Conditions: Primary Biliary Cholangitis Primary Biliary Cirrhosis Cholangitis Cholestasis Biliary Tract Diseases Bile Duct Stricture
Keywords: Open-label
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: HTD1801 (BUDCA) 250 mg tablets. Dosed at 1000 mg BID with food.

Interventions: intervention 1: HTD1801 (BUDCA)
Intervention descriptions: intervention 1: HTD1801 (BUDCA) 250 mg tablets. Dose 1000 mg twice daily with food for 12 weeks.

Protocol document:
Prot_000.pdf: 
 
 
 
 
CLINICAL PROTOCOL 
 
A Phase 2 Open Label Proof-of-Concept Study of HTD1801 in Adult Subjects 
with Primary Biliary Cholangitis (PBC) and an Inadequate Response to 
Standard Therapy 
(PRONTO-PBC) 
 
Protocol HTD1801.PCT013 
IND 136137 
NCT04604652 
 
 
Study Sponsor: 
HighTide Biopharma Pty. Ltd. 
 
Level 13, Citigroup Tower  
 
2 Park Street 
 
Sydney, NSW 2000 
 
Australia 
 
 
 
 
Date of issue: 17 August 2021 
 
Version number: 4.0 
 
 
 
 
CONFIDENTIAL 
 
 
 




CONFIDENTIAL 
HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
3
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
STATEMENT OF COMPLIANCE .................................................................................................8 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................14 
1.3. 
Schedule of Activities .................................................................................................15 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Background .................................................................................................................18 
2.1.1. 
Primary Biliary Cholangitis ........................................................................................18 
2.1.2. 
HTD1801 ....................................................................................................................18 
2.2. 
Study Rationale ...........................................................................................................19 
2.3. 
Risk/Benefit Assessment ............................................................................................19 
2.3.1. 
Known Potential Risks ...............................................................................................19 
2.3.2. 
Known Potential Benefits ...........................................................................................19 
2.3.3. 
Assessment of Potential Risks and Benefits ...............................................................19 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................20 
4. 
STUDY DESIGN .......................................................................................................21 
4.1. 
Overall Design ............................................................................................................21 
4.2. 
Scientific Rationale for Study Design ........................................................................21 
4.3. 
Justification for Dose ..................................................................................................21 
4.4. 
End of Study Definition ..............................................................................................22 
5. 
STUDY POPULATION .............................................................................................23 
5.1. 
Inclusion Criteria ........................................................................................................23 
5.2. 
Exclusion Criteria .......................................................................................................24 
5.3. 
Screen Failures ............................................................................................................25 
6. 
STUDY INTERVENTION ........................................................................................26 
6.1. 
Study Intervention Administration .............................................................................26 
6.1.1. 
Study Intervention Description ...................................................................................26 
6.1.2. 
Dosing and Administration .........................................................................................26 
6.1.3. 
Dose Modification ......................................................................................................26 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................27 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
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6.2.1. 
Acquisition and Accountability ..................................................................................27 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ..................................................27 
6.2.3. 
Product Storage and Stability .....................................................................................27 
6.3. 
Study Intervention Compliance ..................................................................................27 
6.4. 
Concomitant Therapy .................................................................................................28 
6.4.1. 
Permitted Concomitant Medications ..........................................................................28 
6.4.2. 
Prohibited Concomitant Medications .........................................................................28 
6.4.2.1. 
Prohibited medications that are active against PBC ...................................................28 
6.4.2.2. 
Prohibited medications for the treatment of AIH .......................................................28 
6.4.2.3. 
Prohibited medications with potential for drug-drug interaction ...............................28 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................30 
7.1. 
Decrease in dose of study drug ...................................................................................30 
7.2. 
Discontinuation of Study Intervention........................................................................30 
7.3. 
Participant Discontinuation/Withdrawal from the Study ...........................................30 
7.4. 
Study Stopping Criteria ..............................................................................................31 
8. 
STUDY PROCEDURES AND EVALUATIONS .....................................................32 
8.1. 
Pre-screening (Days -56 to -28) ALP .........................................................................32 
8.2. 
Screening (Days -28 to -1) ..........................................................................................32 
8.3. 
Baseline/Day 0 ............................................................................................................33 
8.4. 
Week 2 and Week 4 Visits (±3 days) .........................................................................34 
8.5. 
Week 6 Visit (±3 days) ...............................................................................................34 
8.6. 
Week 8 Visit (±3 days) ...............................................................................................35 
8.7. 
Week 12 Visit (±3 days) .............................................................................................35 
8.8. 
Week 16 Visit (±5 days) .............................................................................................36 
8.9. 
Early Termination Visit ..............................................................................................37 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................38 
9.1. 
Efficacy Assessments .................................................................................................38 
9.1.1. 
Serum Alkaline Phosphatase Endpoints .....................................................................38 
9.1.2. 
Secondary Efficacy Endpoints ....................................................................................38 
9.2. 
Safety and Other Assessments ....................................................................................38 
9.2.1. 
Demographics and Medical History ...........................................................................38 
9.2.2. 
Adverse Events ...........................................................................................................38 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
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9.2.3. 
Physical Examinations ................................................................................................38 
9.2.4. 
Vital Signs, Height, and Weight .................................................................................39 
9.2.5. 
Electrocardiograms .....................................................................................................39 
9.2.6. 
Safety Related Laboratory Assessments .....................................................................39 
9.2.7. 
GLOBE Score .............................................................................................................40 
9.2.8. 
Pruritus VAS ...............................................................................................................40 
9.2.9. 
Pharmacokinetic (PK) sub-study ................................................................................41 
9.3. 
Adverse Events and Serious Adverse Events .............................................................41 
9.3.1. 
Definition of Adverse Event (AE) ..............................................................................41 
9.3.2. 
Definition of Serious Adverse Event (SAE) ...............................................................42 
9.3.3. 
Classification of an Adverse Event .............................................................................43 
9.3.3.1. 
Severity of Event ........................................................................................................43 
9.3.3.2. 
Relationship to Study Intervention .............................................................................44 
9.3.3.3. 
Expectedness ...............................................................................................................45 
9.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up ...........................45 
9.3.5. 
Adverse Event Reporting ............................................................................................45 
9.3.6. 
Serious Adverse Event Reporting ...............................................................................46 
9.3.7. 
Reporting Events to Participants ................................................................................46 
9.3.8. 
Events of Special Interest ...........................................................................................47 
9.3.8.1. 
Gastrointestinal Event .................................................................................................47 
9.3.8.2. 
Treatment Failure due to HTD1801 Dose Reduction .................................................47 
9.3.8.3. 
Reporting of Pregnancy ..............................................................................................47 
10. 
DRUG-INDUCED LIVER INJURY (DILI) MONITORING AND 
STOPPING RULES....................................................................................................48 
10.1. 
Protocol Definition of Normal or Near Normal and Elevated ALT ...........................48 
10.1.1. 
Detection of Potential DILI in Subjects with Normal or Near Normal ALT 
levels at baseline .........................................................................................................48 
10.1.2. 
Detection of Potential DILI in Subjects with Elevated ALT levels at baseline .........48 
10.1.3. 
Process for DILI Monitoring ......................................................................................48 
11. 
COVID-19 PANDEMIC CONTINGENCIES ...........................................................53 
11.1. 
Potential Impact of COVID-19 on Study Conduct .....................................................53 
11.2. 
Operational Contingencies related to COVID-19 Pandemic ......................................53 
12. 
STATISTICAL CONSIDERATIONS .......................................................................54 


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Clinical Protocol  
Study HTD1801.PCT013 
 
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12.1. 
Statistical Hypotheses .................................................................................................54 
12.2. 
Sample Size Determination ........................................................................................54 
12.3. 
Populations for Analyses ............................................................................................54 
12.4. 
Statistical Analyses .....................................................................................................54 
12.4.1. 
General Approach .......................................................................................................54 
12.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................55 
12.4.3. 
Analysis of the Secondary Endpoint(s) ......................................................................55 
12.4.4. 
Safety Analyses ..........................................................................................................55 
12.4.5. 
Pharamacokinetic Analyses ........................................................................................55 
12.4.6. 
Baseline Descriptive Statistics ....................................................................................55 
12.4.7. 
Planned Interim Analyses ...........................................................................................55 
13. 
STUDY ADMINISTRATION ...................................................................................56 
13.1. 
Informed Consent and Authorization For Use and Disclosure of Protected 
Health Information ......................................................................................................56 
13.2. 
Study Discontinuation and Closure ............................................................................56 
13.3. 
Study Documentation .................................................................................................56 
13.3.1. 
Investigator Information .............................................................................................56 
13.3.2. 
Investigator’s Study Files ...........................................................................................57 
13.3.3. 
Case Report Forms and Source Documentation .........................................................57 
13.3.4. 
Retention of Study Documents ...................................................................................57 
13.4. 
Confidentiality ............................................................................................................57 
13.4.1. 
Data .............................................................................................................................57 
13.4.2. 
Subject Anonymity .....................................................................................................58 
13.5. 
Protocol Compliance ..................................................................................................58 
13.6. 
Study Monitor Functions and Responsibility .............................................................58 
13.7. 
Quality Assurance and Quality Control ......................................................................58 
13.8. 
General Information ....................................................................................................59 
14. 
ABBREVIATIONS ....................................................................................................60 
15. 
REFERENCES ...........................................................................................................62 
APPENDIX A. GLOBE SCORE ................................................................................................63 
APPENDIX B. PRURITUS VAS SCORE .................................................................................64 
 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
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LIST OF TABLES 
Table 1 
Schedule of Events .....................................................................................................15 
Table 2: 
Prohibited Medications with potential for drug-drug interaction ...............................29 
Table 3 
Laboratory Analytes ...................................................................................................40 
Table 4 
Classification of Adverse Events (AEs) by Severity ..................................................44 
Table 5 
Assessment of Causality of AEs .................................................................................45 
Table 6 
Timeline for Reporting SAEs .....................................................................................46 
Table 7: 
Liver Monitoring Procedure – For Subjects with Normal or Near Normal 
Baseline ALT ( ≤60 U/L) ...........................................................................................49 
Table 8: 
Liver Monitoring Procedure – For Subjects with Calculated Baseline ALT 
>60 U/L (Elevated ALT) ............................................................................................51 
 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
8
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations 
(CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR 
Part 312, and/or 21 CFR Part 812). The Principal Investigator will assure that no deviation from, 
or changes to the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor and documented approval from the Institutional Review Board (IRB), 
except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
9
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of sponsor company: HighTide Biopharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate  
Title of study: A Phase 2 Open Label Proof-of-Concept Study of HTD1801 in Adult Subjects with 
Primary Biliary Cholangitis (PBC) and an Inadequate Response to Standard Therapy (PRONTO-PBC) 
Investigator(s): Multicenter 
Number of sites:  Up to 20 
Study periods:  
Pre-screening:  Up to 28 days 
Screening:  Up to 28 days 
Open-label treatment:  12 weeks 
Follow-up:  28 days after last dose of investigational product (IP) 
Phase of development: 2 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the effects of HTD1801 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. 
Primary Endpoint: 
• Percent change in ALP at Week 12 compared to 
Baseline. 
Additional ALP Secondary Endpoints: 
• Absolute change in ALP at Week 12 compared to 
Baseline 
• Proportion of subjects who have ≥20% decrease in 
ALP from Baseline to Week 12 
• Proportion of subjects who have ≥40% decrease in 
ALP from Baseline to Week 12 
• The proportion of subjects who normalize ALP at 
Week 12 
Secondary Objectives: 
Secondary Endpoints: 
To evaluate the effects of HTD1801 on 
serum markers of cholestasis 
• Change in total bilirubin from Baseline to Week 12 
• Change in serum gamma-glutamyl transferase 
(GGT) between Baseline and Week 12 
• Change in ALT from Baseline to Week12 
• Change in AST from Baseline to Week 12 
To evaluate the effects of HTD1801 on 
serum lipids 
• Change in serum cholesterol (total and LDL) and 
triglyceride levels between Baseline and Week 12 
To evaluate the effects of HTD1801 on 
serum markers of inflammation 
• Change in inflammatory serum markers including 
fibrinogen, CRP, Haptoglobin, ELF and serum 
immunoglobulins between Baseline and Week 12 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
10 
To evaluate the safety and tolerability 
of HTD1801 over 12 weeks of 
treatment in adult subjects with PBC 
• Change in GLOBE score between Baseline and 
Week 12 
• Change in pruritus as measured by Pruritus visual 
analog score (VAS) between Baseline and Week 12 
• Adverse events and changes in physical 
examination, vital signs, and clinical laboratory 
values 
To evaluate the pharmacokinetic profile 
of HTD1801in a subset of subjects 
participating in this study 
Descriptive statistics on plasma concentrations of 
measured analytes for berberine and UDCA and its 
conjugates 
Study Design: A single arm, 12-week open-label study with follow-up 28 days after last dose of IP. 
Upon confirmation of eligibility, subjects will be enrolled and will receive HTD1801 1000 mg BID for 
12 weeks. 
Number of subjects: Up to 30 subjects. If a subject discontinues from the study for any reason other 
than safety prior to the first post-dose assessment, an additional subject may be enrolled. 
Inclusion criteria:  
1. 
Male or female between 18 and 75 years of age, inclusive 
2. 
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: 
a) Biochemical evidence of cholestasis with elevation of ALP activity 
b) Presence of antimitochondrial antibody (AMA) 
c) Histopathologic evidence of nonsuppurative 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. 
3. 
Has been taking a stable, adequate dose (at minimum 13mg/kg/day) of UDCA for at least 6 
months, with a serum ALP of  ≥1.5 × ULN 
4. 
Has two consecutive values of ALP >1.5x ULN (historical and screening values) of which the 
second ALP value must not be down trending relative to the first ALP value 
a. If the historical ALP value was obtained more than 6 months prior to study start as part of 
standard of care, a more recent historical value should be obtained as a part of a pre-screening 
visit.  If this more recent value is ≥1.5 × ULN, the subject may be scheduled for full screening as 
soon as 4 weeks later and a second ALP value should be obtained as part of full screening.  Both 
values must be >1.5x ULN. 
b. If the historical ALP value 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.  Both values 
must be ≥1.5x ULN. 
c. If the screening ALP value is more than ≥30% lower than the historical value obtained 
as part of standard of care, the subject will not qualify for enrollment but may be re-
screened as soon as 4 weeks later.  If on re-screening the ALP value continues to be 
>30% lower, the subject will not be eligible to be in the study.  Because there may be 


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
11 
considerable variability in the reference range for ALP obtained for the historical value, 
the estimation of downward trends of more than 30% should take this into account 
5. 
Be willing to discontinue UDCA the day prior to the start of IP dosing 
6. 
Be willing to discontinue the use of berberine supplements or berberine herbal products the day 
prior to the start of IP dosing  
7. 
If the subject is taking cholestyramine or other bile acid sequestrant for pruritus, the subject must 
be on a stable dose and taking it 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  
8. 
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 
9. 
Be able to understand and sign a written or electronic informed consent form (ICF) 


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Clinical Protocol  
Study HTD1801.PCT013 
 
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Exclusion criteria: 
1. 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.  Use of medications other than prednisone or azathioprine for the treatment 
of AIH is prohibited (e.g., Mycophenolate).  Stable use of immunosuppressives for 
other indications may be permitted (see below).  Enrollment of subjects with 
controlled AIH will be limited to a total of 5 subjects. 
2. Other plausible reasons for elevations in serum alkaline phosphatase such as drug-
induced liver injury, concomitant cholestatic liver disease or bone disease. 
3. History of alcohol or substance abuse 
4. Prior liver transplantation or currently listed for liver transplantation 
5. History of chronic viral hepatitis, types B or C  
6. 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 
7. Total bilirubin >1.3 mg/dL unless subject has Gilbert’s Syndrome.  If subject has 
increased total bilirubin due to Gilbert’s Syndrome, then direct bilirubin should be 
<0.3 mg/dL. 
8. Hemoglobin <10 g/dL for males or females 
9. Serum TSH level <0.1 or >10 u/mL (subject may be re-screened if hyper- or 
hypothyroidism has been corrected) 
10. Renal impairment with eGFR <60ml/min/1.73 m^2 (CKD stages 3, 4 or 5) 
11. Human immunodeficiency virus (HIV)-1 or HIV-2 infection by history 
12. Glucose-6-phosphate dehydrogenase (G6PD) deficiency,  a screening assay will be 
performed.  If serum level is below normal, clinical evaluation and further testing may 
be needed to confirm a diagnosis of G6PD deficiency. 
 
13. History of malignancy within the past 2 years or ongoing malignancy other than basal 
cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma 
14. Active, serious infections that require parenteral antibiotic or antifungal therapy 
within 30 days prior to Screening 
15. Major surgical procedure within 30 days of Screening or prior solid organ 
transplantation 
16. Females who are pregnant or breastfeeding 
17. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic 
agents, and immune-modulating agents (such as interleukins, interferons).  Chronic, 
stable use of immunosuppressive medication may be allowed with medical monitor 
approval 
18. Allergy to the clinical trial material or its components 
19. Having received any experimental medications within 28 days prior to Screening 


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Clinical Protocol  
Study HTD1801.PCT013 
 
13 
20. Use of bezafibrate or fenofibrate within 28 days prior to first day of IP dosing 
21. Use of obeticholic acid (OCA) within 28 days prior to first day of IP dosing 
22. 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 
Test product, dose, and mode of administration:  
HTD1801:  1000 mg administered as tablets twice daily with food  
Reference therapy, dose and mode of administration:  N/A 
Duration of treatment: Up to 12 weeks 
Criteria for Evaluation: 
Efficacy Evaluation 
Efficacy endpoints will be evaluated with descriptive statistics to include 95% confidence intervals. 
Testing will be used. For the primary endpoint a one sample t-test against a null hypothesis of no 
change, will be used with a 5% one-sided alpha level. The safety population will include all treated 
subjects and the efficacy population will include all treated subjects with at least one post dose ALP 
assessment. Baseline will be assigned to the last available assessment prior to the start of treatment. 
Safety Evaluation 
Adverse events and changes in clinical laboratory assessments will be used to evaluate safety and 
tolerability. Safety data will be summarized using descriptive analysis. 
Sample Size: 
A sample size of 30 subjects provides ≥90% power for the primary endpoint assuming a mean percent 
reduction in ALP of 15% and a SD of 25%. Power calculations use a 5% one sided alpha and a t-test. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
14 
1.2. 
Schema 
 
 
Optional 
Pre-
Screening 
for ALP 
Screening 
Baseline 
Initiate IP 
Dosing 
IP Dosing 
HTD1801 1000 mg BID 
Follow-Up 
End of 
Study 
Day -56 to 
Day -28 
Day -28 to 
Day -1 
Day 0 
Week 2 
Day 14 
±3 days 
Week 4 
Day 28 
±3 days 
Week 6 
Day 42 
±3 days 
Week 8 
Day 56 
±3 days 
Week 12 
Day 84 
±3 days 
Week 16 
Day 112 
±5 days 
PK Sampling:  
-30 minutes 
prior to dosing, 
4 hours ±30 
minutes and 
8 hours ±30 
minutes post-
dosing 
for subset of at 
least 6 subjects 
PK Sampling:  
-30 minutes 
prior to dosing, 
4 hours ±30 
minutes and 
8 hours ±30 
minutes post-
dosing 
for subset of at 
least 6 subjects 


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Clinical Protocol  
Study HTD1801.PCT013 
 
15 
1.3. 
Schedule of Activities 
Table 1 
Schedule of Events 
 
Optional  
Pre-screeing Screening Baseline 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk12 
ETh 
Wk 16 Follow-
up 
Visit Day 
-56 to -28 
-28 to -1 
0 
14 
28 
42 
56 
84 
NA 
+28d (Day 112) 
Procedure / Window 
 
- 
- 
±3d 
±3d 
±3d 
±3d 
±3d 
±5d 
Clinic visit 
X 
X 
X 
Xd 
Xd 
X 
Xd 
X 
Xd 
Xi 
Informed consent 
X 
Xj 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
X 
Xa 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
Xa 
 
 
 
 
 
 
 
Assign subject ID# 
X 
X 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
 
X 
 
 
 
 
Return study drug  
 
 
 
 
 
Xb 
 
Xb 
Xb 
 
Study discharge 
 
 
 
 
 
 
 
 
X 
X 
Complete physical examination 
 
X 
 
 
 
 
 
 
 
 
Targeted physical examination c 
 
 
Xc 
 
 
Xc 
 
Xc 
Xc 
Xc 
Vital signs 
 
X 
X 
 
 
X 
 
X 
X 
X 
Weight 
 
X 
X 
 
 
X 
 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
BMI (calculated within EDC) 
 
X 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
 
 
X 
X 
 
Serum chemistry panel including 
GGT 
X 
X 
X 
Xd 
Xd 
X 
Xd 
X 
Xd 
Xd 
Lipid panel (triglycerides, HDL-
c, LDL-c, and total cholesterol) 
 
Xi 
Xi 
 
 
Xi 
 
Xi 
Xi 
 
CBC with differential (no smear) 
 
X 
X 
 
 
X 
 
X 
X 
 
INR 
 
X 
 
 
 
X 
 
X 
X 
 
Fibrinogen 
 
X 
X 
 
 
X 
 
X 
X 
 


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Clinical Protocol  
Study HTD1801.PCT013 
 
16 
 
Optional  
Pre-screeing Screening Baseline 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk12 
ETh 
Wk 16 Follow-
up 
Visit Day 
-56 to -28 
-28 to -1 
0 
14 
28 
42 
56 
84 
NA 
+28d (Day 112) 
Procedure / Window 
 
- 
- 
±3d 
±3d 
±3d 
±3d 
±3d 
±5d 
CRP 
 
X 
X 
 
 
X 
 
X 
X 
 
Haptoglobulin  
 
X 
X 
 
 
X 
 
X 
X 
 
ELF 
 
X 
X 
 
 
X 
 
X 
X 
 
G6PD 
 
X 
 
 
 
 
 
 
 
 
IgM 
 
X 
X 
 
 
X 
 
X 
X 
 
IgG 
 
X 
X 
 
 
X 
 
X 
X 
 
Bile acid panele 
 
 
Xe 
 
 
Xe 
 
Xe 
Xe 
 
AMA  
 
X 
 
 
 
 
 
 
 
 
ANA 
 
X 
 
 
 
 
 
 
 
 
TSH 
 
X 
 
 
 
 
 
 
 
 
FSHf 
 
Xf 
 
 
 
 
 
 
 
 
PK blood drawg 
 
 
 
 
 
Xg 
 
Xg 
 
 
Urine Pregnancy Test 
 
 
Xk 
 
 
 
 
Xk 
Xk 
 
GLOBE Score 
 
 
Xl 
 
 
Xl 
 
Xl 
Xl 
 
Pruritus VAS 
 
X 
X 
 
 
X 
 
X 
X 
 
Adverse event monitoring 
 
 
Xa 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant 
medications 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AMA = antimitochondrial antibody; ANA = antinuclear antibody; BMI = body mass index; CBC = complete blood count; CRP = C-reactive 
protein; ECG = electrocardiogram; EDC = electronic data capture; ELF = enhanced liver fibrosis; FSH = follicle stimulating hormone; G6PD = glucose-6-
phosphate dehydrogenase; GGT = gamma-glutamyl transferase; HDL-c = high-density lipoprotein cholesterol; IgG = immunoglobulin G; IgM = 
immunoglobulin M; INR = international normalized ratio; LDL-c = low-density lipoprotein cholesterol; PBC = primary biliary cholangitis; TSH = thyroid 
stimulating hormone; VAS = visual analogue scale 
a Confirm continued eligibility 
b IP return and reconciliation 
c Targeted PE to include assessment of only those findings that were abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered by 
subject 
d Optional “in-home” blood draw for COVID-19 contingency measures  


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Clinical Protocol  
Study HTD1801.PCT013 
 
17 
e Bile Acid Panel only for those subjects for whom a sample was obtained at Baseline 
f Female subjects only, To confirm menopausal status 
g Drawn -30 minutes prior to dosing at Week 6 and Week 12; drawn 4 hours (±30 minutes) and 8 hours (±30 minutes) post investigational study drug dosing at Week 6 and Week 
12 
h Subject who ET will be requested to come back 28 days after their last study dose 
i Subjects to fast but may have unsweetened, clear coffee, tea or water but no food after supper the evening before 
j If consent not obtained prior to optional pre-screening visit 
k Only for women of childbearing potential 
l GLOBE score calculated by the biostatistician at the completion of the study  


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Clinical Protocol  
Study HTD1801.PCT013 
 
18 
2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Primary Biliary Cholangitis 
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic, 
slowly progressive autoimmune liver disease. PBC mainly affects women (90%) and, typically, 
is diagnosed between the ages of 35 - 60. It is characterized by inflammation and destruction of 
small bile ducts, accompanied by fibrosis (excess fibrous connective tissue) and eventually 
cirrhosis (extensive scarring of the liver). Another key feature is the presence of specific anti-
mitochondrial antibodies (AMA) in the blood in over 90% of the patients.  
PBC is a relatively rare disease and occurs worldwide. The incidence and prevalence in various 
countries and regions differ considerably and have been reported to vary from 0.33 to 5.8 and 
1.91 to 40.2 cases per 100 000 inhabitants, respectively. 
Many PBC patients do not experience any symptom at diagnosis or during the course of the 
disease and are diagnosed after the finding of abnormal liver tests at screening or testing for 
other conditions. However, a significant proportion of patients do have symptoms that can 
markedly influence the quality of life. The most common symptoms are fatigue and itching. 
Treatment with ursodeoxycholic acid (UDCA) is standard for PBC and can improve liver 
function tests and slow the progression of disease. UDCA was first approved in 1997 in the US 
for the treatment of PBC (URSO 250 and URSO Forte Prescribing Information 2013). In a study 
of 180 patients with PBC, UDCA at doses of 13 to 15 mg/kg/day was shown to improve liver 
biochemistry, delay the progression of liver disease, and prevent the need for liver 
transplantation relative to placebo treatment (Levy 2003, Lindor 1996). The results of another 
randomized, double-blind, placebo-controlled trial enrolling 103 patients with PBC showed that 
13 to 15 mg/kg/day UDCA was associated with a 5-fold lower progression rate from early stage 
disease to extensive fibrosis or cirrhosis (Corpechot 2000). Up to 40% of PBC patients have an 
inadequate response to UDCA and may continue to have disease progression. Obeticholic acid 
(OCALIVA, OCA), a farnesoid X receptor (FXR) agonist, is indicated for the treatment of PBC 
in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy 
in adults unable to tolerate UDCA (OCALIVA Prescribing Information 2020). The addition of 
OCA to UDCA can significantly improve serum ALP, GGT, ALT and total bilirubin, which are 
markers of clinical outcome in PBC (Bahar 2018; Hirschfield 2015).  
2.1.2. 
HTD1801  
HTD1801 is a novel salt formed between berberine (BBR) and ursodeoxycholic acid (UDCA) 
with a stoichiometry of 1:1. HTD1801 is currently being developed as an oral treatment for PBC, 
primary sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH). HTD1801 is 
expected to dissociate into BBR salt and UDCA after oral administration. Due to the different 
mechanisms of the two products, at least an additive, and possibly an additive or synergistic 
effect may occur when they are administered together in the form of HTD1801. This study will 
evaluate HTD1801 in adult subjects with PBC by assessing effects of alkaline phosphatase 
(ALP) over 12 weeks. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
19 
Further information on the use of HTD1801 in clinical and nonclinical studies can be found in 
the Investigator’s Brochure. 
2.2. 
Study Rationale 
HTD1801 is a salt of ursodeoxycholic acid (UDCA) and berberine (BBR). UDCA has been the 
mainstay of primary biliary cholangitis (PBC) for many years and has dramatically improved the 
prognosis of the disease. UDCA is now registered around the world for the first-line treatment of 
the disease. Unfortunately, around 40 to 50% of PBC patients do not respond to UDCA or do not 
maintain an adequate response to UDCA. An inadequate response to UDCA is defined as a 
persistence of a biochemical cholestatic syndrome and is generally expressed as a persistent 
increase of serum alkaline phosphatase (ALP) above 1.67 times the upper limit of normal for the 
laboratory performing the analysis. Unfortunately, around 50% of PBC patients who are 
incomplete responders to UDCA do not respond to the addition of obeticholic acid. In addition, 
treatment with obeticholic acid may induce or exacerbate pruritus, a symptom frequently 
affecting PBC patients, and thus may lead to treatment discontinuation. Hence, there is still an 
unmet medical need in PBC patients. 
The addition of BBR to UDCA, as a salt, in HTD1801 could deliver a benefit to PBC patients 
who are inadequate responders to UDCA alone. While BBR alone has not been studied in PBC, 
non-clinical data obtained with HTD1801 support studying the drug in PBC. In a rat model of 
cholestasis and liver inflammation, the bile duct ligation model, HTD1801 was effective in 
decreasing liver inflammation and necrosis, and improving bile duct health by reducing 
inflammation in the portal area and controlling bile duct proliferation. In addition, HTD1801 
treatment was associated with an improvement in serum markers of cholestasis (ALP and GGT). 
In this model, UDCA generally gives mixed results and thus the improvement could be 
rationalized to come from the association of BBR and UDCA in HTD1801.  
2.3. 
Risk/Benefit Assessment 
2.3.1. 
Known Potential Risks 
HTD1801 has been evaluated in a clinical study in patients with NASH and type II diabetes. In 
that study, HTD1801 was well tolerated at 1000 mg BID and 500 mg BID dose levels. The most 
common treatment-related AEs were gastrointestinal disorders (diarrhea and nausea), which 
occurred more frequently in the HTD1801 1000 mg BID dose group compared with the 500 mg 
BID dose group. 
2.3.2. 
Known Potential Benefits 
Based on nonclinical and clinical data in other indications with HTD1801, and the known 
clinical benefits of BBR and UDCA, it is reasonable to expect potential benefit of HTD1801 in 
subjects with PBC. 
2.3.3. 
Assessment of Potential Risks and Benefits 
The known and potential risks anticipated with HTD1801 appear justified by the potential 
benefits that may be afforded to subjects with PBC. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
20 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Objective: 
To evaluate the effects of 
HTD1801 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 
Primary Endpoint: 
• Percent change in ALP at Week 12 compared to 
Baseline. 
Additional ALP Secondary Endpoints: 
• Absolute change in ALP at Week 12 compared to 
Baseline 
• Proportion of subjects who have ≥20% decrease in ALP 
from Baseline to Week 12 
• Proportion of subjects who have ≥40% decrease in ALP 
from Baseline to Week 12 
• The proportion of subjects who normalize ALP at Week 
12 
Secondary Objectives: 
Secondary Endpoints: 
To evaluate the effects of 
HTD1801 on serum markers of 
cholestasis 
• Change in total bilirubin from Baseline to Week 12 
• Change in serum gamma-glutamyl transferase (GGT) 
between Baseline and Week 12 
• Change in ALT from Baseline to Week12 
• Change in AST from Baseline to Week 12 
To evaluate the effects of 
HTD1801 on serum lipids 
• Change in serum cholesterol (total and LDL) and 
triglyceride levels between Baseline and Week 12 
To evaluate the effects of 
HTD1801 on serum markers of 
inflammation 
•  Change in inflammatory serum markers including 
fibrinogen, CRP, Haptoglobin, ELF and serum 
immunoglobulins between Baseline and Week 12 
To evaluate the safety and 
tolerability of HTD1801 over 12 
weeks of treatment in adult subjects 
with PBC 
• Change in GLOBE score between Baseline and Week 12 
• Change in pruritus as measured by Pruritus visual analog 
score (VAS) between Baseline and Week 12 
• Adverse events and changes in physical examination, 
vital signs, and clinical laboratory values 
To evaluate the pharmacokinetic 
profile of HTD1801in a subset of 
subjects participating in this study 
• Descriptive statistics on plasma concentrations of 
measured analytes for berberine and UDCA and its 
conjugates 


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Clinical Protocol  
Study HTD1801.PCT013 
 
21 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, multicenter, single arm, 12-week open-label proof-of-concept study of 
HTD1801 is adult subjects with PBC with 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. Up to 30 subjects may be enrolled at up to 20 participating clinical 
sites.  
Subjects may be pre-screened 28 to 56 days prior to the screening day visit using the central 
laboratory to confirm that their alkaline phosphatase is ≥1.5 x ULN and then will enter a 
screening period of up to 28 days prior to initiating therapy. Upon confirmation of eligibility, 
subjects will be enrolled and will receive HTD1801 1000 mg BID for 12 weeks. Study visits will 
occur at Day 0, Weeks 2, 4, 6, 8, and 12. A final follow-up visit will occur at Week 16, 4 weeks 
after the last dose of study drug. The Week 2, 4, and 8 visits may be performed remotely (home 
visits). 
4.2. 
Scientific Rationale for Study Design 
This is a single arm, open-label proof-of-concept study. All subjects will receive active study 
drug treatment. This study design is appropriate for a proof-of-concept study for an intervention 
in a new indication for PBC patients where the laboratory markers do not improve spontaneously 
and over time, are expected to get worse. Hence, seeing improvements, even without a control 
arm, is sufficient to meet the scientific goal of providing an indication of efficacy while also 
providing safety data. 
4.3. 
Justification for Dose 
The justification for the dose of HTD1801 selected for this study is based on HighTide’s 
experience with this agent in previous clinical trials in other diseases.  A Phase 1b/2a study was 
conducted in subjects with hyperlipidemia and a Phase 2 study was conducted in subjects with 
NASH. Even though these are different patient populations from the population to be evaluated 
in study HTD1801.PCT013, the observations from these studies help inform dose selection in 
PBC. 
In the Phase 1b/2a study (study HTD1801.PCT004), in patients with hyperlipidemia, multiple 
ascending doses of HTD1801 500 mg, 1000 mg and 2000 mg per day were evaluated for up to 
28 days. In this study HTD1801 2000 mg per day was effective in lowering serum cholesterol 
levels by approximately 11% (Di Bisceglie 2020). 
In the Phase 2 study in NASH (Study HTD1801.PCT012), two doses of HTD1801 were 
evaluated – 1000 mg per day and 2000 mg per day both given for 18 weeks. The dose of 2000 
mg per day was effective in decreasing liver fat content and improving glycemic control, more so 
than the 1000 mg per day dose (Harrison et al. 2020).  
In this same study, it was found that the relationship between decrease in liver fat content and 
body weight at baseline revealed no meaningful trends, implying that the pharmacodynamic 
changes associated with HTD1801 are relatively unaffected by body weight (see Figure 1; Study 
# HTD1801.PCT012) (Harrison et al. 2020).  


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HighTide Biopharma Pty. Ltd. 
Clinical Protocol  
Study HTD1801.PCT013 
 
22 
The dose of HTD1801 to be used in this study, 1000 mg BID, is therefore expected be sufficient 
to show a preliminary treatment response in this 12-week study and also be generally well 
tolerated. HTD1801 has been shown in previous clinical studies, including in subjects with 
NASH and PSC, to have a favorable safety profile; gastrointestinal (GI) events were the most 
common adverse event in these studies; in the study in NASH 12% of subjects who received 
1000 mg BID administration discontinued study drug due to GI events whereas there were no 
discontinuations due to these events in the study in PSC. 
For the reasons cited above, the dosage of HTD1801 selected for this study (1000mg BID) is 
considered appropriate for use in the study population. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities, Section 1.3. 
The end of the study is defined as the date of completion of the last visit or procedure shown in 
the Schedule of Activities in the trial globally for the last subject in the study. 
The end of enrollment if less than 30 subjects will be a collaborative decision between regulatory 
and Sponsor entities. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
23 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Male or female between 18 and 75 years of age 
2. Has a clinical diagnosis of PBC as confirmed by patient history consistent with the 
American Association for the Study of Liver Diseases (AASLD) Practice Guideline 
(Lindor 2019) confirmed by two of the following three criteria: 
a. Biochemical evidence of cholestasis with elevation of ALP activity 
b. Presence of antimitochondrial antibody (AMA) 
c. Histopathologic evidence of nonsuppurative 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. 
3. Has been taking a stable, adequate dose (at minimum 13 mg/kg/day) of UDCA for at least 
6 months with a serum ALP of  ≥1.5 × ULN.  
4. Has two consecutive values of ALP ≥1.5 × ULN (historical and screening values) of 
which the second ALP value must not be down trending relative to the first ALP value 
a. If the historical ALP value was obtained more than 6 months prior to study start as 
part of standard of care, a more recent historical value should be obtained either using 
the local laboratory or alternatively, a chemistry sample can be submitted to the 
central laboratory as a part of an optional pre-screening visit.  If this more recent value 
is ≥1.5 × ULN, the subject may be scheduled for a full screening visit as soon as 4 
weeks later and a second ALP value should be obtained as part of full screening. Both 
values must be ≥1.5 x ULN. 
b. If the historical ALP value 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 ALP 
values.  Both values must be ≥1.5 x ULN. 
c. If the screening ALP value is more than ≥30% lower than the historical value 
obtained as part of standard of care, the subject will not qualify for enrollment but 
may be re-screened as soon as 4 weeks later.  If on re-screening the ALP value 
continues to be >30% lower, the subject will not be included in the study. Because 
there may be considerable variability in the reference range for ALP obtained for the 
historical value, the estimation of downward trends of more than 30% should take this 
into account. 
5. Be willing to discontinue UDCA the day prior to the start of IP dosing. 
6. Be willing to discontinue the use of berberine supplements or berberine herbal products the 
day prior to the start of IP dosing  


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Clinical Protocol  
Study HTD1801.PCT013 
 
24 
7. If the subject is taking cholestyramine or other bile acid sequestrant for pruritus, the 
subject must be on a stable dose and taking it 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. 
8. 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 
9. Be able to understand and sign a written or electronic informed consent form (ICF) 
5.2. 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in the 
study. 
1. 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.  
Use of medications other than prednisone or azathioprine for the treatment of AIH is prohibited 
(e.g., Mycophenolate). Stable use of immunosuppressives for other indications may be permitted 
(see below).  Enrollment of subjects with controlled AIH will be limited to a total of 5 subjects. 
2. Other plausible reasons for elevations in serum alkaline phosphatase such as drug-
induced liver injury, concomitant cholestatic liver disease or bone disease. 
3. History of alcohol or substance abuse 
4. Prior liver transplantation or currently listed for liver transplantation 
5. Presence of chronic viral hepatitis, types B or C.  
6. 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 esophageal variceal bleeding 
7. Total bilirubin >1.3 mg/dL unless subject has Gilbert’s Syndrome.  If subject has 
increased total bilirubin due to Gilbert’s Syndrome, then direct bilirubin should be <0.3 
mg/dL. 
8. Hemoglobin <10 g/dL for males or females 
9. Serum TSH level <0.1 or >10 u/mL (subject may be re-screened if hyper- or 
hypothyroidism has been corrected) 
10. Renal impairment with eGFR <60ml/min/1.73 m^2  (CKD stages 3, 4 or 5) 
11. Human immunodeficiency virus (HIV)-1 or HIV-2 infection by history 
12. Glucose-6-phosphate dehydrogenase (G6PD) deficiency.  A screening assay will be 
performed.  If serum level is below normal, clinical evaluation and further testing may be 
needed to confirm a diagnosis of G6PD deficiency. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
25 
13. History of malignancy within the past 2 years or ongoing malignancy other than basal 
cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma 
14. Active, serious infections that require parenteral antibiotic or antifungal therapy within 
30 days prior to Screening 
15. Major surgical procedure within 30 days of Screening or prior solid organ transplantation 
16. Females who are pregnant or breastfeeding 
17. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic 
agents, and immune-modulating agents (such as interleukins, interferons).  Chronic, 
stable use of immunosuppressive medications may be allowed with medical monitor 
approval 
18. Allergy to the clinical trial material or its components 
19. Having received any experimental medications within 28 days prior to Screening 
20. Use of bezafibrate or fenofibrate within 28 days prior to first day of IP dosing 
21. Use of obeticholic acid (OCA) within 28 days prior to first day of IP dosing 
22. 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 
5.3. 
Screen Failures 
Potential subjects who do not meet all eligibility criteria at Screening will be allowed to rescreen 
once if the Investigator believes that there has been a change in eligibility status. If a potential 
subject fails to meet eligibility criteria upon rescreen, he/she will remain ineligible for the study. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
26 
6. 
STUDY INTERVENTION 
6.1. 
Study Intervention Administration 
6.1.1. 
Study Intervention Description 
The HTD1801 drug substance, berberine ursodeoxycholate, is the salt formed between BBR and 
UDCA with a stoichiometry of 1:1. The HTD1801 drug product is a film coated tablet containing 
250 mg of berberine ursodeoxycholate. 
6.1.2. 
Dosing and Administration  
HTD1801 tablets (1000 mg dose) are administered twice daily (BID) with food. Subjects are 
instructed to take the entire contents of 1 pouch of study drug each morning and each evening 
with water and food (e.g., meal or snack). Each pouch will contain 4 identical white tablets. 
Subjects should retain the empty pouches and return them to the investigational site at the Week 
6 study visit and Week 12 or Early Termination visit should it occur, along with any unused 
study drug. Returned unused study drug must not be re dispensed to subjects. 
6.1.3. 
Dose Modification 
In the event of gastrointestinal (GI) discomfort as outlined in Section 9.3.8 at the starting dose of 
1000 mg BID (4 tablets in the morning after a meal and 4 tablets in the evening after a meal), 
dose reduction is allowed per the following guidelines: 
• For GI symptoms that are difficult for the subject to tolerate, decrease dose to 
1500 mg per day (3 tablets in the morning after a meal and 3 tablets in the evening 
after a meal) for 1 week. If symptoms improve, subject should stay on that dose and 
not attempt to go back up to full dose. 
• If symptoms persist after 1 week at the lower 1500 mg per day dose, decrease dose to 
1000 mg per day (2 tablets in the morning after a meal and 2 tablets in the evening 
after a meal) for 1 week. If symptoms improve, subject should stay on that dose and 
not attempt to go back up to full dose. 
• If symptoms persist after 1 week at the lower 1000 mg per day dose and are 
intolerable for the subject at this point, study drug is to be discontinued but the 
subject should continue to be followed as per the Schedule of Activities. 
Subjects who will have their dose of study drug decreased will be monitored closely with serum 
ALP, aminotransferases and bilirubin levels being measured every 2 to 4 weeks.  Elevations in 
ALP or bilirubin will be promptly recognized by the site PI and by the medical monitor because 
this is an open label study.  If ALP levels after having been lowered on initial treatment go back 
up to baseline or higher on two subsequent occasions (baseline being the average of the historical 
value and the value at screening)., the subject will be deemed to be a treatment failure and will 
discontinue investigational study drug (see Section 7.3). 


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Clinical Protocol  
Study HTD1801.PCT013 
 
27 
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Acquisition and Accountability 
HTD1801 250 mg tablets will be supplied by HighTide to each investigational site. The 
Investigator will be fully responsible for the security, accessibility, and storage of the study drugs 
while they are at the investigational site. The Investigator is also responsible for the education of 
site staff in the correct administration of the study drugs and must ensure that appropriate study 
drug accountability records are maintained. 
The PI and study personnel are responsible for ensuring full investigational product 
accountability. 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling 
The HTD1801 drug product is a white to off-white film-coated tablet containing 250 mg of 
HTD1801.  
Inactive excipients include a silicified microcrystalline cellulose (SMCC90), sodium 
carboxymethyl starch, and magnesium stearate. The tablets are coated with Opadry® immediate 
release film (product grade: 03A18375), resulting in an average gain of 15 mg/tablet. The 
qualities of all excipients are consistent with both the Chinese and US Pharmacopeia standards. 
HTD1801 tablets are packaged into polyethylene terephthalate/aluminum foil/polyethylene 
(PET/AL/PE) pouches. Each pouch will contain 4 HTD1801 250 mg tablets and be affixed with 
a single-panel label that will describe the following information at a minimum: study drug, dose, 
kit number, Sponsor name, instructions for storage between 36°F and 46°F (2°C and 8°C), and 
includes the statements “Caution: New Drug - Limited by United States law to investigational 
use” and “Keep out of reach of children.” 
An adequate supply of pouches will be placed into kits packaged for weekly use, and each 
subject will receive the appropriate number of kits to provide enough supplies until the Week 6 
study visit to the investigational site. Each kit will bear a label describing the following 
information at a minimum: kit number, Sponsor name, instructions for storage between 36°F and 
46°F (2°C and 8°C), and includes the statements “Caution: New Drug - Limited by United States 
law to investigational use” and “Keep out of reach of children.” 
6.2.3. 
Product Storage and Stability 
HTD1801 tablets should be stored at 2-8oC in the original container and protected from moisture 
and light. 
6.3. 
Study Intervention Compliance 
At applicable clinical visits during the study, subjects will be queried about their compliance 
with taking their assigned study drug as instructed. The number of full and empty study drug 
pouches will be captured on the eCRF. 


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Clinical Protocol  
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28 
6.4. 
Concomitant Therapy 
6.4.1. 
Permitted Concomitant Medications 
The use of permitted concomitant medications may continue during the study at the same dosage 
strength and frequency. 
For subject 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. 
6.4.2. 
Prohibited Concomitant Medications 
6.4.2.1. 
Prohibited medications that are active against PBC 
Use of the following medications, active against PBC, will be prohibited during the study from 
Baseline through 28 days after completion: 
UDCA 
Obeticholic acid 
Bezafibrate 
Fenofibrate 
It is important to emphasize that subjects will be counseled before starting investigational drug 
and at each visit not to take both UDCA and/or berberine  together with HTD1801, as HTD1801 
contains both UDCA and berberine. 
 
6.4.2.2. 
Prohibited medications for the treatment of AIH 
 Use of medications for the treatment of AIH other than prednisone or azathioprine is prohibited 
(e.g., Mycophenolate).  Stable use of immunosuppressives for other indications may be permitted (see 
above).   
6.4.2.3. 
Prohibited medications with potential for drug-drug interaction 
In addition, certain concomitant medications have been identified for exclusion from this proof-
of-concept study and are not to be taken at any time during the entire study (i.e., from Screening 
through Follow-Up). These exclusions are primarily due to the potential drug interaction profile 
of the BBR component of HTD1801. Table 2 lists medications known to be strong inhibitors of 
P glycoprotein (P-gp), CYP3A4, and CYP2D6; strong inducers of CYP3A4, as well as P-gp 
substrates with a narrow therapeutic index, and that are prohibited from concomitant use during 
this study. 
Supplements with potential for drug-drug interaction should be discussed with the medical 
monitor prior to enrolling a subject. 


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Clinical Protocol  
Study HTD1801.PCT013 
 
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Table 2: 
Prohibited Medications with potential for drug-drug interaction  
Single Agents: 
P-glycoprotein 
CYP3A4 
CYP2D6 
Clarithromycin 
Clarithromycin 
Ritonavir 
bupropion 
Erythromycin 
Telithromycin 
Saquinavir 
fluoxetine 
Amiodarone 
Troleandomycin 
Telaprevir 
fluvoxamine 
Digitalis 
Nefazodone 
Tipranavir 
paroxetine 
Dronedarone 
St. John's wort 
chloramphenicol 
Quinidine 
Carvedilol 
Itraconazole 
Rifampin 
Terbinafine 
Propafenone 
Ketoconazole 
Cobicistat 
 
Quinidine 
Posaconazole 
grapefruit juice 
 
Ranolazine 
Voriconazole 
conivaptan 
 
Verapamil 
Atazanavir 
Diltiazem 
 
Sildenafil 
Boceprevir 
Idelalisib 
 
Itraconazole 
Darunavir 
enzalutamide 
 
Ketoconazole 
Indinavir 
Mitotane 
 
Ritonavir 
Lopinavir 
carbamazepine 
 
Saquinavir 
Nelfinavir 
Phenytoin 
 
Telaprevir 
 
 
 
Lapatinib 
 
 
 
Combination Agents: 
P-glycoprotein 
CYP3A4 
lopinavir and ritonavir 
danoprevir and ritonavir 
saquinavir and ritonavir 
elvitegravir and ritonavir 
tipranavir and ritonavir 
indinavir and ritonavir 
 
lopinavir and ritonavir 
 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
 
saquinavir and ritonavir 
 
tipranavir and ritonavir 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm (Tables 2-2, 2-3, 3-2, 3-3, and 5-2) 


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7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Decrease in dose of study drug 
Subjects who have their dose of study drug decreased will be monitored closely with serum 
alkaline phosphatase, aminotransferases and bilirubin levels being measured every 2 to 4 weeks.  
Elevations in ALP or bilirubin will be promptly recognized by the site PI and by the medical 
monitor because this is an open label study.  If subjects are deemed to be treatment failures when 
their dose of study drug is decreased, study drug will be discontinued (see Section 7.2). 
7.2. 
Discontinuation of Study Intervention 
HTD1801 treatment must be discontinued for a subject if any of the following criteria are met. 
• Adverse event that may jeopardize subject’s safety  
• Grade 3 and above adverse events (AEs) for which the causality is considered as 
related to investigational agent 
• Discontinuation due to drug-induced liver injury (refer to Section 10) 
• Request by the subject 
• Pregnancy 
For subjects who discontinue investigational study drug, an Early Termination Visit should be 
conducted at the time the investigational study drug is discontinued (see Section 7.3). Subjects 
who terminate from the study prior to Study Visit Week 12 will be requested to return to the 
clinic 28 days after the date of last dose of investigational study drug and complete the 
equivalent of the Week 16 follow up visit assessments.  If necessary, arrangements can be made 
with the site and the subject to conduct the visit virtually and make use of a local laboratory for 
the study required Study Visit Week 16 lab tests.   
7.3. 
Participant Discontinuation/Withdrawal from the Study 
Subjects may be discontinued from the study for any of the following reasons: 
• Noncompliance 
o Failure to receive study medication or treatment  
o Failure to comply with protocol requirements 
o Unauthorized, subject-initiated changes in dosing regimen 
• Withdrawal of consent 
o Any subject who withdraws consent for any reason at any time during the 
study will be discontinued from the study, and the reason(s) will be 
documented on the appropriate eCRF page.  
• Lost to Follow-Up 


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o For subjects who cannot be contacted for either a return for a scheduled clinic 
visit or for follow-up assessments as described, and who may be considered 
“lost to follow-up,” at least 3 documented attempts should be made to 
establish contact with and to instruct the subject on how to complete study 
procedures. In the final attempt to contact the subject, a letter should be sent 
by certified mail to the subject’s last known address 
• Adverse Events   
o Study drug will be discontinued in an individual subject if the subject 
experiences a grade 3 and above adverse event (AE) for which the causality is 
considered as related to investigational study drug 
• Treatment Failure 
o If any subject fails treatment after having their dose of HTD1801 reduced, 
their participation in the study will be ended and they will be allowed to 
resume their pre-study treatment for PBC.  A subject will be deemed to have 
failed treatment if serum ALP, after having been lowered on initial treatment, 
returns to baseline or higher on two subsequent occasions (baseline being the 
average of the historical value and the value at screening). 
7.4. 
 Study Stopping Criteria 
If there is one death (grade 5 AE) or two subjects meeting the same grade 4 AE (life threatening 
or disabling AE), or three subjects meeting the same grade 3 AE (severe AE), the trial will be 
paused and the AEs assessed for causality.  The event data will be submitted to the FDA with a 
request to resume conduct of the trial. 


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Clinical Protocol  
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8. 
STUDY PROCEDURES AND EVALUATIONS 
Study procedures are summarized across all scheduled study visits as indicated in the Study 
Schema (Section 1.2) and Table 1 Schedule of Activities (Section 1.3). Unscheduled visits may 
also occur at any time if medically warranted. Study related assessments performed at all visits 
will be recorded in the eCRF.   
Refer to Section 11 for COVID-19 contingency measures for Study Visit Week 2, 4, 8, 16 and 
ET in case a subject is unable or unwilling to participate in an on-site visit due to the COVID-19 
pandemic. 
8.1. 
Pre-screening (Days -56 to -28) ALP 
Prior to any clinical procedures and evaluations, written signed informed consent must be 
obtained.  If the historical ALP that was obtained as part of standard of care is not ≥1.5 x ULN or 
is not within 6 months of the screening visit, a pre-screening visit must be conducted in order to 
collect a chemistry lab sample to determine the ALP value using the central laboratory.  
Informed consent needs to be obtained from the subject before proceeding with any study-
specific procedures. The pre-screening ALP sample through the central laboratory needs to be 
obtained at least 28 days prior to full screening visit. 
•  Informed consent 
• Assign subject ID# 
• Chemistry sample for alkaline phosphatase 
8.2. 
Screening (Days -28 to -1) 
Screening procedures must be completed within 28 days prior to the Baseline visit and can be 
performed across multiple days during this period.  Screening clinical laboratory tests may be 
repeated once during Screening if the Investigator believes the results to be erroneous.  In the 
event that Screening tests are repeated, the most current results will be used to determine 
eligibility.  If screening procedures are completed and subject eligibility is confirmed, the full 
28-day screening period may not be necessary. 
During Screening, the following procedures must be conducted and assessments obtained.  The 
information will be collected in the investigational site’s standard source documents or in source 
document templates provided by the Sponsor. 
• Informed consent if not obtained at pre-screening visit 
• Confirm eligibility criteria 
• Demographic information 
• Medical history 
• Assign subject ID # if not obtained at pre-screening visit  
• Complete physical examination 
• Vital signs 
• Weight, height 
• Electrocardiogram, 12 lead (ECG) 


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• Serum chemistry panel including GGT, Lipid panel -– fasting, unsweetened clear 
coffee, tea or water permitted but no food after supper the evening before 
• Complete blood count (CBC) with differential (no smear) 
• INR 
• Fibrinogen 
• CRP 
• Haptoglobulin 
• ELF 
• G6PD 
• IgM 
• IgG 
• AMA 
• ANA 
• TSH 
• FSH (if needed to confirm menopausal status) 
• Pruritus VAS 
• Prior and concomitant medications 
Subjects will be instructed to stop all prohibited medications (see Section 6.4) prior to beginning 
Baseline procedures.  In particular, subjects will be cautioned against the use of UDCA until 
their participation in this study is complete. 
NOTE: If the screening ALP value is more than ≥30% lower than the historical value obtained as 
part of standard of care, the subject will not qualify for enrollment but may be re-screened as 
soon as 4 weeks later.  If on re-screening the ALP value continues to be >30% lower, the subject 
will not be included in the study. 
8.3. 
Baseline/Day 0 
Potential subjects who have successfully completed all of the Screening procedures and have met 
all the eligibility criteria (see Sections 5.1 and 5.2) will be eligible for enrollment in the study. 
Subjects will undergo the following Baseline procedures and assessments prior to the first dose 
of study drug:  
• Confirmation of continued eligibility 
• Update of medical history information  
• Targeted physical examination (to include assessment of only findings that were 
abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered 
by subject) 
• Vital signs 
• Weight 
• Serum chemistry panel including GGT 


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Clinical Protocol  
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• Lipid panel -– fasting, unsweetened clear coffee, tea or water permitted but no food 
after supper the evening before 
• CBC with differential 
• Fibrinogen 
• CRP 
• Haptoglobin 
• ELF 
• IGM 
• IgG 
• Bile acid panel 
• Urine pregnancy test for women of childbearing potential 
• GLOBE Score (calculated by biostatistical programming based upon age, total 
bilirubin, alkaline phosphatase, albumin and platelet count) 
• Pruritus VAS 
• Adverse event monitoring 
• Concomitant medications 
• Dispense study drug 
8.4. 
Week 2 and Week 4 Visits (±3 days)  
Week 2 and Week 4 visits are conducted as in-clinic visits or optional in-home  visits. The 
following procedures and assessments will be conducted at these visits: 
• Serum chemistry panel including GGT 
• Adverse event monitoring 
• Concomitant medications 
Refer to Section 11 for COVID-19 contingency measures for Study Visits Week 2 and Week 4 in 
case a subject is unable or unwilling to participate in an on-site visit due to the COVID-19 
pandemic. 
8.5. 
Week 6 Visit (±3 days)  
The following procedures and assessments will be performed during the Week 6 clinic visit: 
• Targeted physical examination (to include assessment of only findings that were 
abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered 
by subject) 
• Vital signs 
• Weight 
• Serum chemistry panel including GGT 
• Lipid panel - fasting, unsweetened clear coffee, tea or water permitted but no food 
after supper the evening before 


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• CBC with differential 
• INR 
• Fibrinogen 
• CRP 
• Haptoglobin 
• ELF 
• IGM 
• IgG 
• Bile acid panel 
• PK blood draw for at least 6 subjects who consent to participate in the PK sub-study 
o PK lab draw at -30 minutes prior to investigational study drug dosing 
o PK lab draw at ±30 minutes 4 hours post investigational study drug dosing 
o PK lab draw at ±30 minutes 8 hours post investigational study drug dosing 
• GLOBE Score (calculated by biostatistical programming based upon age, total 
bilirubin, alkaline phosphatase, albumin and platelet count) 
• Pruritus VAS  
• Adverse event monitoring 
• Concomitant medications 
• Return study drug/reconciliation 
• Dispense study drug 
8.6. 
Week 8 Visit (±3 days) 
The Week 8 visit is conducted as an in-clinic visit or optional in-home lab visit. The following 
procedures and assessments will be conducted at this visit: 
• Serum chemistry panel including GGT 
• Adverse event monitoring 
• Concomitant medications 
Refer to Section 11 for COVID-19 contingency measures for Study Visit Week 8 in case a 
subject is unable or unwilling to participate in an on-site visit due to the COVID-19 pandemic. 
8.7. 
Week 12 Visit (±3 days)  
The following procedures and assessments will be performed during the Week 12 clinic visit: 
• Targeted physical examination (to include assessment of only findings that were 
abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered 
by subject) 
• Vital signs 
• Weight 
• ECG 


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• Serum chemistry panel including GGT 
• Lipid panel - fasting, unsweetened clear coffee, tea or water permitted but no food 
after supper the evening before 
• CBC with differential 
• INR 
• Fibrinogen 
• CRP 
• Haptoglobin 
• ELF 
• IGM 
• IgG 
• Bile acid panel 
• PK blood draw for at least 6 subjects who consent to participate in the PK sub-study 
o PK lab draw at -30 minutes prior to investigational study drug dosing 
o PK lab draw at ±30 minutes 4 hours post investigational study drug dosing 
o PK lab draw at ±30 minutes 8 hours post investigational study drug dosing 
• Urine pregnancy test for women of childbearing potential 
• GLOBE Score (calculated by biostatistical programming based upon age, total 
bilirubin, alkaline phosphatase, albumin and platelet count) 
• Pruritus VAS 
• Adverse event monitoring 
• Concomitant medications 
• Return study drug/reconciliation 
8.8. 
Week 16 Visit (±5 days)  
The final study visit will occur 28 days after the last dose of study drug at a Week 16 follow-up 
visit. The Week 16 visit is conducted as an in-clinic visit or optional in-home lab visit. The 
following procedures and assessments will be conducted at this visit: 
• Study discharge 
• Targeted physical examination (to include assessment of only findings that were 
abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered 
by subject) 
• Vital signs 
• Weight 
Serum chemistry panel including GGT 
• Adverse event monitoring 
• Concomitant medications 


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Refer to Section 11 for COVID-19 contingency measures for Study Visit Week 16 in case a 
subject is unable or unwilling to participate in an on-site visit due to the COVID-19 pandemic. 
8.9. 
Early Termination Visit 
In the event of early termination from the study, the subject should return to the clinic for the 
following end of study assessments but may be conducted as an in-home lab visit by a nurse if 
the subject is unwilling or unable to attend the visit in person due to the COVID-19 pandemic: 
• Study discharge 
• Targeted physical examination (to include assessment of only findings that were 
abnormal at Screening/Baseline visit and any new symptoms exhibited or volunteered 
by subject) 
• Vital signs 
• Weight 
• ECG 
• Serum chemistry panel including GGT 
• Lipid panel 
• CBC with differential 
• INR 
• Fibrinogen 
• CRP 
• Haptoglobin 
• ELF 
• IGM 
• IgG 
• Bile acid panel 
• Urine pregnancy test for women of childbearing potential 
• GLOBE Score (calculated by biostatistical programming based upon age, total 
bilirubin, alkaline phosphatase, albumin and platelet count) 
• Pruritus VAS 
• Adverse event monitoring 
• Concomitant medications 
• Return study drug/reconciliation 
Subjects who terminate from the study prior to Study Visit Week 12 will be requested to return 
to the clinic 28 days after the date of last dose of investigational study drug and complete the 
equivalent of the Week 16 follow up visit assessments.  This final study visit is conducted as an 
in-clinic visit or optional in-home lab visit.  
Refer to Section 11 for COVID-19 contingency measures for Early Termination Visit in case a 
subject is unable or unwilling to participate in an on-site visit dur to the COVID-19 pandemic. 


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9. 
STUDY ASSESSMENTS AND PROCEDURES 
9.1. 
Efficacy Assessments 
9.1.1. 
Serum Alkaline Phosphatase Endpoints  
The ALP endpoints including the primary endpoint are based upon laboratory results. Results 
will be assigned to time points based upon the timing of the sample. Baseline will be the last 
available ALP result available prior to treatment with HTD1801 and change from baseline and 
percent change will be based upon this baseline value and the value as the respective timepoint. 
The binary ≥20% and ≥40% decrease endpoints will be based upon the percent change from 
baseline measure (did or did not have a percent change of this size). The normalization of ALP 
endpoint will be based upon the result and the associated normal range provided by the 
laboratory. 
9.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are each based upon laboratory results and the change from 
baseline of these results. As with the ALP endpoint baseline will be the last available pre-
treatment result, change from baseline will be based upon this baseline result and the result at the 
timepoints. Results will be assigned to timepoints based the timing of the result. 
9.2. 
Safety and Other Assessments 
9.2.1. 
Demographics and Medical History 
The Investigator or qualified designee will obtain demographic data, medical history, and 
medication history for each potential subject at Screening. Demographic data will include, at a 
minimum, the subject’s age and/or date of birth, sex, race, and ethnicity. Medical and medication 
history will include relevant medical conditions and treatments. 
9.2.2. 
Adverse Events 
Adverse events will be collected from the time at which the potential subject signs the ICF. 
Subjects will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study until at least 30 days after discontinuing the study drug. 
General and non-leading questions such as “How are you feeling?” should be asked when 
assessing the occurrence of AEs. The definition, reporting, and recording requirements for AEs 
are described in Section 9.3. 
9.2.3. 
Physical Examinations 
Physical examinations must be performed at investigational sites by medically qualified 
individuals according to local requirements. Abnormal physical examination findings that the 
Investigator considers clinically significant are to be reported as AEs if they began after the start 
of treatment and as medical history if they were present prior to treatment. 
The comprehensive physical examination will include the assessment of the following: skin; 
head, neck, eyes, ears, nose, throat; upper and lower extremities; chest and lungs; abdomen; 
cardiovascular system; and a brief neurological examination. The targeted physical examination 


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will be a symptom-driven assessment of body systems or organs as indicated by AEs or other 
findings. 
9.2.4. 
Vital Signs, Height, and Weight 
Vital sign measurements must be performed at investigational sites by medically qualified 
individuals according to local requirements. Measurements include blood pressure, pulse, 
respiratory rate, and body temperature. Blood pressure and pulse will be taken in a recumbent, 
semi recumbent, or sitting position after 5 minutes of rest. Height (at Screening only) and weight 
will also be performed. Abnormal findings seen after the start of treatment that the Investigator 
considers clinically significant are to be reported as AEs. 
9.2.5. 
Electrocardiograms 
Twelve-lead ECGs will be performed at the investigational site with the subject in a recumbent 
or semi-recumbent position after 5 minutes of rest. Local institutional standards for QT interval 
corrections should be utilized. Interpretation of ECG results for the ongoing assessment of safety 
will be performed by the Investigator or qualified designee during the scheduled visit. Abnormal 
ECG readings seen after the start of treatment are to be reported as AEs only if they are 
considered clinically significant by the Investigator. Additionally, the Investigator should consult 
the Medical Monitor, when possible, for any abnormal, clinically significant ECG findings that 
may result in a change to the subject’s treatment or management. 
9.2.6. 
Safety Related Laboratory Assessments 
A central laboratory will be utilized to perform safety related clinical laboratory assessments as 
specified in the Schedule of Activities Table 1 and as described below in Table 3. Samples for 
laboratory assessments performed at Baseline must be collected prior to study drug dosing. The 
Investigator or qualified designee must review the results of all central laboratory testing to 
assess subject eligibility at Screening and Baseline, as well as continued study participation for 
the duration of the study. Procedures for sample collection and handling will be detailed in the 
central laboratory manual and/or Study Procedures Manual (SPM). 


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Table 3 
Laboratory Analytes 
Serum Chemistry 
Hematology 
Lipids 
Coagulation 
Comprehensive metabolic 
panel: 
• 
Albumin 
• 
ALP 
• 
ALT 
• 
AST 
• 
Bicarbonate 
• 
Bilirubin, total 
• 
Bilirubin, direct 
• 
Blood urea nitrogen 
(BUN) 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
eGFR (calculated) 
• 
Creatine kinase 
• 
GGT 
• 
Glucose 
• 
Lactate dehydrogenase 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
Complete blood count, 
including: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
• 
Reticulocyte count 
 
White blood cell count 
differential, including: 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
 
Endocrinology: 
TSH 
Total cholesterol 
LDL-c 
HDL-c 
Triglycerides 
INR 
Other 
Fibrinogen 
CRP 
Haptoglobin 
ELF 
G6PD 
IgG 
IgM 
Bile acids panel 
AMA 
ANA 
Serum and urine pregnancy 
tests 
FSH test 
9.2.7. 
GLOBE Score 
The GLOBE score is a validated risk assessment tool, able to accurately stratify PBC patients to 
high and low risk for future adverse events (Lammers 2015). See Appendix A and 
https://www.globalpbc.com/globe for details on calculating the GLOBE score.  While the 
variables that are used to calculate the GLOBE score are collected as part of the study 
assessments, actual calculation of the GLOBE score will be completed by biostatistical 
programming. 
Although the GLOBE score calculation is a validated tool for subjects who have been on UDCA 
therapy for at least 12 months, for the purpose of this study, biostatistics will program a listing 
that separates subjects by duration of UDCA exposure, i.e., subjects who have been on UDCA 
for ≥12 months and subjects who have been on UDCA at least 6 months but <12 months. 
9.2.8. 
Pruritus VAS 
Subjects will complete an analogue rating scale at the indicated timepoints to describe their 
severity of pruritus over the last 24 hours prior to their clinic visit (see Appendix B). 


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9.2.9. 
Pharmacokinetic (PK) sub-study 
At least 6 subjects will be asked to participate in a PK sub-study to evaluate the plasma 
concentrations of UDCA and berberine.  Subjects who consent to participate in this sub-study 
will receive their dose of study drug in clinic and then provide one pre-dose (-30 minutes prior to 
dosing) and 2 post-dose samples at 4 hours±30 minutes and at 8 hours±30 minutes at Study 
Visits Weeks 6 and 12.   
9.3. 
Adverse Events and Serious Adverse Events 
9.3.1. 
Definition of Adverse Event (AE) 
The following definition of an AE will be used for this study: Adverse event means any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of the 
investigational product, regardless of whether it is considered to be related to the investigational 
product. 
The following are examples of AEs: 
• Significant or unexpected worsening or exacerbation of the indication under study. 
• Exacerbation of a chronic or intermittent preexisting condition, including an increase 
in frequency or intensity of the condition. 
• New conditions detected or diagnosed after investigational product administration, 
even if they were present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with another 
medical product. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication. 
Overdose should not be reported as an AE or serious adverse event (SAE), but rather the 
symptoms resulting from the overdose should be reported as such. 
Examples of AEs do not include the following: 
• Medical or surgical procedures (e.g., endoscopy, appendectomy). The medical 
condition that led to the procedure as the AE should be reported. 
• Situations that are unwanted by the subject but in which an untoward medical 
occurrence did not occur, for example social inconvenience after admission to a 
hospital. 
• Anticipated day-to-day fluctuations of a pre-existing disease or condition (present or 
detected before enrollment) that does not worsen overall. 


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• Expected progression of the disease being studied, including signs or symptoms of 
the disease, unless progression is more severe than expected for the subject’s 
condition. 
Adverse events may include post-treatment events that occur as a result of protocol-mandated 
procedures (e.g., invasive procedures, modification of the subject’s previous therapeutic 
regimen). 
Adverse events should be captured even if they occur during periods without drug treatment, 
post-treatment periods, known placebo treatment, or in a reference or control group receiving 
drug or nondrug therapy. 
The Investigator is responsible for all AE assessments. The Investigator and investigational site 
staff will note all AEs mentioned by the subject at Screening, Baseline and during study drug 
administration. All clinical complaints volunteered by or elicited from the subject during the 
study will be recorded on the appropriate page of the eCRF for the study period indicated. The 
subject will receive appropriate treatment and medical supervision for any AE that occurs. 
All AEs judged to be clinically significant, including clinically significant laboratory 
abnormalities, will be followed until resolution. All AEs will be summarized in the clinical study 
report and the annual report or more frequently if requested by the regulatory agency. Serious 
adverse events require special reporting in addition to documentation in the eCRF as described in 
Section 9.3.6. 
The severity of adverse events will be assessed according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refer
ence_5x7.pdf) 
9.3.2. 
Definition of Serious Adverse Event (SAE) 
In this study, an SAE is defined as an AE that meets any of the following criteria: 
• Results in death. 
• Is life-threatening. The term life-threatening in the definition of an SAE refers to an 
event in which the subject was at risk of death at the time of the event. The term 
life-threatening does not refer to an event that, had it occurred in a more severe form, 
might have caused death.  
• Requires hospitalization or a prolongation of an existing hospitalization. In general, 
hospitalization signifies that the subject has been detained at the hospital or 
emergency ward for observation or treatment that would not have been appropriate in 
the physician’s office or out-patient setting. Complications that occur during 
hospitalization are AEs, but not necessarily SAEs. A medical occurrence or 
complication that prolongs hospitalization is an SAE. When there is doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered an 
SAE. Hospitalization for elective treatments of a preexisting condition that did not 
worsen from its original Baseline level is not considered an SAE. 


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• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. This does not include AEs of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza 
and accidental trauma (e.g., sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
• A congenital anomaly or birth defect. This refers to the offspring of a study subject. 
• Any other important medical event. Medical or scientific judgment should be 
exercised when deciding whether reporting is appropriate for other important medical 
events that may not result in death, be life-threatening, or require hospitalization but 
still may jeopardize the subject or may require medical intervention to prevent one of 
the outcomes listed in this definition. These events should also be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization or in the development of drug dependency or drug abuse. 
An SAE requires additional detailed reports and follow-up. The content of these detailed reports 
must address the Investigator’s estimate of causality. The Medical Monitor will review the SAE 
to determine if it is an expected SAE (i.e., whether or not the SAE is identified in nature, 
severity, and frequency in the Investigator’s Brochure).  
9.3.3. 
Classification of an Adverse Event 
9.3.3.1. 
Severity of Event 
The Investigator will assess the severity for each AE and SAE reported during the study on the 
basis of his or her clinical judgment. Table 4 shows an overview of the severity classification as 
outlined in CTACE version 5.0.  For the purposes of assigning severity of each AE recorded in 
the source documentation and subsequently, in the eCRF, investigators are encouraged to refer to 
CTCAE v 5.0 for a more detailed description of any specific AE that may occur. 


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Table 4 
Classification of Adverse Events (AEs) by Severity 
Severitya 
Definition 
Mild AE 
(Grade 1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Moderate AE 
(Grade 2) 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
Severe AE 
(Grade 3) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care activities of daily living 
Life-threatening or 
disabling AE 
(Grade 4) 
Life-threatening consequences; urgent intervention indicated. 
Death related to AE 
(Grade 5) 
Death related to AE. 
 
a From Common Terminology Criteria for Adverse Events, Version 5.0 
Any AE that changes in severity or grade during a single occurrence of an AE will be recorded in 
the eCRF at the highest level experienced by the subject. 
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
used for rating the intensity of an AE (such as mild, moderate, or severe myocardial infarction). 
However, an AE itself may be of relatively minor medical significance, such as a severe 
headache. Both AEs and SAEs can be assessed as severe. An AE is considered serious when it 
meets one of the predefined outcomes described in Section 9.3.2. 
9.3.3.2. 
Relationship to Study Intervention 
The Investigator must estimate the relationship between the investigational product and the 
occurrence of each AE or SAE by using his or her best clinical judgment. Elements to consider 
for this estimate include the history of the underlying disease, concomitant therapy, other risk 
factors, and the temporal relationship of the AE or SAE to the investigational product. The 
Investigator will also consult the Investigator’s Brochure or product label for marketed products 
in estimating the relationship. 
Because of reporting timelines, the Investigator might have minimal information to include in the 
initial SAE report. However, the Investigator must always make an assessment of causality for 
every SAE before the transmission of the SAE report. The Investigator may change his or her 
opinion of the causality in light of follow-up information, with subsequent amendment of the 
SAE report. Causality assessment is a criterion used to determine regulatory reporting 
requirements and should not be left blank on the eCRF. The same applies to AEs that are to be 
processed as SAEs. 
Table 5 provides some definitions to use in the assessment. 


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Table 5 
Assessment of Causality of AEs 
Term 
Definition 
Possibly related 
The AE may be related to the investigational agent(s) or intervention: the AE 
has a temporal relationship to the administration of the investigational agent(s) 
or research intervention. 
Unrelated 
(or not related) 
The AE is clearly not related to the investigational agent(s) or intervention: the 
AE has no temporal relationship to the administration of the investigational 
agent(s) or research intervention, and follows no known or suspected pattern of 
response, and an alternative cause is present.  
9.3.3.3. 
Expectedness 
An expected AE is one that is consistent with the known risk information described in the 
product label (if applicable) or the current Investigator’s Brochure. The expectedness of an SAE 
will be assessed by the Medical Monitor and Sponsor on receipt of the initial SAE report. 
9.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up 
AEs will be recorded starting after Screening and at every visit through the Week 16 Follow-Up 
Visit.  
After the initial AE or SAE report, the investigator is required to proactively follow each subject 
and provide further information to the sponsor about the subject’s condition. All AEs and SAEs 
will be followed until the occurrence of one of the following: 
• The condition resolves. 
• The AE or SAE is not related. 
• The subject is lost to follow-up. 
• The subject is followed for 30 days after the End-of-Study Visit (or other appropriate 
time frame). 
• The subject starts another investigational product. 
9.3.5. 
Adverse Event Reporting 
When an AE or SAE occurs, the investigator is responsible for reviewing all documentation 
(e.g., hospital progress notes, laboratory, and diagnostic reports) relative to the event(s). The 
investigator will record all relevant information about any AE (including SAEs) on the AE page 
of the eCRF. It is not acceptable for the investigator to send photocopies of the subject’s medical 
records in lieu of the properly completed AE or SAE pages of the eCRF. These documents 
should not be sent unless they are specifically requested by the pharmacovigilance department. If 
this request occurs, all subject identifiers and protected health information should be blinded on 
the copies of the medical records before submission to the pharmacovigilance department and to 
the appropriate authorities. 
The investigator will also attempt to report a diagnosis, instead of signs, symptoms, or other 
clinical information, for the AE. The diagnosis, not the individual signs and symptoms, should be 
documented on the appropriate page of the eCRF as the AE or SAE. In addition, SAEs need to 


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46 
be reported in the SAE report. Aes being processed as SAEs will also require additional 
documentation. The study procedures manual provides additional guidelines about reporting 
SAEs. 
9.3.6. 
Serious Adverse Event Reporting 
1. Any SAE occurring after the subject signs the ICF and the study drug has been 
administered, as described in Section 9.3.2, must be reported to the Sponsor’s or 
designee’s pharmacovigilance department by phone, fax, or e-mail within 24 hours of the 
time the Investigator becomes aware of the SAE (Table 6). Any SAE reported by phone 
should be immediately followed up with the submission of the completed SAE report 
form. Urgent reporting of SAEs is required for the following reasons: 
a. To enable the Sponsor to fulfill the reporting requirements to the appropriate 
regulatory authority 
b. To facilitate discussion between the Sponsor and the Investigator about appropriate 
follow-up measures (if necessary) 
c. To facilitate the Sponsor’s rapid dissemination of information about AEs to other 
investigators or sites in a multicenter study 
d. To facilitate reporting unanticipated problems involving risk to subjects to the 
institutional review board (IRB) or independent ethics committee (IEC). 
Table 6 
Timeline for Reporting SAEs 
Initial SAE Report 
Follow-up SAE Report 
Time Frame 
Documents 
Time Frame 
Documents 
24 hours 
SAE report 
7 days 
Updated SAE report 
The SAE report will be completed as thoroughly as possible, including the following: 
• Subject identification information 
• Event term 
• All available details about the SAE 
• Causality of each SAE 
• Signature of the Investigator 
The SAE report will be forwarded to the Sponsor’s or designee’s pharmacovigilance department 
within the designated time frames. If additional information to complete the SAE report is 
needed, the Investigator will not wait before notifying the pharmacovigilance department of the 
SAE. The SAE report will be updated by the Investigator when additional information is 
received. 
9.3.7. 
Reporting Events to Participants 
Subjects will be given any new information that is learned about the study drug, or about their 
condition, during the course of the research study that might affect their willingness to continue 
participation. Subjects will be told about any new risks that become known during this research 
study. 


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9.3.8. 
Events of Special Interest 
9.3.8.1. 
Gastrointestinal Event 
Subjects taking HTD1801 may experience GI discomfort related to this therapy. This is variously 
described as diarrhea, abdominal bloating, abdominal discomfort, abdominal pain, and 
sometimes even constipation. Rather than have the subject discontinue and stop treatment 
altogether, downward dose titration from the starting dose of HTD1801 2000 mg per day is 
allowed and even encouraged. 
Guidelines for dose reduction in the event of GI discomfort are outlined in Section 6.1.3. 
9.3.8.2. 
Treatment Failure due to HTD1801 Dose Reduction  
If any subject with PBC fails treatment after having their dose reduced, their study participation 
will be terminated and the subject would be able to resume their pre-study treatment for PBC 
after early termination study-required assessments completed.  A subject will be considered to 
have failed treatment if the serum ALP, after having been lowered on treatment, returns to 
baseline or higher on two subsequent assessments (baseline is calculated as the average of the 
historical value and the value at screening). 
9.3.8.3. 
Reporting of Pregnancy 
When any member of the study staff becomes aware of a subject’s (or subject’s partner’s) 
pregnancy, the site staff must report the pregnancy to the medical monitor and the within 24 
hours by using the Pregnancy Notification Form. The female subject will discontinue study 
medication. The pregnancy will be followed until there is an outcome and the outcome is 
reported to the sponsor. 


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10. 
DRUG-INDUCED LIVER INJURY (DILI) MONITORING AND 
STOPPING RULES 
It is important for study staff to monitor subjects for drug-induced liver injury and to educate 
subjects to recognize DILI symptoms and seek immediate medical attention. 
Liver enzymes and serum bilirubin levels will be assessed at each clinic visit.  Elevated ALTs 
will be assessed and dealt with as shown in Table 7 and Table 8.There are separate DILI 
monitoring plans based on whether the subject had normal or near normal versus elevated ALT 
values at baseline, because some subjects with PBC may have normal or near normal ALT levels 
at baseline.  The Medpace Reference Laboratory (MRL) which will serve as the central 
laboratory for this study has defined its upper limit of normal for ALT as 53 U/L, in both males 
and females.  The study therefore considers up to 60 U/L as being normal or near normal while 
>60 U/L is considered elevated. 
Persistent Cholestatic liver injury is characterized by elevations in serum alkaline phosphatase 
and/or bilirubin (see Table 7 and Table 8). 
10.1. 
Protocol Definition of Normal or Near Normal and Elevated ALT 
10.1.1. 
Detection of Potential DILI in Subjects with Normal or Near Normal ALT levels 
at baseline 
Because some subjects with PBC may have normal or near normal ALT levels at baseline (see 
Hirschfield 2015), an on-treatment ALT value more than 3x the ULN (i.e. >180 u/L) will be the 
threshold for triggering the DILI monitoring plan for these subjects. 
10.1.2. 
Detection of Potential DILI in Subjects with Elevated ALT levels at baseline 
Because subjects to be enrolled in the study have underlying liver disease, it is very likely that 
they may have an elevated ALT level at baseline and therefore multiples of the baseline will be 
used for DILI monitoring where the baseline value is elevated.  The baseline ALT value will be 
calculated as the average of those obtained at the screening and baseline visits.  An on-treatment 
ALT value more than 3x the baseline value will be the threshold for triggering the DILI 
monitoring plan for these subjects. 
10.1.3. 
Process for DILI Monitoring 
Serum ALT will be measured as part of a serum chemistry panel at screening, baseline and at 
weeks 2, 4, 6, 8 and 12.  Serum samples will be shipped to a central or local laboratory for 
testing.  Central lab reports will be faxed or emailed to the clinical site within 24 hours of receipt 
of the sample to be reviewed by the site PI.  Local lab results will need to be entered into eDC. 
Values meeting or exceeding the DILI threshold described in Tables 7 and 8 will be flagged for 
the attention of the medical monitor.  The medical monitor will contact the clinical site to initiate 
the DILI monitoring protocol.   


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Table 7: 
Liver Monitoring Procedure – For Subjects with Normal or Near Normal Baseline ALT ( ≤60 U/L) 
Event 
Observation 
Action 
ALT becomes 
elevated 
Isolated increase in ALT to ≥3x ULN (i.e., ≥180 /L) with no 
increase in serum bilirubin and presence of symptoms of anorexia, 
nausea, fatigue, right upper abdominal discomfort or vomiting 
preceding or following the isolated increase in ALT to ≥3x ULN. 
• 
Promptly repeat serum chemistry panel (ALT, AST, ALP, total bilirubin and 
direct bilirubin) within 2 to 5 days* 
• 
If subject lives remotely from the site, local labs may be obtained   
• 
The PI must review the local lab results promptly and local lab results 
must be entered into an unscheduled visit within the EDC 
• 
Continue investigational study drug 
ALT remains 
elevated 
If ALT remains ≥3x ULN  
• 
Obtain serum chemistry panel (as above) and repeat 2 – 3 x/week until stable 
• 
Frequency of testing can be decreased to once per week or less if abnormalities 
stabilize or the subject is asymptomatic 
• 
Obtain detailed history of symptoms and prior or concurrent medical history 
• 
Obtain history of concomitant drug use including non-prescription 
medications, herbal & dietary preparations, alcohol use, recreational drug use, 
and special diets 
• 
Where appropriate, rule out acute viral hepatitis types A, B, C, D, & E, 
autoimmune or alcoholic hepatitis, NASH, hypoxic/ischemic hepatopathy & 
biliary tract disease 
• 
Obtain a history of exposure to environmental chemical agents 
• 
Obtain additional tests to evaluate liver function, as appropriate (e.g., INR, 
CBC with differential) 
• 
Continue investigational study drug 
ALT decreases 
ALT return to <3x ULN or baseline level 
• 
Resume study-required laboratory assessments as per the Summary of Events 
table and continue investigational study drug 
Elevated Liver 
Function Tests 
Worsen or 
Clinical 
Symptoms 
Develop 
If ALT is >8x ULN of baseline on one occasion, or 
If ALT is >5x ULN of baseline for more than 2 weeks, or 
If ALT is >3x ULN of baseline AND bilirubin is >2X ULN OR 
INR >1.5), or  
• 
Permanently STOP investigational study drug 
• 
Continue monitoring until all abnormalities return to normal or to the baseline 
state 
• 
All DILI monitoring results must be recorded in the DILI monitoring eCRF 


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* The PI must review the local lab results promptly.  Local lab results must be entered into an unscheduled visit within the EDC 
If ALT is >3x ULN of baseline AND subject is symptomatic 
(severe fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
Persistent 
Cholestatic Liver 
Injury 
If serum ALP is >2x ULN and total and direct bilirubin is >2x ULN 
• 
Permanently STOP investigational study drug 
• 
Continue monitoring until all abnormalities return to normal or to the baseline 
state 
• 
All DILI monitoring results must be recorded in the DILI monitoring eCRF 


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Table 8: 
Liver Monitoring Procedure – For Subjects with Calculated Baseline ALT >60 U/L (Elevated ALT) 
Event 
Observation 
Action 
ALT becomes 
elevated 
Isolated increase in ALT to ≥3x ULN (i.e., ≥180 u/L) with no 
increase in serum bilirubin and presence of symptoms of anorexia, 
nausea, fatigue, right upper abdominal discomfort or vomiting  
preceding or following the isolated increase in ALT to >3x ULN. 
• 
Promptly repeat serum chemistry panel (ALT, AST, ALP, total bilirubin and 
direct bilirubin) within 2 to 5 days* 
• 
If subject lives remotely from the site, local labs may be obtained   
• 
The PI must review the local lab results promptly and local lab results 
must be entered into an unscheduled visit within the EDC 
• 
Continue investigational study drug 
ALT remains 
elevated 
If ALT remains ≥3x calculated baseline 
• 
Obtain serum chemistry panel (as above) and repeat 2 – 3 x/week until stable 
• 
Frequency of testing can be decreased to once per week or less if abnormalities 
stabilize or the subject is asymptomatic 
• 
Obtain detailed history of symptoms and prior or concurrent medical history 
• 
Obtain history of concomitant drug use including non-prescription 
medications, herbal & dietary preparations, alcohol use, recreational drug use, 
and special diets. 
• 
Where appropriate, rule out acute viral hepatitis types A, B, C, D, & E, 
autoimmune or alcoholic hepatitis, NASH, hypoxic/ischemic hepatopathy & 
biliary tract disease 
• 
Obtain a history of exposure to environmental chemical agents 
• 
Obtain additional tests to evaluate liver function, as appropriate (e.g., INR, 
CBC with differential) 
• 
Continue investigational study drug 
ALT decreases 
ALT return to <3x ULN or baseline level 
• 
Resume study-required laboratory assessments as per the Summary of Events 
table and continue investigational study drug 
Elevated Liver 
Function Tests 
Worsen 
If ALT is >8x ULN of calculated baseline on one occasion, or 
If ALT is >5x ULN of calculated baseline for more than 2 weeks, or 
If ALT is >3x ULN of calculated baseline AND bilirubin is >2X 
ULN OR INR >1.5), or  
• 
Permanently STOP investigational study drug 
• 
Continue monitoring until all abnormalities return to normal or to the 
calculated baseline state 
• 
All DILI monitoring results must be recorded in the DILI monitoring eCRF 


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* The PI must review the local lab results promptly.  Local lab results must be entered into an unscheduled visit within the EDC 
If ALT is >3x ULN of calculated baseline AND subject is 
symptomatic (severe fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Persistent 
Cholestatic Liver 
Injury 
If serum ALP is >2x ULN and total and direct bilirubin is >2x ULN 
• 
Permanently STOP investigational study drug 
• 
Continue monitoring until all abnormalities return to normal or to the 
calculated baseline state 
• 
All DILI monitoring results must be recorded in the DILI monitoring eCRF 


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11. 
COVID-19 PANDEMIC CONTINGENCIES  
11.1. 
Potential Impact of COVID-19 on Study Conduct 
The potential impact from quarantine restrictions, site closures and travel restrictions may limit 
the site’s and subject’s capability to have on-site visits.  
11.2. 
Operational Contingencies related to COVID-19 Pandemic 
Local site policies and process for COVID-19 monitoring, for example, temperature check, 
COVID-19 exposure history, recent travel history and use of personal protective equipment must 
be followed. 
The study protocol specifies that all visits are in-clinic visits but allows for contingency measures 
for Study Visits Week 2, 4, 8, 16 and the Early Termination visit in the occurrence where a 
subject is unwilling or unable to participate in an in-clinic visit due to the COVID-19 pandemic.  
In that instance, the site will work with the study subject to obtain study-required blood draws at 
a local laboratory or arrangements will be made to have the home health provider obtain the visit 
specific blood draw for the study-required laboratory assessments.  
Other visit assessments will have to occur via a remote visit by telephone or a video conference, 
per site practice and procedures, to assess changes in the subjects’ health condition, make note of 
any changes in concomitant medications, and inquire about adverse events. The visit must be 
documented as a telephone/video conference visit with arrangements for laboratory assessments. 
The site will enter the laboratory results, if obtained at a local laboratory, into the EDC as an 
“unscheduled” visit that will be mapped to the specific visit for which local laboratory data were 
obtained.  If the visit specific blood draw is obtained by the home health service provider, it will 
be shipped to the central laboratory; the results will be entered into the central laboratory 
database and merged with the clinical database at the completion of the study. 
Every effort must be made to complete the full scope of the study visit activities and procedures. 
Any deviation from the procedures and protocol-specified contingency measures due to COVID-
19 must be clearly documented as COVID-19-related and reported to the IRB as applicable.  
The PI and study personnel are responsible for ensuring full investigational product 
accountability.  


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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Statistical Hypotheses 
The primary hypothesis for this study is that treatment with HTD1801 results in reductions in 
ALP: 
𝐻𝐻0: 𝐴𝐴𝐴𝐴𝐴𝐴𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊 12 − 𝐴𝐴𝐴𝐴𝐴𝐴𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
𝐴𝐴𝐴𝐴𝐴𝐴𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
 ≥0 𝑣𝑣𝑣𝑣.  𝐻𝐻𝑎𝑎: 𝐴𝐴𝐴𝐴𝐴𝐴𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊 12 − 𝐴𝐴𝐴𝐴𝐴𝐴𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
𝐴𝐴𝐴𝐴𝐴𝐴𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵
< 0 
The estimand will be the percent change from baseline and will be measured within all subjects 
on treatment and who provide data at Week 12. This estimand is similar to the While on 
Treatment Strategy outlined in ICH e9 R1 but is limited to on treatment results at Week 12 (i.e., 
results from prior to Week 12 are not included in the analysis of the Week 12 results). 
Testing will be one sided using a 5% alpha level. 
12.2. 
Sample Size Determination 
A sample size of 30 subjects provides ≥90% power for the primary endpoint assuming a mean 
percent reduction in ALP of 15% and a SD of 25%. Power calculations use a 5% one sided alpha 
and a t-test. Sample size calculation were performed in PASS (PASS 2014). 
12.3. 
Populations for Analyses 
The following analysis populations will be defined for statistical analysis: 
• Screened population 
o The Screened population will consist of all subjects who sign the study informed 
consent. 
• Intention-to-treat (ITT) population  
o The ITT population will consist of all subjects that receive at least one dose of 
HTD1801. This population will be used for all efficacy, safety, and 
baseline/demographic analyses and summaries. 
• Population undergoing pharmacokinetic testing 
o At least 6 subjects will undergo sparse PK sampling at weeks 6 and 12. 
12.4. 
Statistical Analyses 
12.4.1. 
General Approach 
Endpoints will be summarized using descriptive statistics. For continuous variables n (number of 
subjects with data), mean, standard deviation, median, minimum, and maximum will be used. 
For categorical results the number of subjects and the percent of subjects per category will be 
summarized. Confidence intervals will be generally reported using 95% two-sided confidence 
intervals. When testing is used p-values with four decimal places will be reported; no adjustment 
for multiplicity will be conducted. 


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Missing data will not be imputed for the efficacy analyses. Missing dates for adverse events and 
concomitant medication will be imputed to allow these items to be summarized as on or off 
treatment. 
12.4.2. 
Analysis of the Primary Efficacy Endpoint(s) 
Alkaline phosphatase levels, change from baseline, and percent change from baseline will be 
summarized with descriptive statistics and 95% normal approximation confidence intervals. 
Testing for the percent change endpoint using a t-test will also be performed. Given the limited 
sample size (i.e. less than 30 subjects) and the potential for right skewed data the normality 
assumption may not be fully accurate. Hence, the true alpha level may theoretically not be 5%. 
As such, these tests will be considered descriptive more than confirmatory. 
12.4.3. 
Analysis of the Secondary Endpoint(s) 
The secondary endpoints including the secondary ALP endpoints will be summarized using 
descriptive statistics. Summary statistics at each timepoint that data is captured will be provided 
for the result as well as the change from baseline, when change from baseline is applicable. 
Confidence intervals will be produced for changes in serum bilirubin and change in gamma-
glutamyl transferase. 
12.4.4. 
Safety Analyses 
Safety endpoints will be summarized using descriptive statistics. 
Treatment emergent adverse events (TEAE), events that start on or after the start of treatment, 
will be summarized by system organ class and preferred term. Summaries of all TEAEs, 
treatment emergent SAEs, related TEAEs and TEAEs by severity will be produced. 
Laboratory, vital sign, and ECG results will be summarized as continuous measures (e.g., change 
from baseline). Selected laboratory results will also be summarized as categorical variables (e.g., 
‘in’ versus ‘out’ of the normal range). 
12.4.5. 
Pharamacokinetic Analyses 
Descriptive statistics will be summarized for plasma concentrations of BBR and UDCA as a 
function of study visit.  These concentrations will be used to build a population PK model in 
combination with PK data from other studies to inform model-derived parameters, if applicable.  
12.4.6. 
Baseline Descriptive Statistics 
Subjects who discontinue treatment or withdraw from the study, and the reasons for doing so, 
will be summarized. Subject demographic and baseline characteristics will be summarized. 
12.4.7. 
Planned Interim Analyses 
Enrollment into the study may be stopped early prior to enrollment of 30 subjects should the 
scientific goal (evaluate the effects of HTD1801 on serum ALP) of the study be achieved with 
the currently available data. That is, if prior to enrollment of 30 subjects if the results are robust 
enough to provide preliminary evidence of efficacy that warrant further evaluation in a placebo-
controlled study, enrollment in this study may be terminated. 


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13. 
STUDY ADMINISTRATION 
13.1. 
Informed Consent and Authorization For Use and Disclosure of 
Protected Health Information 
Written informed consent and authorization of use and disclosure of protected health information 
must be obtained from each subject (or the subject’s legally acceptable representative) before 
performing any study-specific Screening or Baseline evaluations. One copy of the signed ICF 
and authorization for use and disclosure of protected health information form will be given to the 
subject, and the Investigator will retain the original. The ICF and authorization for use and 
disclosure of protected health information, which is prepared by the Investigator or the 
investigational site, must have been reviewed and approved by the Sponsor, the Study Monitor, 
and the Investigator’s IRB or IEC and privacy board (if separate from the IRB/IEC) before the 
initiation of the study. The ICF must contain the 20 elements of informed consent described in 
ICH E6, Section 4.8. The authorization for use and disclosure of protected health information 
must contain the elements required by Title 45 of the Code of Federal Regulations, Section 
164.508(b), and any local regulations for valid authorizations. 
13.2. 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigators and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator will promptly inform study participants, the Institutional Review Board (IRB), and 
sponsor and will provide the reason(s) for the termination or suspension. Study participants will 
be contacted, as applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
13.3. 
Study Documentation 
13.3.1. 
Investigator Information  
Investigator information is included in the SPM (or other applicable instructions), which is 
updated as needed. 


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13.3.2. 
Investigator’s Study Files 
Documentation about the Investigator and his/her study staff, the IRB/IEC, and the institution is 
required before site initiation. Copies of these documents will be kept on site in site specific 
binders or electronic folders, along with the following supplemental information: a list of 
Investigator’s obligations; the Investigator’s Brochure; the clinical protocol and amendments; 
safety information; information about the investigational product, biological samples, and the 
applicable laboratory(ies); the SPM (or other applicable instructions) and study logs; eCRFs; 
records of monitoring activities; and correspondence between the Sponsor or Study Monitor and 
the Investigator. 
13.3.3. 
Case Report Forms and Source Documentation  
The Investigator must make study data accessible to the Study Monitor, other authorized 
representatives of the Sponsor, and the appropriate regulatory authority inspectors. The eCRF for 
each subject will be checked against source documents at the investigational site by the Study 
Monitor, and a final copy of the eCRF will be signed by the Investigator with an electronic 
signature. A copy of the final eCRFs will be provided to the Investigator in PDF format on 
computer disc after study closure to be kept in the Investigator’s study files. 
13.3.4. 
Retention of Study Documents 
According to ICH E6, Section 4.9, all eCRFs, as well as supporting paper and electronic source 
documentation and administrative records, must be retained by the Investigator until at least 2 
years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. The Sponsor is responsible for informing the Investigator and 
institution as to when these documents no longer need to be retained. No study documents will 
be destroyed or moved to a new location without prior written approval from the Sponsor. If the 
Investigator relocates, retires, or withdraws from the study for any reason, all records required to 
be maintained for the study should be transferred to an agreed-upon designee, such as another 
Investigator at the institution where the study was conducted. 
Audit trails for electronic documentation must be retained for a period at least as long as the 
period required for the subject’s electronic records to which they pertain. The Investigator must 
retain either the originals of the audit trails or a certified copy of the audit trails. 
13.4. 
Confidentiality 
13.4.1. 
Data 
The Investigator must keep all information confidential about the nature of the proposed 
investigation provided by the Sponsor or Study Monitor to the Investigator (with the exception of 
information required by law or regulations to be disclosed to the IRB/IEC, the subject, or the 
appropriate regulatory authority). 


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58 
13.4.2. 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject ID number on eCRFs and other documents retrieved from the investigational 
site or sent to the Study Monitor, Sponsor, regulatory agencies, central laboratories, or blinded 
reviewers. Documents that identify the subject (e.g., the signed ICF) must be maintained in strict 
confidence by the Investigator, except to the extent necessary to allow auditing by the 
appropriate regulatory authority, the Study Monitor, or Sponsor representatives. 
13.5. 
Protocol Compliance 
Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, assessment variable(s), the number of subjects treated, or the subject-selection 
criteria. Such changes must be prepared as a protocol amendment by the Sponsor and 
implemented only upon joint approval of the Sponsor and the Investigator. A protocol 
amendment must receive IRB/IEC approval before implementation. In parallel with the IRB/IEC 
approval process, the protocol amendment will be submitted to the appropriate regulatory 
authority as an amendment to the regulatory submission under which the study is being 
conducted. If a protocol amendment requires changes in the ICF, the revised ICF prepared by the 
Investigator must also be approved by the Sponsor, Study Monitor, and the IRB/IEC before 
implementation. 
Departures from the protocol eligibility criteria (see Sections 5.1 and 5.2) are not permitted as 
these could jeopardize subject safety, study integrity, or regulatory acceptance of the results. 
Departures from other protocol procedures or requirements are allowed only in situations that 
eliminate an immediate risk to a subject and that are deemed crucial for the safety and wellbeing 
of that subject. The Investigator or the attending physician will also contact the Medical Monitor 
as soon as possible in the case of such a departure. These departures do not require pre-approval 
by the IRB/IEC; however, the IRB/IEC and Medical Monitor must be notified in writing as soon 
as possible after the departure has been made. In addition, the Investigator will document in the 
subject’s eCRF the reasons for the protocol deviation and the ensuing events. 
13.6. 
Study Monitor Functions and Responsibility 
The Study Monitor, in accordance with the Sponsor’s requirements, will ensure that the study is 
conducted and documented properly by carrying out the activities outlined in ICH E6, Section 
5.18.4. 
13.7. 
Quality Assurance and Quality Control  
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 


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59 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
13.8. 
General Information  
The Investigator should refer to the Investigator’s Brochure, SPM (or other applicable 
instructions), and any other information provided about the investigational product and details of 
the procedures to be followed during this study. 


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60 
14. 
ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
AIH 
autoimmune hepatitis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANA 
antinuclear antibody 
AST 
aspartate aminotransferase 
BBR 
berberine 
BID 
twice daily 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CRP 
C-reactive protein 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G6PD 
glucose-6-phosphate dehydrogenase 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HDL-c 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
LDL-c 
low-density lipoprotein cholesterol 
NASH 
nonalcoholic steatohepatitis 
OCA 
obeticholic acid 
PBC 
primary biliary cholangitis 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SD 
standard deviation 
SPM 
Study Procedures Manual 
TEAE 
treatment-emergent adverse event 


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61 
TSH 
thyroid stimulating hormone 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
VAS 
visual analogue scale 


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Study HTD1801.PCT013 
 
62 
15. 
REFERENCES 
Bahar R, Wong KA, Liu CH, Bowlus CL. Update on new drugs and those in development for the 
treatment of primary biliary cholangitis. Gastroenterol Hepatol (NY). 2018;14(3):154-163. 
Chalasani N, Regev A.  Drug-induced liver injury in patients with preexisting chronic liver 
disease in drug development:  How to identify and manage.  Gastroenterology 2016;151:1046-
1051. 
Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid 
therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32(6):1196-
1199. 
Di Bisceglie AM, Watts GF, Lavin P, Yu M, Bai R, Liu L.  Pharmacokinetics and 
pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with 
hyperlipidemia.  Lipids in Health and Disease.  2020;19:239 https://doi.org/10.1186/s12944-
020-01406-4. 
Harrison SA, Gunn N, Neff GW, Kohli A, Liu L, Di Bisceglie AM.  A Phase 2a, Randomized 
Controlled Trial of Berberine Ursodeoxycholate (BUDC) in Patients with Presumed Non-
Alcoholic Steatohepatitis (NASH) and Type 2 Diabetes.  Hepatology 2020:721(suppl):1007A. 
Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary 
biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterol. 2015;148:751-
761. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-
premarketing-clinical-evaluation  
Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring 
system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic 
acid therapy. Gastroenterol. 2015;149(7):1804-1812. 
Levy C, Lindor KD. Treatment Options for Primary Biliary Cirrhosis and Primary Sclerosing 
Cholangitis. Curr Treat Options Gastroenterol. 2003;6(2):93-103. 
Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cholangitis: 2018 practice guidance from 
the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. 
Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of 
ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 
1996;110(5):1515-1518. 
OCALIVA (obeticholic acid) tablets [package insert]. New York, NY. Intercept 
Pharmaceuticals, Inc. 2020. 
PASS 13 Power Analysis and Sample Size Software (2014). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass.  
URSO 250 and URSO Forte (ursodiol) tablets [package insert]. Bridgewater, NJ. Aptalis Pharma 
US, Inc. 2013. 


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63 
APPENDIX A. GLOBE SCORE 
https://www.globalpbc.com/globe  
The GLOBE score for patients with Primary Biliary Cholangitis 
(PBC) 
The GLOBE score is an internationally relevant and validated risk assessment tool, able to accurately 
stratify PBC patients to high and low risk. 
Age, years 
at initiation of UDCA therapy 
 
 
Total bilirubin level, µmol/L or 
mg/dl 
after one year of UDCA therapy 
 
Upper limit of 
normal: 
 
Alkaline phosphatase level, U/L 
after one year of UDCA therapy 
Upper limit of 
normal: 
Albumin, g/L 
after one year of UDCA therapy 
Lower limit of 
normal: 
Platelets, x 109/L 
after one year of UDCA therapy 
 
 
  
Interpretation of the GLOBE score: 
Patients with a GLOBE score corresponding with an estimated transplant-free survival 
comparable with an age- and sex-matched population are at low risk for future adverse events 
and patients with a GLOBE score corresponding with a transplant-free survival that significantly 
deviates from an age- and sex-matched population may benefit from new therapies 
Data of an age- and sex-matched population, a population with a life-expectancy comparable 
with that of other countries participating in the Global PBC Study Group, were retrieved from a 
Dutch registry (Statistics Netherlands, www.cbs.nl).  
The GLOBE score uses age-specific thresholds beyond which survival significantly deviates 
from an age- and sex matched general population. In subgroups of patients aged 66 years, age-
specific GLOBE-score thresholds beyond which survival significantly deviates from matched 
individuals are 0.52, 0.01, 0.60, 1.01 and 1.69, respectively. 


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64 
APPENDIX B. PRURITUS VAS SCORE 
 
 
http://www.pruritussymposium.de/visualanaloguescale.html 
 
Scoring: 
VAS 0= No pruritus 
VAS < 3= Mild pruritus 
VAS ≥ 3-<7= Moderate pruritus 
VAS ≥ 7-<9 = Severe pruritus 
VAS ≥ 9= Very severe pruritus 
 

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STATISTICAL ANALYSIS PLAN 
 
 
A Phase 2 Open Label Proof-of-Concept Study of HTD1801 in Adult Subjects 
with Primary Biliary Cholangitis (PBC) and an Inadequate Response to Standard 
Therapy 
 
(PRONTO-PBC) 
 
Protocol HTD1801.PCT013 
IND 136137 
 
 
Sponsored by: 
HighTide Biopharma Pty. Ltd. 
Level 13, Citigroup Tower 
2 Park Street 
Sydney, NSW 2000 
Australia 
 
Version: 1.0 
Date Approved: 25 Apr 2022 
 
 
 
 
 
 
 
 
 
Confidentiality Statement: 
 
This document is a confidential communication of HighTide Biopharma Pty. Ltd. As such, the 
recipients agree not to disclose or reproduce, without prior written approval, this document and 
any attachments, except to appropriate Institutional Review Boards, Ethics Committees, 
representatives of the US Food and Drug Administration, other regulatory agencies or as 
otherwise required by applicable laws or regulations. 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1 
STUDY DESCRIPTION .......................................................................................... 5 
1.1 
Introduction ........................................................................................................ 5 
1.2 
Objectives ........................................................................................................... 5 
1.3 
Study Design ...................................................................................................... 6 
1.4 
Treatment Blinding ............................................................................................ 8 
1.5 
Decision Rule and Sample Size ......................................................................... 8 
2 
STATISTICAL METHODS .................................................................................... 9 
2.1 
Analysis Populations .......................................................................................... 9 
2.2 
Study Drug Dosing and Compliance .................................................................. 9 
2.3 
Study Endpoints ............................................................................................... 10 
2.3.1 
Alkaline Phosphatase ........................................................................... 11 
2.3.2 
Liver Laboratory Tests ......................................................................... 11 
2.3.3 
Lipid Laboratory Tests ......................................................................... 12 
2.3.4 
Serum Markers of Inflammation .......................................................... 12 
2.3.5 
Enhanced Liver Fibrosis Score ............................................................. 12 
2.3.6 
GLOBE Score ...................................................................................... 13 
2.3.7 
Pruritus Visual Analog Scale ............................................................... 13 
2.3.8 
Safety Parameters ................................................................................. 14 
2.4 
Study Day and Visit Windows ......................................................................... 15 
2.4.1 
Definition of Baseline .......................................................................... 15 
2.5 
Statistical Assessment of the Study Objectives ................................................ 15 
2.5.1 
Primary Analysis .................................................................................. 16 
2.5.2 
Secondary Analyses ............................................................................. 16 
2.5.3 
Subgroups ............................................................................................. 17 
2.6 
Handling of Missing Data ................................................................................ 17 
2.7 
Safety Analyses ................................................................................................ 17 
2.8 
Interim Analyses .............................................................................................. 17 
3 
SUMMARY TABLES, LISTINGS, AND FIGURES ........................................... 18 
3.1 
General Conventions ........................................................................................ 18 
3.2 
Clinical Study Subjects .................................................................................... 18 
3.2.1 
Subject Disposition and Analysis Populations ..................................... 18 
3.2.2 
Demographics and Baseline Characteristics ........................................ 18 
3.2.3 
Concomitant Medications .................................................................... 19 
3.2.4 
Medical History .................................................................................... 20 
3.2.5 
Clinical Study Treatment and Extent of Exposure ............................... 20 
3.3 
Analysis of Efficacy Endpoints ........................................................................ 20 


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3.3.1 
Serum Alkaline Phosphatase ................................................................ 20 
3.3.2 
Secondary Endpoints ............................................................................ 20 
3.3.3 
UDCA Use ........................................................................................... 21 
3.3.4 
ELF Score ............................................................................................. 21 
3.3.5 
GLOBE Score ...................................................................................... 21 
3.4 
Analysis of Safety Endpoints ........................................................................... 21 
3.4.1 
Adverse Events ..................................................................................... 21 
3.4.2 
Pruritus VAS ........................................................................................ 22 
3.4.3 
Clinical Laboratory Evaluations ........................................................... 22 
3.4.4 
Vital Signs ............................................................................................ 22 
3.4.5 
Electrocardiogram Results ................................................................... 22 
3.4.6 
Pregnancy ............................................................................................. 22 
4 
REFERENCES ....................................................................................................... 23 
5 
APPROVAL SHEET ............................................................................................. 24 
 
LIST OF TABLES 
Table 1 
Schedule of Events ...................................................................................... 7 
Table 2 
Analysis Windows .................................................................................... 15 


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LIST OF ABBREVIATIONS 
 
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
AIH 
autoimmune hepatitis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANA 
antinuclear antibody 
AST 
aspartate aminotransferase 
BBR 
berberine 
BID 
twice daily 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CRP 
C-reactive protein 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
FSH 
follicle stimulating hormone 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HDL 
high-density lipoprotein cholesterol 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
LDL 
low-density lipoprotein cholesterol 
NASH 
nonalcoholic steatohepatitis 
OCA 
obeticholic acid 
PBC 
primary biliary cholangitis 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
VAS 
visual analogue scale 


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1 
STUDY DESCRIPTION 
 
1.1 
Introduction 
 
This document outlines the statistical methods to be implemented during the analyses of 
protocol HTD1801.PCT013. The purpose of this plan is to provide specific guidelines from 
which the analyses will proceed. Any deviations from these guidelines will be documented 
in the clinical study report (CSR). 
 
In this study, HTD1801 is being studied for the treatment of Primary Biliary Cholangitis 
(PBC) in adult subjects. PBC is a relatively rare chronic, slowly progressive, autoimmune 
liver disease. It can lead to inflammation, destruction of small bile ducts, fibrosis, and 
eventually cirrhosis. The most common symptoms of PBC are fatigue and itching. 
 
HTD1801 is a novel synthetic small molecule: an ionic salt formed between a base [berberine 
(BBR)] and a weak acid [ursodeoxycholic acid (UDCA)] with a stoichiometry of 1:1 and 
containing a single active ingredient in the final dosage form. The single active ingredient in 
HTD1801 likely dissociates into two active moieties, BBR and UDCA. These moieties work 
in tandem in the salt form to produce, through their interaction, distinct and improved 
properties of HTD1801 that are not observed with either of the individual active moieties. A 
substantial portion of the beneficial effect of the novel HTD1801 salt appears to be derived 
from the interaction of its BBR and UDCA moieties conferring improved physico-chemical 
properties, solubility, and PK properties. 
 
UDCA has been the mainstay of treatment for PBC for many years and is used globally as 
the first-line therapy for the disease. However, approximately 40 to 50% of PBC patients do 
not respond to UDCA or do not maintain an adequate response to UDCA. 
The addition of BBR to UDCA, as a salt, in HTD1801 could deliver a benefit to PBC 
patients who are inadequate responders to UDCA alone. While BBR alone has not been 
studied in PBC, in a rat model of cholestasis and liver inflammation, HTD1801 was effective 
in decreasing liver inflammation and necrosis, and improving bile duct health by reducing 
inflammation in the portal area and controlling bile duct proliferation. In addition, treatment 
with HTD1801 was found to be associated with an improvement in serum markers of 
cholestasis (alkaline phosphatase [ALP] and gamma-glutamyl transferase [GGT]). 
 
1.2 
Objectives 
 
The primary objective of this study is 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 ≥1.5x ULN despite having been on adequate doses of 
UDCA for at least 6 months. 
 
The secondary objectives of this study are to evaluate the following: 
• The effects of HTD1801 on serum markers of cholestasis, serum lipids and serum 
markers of inflammation 
• The safety and tolerability of HTD1801 over 12 weeks of treatment 


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• The pharmacokinetic (PK) profile of HTD1801 in a subset of subjects 
o PK analyses will be covered under a separate analysis plan. 
1.3 
Study Design 
 
This is a Phase 2, single arm, 12-week open-label proof of concept study of HTD1801 in 
adult subjects with PBC with an inadequate response to standard therapy. Inadequate 
response is defined as ALP ≥1.5x ULN despite having been on adequate doses of UDCA for 
at least 6 months. 
 
The study will consist of three periods, for a total study period of 16 weeks: 
• Screening period: Up to 28 days 
• Treatment period: 12 weeks 
• Follow-up period: 28 days after the last dose of study drug 
Upon confirmation of eligibility, approximately 30 subjects with PBC will be enrolled and 
will receive HTD1801 1000 mg twice daily (BID) for 12 weeks. Study visits occur at Day 0, 
Weeks 2, 4, 6, 8, and 12. A final follow-up visit will occur at Week 16, 4 weeks after the last 
dose of study drug. If a subject experiences gastrointestinal discomfort, as outlined in the 
protocol, at the starting dose of 1000 mg BID, dose reduction is allowed. 
 
An abbreviated Schedule of Events for the study can be found in Table 1. 
 
. 


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Table 1 
Schedule of Events 
 
Examination 
Screening 
Baseline 
Week 2 
Clinic/ 
Optional 
Home Visit 
Week 4 
Clinic/Optiona 
l Home Visit 
Week 
6 
Week 8 
Clinic/Optional 
Home Visit 
Week 
12 
ET 
Week 
16 F/U 
Demographics 
X 
Pruritus VAS 
X 
X 
X 
X 
X 
GLOBE Score 
X 
X 
X 
X 
ECG 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Medical history 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
Serum Chemistry panel 
(including GGT) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Endocrine/Reproductive 
X 
Serology, Other labs 
X 
X 
X 
X 
X 
Lipid panel 
X 
X 
X 
X 
X 
Bile acid panela 
X 
X 
X 
X 
PK Blood Draw 
X 
X 
Urine pregnancy test 
X 
X 
X 
Dispense / collect study drug 
X 
X 
X 
X 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
aFor subjects that had a sample obtained at Baseline 


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1.4 
Treatment Blinding 
 
This is an open-label study. 
 
1.5 
Decision Rule and Sample Size 
 
The significance level for this study is 5% (one-sided). If the one-sided p-value is less than 
5% then the null hypothesis of no treatment effect is rejected. 
 
A sample size of 30 subjects provides ≥90% power for the primary endpoint assuming a 
mean percent reduction in ALP of 15% and a standard deviation of 25%. Power 
calculations use a 5% one sided alpha and a t-test. Sample size calculation were performed 
in PASS. 
At least 6 subjects will participate in a PK sub study. 


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2 
STATISTICAL METHODS 
 
2.1 
Analysis Populations 
 
The following analysis populations will be defined for statistical analysis: 
• Screened population - All subjects who sign the study informed consent. 
• Intention-to-treat (ITT) population - All subjects that receive at least one dose of 
HTD1801. This population will be used for the primary endpoint, as well as all 
efficacy, safety, and baseline/demographic analyses and summaries. 
• Per Protocol (PP) Population – All subjects in the ITT population who provide a 
Week 12 assessment and 80% study drug compliance. This population will be used 
for selected efficacy analyses and summaries. 
 
2.2 
Study Drug Dosing and Compliance 
 
HTD1801 tablets are administered BID with water and food. Subjects are instructed to take 
the entire contents of 1 pouch each morning and each evening with water and food (e.g., 
meal or snack). An adequate supply of pouches (containing 4 identical white tablets [250 mg 
per tablet]) will be placed into kits packaged for weekly use. 
Study drug will be dispensed at Baseline and the Week 6 visit. Each subject will receive the 
appropriate number of kits to provide enough supplies until the subsequent visit where study 
drug is dispensed. At the Week 6 and Week 12 visits subjects will return any unused study 
drug to the investigational site. At these visits, the number of full and empty or partially 
empty pouches will be captured on the eCRF. 
The tablet counts reported within the eCRF will be used as the dosing and compliance data 
source. From these data the duration of treatment, number of tablets used, average dose 
received per day, and compliance with treatment will be determined. The duration of 
treatment is calculated as, 
Treatment Duration = treatment end date – treatment start date + 1. 
 
Compliance will be calculated as, 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶(%) = 
𝑇𝑇𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝑇𝑇𝑇𝑇 𝑈𝑈𝑇𝑇𝐶𝐶𝑈𝑈 
. 
𝑇𝑇𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝑇𝑇𝑇𝑇 𝐸𝐸𝐸𝐸𝐶𝐶𝐶𝐶𝐶𝐶𝑇𝑇𝐶𝐶𝑈𝑈 𝑇𝑇𝐶𝐶 𝑇𝑇𝐶𝐶 𝑈𝑈𝑇𝑇𝐶𝐶𝑈𝑈 
 
The number of tablets used will be based upon the counts recorded in the eCRF. The total 
number of tablets used will be the sum across kits. Should study drug reconciliation data be 
missing for a subject, the number of tablets used will also be missing, and therefore 
compliance will be unknown. 
 
If there is no dose interruption or modification, tablets expected to be used is, 
 
Tablets Used = 8*(treatment end date - treatment start date +1) 


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If there was a period of time where there was a dose interruption or modification, the dose 
will be assumed to be 0 for an interruption, and the modified dose will be the number of 
tablets received per day of modification. 
 
This compliance calculation implies a subject who takes treatment for one week but takes all 
expected tablets for that week will be 100% compliant with treatment. 
 
Average dose received per day will be calculated as, 
 
 
𝐴𝐴𝐴𝐴𝐶𝐶𝐴𝐴𝐶𝐶𝐴𝐴𝐶𝐶 𝐷𝐷𝐶𝐶𝑇𝑇𝐶𝐶 𝑅𝑅𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐴𝐴𝐶𝐶𝑈𝑈 𝐶𝐶𝐶𝐶𝐴𝐴 𝐷𝐷𝐶𝐶𝐷𝐷 = 
 
2.3 
Study Endpoints 
𝑇𝑇𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝑇𝑇𝑇𝑇 𝑈𝑈𝑇𝑇𝐶𝐶𝑈𝑈 
. 
𝑇𝑇𝐴𝐴𝐶𝐶𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶𝑇𝑇 𝐷𝐷𝐷𝐷𝐴𝐴𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶 − 𝐷𝐷𝐷𝐷𝐴𝐴𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶 𝐶𝐶𝑜𝑜 𝐼𝐼𝐶𝐶𝑇𝑇𝐶𝐶𝐴𝐴𝐴𝐴𝐷𝐷𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶 
 
The study endpoints are listed below, with greater detail concerning these endpoints provided 
in Sections 2.3.1 to 2.3.8. 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in ALP at Week 12 compared to 
Baseline. 
 
ALP Secondary Efficacy Endpoints 
The ALP secondary efficacy endpoints are as follows: 
• Absolute change in serum ALP at Week 12 compared to Baseline 
• Proportion of subjects who have ≥20% decrease in ALP from Baseline to Week 12 
• Proportion of subjects who have ≥40% decrease in ALP from Baseline to Week 12 
• Proportion of subjects who normalize ALP at Week 12 
Secondary Endpoints 
• Change in total bilirubin from Baseline to Week 12 
• Change in serum GGT between Baseline and Week 12 
• Change in alanine aminotransferase (ALT) from Baseline to Week 12 
• Change in aspartate aminotransferase (AST) from Baseline to Week 12 
• Change in total cholesterol, low-density lipoprotein (LDL) cholesterol, and 
triglyceride levels between Baseline and Week 12 
• Change in fibrinogen, c-reactive protein (CRP), haptoglobin, enhanced liver fibrosis 
(ELF) score, and serum immunoglobulins between Baseline and Week 12 
Safety endpoints include the following: 
• Changes from Baseline to Week 6 and Week 12 in GLOBE Score 


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• Changes from Baseline to Week 6 and Week 12 in pruritus (average and worst) as 
measured by pruritus visual analog score (VAS) 
• Changes from baseline in vital signs, and clinical laboratory values 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• PK parameters including T1/2, Cmax, and AUC 
• The analysis of these PK endpoints will be performed outside of this analysis plan. 
Additional Analyses 
 
• Proportion of subjects who have ≥10% decrease in ALP from Baseline to Week 12 
• Proportion of subjects at Week 12 who had Baseline ALP ≥1.67x ULN and have ALP 
<1.67x ULN, ≥15% decrease in ALP and total bilirubin ≤ULN at Week 12. 
 
• A plot of percent change in ALP at each timepoint through Week 12 for the ratio of 
current to prior dose of UDCA 
• Proportion of subjects that crossed the liver monitoring thresholds will be 
summarized. The liver monitoring threshold is defined as ALT: 
• 3x ULN if the Baseline ALT is ≤60 U/L, or 
• 3x Baseline ALT if Baseline ALT is >60 U/L 
Additional analyses are not listed as endpoints in the protocol but are listed here as 
prespecified extensions of the protocol endpoints. 
 
2.3.1 
Alkaline Phosphatase 
 
ALP results are provided by the central and local laboratory with units of Units per Liter 
(U/L). Baseline is defined as the last available ALP result prior to treatment with change 
from baseline and percent change from baseline based upon this baseline value as the 
respective timepoint. Normalized ALP is defined as having ALP within the normal range 
(37 U/L to 116 U/L). Historical ALP will be summarized in the baseline characteristics table 
but not used otherwise. 
 
2.3.2 
Liver Laboratory Tests 
 
Total bilirubin, GGT, AST, and ALT results are provided by the central and local laboratory. 
The units these parameters are provided in and the normal range for these parameters at the 
central laboratory are provided below. 


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Laboratory Test 
Units 
Normal Range 
Total bilirubin 
mg/dL 
0.25 to 1.21 
GGT 
U/L 
7 to 38 
AST 
U/L 
14 to 43 
ALT 
U/L 
10 to 53 
 
2.3.3 
Lipid Laboratory Tests 
 
Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride results are 
provided by the central and local laboratory. The units these parameters are provided in and 
the normal range for these parameters are provided below. 
 
Laboratory Test 
Units 
Normal Range 
Total Cholesterol 
mg/dL 
100 to 200 
LDL 
mg/dL 
50 to 130 
Triglycerides 
mg/dL 
50 to 150 
 
2.3.4 
Serum Markers of Inflammation 
 
Fibrinogen and c-reactive protein (CRP) results are provided by the central and local 
laboratory. Haptoglobin and serum immunoglobulins results are provided by the central 
laboratory. The units these parameters are provided in and the normal range for these 
parameters are provided below. 
 
Laboratory Test 
Units 
Normal Range 
Fibrinogen 
mg/dL 
200 to 400 
CRP 
mg/L 
0 to 3 
Haptoglobin 
g/L 
0.3 to 2 
Immunoglobulin G 
mg/dL 
700 to 1600 
Immunoglobulin M 
mg/dL 
40 to 230 
 
2.3.5 
Enhanced Liver Fibrosis Score 
 
The ELF score is a set of serum markers that consist of hyaluronic acid (HA), tissue inhibitor 
of metalloproteinases 1 (TIMP-1) N-terminal pro-peptide of type III collagen (PIIINP), and 
tissue inhibitor of metalloproteinases 1 (TIMP-1) used to predict moderate fibrosis and 
cirrhosis (Lichtinghagen et al., 2013). Change from Baseline to Week 6 and Week 12 will be 
presented, along with a shift table for the categorical interpretation. The interpretation of the 
ELF score is as follows: 
 
• None to mild liver fibrosis: ELF score <7.7 
• Moderate liver fibrosis: ELF score ≥7.7 and <9.8 
• Severe liver fibrosis: ELF score ≥9.8 
• Cirrhosis: ELF score >11.3 


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2.3.6 
GLOBE Score 
 
The GLOBE score is a validated risk assessment tool, able to accurately stratify PBC patients 
to high and low risk for future adverse events (AEs), where a higher GLOBE score is 
considered higher risk (Lammers , 2015). Change from Baseline to Week 6 and Week 12 will 
be presented, along with a shift table for the categorical interpretation, as well as Survival 
Risk at 5, 10, and 15 years. The GLOBE score will be calculated using the following 
algorithm: 
GLOBE Score = 0.044378 × 𝐴𝐴𝐴𝐴𝐶𝐶 + 0.93982 × 𝐶𝐶𝐶𝐶 
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 + 0.335648 × 𝐶𝐶𝐶𝐶 
𝐴𝐴𝑈𝑈𝐴𝐴 − 
𝑈𝑈𝑈𝑈𝑈𝑈 
2.266708 × 
𝐴𝐴𝐵𝐵𝐵𝐵𝐵𝐵𝐴𝐴𝐵𝐵𝐵𝐵 − 0.002581 × 𝑃𝑃𝐶𝐶𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝑇𝑇 𝐶𝐶𝐶𝐶𝐷𝐷𝐶𝐶𝑇𝑇 + 1.216865 
𝑈𝑈𝑈𝑈𝑈𝑈 
 
Age (years): at initiation of UDCA therapy. 
𝑈𝑈𝑈𝑈𝑈𝑈 
Units: Bilirubin (µmol/L or mg/dL), ALP (U/L), Albumin (g/L), Platelets (109/L) 
 
𝑆𝑆𝐷𝐷𝐴𝐴𝐴𝐴𝐶𝐶𝐴𝐴𝐶𝐶𝐶𝐶 𝑅𝑅𝐶𝐶𝑇𝑇𝑅𝑅 𝑆𝑆𝐶𝐶𝐶𝐶𝐴𝐴𝐶𝐶 = 1 − 𝐵𝐵𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑆𝑆𝐷𝐷𝐴𝐴𝐴𝐴𝐶𝐶𝐴𝐴𝐶𝐶𝐶𝐶 𝐹𝐹𝐷𝐷𝐶𝐶𝐶𝐶𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶(𝐶𝐶𝐺𝐺𝑈𝑈𝐺𝐺𝐵𝐵𝐺𝐺 𝑆𝑆𝑆𝑆𝑆𝑆𝐵𝐵𝑆𝑆) 
Baseline survival function = 0.9385 (at 5 years); 0. 8429 (10 years); 0.7361 (15 years). 
The interpretation is as follows: 
 
• Higher risk: GLOBE score >0.3 
• Lower risk: GLOBE score <0.3 
2.3.7 
Pruritus Visual Analog Scale 
 
The Pruritus VAS is a validated, self-reported, instrument for measurement of itch intensity. 
It uses a 24-hour recall period and asks subjects to rate the average and worst intensity of 
their itch on a 10 cm horizontal line ranging from 0 cm (no itch) to 10 cm (worst imaginable 
itch). Change from Baseline to Week 6 and Week 12 will be presented for subjects with a 
value of ≤0.5cm at baseline and >0.5cm at baseline. The proportion of subjects with 
improvement (for subjects >0.5cm at baseline) and worsening (for subjects ≤0.5cm at 
baseline) will also be presented, along with a shift table for the categorical interpretation. The 
interpretation for the Pruritus VAS score is as follows: 
 
• No pruritus: VAS=0 
• Mild pruritus: VAS <3 
• Moderate pruritus: VAS 3 to <7 
• Severe pruritus: VAS 7 to <9 
• Very severe pruritus: VAS ≥ 9 


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2.3.8 
Safety Parameters 
 
The following safety parameters are captured within this study. 
2.3.8.1 
Adverse Events and Serious Adverse Events 
 
AEs and SAEs will be recorded starting after Screening and at every visit through the Week 
16 Follow-Up Visit. An AE is considered treatment emergent, TEAE, if it began after study 
drug administration. 
 
AEs will be graded for severity using the Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 to describe the maximum intensity of the AE. As such, severity will be 
reported as Mild, Moderate, Severe, Very Severe, Life Threatening or Disabling, Death 
Related. Causality of an AE will be assessed by the Investigator using the following terms: 
Possibly Related and Unrelated. 
 
AEs and medical history will be coded using MedDRA version 24.0. 
 
2.3.8.2 
Adverse Events of Special Interest 
 
Adverse events of special interest (AESI) include gastrointestinal events, treatment failure 
due to dose reduction of study drug as defined in the protocol. 
 
2.3.8.3 
Other Safety Endpoints 
 
• Vital signs, height, and weight: 
o Blood pressure, pulse, respiratory rate, height, weight, body temperature, and 
the presence of clinically significant abnormal values determined by an 
Investigator. Clinically significant abnormalities identified after the start of 
treatment will be reported as AEs. 
• 12-Lead electrocardiogram (ECG): 
o An Investigator assessment of normal vs abnormal will be available as well as 
clinically significant vs not clinically significant. Abnormal, clinically 
significant ECG readings seen after the start of treatment will be recorded as 
AEs. 
• Laboratory samples will include: 
o Hematology, serum chemistry, lipids, coagulation, and other. Clinically 
significant changes in laboratory values will be recorded by the clinical sites 
as AEs. 
• Post-Treatment Withdrawal Flares: 
o The difference between Week 12 and Week 16 laboratory values for ALP, 
ALT, AST, and GGT will be summarized. 


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2.4 
Study Day and Visit Windows 
 
Summary tables will report data based upon the protocol scheduled time points (Baseline, 
Weeks 2, 4, 6, 8, 12, 16). Assessment will be assigned to these time points based upon the 
study day they are performed on. Study day is defined as 
Study Day = date of assessment - date of first treatment. 
 
The analysis windows used to report endpoints are outlined in Table 2. Assessments are 
assigned to an analysis window based upon the study day it occurred on as well as the 
treatment status at the time the assessment was performed. If more than one assessment is 
available within the range, the assessment closest to the target day is reported for the analysis 
window. If two observations exist with the same distance to the target day, the first 
observation is used. 
 
Table 2 
Analysis Windows 
 
Visit 
Study Day Range 
Target Day 
Treatment Status 
Screening 
< Day –1 
First 
Off Treatmenta 
Baseline Visit 
Day 1 
Day 1 
Off Treatmenta 
Week 2 
Day 2 to Day 21 
Day 14 
On Treatmentb 
Week 4 
Day 22 to Day 35 
Day 28 
On Treatmentb 
Week 6 
Day 36 to Day 49 
Day 42 
On Treatmentb 
Week 8 
Day 50 to Day 70 
Day 56 
On Treatmentb 
Week 12 
Day 71 to Day 90 
Day 84 
On Treatmentb 
Week 16 
> Day 90 
Day 112 
Off Treatmentc 
a Prior to first treatment. 
b After the start of treatment to 1 day after the last dose. 
c More than 1 day after the last dose. 
 
 
2.4.1 
Definition of Baseline 
 
Unless specified elsewhere, baseline is defined as the last available measurement prior to 
administration of study drug. For events that occur on the same day as the first administration 
of study drug (i.e. assessments performed at the Baseline visit), and for which the time of the 
assessment is not available, the assessment will be classified as pre-treatment, hence 
baseline. The exception to this rule will be AEs for which the event will be classified as a 
TEAE. 
 
It should be noted that for the purpose of clinical management, the description of baseline 
varies in the protocol (e.g. inclusion/exclusion and Drug-Induced Liver Injury Monitoring). 
For analysis purposes, only the definition above will be used. 
 
2.5 
Statistical Assessment of the Study Objectives 
 
The efficacy endpoints will be summarized within the ITT population using descriptive 
statistics, with the primary endpoint, GGT and total bilirubin, also summarized within the PP 


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population. As this study includes one treatment group, the hypotheses, tests, and confidence 
intervals are all one sample comparisons to baseline. Confidence intervals will be 95% two- 
sided normal approximation confidence intervals. Testing for the percent change from 
Baseline to Week 12 in ALP using a t-test will also be performed. Testing will be one sided 
using a 5% alpha level. No multiplicity adjustment will be used, and the p-values reported 
for the endpoints will be descriptive in nature. 
 
2.5.1 
Primary Analysis 
 
2.5.1.1 
Hypothesis and Estimand 
 
The primary hypothesis for this study is that treatment with HTD1801 results in reductions in 
ALP: 
 
𝐻𝐻0: 
𝐴𝐴𝐴𝐴𝑃𝑃𝑊𝑊𝑆𝑆𝑆𝑆𝑊𝑊 12 − 𝐴𝐴𝐴𝐴𝑃𝑃𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆 
 
𝐴𝐴𝐴𝐴𝑃𝑃𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆 
 
≥ 0 𝐴𝐴𝑇𝑇. 𝐻𝐻𝐵𝐵: 
𝐴𝐴𝐴𝐴𝑃𝑃𝑊𝑊𝑆𝑆𝑆𝑆𝑊𝑊 12 − 𝐴𝐴𝐴𝐴𝑃𝑃𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆 < 0 
𝐴𝐴𝐴𝐴𝑃𝑃𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆𝐵𝐵𝐵𝐵𝐵𝐵𝑆𝑆 
 
The estimand will have the following characteristics: 
• The target population will be made up of all subjects on treatment who provide data 
at Week 12 
• The endpoint will be the percent change from baseline in ALP 
• Summarized results are limited to on treatment results at Week 12 (i.e., results from 
prior to Week 12 are not included in the analysis of the Week 12 results). Hence 
intercurrent events that take subjects off treatment or prevent ALP data from being 
available at Week 12 will remove subjects from the analysis. 
• The endpoint will be summarized as the mean percent change from baseline in ALP 
2.5.1.2 
Analysis Methods 
 
Serum ALP levels, change from baseline, and percent change from baseline will be 
summarized at each analysis window (see Table 2) using descriptive statistics and 95% 
confidence intervals. A t-test will also be performed to test for the percent change from 
baseline to Week 12. This analysis will be based on observed data without imputation. This 
analysis will be summarized within the ITT and PP population. 
2.5.2 
Secondary Analyses 
 
Secondary endpoints, including the secondary ALP endpoints, will be summarized with 
descriptive statistics by timepoint. These summary measures will include baseline, result at 
the time point that data is captured, change from baseline, and percent change from baseline 
as is appropriate for the endpoint. A 95% confidence interval will be produced for changes in 
laboratory endpoints, within the ITT population. 
 
Endpoints with categorical interpretations (e.g. ELF, GLOBE Score, Pruritus VAS) will 
additionally be summarized by shift tables for Change from Baseline to Week 12 using the 
categories listed above. 


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2.5.3 
Subgroups 
 
The results, change from baseline, and percent change from baseline to week 12 for ALP, 
total bilirubin, GGT, ALT, AST, and ELF will be performed for the following subgroups: 
 
• ALP at Baseline (above and below median value) 
• Total bilirubin at Baseline (above and below median value) 
2.6 
Handling of Missing Data 
 
Summary statistics will generally be reported based upon observed data. Missing data will 
not be imputed for the efficacy analyses. Percentages will be reported for subjects with data. 
Missing dates for AEs and concomitant medications will be imputed to allow these items to 
be summarized as pre-treatment or not. Should a determination of treatment period (on 
treatment or pre-treatment) be required for AEs or concomitant medication, but the 
corresponding date is missing or partial, the event/medication will be considered on 
treatment unless the portions of the date that are available indicate this is not possible. 
 
2.7 
Safety Analyses 
 
Safety endpoints will be summarized with descriptive statistics. All safety summaries and 
analyses will be performed using the ITT population. 
 
Prior and concomitant medications and procedures will be coded by the World Health 
Organization (WHO) Drug Dictionary version Sept2020. Medications and procedures will be 
considered concomitant unless they ended prior to treatment. 
 
2.8 
Interim Analyses 
 
Data will be summarized at study completion, as well as when 15 subjects have reached 
Week 12. At the interim timepoint, the data will be summarized descriptively: primary 
efficacy endpoint, additional ALP secondary endpoints, and TEAEs. For the interim analysis, 
only subjects with completed data who reached Week 12 will be used for efficacy analyses, 
all available data will be used for safety analyses. 
Enrollment into the study may be stopped early prior to enrollment of all 30 subjects should 
the scientific goal (evaluate the effects of HTD1801 on serum ALP) of the study be achieved 
with the currently available data. That is, if prior to enrollment of 30 subjects, the results 
provide sufficient preliminary evidence of efficacy that warrant further evaluation in a 
placebo-controlled study, enrollment in this study may be terminated. 


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3 
SUMMARY TABLES, LISTINGS, AND FIGURES 
 
3.1 
General Conventions 
 
Unless otherwise stated, summary statistics including the number of subjects (n), mean, 
standard deviation, median, minimum, and maximum will be presented for continuous 
variables. Generally, the minimum and maximum values will be presented to the same 
decimal precision as the raw values, the mean and median values to one more, and the 
standard deviation, to two more decimal places than the raw values. For categorical variables, 
per category, the absolute counts (n) and percentages (%) of subjects with data will be 
presented. Percentages will be presented to one decimal place. 
 
For AEs, medical history and concomitant medications will be reported on a per-subject 
basis. The denominator for the percentage calculation will be the number of subjects at risk 
in each treatment group. A subject will be considered at risk if the subject is in the analysis 
set and in the subgroup of interest. 
 
All p-values will be rounded to 4 decimal places. If a p-value is less than 0.0001 it will be 
displayed as “< 0.0001”, a p-value rounding to 1 will be displayed as “> 0.9999”. 
 
3.2 
Clinical Study Subjects 
 
3.2.1 
Subject Disposition and Analysis Populations. 
 
The number of subjects treated and discontinued early (i.e., follow-up visit was not 
completed), will be summarized. The reason for early termination will be summarized. 
Additionally, a summary of subjects who attended each visit result will be produced. 
 
A listing of entry criteria that were not met will be produced. The listed criteria will include 
the criteria language. A table of the violated entry criteria for subjects will be produced, as 
well as a table that summarizes the screen failure reasons for screen failure subjects. 
 
The number of subjects in each analysis population will be summarized. 
 
3.2.2 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized descriptively. This will include 
the following items: 
 
• Age at informed consent 
• Race 
• Ethnicity 
• Sex 
• Height 
• Weight 


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• BMI 
• Duration of Primary Biliary Cholangitis 
• Biochemical evidence of Cholestasis (Yes or No) 
• Age of initiation of UDCA 
• Age at diagnosis of PBC 
• Most recent UDCA dose (mg/kg/day) 
• Presence of antimitochondrial antibody 
• Historical ALP 
• Pruritus VAS 
3.2.2.1 
Baseline Laboratory Assessments 
 
Baseline laboratory assessments will be summarized descriptively. This will include: 
 
• ALP 
• GGT 
• Total Bilirubin 
• AST 
• ALT 
• Albumin 
• Platelets 
• AMA (Positive, Equivocal, or Negative) 
o For positive values, AMA will also be summarized as a continuous measure 
• ANA (Positive, Equivocal, or Negative) 
o For positive values, ANA will also be summarized as a continuous measure 
3.2.3 
Concomitant Medications 
 
Medications with a stop date before the treatment dosing date will be considered prior 
medications/procedures. Medications with a start or stop date on or after the treatment dosing 
date will be considered concomitant. All medications marked as ongoing are concomitant. 
 
A medication with an incomplete stop date will be considered concomitant if: 
 
• Month is missing and year is equal to or after the year of treatment dosing date 
• Day is missing and year is equal to the year of the treatment dosing date and month is 
equal to or after the month of the treatment dosing date. 


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All concomitant medications will be summarized by preferred terms in descending order of 
frequency. All medications, including prior and prohibited medications, will be provided in a 
listing. 
 
3.2.4 
Medical History 
 
Medical history will be tabulated by system organ class and preferred terms and provided in 
a listing. 
 
3.2.5 
Clinical Study Treatment and Extent of Exposure 
 
The total tablets used, duration of treatment, and compliance (see Section 2.2) will be 
summarized. Average dose received per day, along with the number of subjects with dose 
interruption or modification will also be summarized. 
 
3.3 
Analysis of Efficacy Endpoints 
 
3.3.1 
Serum Alkaline Phosphatase 
 
The serum ALP levels, change from baseline, and percent change from baseline will be 
summarized with descriptive statistics by timepoint for the ITT and PP populations. The 
summary measures will include 95% normal distribution confidence intervals of the 
treatment difference. In addition, a t-test will be performed for the percent change from 
baseline to Week 12. Subgroup analyses (see Section 2.5.1.2) will be performed for the 
change from baseline and percent change at Week 12 data. 
 
The proportion of subjects who have ≥20% and the proportion with a ≥40% decrease in ALP 
from Baseline will be summarized at each timepoint with Week 12 being the study specified 
timepoint. Additionally, the proportion of subjects who normalize ALP will be summarized 
by timepoint. 
 
3.3.2 
Secondary Endpoints 
 
Tables for the secondary endpoints, see below, will be summarized for the respective 
laboratory values and the change from baseline results at each timepoint. Total bilirubin and 
GGT will be summarized within the ITT and PP populations. Subgroup analyses for 
specified laboratory parameters (see section 2.5.2) will be performed for the change from 
baseline and percent change at Week 12. Central and local lab data will be used for the 
efficacy analyses. 
 
• Total bilirubin 
• GGT 
• ALT 
• AST 
• Total cholesterol 


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• LDL 
• Triglyceride 
• Fibrinogen 
• CRP 
• Haptoglobin 
• ELF 
• Immunoglobulins (IgM and IgG) 
3.3.3 
UDCA Use 
 
A plot of average percent change in ALP at each timepoint through Week 12 for groups 
defined by the ratio of current to prior dose of UDCA. The ratio groups displayed in the plot 
will be <90%, 90% to 110%, and >110%. Separate subject level plots will also be presented 
for each ratio group through Week 12. 
3.3.4 
ELF Score 
 
The number of subjects within ELF score interpretations will be presented at Week 12 as 
well as the shift within categories for change from baseline to week 12. Summary statistics at 
Week 12 will also be presented. 
3.3.5 
GLOBE Score 
 
The number of subjects within GLOBE score interpretations will be presented along with the 
Fibrosis Score interpretations. Change in GLOBE score from baseline will be summarized 
using descriptive statistics at Week 6 and Week 12. A listing of the GLOBE score will also 
be produced and summarized by duration of UDCA exposure. 
 
Survival risk (%) for 5, 10, and 15 years will be summarized using descriptive statistics at 
Week 12 for the GLOBE Scores. 
 
3.4 
Analysis of Safety Endpoints 
 
Safety Endpoints (Adverse Events, Clinical Laboratory Results, Vital Signs) will be 
presented at the scheduled timepoints as outlined in Table 1, with further detail in the 
protocol. 
 
3.4.1 
Adverse Events 
 
An overview of AEs, which includes subject incidence of TEAEs, treatment-related TEAEs, 
serious TEAEs, AESIs, TEAEs by CTCAE grade and TEAEs leading to permanent 
discontinuation of treatment. For TEAEs presented by CTCAE grade, the worst grade during 
the clinical study will be presented for each subject. 
 
The subject incidence of TEAEs, treatment-related TEAEs and TEAEs leading to permanent 
discontinuation of treatment will be summarized by system organ class and preferred term. 


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TEAEs will also be summarized in a table by CTCAE grade. For TEAEs presented by 
CTCAE grade, the worst grade for each event during the clinical study will be presented for 
each subject. A listing for all off-treatment AEs will be presented similarly. 
 
All AEs will be presented as a listing by subject. TEAEs leading to treatment 
discontinuation will be provided in a separate listing. 
 
3.4.1.1 
Post-Treatment Withdrawal Flares 
 
The difference between Week 12 and Week 16 laboratory values for ALP, ALT, AST, and 
GGT will be summarized using descriptive statistics. 
 
3.4.2 
Pruritus VAS 
 
Change in Pruritus VAS will be summarized using descriptive statistics for the result and 
change from baseline. The proportion of subjects with improvement will be presented for 
subjects >0.5cm at baseline. The proportion of subjects with worsening will be presented for 
subjects ≤0.5cm at baseline. 
 
3.4.3 
Clinical Laboratory Evaluations 
 
Clinical laboratory results, including bile acids, will be summarized by type of laboratory 
assessment (hematology, serum chemistry, lipids, coagulation, other) and timepoint. Both 
central and local laboratory results will be used for the safety lab summaries. Summary 
statistics for actual values and changes from baseline will be tabulated by analysis window. 
Out of range clinical laboratory values based upon the normal range will be tabulated for 
each timepoint. These tables will utilize the normal ranges provided for the individual 
sample. 
 
The proportion of subjects that cross the liver monitoring thresholds will be summarized. A 
listing of ALT values for subjects that meet the liver monitoring threshold will be presented 
similarly to the clinical laboratory listing. Baseline values will be summarized using last 
available measurement prior to administration of study drug. 
 
3.4.4 
Vital Signs 
 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics. 
 
3.4.5 
Electrocardiogram Results 
 
The overall ECG assessment (abnormal or normal) will be summarized by analysis window. 
The QT values will be summarized by analysis window as both the QT value and change 
from baseline. 
 
3.4.6 
Pregnancy 
 
A listing of positive pregnancy tests results will be produced. 


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4 
REFERENCES 
 
Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring 
system to predict outcomes of patients with primary biliary cirrhosis receiving 
ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804-1812.e4. 
 
Lichtinghagen R, Pietsch D, Bantel H, et al. The Enhanced Liver Fibrosis (ELF) score: 
normal values, influence factors and proposed cut-off values. J Hepatol. 2013;59(2):236-42. 


 
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5 
APPROVAL SHEET 
 
 
Product: 
Protocol Number: 
SAP Version: 
Version Date: 
HTD1801 
HTD1801.PCT013 
1.0 
4/25/2022 
 
 
 
The individuals signing below have reviewed and approve this statistical analysis plan. 
 
 
 
 
Abigail Flyer, M.S. 
Project Statistician 
 
 
 
¾eillrman, Ph.D 
- 
Statistician 
 
 
 
 
Cathryn Bennett, B.N., R.N., C.C.R.A. 
VP, Clinical Operations 
 
 
 
Adrian M. Di Bisceglie M.D., FACP, FAASLD 
Chief Medical Officer 
 
 
 
 
 
 
 
 
Confidential 
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Date 
 
 
 
 04/25/2022 
 
Date 
 
 
 
4/25/2022 
 
Date 
 
 
 
4/25/2022 
 
Date 
 
 
 
 
 
 
 
 
Version l.O, Date: 4/25/2022