each as oral medication, possibly with an IV dose. There are nine remote visits involving blood draws and stool samples.

Participant Groups

Group I: BRS201 Arm Active Control 1 Intervention

In Group 1 of the study, subjects will take oral study drug at 1.2g twice daily, PO (2.4g daily) for 4 weeks. In Group 2 of the study, subjects will take oral study drug at 2g twice daily, PO (4g daily) for 4 weeks. In Group 3 of the study, subjects will take receive a one-time 5g IV dose of the study drug using the FDA-approved IV product followed by the oral study drug at 2g twice daily, PO (4g daily) for 4 weeks. In Group 4 of the study, subjects will repeat the previous conditions of the group that proves to be the most effective.

Group II: Placebo Arm Placebo Group 1 Intervention

In Group 1 of the study, subjects will take oral placebo at 1.2g twice daily, PO (2.4g daily) for 4 weeks. In Group 2 of the study, subjects will take oral placebo at 2g twice daily, PO (4g daily) for 4 weeks. In Group 3 of the study, subjects will take receive a one-time 5g IV dose of the study drug using the FDA-approved IV product followed by the oral placebo at 2g twice daily, PO (4g daily) for 4 weeks. In Group 4 of the study, subjects will repeat the previous conditions of the group that proves to be the most effective.

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

In a study of 370 patients with primary sclerosing cholangitis, 13% were diagnosed with cholangiocarcinoma, highlighting the need for regular screening in this population to detect early tumors.

Patients who underwent surgical treatments, such as transplantation or hepatic resection, had significantly better survival outcomes (median survival of 7.6 months for transplantation and 52.8 months for resection) compared to those receiving palliative care (median survival of 2.6 months).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholangiocarcinoma complicating primary sclerosing cholangitis: a 24-year experience. Morris-Stiff, G., Bhati, C., Olliff, S., et al.[2008]

In a study of 219 patients with primary sclerosing cholangitis, a higher dose of ursodeoxycholic acid did not show a statistically significant benefit on survival or prevention of liver transplantation compared to placebo over 5 years.

Despite some trends towards lower liver transplantation rates and decreased liver enzyme levels in the ursodeoxycholic acid group, there were no significant differences in symptoms or quality of life between the treatment and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Olsson, R., Boberg, KM., de Muckadell, OS., et al.[2022]

In a study of 335 patients who underwent liver transplantation for primary sclerosing cholangitis (PSC), biliary strictures (BS) occurred in 36.1% of patients after a mean of 3.9 years, and recurrent PSC (recPSC) was found in 20.3% after 4.6 years, both significantly impacting long-term survival rates.

Independent risk factors for developing BS and recPSC included donor age, inflammatory bowel disease (IBD), and INR levels at the time of transplantation, which can help categorize patients into risk groups for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis. Hildebrand, T., Pannicke, N., Dechene, A., et al.[2022]

The BISCIT study aims to determine if scheduled biliary interventions every 8 weeks can reduce the incidence of cholangiosepsis, liver transplantation, or death in patients with secondary sclerosing cholangitis, involving 104 patients randomized across ten sites.

This study is significant as it seeks to establish a new evidence-based treatment approach for SSC-CIP, which could potentially improve patient outcomes and change the current standard of care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BISCIT: Biliary interventions in critically ill patients with secondary sclerosing cholangitis-a study protocol for a multicenter, randomized, controlled parallel group trial. Stahl, K., Klein, F., Voigtländer, T., et al.[2023]

Ursodeoxycholic acid (UDCA) is the most promising treatment for primary sclerosing cholangitis, as it improves biliary secretion and may reduce the risk of colorectal and bile duct cancers, although its effects on liver histology and survival remain unclear.

Endoscopic treatment of dominant stenoses in patients with primary sclerosing cholangitis has been shown to improve cholestasis and extend survival, highlighting the importance of managing complications associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary sclerosing cholangitis. Rost, D., Kulaksiz, H., Stiehl, A.[2020]

Sclerosing cholangitis is a rare and progressive liver disease primarily affecting the biliary tract, often associated with conditions like autoimmune hepatitis and inflammatory bowel disease, and is more common in males and Caucasians.

While ursodeoxycholic acid can improve biochemical markers, it does not extend survival without a transplant; orthotopic liver transplantation is currently the only effective long-term treatment, offering good survival rates for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sclerosing cholangitis: pediatric perspective. Kerkar, N., Miloh, T.[2021]

Primary sclerosing cholangitis (PSC) is a progressive liver disease with no effective treatments currently available, and it often leads to serious complications like cirrhosis and bile duct cancer over a long period, typically a decade or more.

Management of PSC focuses on symptom relief and addressing complications, with options like balloon dilatation for strictures and liver transplantation for advanced cases, while experimental therapies such as immunosuppressive and choleretic agents are being tested in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Fifth Carlos E. Rubio Memorial Lecture. Sclerosing cholangitis: pathogenesis, pathology, and practice. Larusso, NF.[2018]

Overlap syndrome between primary biliary cholangitis and primary sclerosing cholangitis is extremely rare, with only a few cases reported, highlighting the need for awareness and recognition of this condition in clinical practice.

In two cases of Tunisian female patients, both were successfully treated with ursodeoxycholic acid, demonstrating its potential efficacy in managing symptoms associated with this overlap syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overlap syndrome of primary biliary cholangitis and primary sclerosing cholangitis: two case reports. Yacoub, H., Ben Azouz, S., Hassine, H., et al.[2023]

In a study of 67 patients with IgG4 sclerosing cholangitis (IgG4-SC), the majority were male (76%) with a mean age of 63.3 years, and the most common symptoms were jaundice (62%) and abdominal pain (42%).

Treatment with prednisolone was effective, showing a partial or complete response in 95% of patients, although 42% experienced relapse after stopping the medication; importantly, progression to liver cancer was rare during a median follow-up of 3.9 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study. Kemp, W., Majeed, A., Mitchell, J., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cholangiocarcinoma complicating primary sclerosing cholangitis: a 24-year experience. [2008]

2. United States pubmed.ncbi.nlm.nih.gov

High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

BISCIT: Biliary interventions in critically ill patients with secondary sclerosing cholangitis-a study protocol for a multicenter, randomized, controlled parallel group trial. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Treatment of primary sclerosing cholangitis. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Sclerosing cholangitis: pediatric perspective. [2021]

7. Puerto Rico pubmed.ncbi.nlm.nih.gov

The Fifth Carlos E. Rubio Memorial Lecture. Sclerosing cholangitis: pathogenesis, pathology, and practice. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Overlap syndrome of primary biliary cholangitis and primary sclerosing cholangitis: two case reports. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study. [2022]