Open-Label Study of HTD1801 in Adult Subjects With Primary Biliary Cholangitis

Primary Biliary Cirrhosis Clinical Trial

— PRONTO-PBC  

Official title:

A Phase 2 Open Label, Proof of Concept Study of HTD1801 (BUDCA) in Adult Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to Standard Therapy - PRONTO-PBC

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04604652
• Other study ID #: HTD1801.PCT013
• Status: Completed
• Phase: Phase 2
• Start date: May 27, 2021
• Est. completion date: May 31, 2022

Study information

• Verified date: September 2023
• Source: HighTide Biopharma Pty Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this open-label study is to evaluate the safety and tolerability of HDT1801 (BUDCA) over 12 weeks in adult subjects with PBC who have an inadequate response to standard therapy. Inadequate response is defined as persistently elevated serum alkaline phosphatase at greater than or equal to1.5 times the upper limits of normal for the testing lab in spite of having been on adequate doses of standard therapy with UDCA (ursodeoxycholic acid) at 13-15 mg/kg for at least 6 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: May 31, 2022
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Have a clinical diagnosis of PBC as confirmed by patient history consistent with the American Association for the Study of Liver Diseases (AASLD) Practice Guideline confirmed by two of the following three criteria:

1. Biochemical evidence of cholestasis with elevation of ALP activity

2. Presence of antimitochondrial antibody (AMA)

3. Histopathologic evidence of non-suppurative cholangitis and destruction of small or medium-sized bile ducts if biopsy performed Note: historical AMA and liver biopsy data may be used but must be recorded in source documentation.

• Has been taking a stable, adequate dose of at least (13-15 mg/kg/day) of UDCA for at least 6 months with a serum ALP of at least =1.5 × ULN at any time after being on UDCA for >6 months (historical value) and at Screening. If the historical ALP was obtained less than 6 months prior to study start as part of standard of care, the subject may be screened and a second ALP value should be obtained as part of screening, There must be at least a 4-week interval between the ALP values and the ALP values must be =1.5 × ULN

• If the subject is taking cholestyramine or other bile acid sequestrant for pruritus, must be on a stable dose no more than once a day for at least 8 weeks prior to Baseline visit. Must be willing and able to take cholestyramine at least 2 hours before or after study medication

• Females of child-bearing potential and males participating in the study must either agree to use at least two approved barrier methods of contraception or be completely abstinent from sexual intercourse, if this is their usual and preferred lifestyle, throughout the duration of the study and for three months after stopping study drug. Females who are postmenopausal must have appropriate documentation

• Able to provide consent

Exclusion Criteria:

• Uncontrolled concomitant autoimmune hepatitis (AIH). Subject should be on no more than 5 mg per day of prednisone (or equivalent dose for other corticosteroids) or no more than 150 mg per day of azathioprine at stable doses and serum ALT should be = 5 × ULN. Enrollment of subjects with controlled AIH will be limited to a total of 5 subjects.

• History of alcohol or substance abuse

• Prior liver transplantation or currently listed for liver transplantation

• History of chronic viral hepatitis, types B or C

• Platelet count =150,000/mm3, albumin <3.0 g/dL, International Normalized Ratio (INR) >1.2, or a history of ascites, or encephalopathy, or history of variceal bleeding

• Total bilirubin >1.3 × ULN unless subject has Gilbert Syndrome. If subject has increased total bilirubin due to Gilbert's Syndrome, then direct bilirubin should be <0.3 mg/dL.

• Hemoglobin <10 g/dL for males or females

• Serum TSH level <0.1 or >10 u/mL (subject may be re-screened if hyper- or hypothyroidism has been corrected)

• Renal impairment with eGFR <60 ml/min (CKD stages 3, 4 or 5)

• Human immunodeficiency virus (HIV)-1 or HIV-2 infection by history

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency

• History of malignancy within the past 2 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma

• Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to Screening

• Major surgical procedure within 30 days of Screening or prior solid organ transplantation

• Females who are pregnant or breastfeeding

• Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents, and immune-modulating agents (such as interleukins, interferons)

• Diseases that may result in increased serum ALP activities from sources other than the biliary system (e.g., Paget's disease of bone, osteomalacia)

• Allergy to the clinical trial material or its components

• Having received any experimental medications within 28 days prior to Screening

• Use of bezafibrate or fenofibrate within 28 days prior to first day of IP dosing

• Use of obeticholic acid (OCA) within 28 days prior to first day of IP dosing

• Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements

Related Conditions & MeSH terms

• Bile Duct Stricture
• Biliary Tract Diseases
• Cholangitis
• Cholestasis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis
• Primary Biliary Cirrhosis

Intervention

Drug:
• HTD1801 (BUDCA)
HTD1801 (BUDCA) 250 mg tablets. Dose 1000 mg twice daily with food for 12 weeks.

Locations

Country	Name	City	State
United States	Piedmont Healthcare	Atlanta	Georgia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Baylor Research Institute	Dallas	Texas
United States	Henry Ford Health Services	Detroit	Michigan
United States	Northshore University Hospital	Manhasset	New York
United States	University of Miami Schiff Center for Liver Disease	Miami	Florida
United States	Liver Institute of Virginia	Newport News	Virginia
United States	University GI	Providence	Rhode Island
United States	Bon Secours Liver Institute of Richmond	Richmond	Virginia
United States	St. Louis University	Saint Louis	Missouri
United States	The Texas Liver Institute	San Antonio	Texas
United States	Liver Institute Northwest	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
HighTide Biopharma Pty Ltd

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change in Alkaline Phosphatase (ALP) at Week 12 Compared to Baseline	To evaluate the effects of HTD1801 on serum ALP in adult subjects with PBC who have experienced an inadequate response to standard therapy.; Inadequate response is defined as ALP =1.5 × upper limit of normal (ULN) despite having been on adequate doses of ursodeoxycholic acid (UDCA) for at least 6 months. A reduction in ALP represents an improvement.	Baseline to Week 12
Secondary	Change in Total Bilirubin From Baseline to Week 12	To evaluate the effects of HTD1801 on serum markers of cholestasis. A reduction in total bilirubin represents an improvement in a marker of cholestasis.	Baseline to Week 12
Secondary	Change in Serum Gamma-glutamyl Transferase (GGT) From Baseline to Week 12	To evaluate the effects of HTD1801 on serum markers of cholestasis. A decrease in GGT represents an improvement in a marker of cholestasis.	Baseline to Week 12
Secondary	Change in Serum Total Cholesterol From Baseline to Week 12	To evaluate the effects of HTD1801 on serum lipids. A reduction in total cholesterol represents an improvement in serum lipids.	Baseline to Week 12
Secondary	Change in Immunoglobulin M (IgM) From Baseline to Week 12	To evaluate the effects of HTD1801 on serum markers of inflammation. A reduction in IgM represents an improvement in a marker of inflammation.	Baseline to Week 12
Secondary	Change in GLOBE Score Between Baseline and Week 12	The GLOBE score is a validated risk assessment tool providing an estimate of transplant-free survival for patients with PBC. It was developed by the GLOBAL PBC Study Group using Cox regression model on over 4,000 patients with PBC. Lower GLOBE score predicts lower risk. It is calculated using age and levels of ALP, total bilirubin, platelets, and albumin.	Baseline to Week 12
Secondary	Change in Pruritus as Measured by Pruritus Visual Analog Score (VAS) From Baseline to Week 12	Pruritus Visual Analog Scale (VAS) is a self-reported instrument for measurement of itch intensity using 24-hour recall period. Subjects were asked to rate the average intensity of their itch on a 10 cm horizontal line ranging from 0 cm (no itch) to 10 cm (worst imaginable itch). A decrease in the Pruritus VAS represents an improvement in itch intensity.	Baseline to Week 12.