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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: HTD1801 (BUDCA)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single group open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label<br>HTD1801 (BUDCA) 250 mg tablets. Dosed at 1000 mg BID with food. | Drug: HTD1801 (BUDCA)<br>* HTD1801 (BUDCA) 250 mg tablets. Dose 1000 mg twice daily with food for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum bilirubin from Baseline to Week 12 | To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis | 12 weeks | 
| Change in serum gamma-glutamyl transferase (GGT) between Baseline and Week | To evaluate the effects of HTD1801 (BUDCA) on serum markers of cholestasis | 12 weeks | 
| Change in serum cholesterol (total and LDL) and triglyceride levels between Baseline and Week 12 | To evaluate the effects of HTD1801 on serum lipids | 12 weeks | 
| 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 | 12 weeks | 
| 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 | 12 weeks | 
| 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 | 12 weeks | 
| 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 | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-label