A POC and Dose-Ranging Study of HTD1801 in PSC Patients | NCT03333928

Label	Type	Intervention Names
HTD1801 500 mg BID	Active Comparator	Drug: HTD1801
HTD1801 1000 mg BID	Active Comparator	Drug: HTD1801
Placebo BID	Placebo Comparator	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
HTD1801	Drug	HTD1801 tablets, 250 mg	HTD1801 1000 mg BID HTD1801 500 mg BID

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

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

Eligibility Module

Eligibility Criteria

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;

Name	Affiliation	Role
Adrian Di Bisceglie, MD,FACP,FAASLD	HighTide Therapeutics USA, LLC	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Arizona Liver Health		Chandler	Arizona	85224	United States
Arizona Liver Health

PubMed Identifier	Type	Citation	Retractions
36327436	Derived	Kowdley KV, Forman L, Eksteen B, Gunn N, Sundaram V, Landis C, Harrison SA, Levy C, Liberman A, Di Bisceglie AM, Hirschfield GM. A Randomized, Dose-Finding, Proof-of-Concept Study of Berberine Ursodeoxycholate in Patients With Primary Sclerosing Cholangitis. Am J Gastroenterol. 2022 Nov 1;117(11):1805-1815. doi: 10.14309/ajg.0000000000001956. Epub 2022 Aug 22.

ID	Title	Description
FG000	500mg HTD1801 BID	HTD1801: HTD1801 tablets, 250 mg
FG001	1000 mg HTD1801 BID	HTD1801: HTD1801 tablets, 250 mg

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 7, 2019	May 7, 2021

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Absolute Change in Serum Alkaline Phosphatase (ALP) From Baseline to Week 6 in Period 1

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.

Posted

Mean

Standard Error

U/L

Baseline to Week 6

ID	Title	Description
OG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets

Units	Counts
Participants	OG00015 OG00123 OG00216

Title

Denominators

Categories

Title	Measurements
	OG000-71± 136.9 OG001-73± 139.9 OG00294± 261.7

Secondary

Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 6 (Period 1)

Period 1 mITT population: 54 subjects.

Posted

Count of Participants

Participants

Baseline to Week 6

ID	Title	Description
OG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets

Units	Counts
Participants	OG000

Secondary

Percentage of Subjects Who Achieve a 50% Decrease in ALP at the End of Week 6 (Period 1)

Period 1 mITT population: 54 subjects.

Posted

Count of Participants

Participants

Baseline to Week 6

ID	Title	Description
OG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets

Units	Counts
Participants	OG000

Secondary

Percentage of Subjects Who Normalize ALP at the End of Week 6 (Period 1)

Period 1 mITT population: 54 subjects.

Posted

Count of Participants

Participants

Baseline to Week 6

ID	Title	Description
OG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets

Units	Counts
Participants	OG000

Secondary

Absolute Change in Serum Total Bilirubin at the End of Week 6 (Period 1)

Period 1 mITT population: 54 subjects.

Posted

Mean

Standard Deviation

mg/dL

Baseline to Week 6

ID	Title	Description
OG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250 mg
OG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets

Units	Counts
Participants	OG000

Secondary

Absolute Change in Serum ALP From Week 6 to Week 12 (Period 2)

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.

Posted

Mean

Standard Deviation

U/L

Week 6 to Week 12

ID	Title	Description
OG000	Placebo to HTD1801 500 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 500 mg BID in Period 2
OG001	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects randomized to receive HTD1801 500 mg BID in Period 1 continuing to receive HTD1801 500 mg BID in Period 2
OG002	Placebo to HTD1801 1000 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 1000 mg BID in Period 2
OG003	HTD1801 1000 mg BID to HTD1801 1000 mg BID

Secondary

Percentage of Subjects Who Achieve ALP of <1.5 x ULN at the End of Week 12 (Period 2)

51 subjects in the mITT population who completed Period 1 and began Period 2.

Posted

Count of Participants

Participants

Week 6 to Week 12

ID	Title	Description
OG000	Placebo to HTD1801 500 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 500 mg BID in Period 2
OG001	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects randomized to receive HTD1801 500 mg BID in Period 1 continuing to receive HTD1801 500 mg BID in Period 2
OG002	Placebo to HTD1801 1000 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 1000 mg BID in Period 2
OG003	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects randomized to receive HTD1801 1000 mg BID in Period 1 continuing to receive HTD1801 1000 mg BID in Period 2

Secondary

Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 12 (Period 2)

51 subjects in the mITT population who completed Period 1 and began Period 2.

Posted

Count of Participants

Participants

Week 6 to Week 12

ID	Title	Description
OG000	Placebo to HTD1801 500 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 500 mg BID in Period 2
OG001	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects randomized to receive HTD1801 500 mg BID in Period 1 continuing to receive HTD1801 500 mg BID in Period 2
OG002	Placebo to HTD1801 1000 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 1000 mg BID in Period 2
OG003	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects randomized to receive HTD1801 1000 mg BID in Period 1 continuing to receive HTD1801 1000 mg BID in Period 2

Secondary

Percentage of Patients Who Normalize ALP at the End of Week 12 (Period 2)

51 subjects in the mITT population who completed Period 1 and began Period 2.

Posted

Count of Participants

Participants

Week 6 to Week 12

ID	Title	Description
OG000	Placebo to HTD1801 500 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 500 mg BID in Period 2
OG001	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects randomized to receive HTD1801 500 mg BID in Period 1 continuing to receive HTD1801 500 mg BID in Period 2
OG002	Placebo to HTD1801 1000 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 1000 mg BID in Period 2
OG003	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects randomized to receive HTD1801 1000 mg BID in Period 1 continuing to receive HTD1801 1000 mg BID in Period 2

Secondary

Absolute Change in Serum Total Bilirubin at the End of Week 12 (Period 2)

49 subjects in the mITT population who completed Period 2.

Posted

Mean

Standard Deviation

mg/dL

Week 6 to Week 12

ID	Title	Description
OG000	Placebo to HTD1801 500 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 500 mg BID in Period 2
OG001	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects randomized to receive HTD1801 500 mg BID in Period 1 continuing to receive HTD1801 500 mg BID in Period 2
OG002	Placebo to HTD1801 1000 mg BID	Subjects randomized to receive Placebo BID in Period 1 re-randomized to receive HTD1801 1000 mg BID in Period 2
OG003	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects randomized to receive HTD1801 1000 mg BID in Period 1 continuing to receive HTD1801 1000 mg BID in Period 2

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

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.

Posted

Mean

Standard Deviation

U/L

Week 12 to Week 18

ID	Title	Description
OG000	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 500 mg BID in Period 3.
OG001	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 1000 mg BID in Period 3.
OG002	HTD1801 500 mg BID to Placebo	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.
OG003	HTD1801 1000 mg BID to Placebo

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)

50 subjects in the mITT population who completed Period 2 and began Period 3.

Posted

Count of Participants

Participants

Week 12 to Week 18

ID	Title	Description
OG000	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 500 mg BID in Period 3.
OG001	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 1000 mg BID in Period 3.
OG002	HTD1801 500 mg BID to Placebo	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.
OG003	HTD1801 1000 mg BID to Placebo	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.

Secondary

Percentage of Patients Who Achieve a 50% Decrease in ALP at the End of Week 18 (Period 3)

50 subjects in the mITT population who completed Period 2 and began Period 3.

Posted

Count of Participants

Participants

Week 12 to Week 18

ID	Title	Description
OG000	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 500 mg BID in Period 3.
OG001	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 1000 mg BID in Period 3.
OG002	HTD1801 500 mg BID to Placebo	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.
OG003	HTD1801 1000 mg BID to Placebo	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.

Secondary

Percentage of Subjects Who Normalize ALP at the End of Week 18 (Period 3)

50 subjects in the mITT population who completed Period 2 and began Period 3.

Posted

Count of Participants

Participants

Week 12 to Week 18

ID	Title	Description
OG000	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 500 mg BID in Period 3.
OG001	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 1000 mg BID in Period 3.
OG002	HTD1801 500 mg BID to Placebo	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.
OG003	HTD1801 1000 mg BID to Placebo	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.

Secondary

Absolute Change in Serum Total Bilirubin at the End of Week 18 (Period 3)

49 subjects in the mITT population who completed Period 3.

Posted

Mean

Standard Deviation

mg/dL

Week 12 to Week 18

ID	Title	Description
OG000	HTD1801 500 mg BID to HTD1801 500 mg BID	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 500 mg BID in Period 3.
OG001	HTD1801 1000 mg BID to HTD1801 1000 mg BID	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to continue receiving HTD1801 1000 mg BID in Period 3.
OG002	HTD1801 500 mg BID to Placebo	Subjects who received 500 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.
OG003	HTD1801 1000 mg BID to Placebo	Subjects who received 1000 mg HTD1801 BID in Period 2 re-randomized to receive Placebo in Period 3.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0017 affected31 at risk EG0020 affected35 at risk
Nausea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0014 affected31 at risk EG0020 affected35 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Constipation	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Frequent bowel movements	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Vomiting	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0012 affected31 at risk EG0020 affected35 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Ascites	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Colitis Ulcerative	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Gastritis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Inflammatory Bowel Disease	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Intestinal Obstruction	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Nasopharyngitis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0013 affected31 at risk EG0022 affected35 at risk
Upper Respiratory Tract Infection	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0012 affected31 at risk EG0021 affected35 at risk
Sinusitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Bronchitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Clostridium Difficile Colitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Cystitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Influenza	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Laryngitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Localised Infection	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Oral Herpes	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Tonsillitis	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0002 affected22 at risk EG0015 affected31 at risk EG0022 affected35 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0012 affected31 at risk EG0020 affected35 at risk
Hair Texture Abnormal	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Night Sweats	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Rosacea	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Spider Naevus	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Blood Alkaline Phosphatase Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0025 affected35 at risk
Alanine Aminotransferase Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0023 affected35 at risk
Aspartate Aminotransferase Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0023 affected35 at risk
Gamma-Glutamyltransferase Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0023 affected35 at risk
Liver Function Test Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0023 affected35 at risk
Blood Bilirubin Increased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Blood Potassium Decreased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Pyrexia	General disorders	MedDRA 20.1	Systematic Assessment	EG0002 affected22 at risk EG0012 affected31 at risk EG0021 affected35 at risk
Influenza Like Illness	General disorders	MedDRA 20.1	Systematic Assessment	EG0002 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Fatigue	General disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Chest Pain	General disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Chills	General disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Headache	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0012 affected31 at risk EG0021 affected35 at risk
Dizziness	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Lethargy	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0021 affected35 at risk
Cervical Radiculopathy	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Lumbar Radiculopathy	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Migraine	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Flank Pain	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Intervertebral Disc Protrusion	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Osteoporosis	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Tendonitis	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0012 affected31 at risk EG0021 affected35 at risk
Dry Throat	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Pulmonary Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Sinus Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Sputum Increased	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Tachycardia	Cardiac disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0012 affected31 at risk EG0020 affected35 at risk
Arrhythmia	Cardiac disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Joint Injury	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Limb Injury	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Spinal Column Injury	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Stoma Site Haemorrhage	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Deep Vein Thrombosis	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Hot Flush	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Hypotension	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Cholangitis	Hepatobiliary disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Lipoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Melanocytic Naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected22 at risk EG0010 affected31 at risk EG0020 affected35 at risk
Vision Blurred	Eye disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Hypersensitivity	Immune system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Insomnia	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0010 affected31 at risk EG0021 affected35 at risk
Chromaturia	Renal and urinary disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk
Gynaecomastia	Reproductive system and breast disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected22 at risk EG0011 affected31 at risk EG0020 affected35 at risk

ID	Term
D002761	Cholangitis
D001649	Bile Duct Diseases
D001660	Biliary Tract Diseases
D004066	Digestive System Diseases

ID	Title	Description
BG000	HTD1801 500 mg BID	HTD1801: HTD1801 tablets, 250mg
BG001	HTD1801 1000 mg BID	HTD1801: HTD1801 tablets, 250mg
BG002	Placebo BID	Placebo: tablets manufactured to mimic HTD1801 tablets
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	500mg HTD1801 bid	HTD1801: HTD1801 tablets, 250mg	22	1	22	14	22
EG001	1000mg HTD1801 bid	HTD1801: HTD1801 tablets, 250mg	31	3	31	20	31
EG002	placebo bid	Placebo: tablets manufactured to mimic HTD1801 tablets	35	0	35	18	35