A POC and Dose-Ranging Study of HTD1801 in PSC Patients

Study Overview
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Brief Summary
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The study was a dose-ranging, 18-week study comparing two doses of HTD1801 (500 mg BID and 1000 mg BID) to placebo in adult subjects with PSC.

Official Title
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A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adult Subjects With Primary Sclerosing Cholangitis (PSC)

Conditions
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Primary Sclerosing Cholangitis (PSC)

Intervention / Treatment
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* Drug: HTD1801
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between 18 and 75 years of age; Have a clinical diagnosis of PSC as evident by chronic cholestasis of more than six months duration with either a consistent magnetic resonance cholangiopancreatography (MRCP)/endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis; If subjects have Inflammatory Bowel Disease (IBD) they will be eligible to participate. If a subject has IBD, documented evidence of IBD must have been evident by prior endoscopy or in previous medical records for ≥6 months. In addition, subjects may only enter the study with a Partial Mayo Score of 0-4, inclusively. Subjects who are on treatment are allowed, provided they are stable for 3 months if taking: 5-amino salicylic acid drugs, azathioprine, 6-mercaptopurine, or methotrexate biologics; Have a serum ALP ≥1.5 × upper limit of normal (ULN); Be able to understand and sign a written informed consent form (ICF); Subjects receiving allowed concomitant medications need to be on stable therapy for 28 days prior to the Baseline visit, with the exception of ursodeoxycholic acid (UDCA), which should be stable for at least 6 weeks prior to the Baseline visit. Exclusion Criteria: Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis) on prior clinical investigations; Small duct PSC; Presence of percutaneous drain or bile duct stent; History of cholangiocarcinoma or clinical suspicion of new dominant stricture within 1 year by MRCP/ERCP. Presence of dominant stricture without ERCP evidence of cholangiocarcinoma is acceptable if stable for ≥ 1 year; Ascending cholangitis within 60 days prior to Screening; History of alcohol or substance abuse or dependence; Prior or planned liver transplantation; Presence of alternative causes of chronic liver disease, including alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis; Platelet count below 125,000/mm3, albumin below 3.0 g/dL, International Normalized Ratio (INR) > 1.2, or a history of ascites, or encephalopathy, or history of esophageal variceal bleeding; Severe active IBD or flare in colitis activity within the last 90 days requiring intensification of therapy beyond baseline treatment;

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A primary parallel group comparison for a 6-week treatment period (Period 1), followed by a 6-week dose-controlled extension (Period 2), and followed by a 6-week placebo-controlled randomized withdrawal (Period 3).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HTD1801 500 mg BID<br> | Drug: HTD1801<br>* HTD1801 tablets, 250 mg<br>|
| Active Comparator: HTD1801 1000 mg BID<br> | Drug: HTD1801<br>* HTD1801 tablets, 250 mg<br>|
| Placebo Comparator: Placebo BID<br> | Drug: Placebo<br>* tablets manufactured to mimic HTD1801 tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1 |  | Baseline to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1) |  | Baseline to Week 6 | 
| Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1) |  | Baseline to Week 6 | 
| Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1) |  | Baseline to Week 6 | 
| Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1) |  | Baseline to Week 6 | 
| Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2) |  | Week 6 to Week 12 | 
| Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2) |  | Week 6 to Week 12 | 
| Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2) |  | Week 6 to Week 12 | 
| Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2) |  | Week 6 to Week 12 | 
| Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2) |  | Week 6 to Week 12 | 
| Absolute Change in Serum ALP From Week 12 to Week 18 (Period 3) | Change in serum ALP between a new baseline at Week 12 and the final value at Week 18 for all subjects following the randomized withdrawal | Week 12 to Week 18 | 
| Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | The percentage of patients who achieve ALP of <1.5 x ULN at the end of week 18 (Period 3) | Week 12 to Week 18 | 
| Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3) |  | Week 12 to Week 18 | 
| Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3) |  | Week 12 to Week 18 | 
| Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3) |  | Week 12 to Week 18 |