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Open-Label Study of HTD1801 in Adult Subjects With Primary Biliary Cholangitis (PRONTO-PBC)

Primary Purpose

Primary Biliary Cholangitis, Primary Biliary Cirrhosis, Cholangitis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
HTD1801 (BUDCA)
Sponsored by
HighTide Biopharma Pty Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Biliary Cholangitis focused on measuring Open-label

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 cholestramine 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

Sites / Locations

  • University of Miami Schiff Center for Liver Disease
  • Piedmont Healthcare
  • Massachusetts General Hospital
  • Henry Ford Health Services
  • St. Louis University
  • Northshore University Hospital
  • University GI
  • Baylor Research Institute
  • The Texas Liver Institute
  • Liver Institute of Virginia
  • Bon Secours Liver Institute of Richmond
  • Liver Institute Northwest

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-label

Arm Description

HTD1801 (BUDCA) 250 mg tablets. Dosed at 1000 mg BID with food.

Outcomes

Primary Outcome Measures

Percent change in alkaline phosphatase at Week 12 compared to Baseline
To evaluate the effects of HTD1801 (BUDCA) on serum alkaline phosphatase (ALP) in adult subjects with PBC who have experienced an inadequate response to standard therapy. Inadequate response is defined as ALP ≥1.5 × ULN despite having been on adequate doses of UDCA for at least 6 months

Secondary Outcome Measures

Change in serum bilirubin from Baseline to Week 12
To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis
Change in serum gamma-glutamyl transferase (GGT) between Baseline and Week
To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis
Change in serum cholesterol (total and LDL) and triglyceride levels between Baseline and Week 12
To evaluate the effects of HTD1801 on serum lipids
Change in inflammatory serum markers including fibrinogen, CRP, Haptoglobin, ELF and serum immunoglobulins between Baseline and Week 12
To evaluate the effects of HTD1801 (BUDCA) on serum markers of inflammation
Change in GLOBE score between Baseline and Week 12
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC
Change in pruritus as measured by Pruritus visual analog score (VAS) between Baseline and Week 12
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC
Adverse events and changes in physical examination, vital signs, and clinical laboratory values
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC

Full Information

First Posted
October 16, 2020
Last Updated
June 24, 2022
Sponsor
HighTide Biopharma Pty Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT04604652
Brief Title
Open-Label Study of HTD1801 in Adult Subjects With Primary Biliary Cholangitis
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
May 27, 2021 (Actual)
Primary Completion Date
May 31, 2022 (Actual)
Study Completion Date
May 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
HighTide Biopharma Pty Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Biliary Cholangitis, Primary Biliary Cirrhosis, Cholangitis, Cholestasis, Biliary Tract Diseases, Bile Duct Stricture
Keywords
Open-label

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single group open label
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open-label
Arm Type
Experimental
Arm Description
HTD1801 (BUDCA) 250 mg tablets. Dosed at 1000 mg BID with food.
Intervention Type
Drug
Intervention Name(s)
HTD1801 (BUDCA)
Intervention Description
HTD1801 (BUDCA) 250 mg tablets. Dose 1000 mg twice daily with food for 12 weeks.
Primary Outcome Measure Information:
Title
Percent change in alkaline phosphatase at Week 12 compared to Baseline
Description
To evaluate the effects of HTD1801 (BUDCA) on serum alkaline phosphatase (ALP) in adult subjects with PBC who have experienced an inadequate response to standard therapy. Inadequate response is defined as ALP ≥1.5 × ULN despite having been on adequate doses of UDCA for at least 6 months
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Change in serum bilirubin from Baseline to Week 12
Description
To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis
Time Frame
12 weeks
Title
Change in serum gamma-glutamyl transferase (GGT) between Baseline and Week
Description
To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis
Time Frame
12 weeks
Title
Change in serum cholesterol (total and LDL) and triglyceride levels between Baseline and Week 12
Description
To evaluate the effects of HTD1801 on serum lipids
Time Frame
12 weeks
Title
Change in inflammatory serum markers including fibrinogen, CRP, Haptoglobin, ELF and serum immunoglobulins between Baseline and Week 12
Description
To evaluate the effects of HTD1801 (BUDCA) on serum markers of inflammation
Time Frame
12 weeks
Title
Change in GLOBE score between Baseline and Week 12
Description
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC
Time Frame
12 weeks
Title
Change in pruritus as measured by Pruritus visual analog score (VAS) between Baseline and Week 12
Description
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC
Time Frame
12 weeks
Title
Adverse events and changes in physical examination, vital signs, and clinical laboratory values
Description
To evaluate the safety and tolerability of HTD1801 over 12 weeks of treatment in adult subjects with PBC
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Biochemical evidence of cholestasis with elevation of ALP activity Presence of antimitochondrial antibody (AMA) 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 cholestramine 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrian DiBisceglie, MD
Organizational Affiliation
HighTide Therapeutics Biopharma Pty.
Official's Role
Study Director
Facility Information:
Facility Name
University of Miami Schiff Center for Liver Disease
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Piedmont Healthcare
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Henry Ford Health Services
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
St. Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Northshore University Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
University GI
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02905
Country
United States
Facility Name
Baylor Research Institute
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
The Texas Liver Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
Liver Institute of Virginia
City
Newport News
State/Province
Virginia
ZIP/Postal Code
23602
Country
United States
Facility Name
Bon Secours Liver Institute of Richmond
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23226
Country
United States
Facility Name
Liver Institute Northwest
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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