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

Phase 2

Completed

Conditions: Primary Biliary Cholangitis
Primary Biliary Cirrhosis
Cholestasis
Biliary Tract Diseases
Bile Duct Stricture
Cholangitis

Interventions: Drug: HTD1801 (BUDCA)

Registration Number: NCT04604652

Lead Sponsor: HighTide Biopharma Pty Ltd

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label	HTD1801 (BUDCA)	HTD1801 (BUDCA) 250 mg tablets. Dosed at 1000 mg BID with food.

Primary Outcome Measures

Name	Time	Method
Percent Change in Alkaline Phosphatase (ALP) at Week 12 Compared to Baseline	Baseline to Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Change in Total Bilirubin From Baseline to Week 12	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.
Change in Serum Total Cholesterol From Baseline to Week 12	Baseline to Week 12	To evaluate the effects of HTD1801 on serum lipids. A reduction in total cholesterol represents an improvement in serum lipids.
Change in Serum Gamma-glutamyl Transferase (GGT) From Baseline to Week 12	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.
Change in Immunoglobulin M (IgM) From Baseline to Week 12	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.
Change in Pruritus as Measured by Pruritus Visual Analog Score (VAS) From Baseline to Week 12	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.
Change in GLOBE Score Between Baseline and Week 12	Baseline to 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.

Trial Locations

Locations (12): Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Northshore University Hospital
🇺🇸
Manhasset, New York, United States
Liver Institute Northwest
🇺🇸
Seattle, Washington, United States
University GI
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Providence, Rhode Island, United States
Liver Institute of Virginia
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Newport News, Virginia, United States
Bon Secours Liver Institute of Richmond
🇺🇸
Richmond, Virginia, United States
Piedmont Healthcare
🇺🇸
Atlanta, Georgia, United States
University of Miami Schiff Center for Liver Disease
🇺🇸
Miami, Florida, United States
Henry Ford Health Services
🇺🇸
Detroit, Michigan, United States
The Texas Liver Institute
🇺🇸
San Antonio, Texas, United States
Baylor Research Institute
🇺🇸
Dallas, Texas, United States
St. Louis University
🇺🇸
Saint Louis, Missouri, United States