Primary Sclerosing Cholangitis (PSC)
Conditions
Brief summary
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.
Interventions
DRUGHTD1801
HTD1801 tablets, 250 mg
DRUGPlacebo
tablets manufactured to mimic HTD1801 tablets
Sponsors
HighTide Therapeutics (Hong Kong) Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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: 1. 5-amino salicylic acid drugs, 2. azathioprine, 3. 6-mercaptopurine, or methotrexate 4. 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;
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1 | Baseline to Week 6 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Week 12 to Week 18 | 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 |
| Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | Week 12 to Week 18 | The percentage of patients who achieve ALP of \<1.5 x ULN at the end of week 18 (Period 3) |
| 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 | — |
| 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 Patients Who Achieve a 50% Decrease in ALP at the End of 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 | — |
Countries
Canada, United States
Contacts
STUDY_DIRECTORAdrian Di Bisceglie, MD,FACP,FAASLD
HighTide Therapeutics USA, LLC
Participant flow
Recruitment details
Fifty-nine subjects were recruited from 23 academic medical centers and community clinics in the US and Canada. The first subject was enrolled on 18 June 2018 and the last subject last visit was completed on 10 Aug 2020.
Participants by arm
| Arm | Count |
|---|---|
| HTD1801 500 mg BID HTD1801: HTD1801 tablets, 250mg | 15 |
| HTD1801 1000 mg BID HTD1801: HTD1801 tablets, 250mg | 24 |
| Placebo BID Placebo: tablets manufactured to mimic HTD1801 tablets | 16 |
| Total | 55 |
Baseline characteristics
| Characteristic | HTD1801 500 mg BID | HTD1801 1000 mg BID | Placebo BID | Total |
|---|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 13.6 | 45 years STANDARD_DEVIATION 13.7 | 40 years STANDARD_DEVIATION 15.8 | 43 years STANDARD_DEVIATION 14.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 14 Participants | 19 Participants | 13 Participants | 46 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 7 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 31 | 0 / 35 |
| other Total, other adverse events | 14 / 22 | 20 / 31 | 18 / 35 |
| serious Total, serious adverse events | 1 / 22 | 3 / 31 | 0 / 35 |
Outcome results
Primary
Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1
Time frame: Baseline to Week 6
Population: Modified Intent-to-Treat (mITT) population: 59 subjects were randomized; however, 4 subjects did not receive the study drug. The remaining 55 subjects were dosed with study drug; however, 1 subject was excluded due to the absence of baseline assessments and withdrew due to AE on Day 2. The mITT population consisted of the remaining 54 subjects. Subjects were randomized to receive HTD1801 BID doses of 500 mg, 1000 mg, or matching placebo for 6 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1 | -71 U/L | Standard Error 136.9 |
| HTD1801 1000 mg BID | Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1 | -73 U/L | Standard Error 139.9 |
| Placebo BID | Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1 | 94 U/L | Standard Error 261.7 |
Secondary
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
Time frame: Week 12 to Week 18
Population: All subjects were re-randomized to either continue on the active treatment they received in Period 2 or be assigned to placebo. 50 subjects in the mITT population started Period 3. 49 subjects in the mITT population completed Period 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum ALP From Week 12 to Week 18 (Period 3) | -63 U/L | Standard Deviation 88.9 |
| HTD1801 1000 mg BID | Absolute Change in Serum ALP From Week 12 to Week 18 (Period 3) | 21 U/L | Standard Deviation 141.7 |
| Placebo BID | Absolute Change in Serum ALP From Week 12 to Week 18 (Period 3) | 183 U/L | Standard Deviation 292 |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Absolute Change in Serum ALP From Week 12 to Week 18 (Period 3) | 142 U/L | Standard Deviation 163.7 |
Secondary
Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2)
Time frame: Week 6 to Week 12
Population: Subjects previously randomized in Period 1 to HTD1801 500 mg BID or HTD1801 1000 mg BID continued for 6 more weeks at that previous dose, while subjects previously randomized to placebo were re-randomized to receive 6 weeks of either HTD1801 500 mg BID or HTD1801 1000 mg BID. 51 subjects in the mITT population started Period 2. 49 subjects in the mITT population completed Period 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2) | -34 U/L | Standard Deviation 180.3 |
| HTD1801 1000 mg BID | Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2) | -14 U/L | Standard Deviation 74.6 |
| Placebo BID | Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2) | -189 U/L | Standard Deviation 270.7 |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2) | 10 U/L | Standard Deviation 65.9 |
Secondary
Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2)
Time frame: Week 6 to Week 12
Population: 49 subjects in the mITT population who completed Period 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2) | -0.1 mg/dL | Standard Deviation 0.28 |
| HTD1801 1000 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2) | 0.0 mg/dL | Standard Deviation 0.25 |
| Placebo BID | Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2) | -0.4 mg/dL | Standard Deviation 0.16 |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2) | 0.0 mg/dL | Standard Deviation 0.49 |
Secondary
Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3)
Time frame: Week 12 to Week 18
Population: 49 subjects in the mITT population who completed Period 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3) | -0.2 mg/dL | Standard Deviation 0.19 |
| HTD1801 1000 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3) | 0.0 mg/dL | Standard Deviation 0.23 |
| Placebo BID | Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3) | 0.1 mg/dL | Standard Deviation 0.36 |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3) | 0.1 mg/dL | Standard Deviation 0.22 |
Secondary
Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1)
Time frame: Baseline to Week 6
Population: Period 1 mITT population: 54 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTD1801 500 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1) | -0.2 mg/dL | Standard Deviation 0.52 |
| HTD1801 1000 mg BID | Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1) | 0.0 mg/dL | Standard Deviation 0.5 |
| Placebo BID | Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1) | 0.1 mg/dL | Standard Deviation 0.26 |
Secondary
Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2)
Time frame: Week 6 to Week 12
Population: 51 subjects in the mITT population who completed Period 1 and began Period 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2) | 1 Participants |
| HTD1801 1000 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2) | 0 Participants |
| Placebo BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2) | 2 Participants |
Secondary
Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3)
Time frame: Week 12 to Week 18
Population: 50 subjects in the mITT population who completed Period 2 and began Period 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3) | 1 Participants |
| HTD1801 1000 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3) | 0 Participants |
| Placebo BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3) | 1 Participants |
Secondary
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)
Time frame: Week 12 to Week 18
Population: 50 subjects in the mITT population who completed Period 2 and began Period 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | 1 Participants |
| HTD1801 1000 mg BID | Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | 4 Participants |
| Placebo BID | Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Patients Who Achieve ALP of <1.5 x ULN at the End of Week 18 (Period 3) | 1 Participants |
Secondary
Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2)
Time frame: Week 6 to Week 12
Population: 51 subjects in the mITT population who completed Period 1 and began Period 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2) | 0 Participants |
| HTD1801 1000 mg BID | Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2) | 0 Participants |
| Placebo BID | Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2) | 2 Participants |
Secondary
Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1)
Time frame: Baseline to Week 6
Population: Period 1 mITT population: 54 subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1) | 1 Participants |
| HTD1801 1000 mg BID | Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1) | 4 Participants |
| Placebo BID | Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1) | 0 Participants |
Secondary
Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2)
Time frame: Week 6 to Week 12
Population: 51 subjects in the mITT population who completed Period 1 and began Period 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2) | 0 Participants |
| HTD1801 1000 mg BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2) | 2 Participants |
| Placebo BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2) | 6 Participants |
Secondary
Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1)
Time frame: Baseline to Week 6
Population: Period 1 mITT population: 54 subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1) | 2 Participants |
| HTD1801 1000 mg BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1) | 6 Participants |
| Placebo BID | Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1) | 1 Participants |
Secondary
Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3)
Time frame: Week 12 to Week 18
Population: 50 subjects in the mITT population who completed Period 2 and began Period 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3) | 0 Participants |
| HTD1801 1000 mg BID | Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3) | 1 Participants |
| Placebo BID | Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3) | 0 Participants |
| HTD1801 1000 mg BID to HTD1801 1000 mg BID | Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3) | 0 Participants |
Secondary
Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1)
Time frame: Baseline to Week 6
Population: Period 1 mITT population: 54 subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HTD1801 500 mg BID | Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1) | 0 Participants |
| HTD1801 1000 mg BID | Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1) | 2 Participants |
| Placebo BID | Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1) | 0 Participants |