Bile Duct Stricture, Biliary Tract Diseases, Cholangitis, Cholestasis, Primary Biliary Cholangitis, Primary Biliary Cirrhosis
Conditions
Keywords
Open-label
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.
Interventions
DRUGHTD1801 (BUDCA)
HTD1801 (BUDCA) 250 mg tablets. Dose 1000 mg twice daily with food for 12 weeks.
Sponsors
HighTide Therapeutics (Hong Kong) Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single group open label
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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 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. |
| 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. |
Countries
United States
Contacts
STUDY_DIRECTORAdrian DiBisceglie, MD
HighTide Therapeutics Biopharma Pty.
Participant flow
Pre-assignment details
A total of 46 subjects were screened of which 24 subjects were eligible and enrolled in the study. Subjects discontinued use of ursodeoxycholic acid (UDCA) at baseline prior to transitioning to HTD1801.
Participants by arm
| Arm | Count |
|---|---|
| HTD1801 1000 mg BID All subjects received HTD1801 1000 mg (4 x 250 mg tablets) administered orally twice daily with food for 12 weeks. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | HTD1801 1000 mg BID |
|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 10.8 |
| Alkaline Phosphatase (ALP) | 289.6 U/L STANDARD_DEVIATION 119.8 |
| Gamma-glutamyl Transferase (GGT) | 211.0 U/L STANDARD_DEVIATION 187.6 |
| GLOBE score | 0.3 units on a scale STANDARD_DEVIATION 0.7 |
| Immunoglobulin M (IgM) | 340.6 mg/dL STANDARD_DEVIATION 246.1 |
| Pruritus Visual Analog Scale (VAS; average itch) | 1.0 cm STANDARD_DEVIATION 1.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 2 Participants |
| Total Bilirubin | 0.7 mg/dL STANDARD_DEVIATION 0.3 |
| Total Cholesterol | 216.7 mg/dL STANDARD_DEVIATION 47.8 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 23 / 24 |
| serious Total, serious adverse events | 1 / 24 |
Outcome results
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.
Time frame: Baseline to Week 12
Population: ITT Population: Included all subjects that received at least one dose of HTD1801
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Percent Change in Alkaline Phosphatase (ALP) at Week 12 Compared to Baseline | -7.7 percent change | Standard Deviation 23.3 |
Comparison: A t-test was performed to test for the percent change from baseline to Week 12. This analysis was based on observed data without imputation. Testing was one sided using a 5% alpha level. No multiplicity adjustment was used, and the p-values reported for the endpoints were descriptive in nature.p-value: =0.077t-test, 1 sided
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.
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in GLOBE Score Between Baseline and Week 12 | -0.07 units on a scale | Standard Deviation 0.3 |
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.
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in Immunoglobulin M (IgM) From Baseline to Week 12 | -36.8 mg/dL | Standard Deviation 71.4 |
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.
Time frame: Baseline to Week 12.
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in Pruritus as Measured by Pruritus Visual Analog Score (VAS) From Baseline to Week 12 | -0.9 units on a scale | Standard Deviation 1.5 |
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.
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in Serum Gamma-glutamyl Transferase (GGT) From Baseline to Week 12 | -34.1 U/L | Standard Deviation 153.8 |
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.
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in Serum Total Cholesterol From Baseline to Week 12 | -18.8 mg/dL | Standard Deviation 35.1 |
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.
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 1000 mg BID | Change in Total Bilirubin From Baseline to Week 12 | -0.10 mg/dL | Standard Deviation 0.2 |